Probiotics, Atopy, and Asthma

Posted on by

Moving from theory to practice with probiotics has been problematic in many areas.  That is, theoretically probiotics by altering the microbiome should have numerous beneficial effects; however, demonstrating these positive effects in practice has been difficult for many conditions.  A recent study (thanks to Mike Hart for this reference) highlights this issue with regard to asthma:  Pediatrics 2013; 132: e666-76. Full article:

http://pediatrics.aappublications.org/content/132/3/e666.full.html

Background: Due to the immune modulating effects of probiotics and mindful of the hygiene hypothesis regarding the rise of atopic diseases, some have proposed the use of probiotics to reduce the risk of atopy and asthma in children.

Methods: In this study, the authors performed a meta-analysis of numerous randomized studies.  Out of a total of 1081 articles, 25 studies met predefined criteria, with a total of 4031 participants (see Table 1 in publication).  Numerous probiotics were administered.  The most common probiotic in these trials, Lactobacillus GG,  was used in 8 of the studies.

Results:

  • For serum immunoglobulin E (IgE) levels, 9 of the trials (n=1103) provided data.  Probiotics were associated with a -7.59 U/mL reduction in total IgE (P= .044).  The effect of probiotics was more pronounced with longer, follow-up periods.
  • Probiotics, in comparison to placebo, were associated with a reduced risk of atopic sensitization based on positive skin prick and/or elevated specific IgE to common allergens.  This was true whether the probiotic was administered prenatally (relative risk 0.88, P=.035) or postnatally (relative risk 0.86, P=.027)
  • Probiotics did not reduce the risk of asthma/wheeze (relative risk 0.96 [95% CI 0.85-1.07]

Study limitations: heterogeneity of clinical trials in meta-analysis, various probiotic strains, variable duration and timing of probiotic use.

Related blog posts:

Should Physicians Dispense Drug Coupons?

Posted on by

This is a good question.  Before you answer, consider some of the following information from a recent commentary (NEJM 2013; 369: 1188-89):

  • “Commercial drug-insurance…have tiered pharmaceutical formularies..requiring small patient copayments…for inexpensive generic drugs and higher copayments…for brand-name drugs. Manufacturers use coupons…so that…the out-of-pocket costs are the same as those for generic drugs.”
  • “Coupons were used for approximately 100 million dispensed prescriptions in 2010 –about 11% of prescriptions for brand-name drugs.”
  • The authors performed analysis ‘by manually abstracting information on each coupon advertised in March 2013 at http://www.internetdrugcoupons.com.”  They found that with 62% of coupons there were lower-cost therapeutic alternatives available.  58% had generic alternatives and 8% had less-expensive brand-name therapeutic equivalents (some drugs had both generic alternatives and less-expensive brand competitors).

The arguments against coupons:

  1. “On a population level, drug coupons undermine the tiered-formulary system that commercial insurers have implemented to limit prescription-drug spending.”  Insurers must still pay the higher cost of the brand-name drug.  This leads to higher insurance coverage rates for all patients.
  2. Some have argued that these coupons should be disallowed as illegal kickbacks by subverting the cost-sharing arrangements in patients’ insurance contracts.
  3. The costs for these medications for the patient usually are more in the long run as these coupon offers are often limited to 6-12 months.

Bottomline: when there are lower cost therapeutic alternatives, drug coupon programs increase long-term costs and undermine efforts for patients to have ‘skin in the game.’

Related blog:

Can the FDA prohibit free speech? | gutsandgrowth

Thiopurines = Low Efficacy for Crohn’s

Posted on by

The enthusiasm for thiopurine therapy for Crohn’s disease (CD) had already dropped a lot before two pivotal articles were recently published that confirmed the modest efficacy:

  • Cosnes J, et al. Gastroenterol 2013; 145: 758-65
  • Panes J, et al. Gastroenterol 2013; 145: 766-74
  • Gastroenterol 2013; 145: 714-16 (editorial)

The Cosnes study (from the GETAID group) reports an open-label randomized trial in 147 adult patients with newly diagnosed CD (from 2005–>2010) and risk factors for disabling disease who were recruited from 24 French centers.  Risk factors for disabling disease:

  • Age <40 years
  • Active perianal lesions
  • Corticosteroid use within 3 months of diagnosis

The characteristics and Paris classification are detailed in the paper’s Table 1. Patients were divided into early azathioprine or “conventional” treatment. Patient’s were followed for 3 years.  Azathioprine was dosed at 2.5 mg/kg/day.  The primary endpoint was the proportion of trimesters spent in corticosteroid-free and anti-tumor necrosis factor (TNF)-free remission.

Results:

  • 67% of azathioprine group achieved the primary endpoint compared with 56% in the conventional group.  The difference in achieving the primary endpoint was not statistically significant between the two groups.  Also, 41 (61%) of the conventional group were placed on azathioprine (mean time 11 months after enrollment).
  • The azathioprine group patients were more likely to not have perianal surgery (96%) compared with the conventional group patients (82%).
  • Adverse events included pancreatitis in 7 (10%) of azathioprine group compared with 1 (1%) of conventional group.  Elevated liver function tests were noted in 3 (4%) compared with 1 (1%) respectively.  No cases of neutropenia were noted in early azathioprine group.

