Pet Peeves -Cough and Cold Medicines and Antibiotic Usage

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Although upper respiratory illnesses are not a primary focus for pediatric gastroenterologists, due to their frequency, we see them quite a bit.  Even with my limited exposure, I frequently receive requests for medications to reduce the symptoms of cough and runny nose.

My approach has typically been to explain that I don’t believe that cough and cold medicines (CCMs) are effective and can be harmful, especially in young children.  This explanation is in agreement with efforts that both the pharmaceutical industry and the Food and Drug Administration (FDA) took in 2007 and 2008 to limit the use of over the counter (OTC) CCMs in young children.  The American Academy of Pediatrics has gone further and advised against their usage in children under age 6 years.  These recommendations came in part due to lack of efficacy of these agents but also due to the recognized potential for adverse effects, including fatalities.

Recently, a study (J Pediatr 2014; 165:1024-8) has shown that despite labeling changes on CCMs there has been virtually no impact on the use of OTC CCMs.  Using information from administrative databases, this study compared prescribing patterns 2005-2006 with 2009-2010 in children aged ≤ 12 years.  Results: There was an increase in use of OTC CCM used in ambulatory clinics (6.3% to 11.1%) but a decrease in the use of prescription CCMs 6.7% to 2.9%.  The OTC CCM use in children <2 years was essentially unchanged between the two timeframes (6.8% compared to 6.5%)

Bottomline: If parents and physicians want to do what is best for the children they care for, then more effort is needed to stop the widespread use of CCMs.  Prevention with influenza vaccination and proper hand hygiene are measures which can help.

A separate problem is the misuse of antibiotics for upper respiratory illnesses.  This is widespread as well.  While this blog has discussed antibiotic resistance and antimicrobial stewardship, a recent article (NEJM 2014; 371: 1761-63) provided a few new ideas on this subject.

  • First, the authors note that modern medicine is entirely dependent on antibiotics.  “Two major ways that modern medicine saves lives are through antibiotic treatment of severe infections and the performance of medical and surgical procedures under the protection of antibiotics.”
  • Second, the authors note that “as people in wealthier regions run out of effective antibiotics, they come to share the lot of people in poorer regions who can’t afford them to begin with.”
  • Third, the authors point out that antibiotic resistance was recognized in 1945 by Alexander Fleming and Howard Walter Florey when they accepted the Nobel Prize for the discovery of penicillin.

The authors then outline the areas that need to be addressed to diminish the prospects of ineffective antibiotics:

  • Prevention with vaccination and sanitation
  • Leadership to coordinate global surveillance and manage rewards for proper usage
  • Access to subsidized appropriate usage in poorer countries
  • Conservation of antibiotic usage –restrain use of antibiotics in agriculture/farming
  • Conservation through appropriate use of prescriptions

Related blog posts:

Maternal Obesity and Neurodevelopmental Outcomes

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If there were not enough reasons to be concerned about the prevalence of obesity already, here’s another: there is growing evidence that maternal obesity (i.e. obesity in the mother at the beginning or prior to pregnancy) is associated with an increased risk for a number of neurodevelopment outcomes (J Pediatr 2014; 165: 891-6).  According to this medical progress report, there are a number of limitations in interpreting the studies associating obesity with these outcomes.

  1. Unclear what is the best measure of obesity and the best timing of measuring obesity
  2. “It is unclear whether obesity per se is the entity that causes adverse outcomes, or whether  obesity is only a marker for other factors” (eg. diet and activity)

With these limitations in mind, the authors review a number of studies.  Key points:

  • Cerebral palsy: “a dose-response relationship was seen, with any diagnosis of maternal obesity carrying a relative risk (RR) of 1.30 (95% CI 1.09-1.55) for CP.  With any diagnosis of morbid obesity, the RR was 2.70 (CI 1.89-3.86)
  • Autism: the risk of developing ASD (OR 1.67; CI 1.10-2.56) and NDD [neurodevelopmental delay] (OR 2.08; CI 1.20-3.61)
  • Cognitive deficits: maternal BMI “was inversely associated wit age 5 years IQ”
  • Behavioral/psychiatric disorders: “children of women who were both overweight and gained excess weight during pregnancy had a 2-fold (OR 2.10; CI 1.19-3.72) increased risk of ADHD symptoms compared with offspring of normal-weight women.” Also, some studies have shown an increased risk for schizophrenia in children of mothers with BMI >30.

Bottomline: obesity is not good for individuals and is associated with increased neuodevelopmental risk in offspring as well.

 

Exceptions for Valproate-Associated Liver Failure

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Recent guidelines (AASLD/NASPGHAN 2014 Guidelines for Evaluation of Pediatric …) have included valproate-associated acute liver failure (VPA-ALF) as an absolute contraindication to liver transplantation.  The reason is that most of these VPA-ALF patients have Alpers-Huttenlocher syndrome (AS) and have done poorly after transplantation due to progressive neurological decline.

AS in turn has been recognized as secondary to mutations in DNA polymerase subunit gamma (POLG1).  This gene product’s role is to maintain the integrity of mitochondrial DNA (mtDNA).

New data (Liver Transplantation 2014; 20: 1402-14, editorial 1287-89) suggests that there are exceptions for some cases of VPA-ALF.  In this report, 4 VPA-ALF patients with POLG1 mutations underwent successful liver transplantation.  Three are alive at followup 4-19 years later and one died suddenly 2 years after transplantation.

Key findings:

  • These cases had mutations in POLG1 associated with later onset and milder disease.
  • In the three long-term survivors, VPA was introduced at 14, 20 , and 21 years of life.

Take-home points:

  • For children less than 10 years of age, “VPA-ALF should remain an absolute contraindication to LT because neurological progression is almost inevitable.”  Supportive treatment, including N-acetylcysteine and carnitine should continue.
  • There is a “strong case for screening for POLG1 mutations before VPA use…even a single mutation should be seen as a contraindication to VPA.”

Related blog posts:

Also, I added a link on yesterday’s post regarding measles to a story on NPR which explores the most recent increase in cases and provides background information.  For example: “Before a vaccine was developed in the 1960s, measles caused more than 2 million deaths per year.”  And worldwide, even now, “nearly 400 kids die from measles each day. In 2013, more than 70 percent of measles deaths were confined to six countries: the Democratic Republic of Congo (DRC), Ethiopia, India, Indonesia, Nigeria and Pakistan.”

Measles Epidemic 1991 -Compelling Narrative

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I saw two personal heroes yesterday –Donald Schaffner and Paul Offit.  This happened at the 13th annual Donald Schaffner conference.

Dr. Schaffner is a former surgeon at Children’s Healthcare of Atlanta .  In recent years, he has battled a number of medical problems.  During my early years as an attending, he and I worked together to help a number of children.  His patience, caring, and dedication to providing the best care were unrivaled.

I had never met Dr. Offit in person and this was the first time that I heard him speak.  However, he has been an outspoken advocate for vaccines and has written extensively on this subject; in addition, he has cast a critical eye on some alternative medicine practices.  I have quoted him numerous times on this blog (see links below). His topic for this conference: “The Philadelphia Measles Epidemic of 1991: Lesson from the Past or Prologue to the Future.”

This was an amazing narrative of the measles epidemic combining the epidemiology, with journalism, law, politics, and the history of refusing vaccines.  I did not take any notes, though I did take two pictures.  The lecture was effective because it was presented like any good story with lots of details, facts, and passion.  The lies and mistakes were discussed as well.

Legal Foundation for Compulsory Vaccination during Measles Epidemic

Legal Foundation for Compulsory Vaccination during Measles Epidemic

High case fatality among those who claimed religious exemptions to vaccine

High case fatality among those who claimed religious exemptions to vaccine

Key points:

  • Religious vaccine exemption was claimed initially by Christian Scientists. This has been expanded by other groups claiming personal beliefs.
  • Vaccine successes have made people forget how dangerous diseases like measles can be; unfortunately, resurgence of these diseases may be necessary to convince people that vaccination is worthwhile

One more link -yesterday on NPR: Measles Still Kills

Related blog posts:

Microcytic Anemia Review

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A useful review of microcytic anemia (NEJM 2014; 371: 1324-31) discusses the most common causes, mechanisms and treatment of microcytic anemia.

Common causes discussed include thalassemia, iron deficiency anemia, and anemia of inflammation.  With the latter, the authors review the pathophysiology: “the cause of this anemia is twofold. First, renal production of erythropoietin is suppressed by inflammatory cytokines, resulting in decreased red-cell production. Second, lack of iron availability for developing red cells can lead to microcytosis.  The lack of iron is largely due to the protein hepcidin, an acute-phase reactant that leads to both reduced iron absorption and reduced release of iron from body stores.”

Treatment of iron deficiency anemia –pointers:

  • Ferrous sulfate (325 mg [65 mg of elemental iron] orally three times a day -considered first line for adults.  Ferrous gluconate at a daily dose of 325 mg [35 mg elemental] is an alternative.
  • “Several trials suggest that lower doses of iron, such as 15 to 20 mg of elemental iron daily can be as effective as higher doses and have fewer side effects.”
  • “There are many oral iron preparations, but no one compound appears to be superior to another.”
  • In those with an inadequate response to oral iron therapy, parenteral iron can be helpful.  The authors note that low-molecular-weight iron dextran (INFeD) is “associated with an incidence of reactions that is similar to that with the newer products but allows for higher doses of iron replacement.”  Typical dosing for adults: 25 mg test dose, and if tolerated for 1 hr, can give 975 mg (1000 mg total) over 4-6 hours.  The low-molecular-weight iron dextran should not be used in patients with previous iron dextran hypersensitivity reactions.
  • Alternative IV iron products: Ferric gluconate [Ferrlecit] 125 mg adult dose over 1 hour -given weekly (8 doses = 1000 mg) or Iron Sucrose [Venofer] 200 mg adult dose over 15-60 min, 300 mg over 1.5 hr, or 500 mg over 4 hr; can repeat in subsequent sessions until total dose of 1000 mg.

Related blog posts:

Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.

John Snow and Hepatology Potpouri

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If you mention the name “John Snow,” I bet most people would think about one of the characters from Game of Thrones.  However, a more important John Snow is referenced in a recent Hepatology review (Hepatology 2014; 60: 1124-25).  “In 1855, the physician and epidemiologist John Snow used the technique of medical geography to stem the cholera epidemic in London.  By mapping the number of choleras case and the local water supply, he found that the Broad Street pump station was responsible and after the pump handle was removed, incident cases declined.”

Hepatology 2014; 60: 1150-59, editorial 1124-25.  Using spatial (clustering) epidemiology, the authors show that parenteral antischistosomal therapy (PAT) alone cannot explain the high HCV prevalence in Egypt.  Other iatrogenic exposures and poor infection control are likely contributing factors.

Hepatology 2014; 60: 1222-30, editorial 1130.  In a prospective study (western Europe), the authors show that vitamin D (25-OH) levels were inversely associated with the risk of hepatocellular carcinoma (HCC).  What is remarkable about this study is the levels were obtained on average 6 years before HCC diagnosis.  Also, this study uses tertiles -comparing those in the top third to those in the lowest third.

Hepatology 2014; 60: 1399-1408.  More data showing injury from Herbals and dietary supplements.  Liver injury caused by bodybuilding herbal supplements (often anabolic steroids) were typically less severe than liver injury induced in non-bodybuilding herbals (predominantly middle-aged women). Table 3 identifies by name many of the herbal supplements/dietary supplements associated with death or liver transplantation.  “Contrary to popular belief, this study demonstrates that HDS products are not always safe.”

Lysosomal Acid Lipase Deficiency -Another Needle in a Haystack

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A recent article (Atherosclerosis 2014; 235: 21-30) reviews lysosomal acid lipase deficiency (LAL-D) and how this rare disease needs to be considered by pediatric hepatologists.

LAL-D is a rare lysosomal storage disease which encompasses a rapidly progressive disease in infants (previously referred to as Wolman disease) as well as a later-onset condition called cholesteryl ester storage disease (CESD).  Both of these diseases are caused by mutations in the LIPA gene and share the same pathophysiology related to deficiency of LAL. The disease prevalence estimates vary widely (1 in 40,000 to 1 in 300,000) and depend on ethnicity and location.  Jewish, Iraqi, and Iranian infants appear to be at highest risk.

According to the review algorithm, patients with three or more of the following should be considered for screening:

  • ALT >1.5 ULN
  • Hepatomegaly (may be mild)
  • HDL <50 mg/dL
  • Low BMI (in adults <30 kg/m2)
  • Liver biopsy with microvesicular steatosis; grossly the liver may appear orange

Thus, the potential target patients:

  1. Non-obese individuals with persistent increases in LFTs –usually with LDL >160 and low HDL <50
  2. Non-obese NAFLD/microvesicular steatosis

Given the potential for treatment with recombinant sebelipase alfa (Synageva Biopharma) and the widely available testing, looking for LAL-D makes sense in selected patients; though, even in highly selected patients, finding cases may truly be like finding the so-called ‘needle in a haystack’ given the huge numbers of individuals with elevated ALTs who do not have LAL-D.

Note: many of the review’s authors received research grants from Synageva.  (I do not have any financial conflicts to disclose.)

More Measles Cases -Here’s the Data

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This past month a recent perspective article (NEJM 2014; 371: 1661-3) provides an update on measles and the problems with vaccination rates.

Key points:

  • More measles cases in 2014 (592 thru Aug 29) than in any year in the past 20.  Already, the number of cases this year is >3-fold the number in 2013 and ~10-fold more than in 2012
  • Most cases are due to infections acquired during travel or due to cases being brought into U.S. by foreign travelers
  • Problem has expanded due to increasing number of unvaccinated children.  Vaccines “that remain in the vial are completely ineffective.”
  • Measles remains one of the most contagious illnesses and typically one person can infect up to 18 susceptible persons.  Due to its contagiousness, a high level of herd immunity (>92-94% immune) is needed to prevent sustained spread of virus.
  • Measles can be deadly with case fatality rate of 0.2% to 0.3% in the developed world and much higher in the developing world (2-15%).
  • Even a few cases are very expensive to control. A 2004 Iowa outbreak of only three patients cost more than $140,000 to contain/investigate.  An outbreak in Arizona with only 7 patients cost more than $800,000.

Related blog posts:

Cheap Technology for Button Battery Ingestions

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Typical Button Battery

Typical Button Battery

An NPR report regarding “the results of .. experiments published Monday in the Proceedings of the National Academy of Sciences show that a prototype shield is effective at keeping small, 11 millimeter batteries from damaging the esophagus after being swallowed.”  This would be worthy endeavor to pursue.  The larger buttons (20 millimeters in diameter) “are particularly dangerous. One out of 8 children [under 6 years old] who swallow this larger battery are going to have a serious debilitating complication.”  Here’s the link: Battery Shield

Here’s an excerpt regarding the shield:

Microscopic metal particles are embedded in the shield, which is a millimeter thick. When a battery is inserted into a device, the pressure from the device’s cover or a spring that holds the battery in place pushes the metal particles together. The shield then acts like a switch, conducting electricity.

When the battery is free, floating down a child’s esophagus, for instance, there’s not enough pressure to make the microparticles smush together. The shield then acts as an insulator…

The shield’s material is commercially available and currently used in touch-screen devices where a gentle press of a fingertip can complete a circuit.

Related blog posts:

 

"Great Power" for Damaging an Esophagus

“Great Power” for Damaging an Esophagus

NASPGHAN Notes –Last Word for this Year

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This blog entry has abbreviated/summarized several presentations. Though not intentional, some important material is likely to have been omitted; in addition, transcription errors are possible as well.

IBD Treatment: Targets for the Modern Age –Eric Benchimol (Children’s Hospital of Eastern Ontario)

Goal: Review mucosal healing and best targets to measure to predict prognosis

Treat-to-target:

  • Regular assessment of disease activity using objective outcome measures.
  • Adjust treatment if not accomplishing goal.
  • Proven helpful in rheumatoid arthritis, hypertension, diabetes, and hypercholesterolemia.

Old targets:

  • “Clinical remission”
  • “Feeling better”
  • Indices: PCDAI, CDAI, Harvey-Bradshaw
  • Problem: Active disease is not well-predicted by symptoms or laboratory markers
  • 2nd Problem: Active symptoms not always due to active IBD (could be due to functional complaints)
  • PUCAI score in ulcerative colitis does reflect ulcerative colitis severity fairly well

New Targets

  • High correlation with outcomes
  • Cost-effective
  • Available

Is mucosal healing achievable?   If you were scoped and adjustments made in therapy, then much higher rate (HR >4) of remission. Bougen, Clin Gastroenterol Hepatol 12: 978.  Endoscopy may be best way to assess mucosal healing.  Since it is invasive, efforts have been made to identify surrogate markers.

Treat-to-Target Algorithm

Treat-to-Target Algorithm

Surrogate Markers

  • Ultrasound –can be useful but operator-dependent
  • MRE had 83% accuracy for endoscopic remission: Gastroenterol 2014; 146: 374.
  • Calprotectin not as accurate in children? Am J Gastroenterol 2014; 109: 637. Sensitivity high 97%, specificity for remission 68%
  • CRP –if elevated, higher risk of complications or surgery. However, sensitivity is much lower for disease activity than calprotectin/imaging studies for active disease
  • Drug levels. Therapeutic IFX trough levels (and adalimumab) are highly predictive of mucosal healing.

Bottomline (my interpretation): Resolution of clinical symptoms and improvement in bloodwork is not good enough.  When/timing to assess with sensitive surrogate markers is still uncertain.  In many patients, endoscopy is needed to assure adequate improvement; however, in others, a followup imaging study (eg. MRE) or sensitive stool assays may be the best approach.

A related story (from AGA’s Today in Medicine email feed & pointed out to me by Ben Gold) indicates that estimation of clinical symptoms is not accurate:

Survey Suggests Severity Of IBD Is Underestimated By Gastroenterologists.

MedPage Today (10/31, Walsh, 186K) reports that survey results presented at a medical conference indicate that “the severity of inflammatory bowel disease is significantly underestimated by gastroenterologists.” Researchers found that “a total of 55% and 67% of physicians who participated in a web-based survey rated cases of Crohn’s disease and ulcerative colitis as being mild when they were actually moderate.” Meanwhile, “for case studies that represented severe disease, 76% and 81% of the physicians gave ratings of either moderate or mild for Crohn’s disease and ulcerative colitis, respectively.”

 

Related blog posts:

Risk Stratification in Pediatric IBD: Are we there yet? Jeffrey Hyams (Connecticut Children’s

Initially, Dr. Hyams described the exploding head syndrome; many attendees might have thought they had this due to information/”big data” overload, but this syndrome is a sleep disorder/parasomnia event.  Here’s a link to the image from his talk.  Then, Dr. Hyams reviewed data on risk stratification:

  • Mutations: Some genetic mutations are associated with disease severity
  • Still needed: specific pediatric data
  • Microbiome: Some profiles associated as prognostic factors in pediatric RISK study
  • Early anti-TNF associated with improved outcomes (using propensity analysis) Gastroenterol 2014; 146: 383.

Bottomline: Not there yet with risk stratification. Many factors environmental, genetic susceptibility, immune response, and treatment need to be sorted out with “big data.”

Key Clinical Questions for your practice at this time:

  • Does this patient have known risk factors for doing poorly?
  • Am I using current therapies properly?
  • What is the risk of undertreated disease? This needs to be considered with discussion of safety of IBD meds.

Cross Examination of Cross-Sectional Imaging in IBD –Sudha Anupindi (Radiology/CHOP)

  • For the most part, barium studies discouraged (eg. UGI/SBFT) by speaker; radiation ~1 mSv.
  • CT (conventional) widely available and easy –if needed urgently/middle of night.

Initial presentation: imaging of choice

  • MR enterography –no radiation, better contrast resolution, best for perianal disease, able to evaluated peristalsis. Two limitations: cost, interpretation
  • CT enterography –fewer motion artifacts (0.6 seconds), lower cost, increased availability, better spatial resolution radiation reduced with current technology at most Children’s hospitals: 1-2 mSv

Abdominal ultrasound holds promise as alternative imaging with lower cost.