The latter finding is interesting especially as the authors did not check thiopurine methyltransferase (TPMT) assays in a systematic manner.

Panes et al (for the AZTEC study group) performed a prospective double-blind trial of adult patients with a recent CD diagnosis (<8 weeks).  This study enrolled 131 patients from 31 centers in Spain.  68 received azathioprine (2.5 mg/kg/day) and 63 received placebo.

Results:

  • After 76 weeks of treatment, 30 (44.1%) azathioprine patients and 23 (36.5%) placebo-treated patients were in sustained corticosteroid-free remission (P= .48).
  • Relapse rates were lower in azathioprine group compared with placebo: 11.8% vs 30.2%.
  • Serious adverse effects were more frequent in the azathioprine group compared with placebo: 20.6% vs. 11.1% (P= .16).  In the azathioprine group, 7 (10%) developed pancreatitis, 16 (24%) developed leukopenia, 9 (13%) developed anemia, and 9 (13%) developed abnormal liver function tests.  Infections were more common in the placebo-treated group (24%) compared with 12% in the azathioprine group

The accompanying editorial should be mandatory reading for all health care providers who help manage inflammatory bowel disease (IBD) patients.  The editorial traces how thiopurines (azathioprine and 6-mercaptopurine) became an accepted cornerstone of IBD treatment.  In adults, after initial disappointing results from Summers et al (Gastroenterol 1979; 77: 847-69), efficacy was demonstrated in a seminal study by Present et al (NEJM 1980; 302: 981-87).  However, the authors note that a recent Cochrane review reported that “thiopurines are not effective for induction of remission, but are effective for maintenance of remission.”

The editorial notes that a high degree of efficacy was demonstrated from a small but influential pediatric study of 55 patients.  After a high remission rate (89%) for all patients, this study showed that among those in remission, “1 patient (4%) in the 6MP group had a relapse within 180 days of achieving remission, compared with 7 patients (28%) in the placebo group.”

The editorial draws the following conclusions from the current studies:

  • “The remaining indications for primary therapy with thiopurines are maintenance of steroid-induced remission/steroid sparing in patients with CD that is not newly diagnosed, and prevention of postoperative recurrence.”
  • “The strongest indication for thiopurines may be as part of combination therapy.”
  • “If TNF antagonists had a similar low cost as generic thiopurines, there would likely be little debate regarding an evolution toward treatment of CD with TNF antagonists, either as monotherapy or ideally as combination therapy.  Currently, the annual costs of TNF antagonists is 10-20 times that of thiopurines.”
  • Because of the difference in cost.., “the use of thiopurines in CD is likely to persist, despite the shrinking number of indications, the modest effect size, and the suboptimal safety profile.”

Related blog posts:

Pediatric Fatty Liver Disease -in the news

Posted on by

An excerpt from The Wall Street Journal, Fatty Liver Disease: More Prevalent in Children (also covered by this blog previously: Increasing prevalence of pediatric NAFLD | gutsandgrowth):

A type of liver disease once thought to afflict primarily adult alcoholics appears to be rampant in children.

image

Some 1 in 10 children in the U.S., or more than 7 million, are thought to have the disease, according to recent studies.

The condition, in which the normally rust-colored organ becomes bloated and discolored by yellowish fat cells, has become so common in non-drinkers that it has been dubbed nonalcoholic fatty liver disease.

The disease’s prevalence is alarming doctors who worry about its progression to nonalcoholic steatohepatitis, or NASH, when the fatty liver becomes inflamed and cells are damaged. That leads to the end stage of cirrhosis, when the liver forms scar tissue and ultimately stops working.

Organ Damage

Some facts about nonalcoholic fatty liver disease:

  • About 10% of children in the U.S. are thought to have the condition.
  • Several factors likely contribute, including genetics, obesity, diet and insulin resistance.
  • It has no detectable symptoms.
  • Weight loss is the standard treatment for earlier stages of liver disease.

The condition’s rise is tied to the obesity epidemic—about 40% of obese children have it—but isn’t caused solely by being overweight. The disease appears to be growing among normal-weight children too, experts say.

And even though obesity rates are starting to level off, the prevalence of fatty liver disease continues to rise, they say.

It also has no symptoms, which means a person could have it for decades without knowing. 

Full link:

Fatty Liver Disease: More Prevalent in Children

Related blog entries:

Review of Button Batteries

Posted on by

A recent open access article reviews button batteries and reiterates algorithm from poison control (noted in previous blog post: Button Battery Algorithm Link | gutsandgrowth).  This article has some excellent figures detailing the extent of the problem and has relevant pictures of radiographs and mucosal damage.

Here’s the reference:

International Journal of Pediatric Otorhinolaryngology 77 (2013) 1392–1399

Here’s the link:

http://authors.elsevier.com/offprints/PEDOT6686/7551db6b14c8aabfa827016d69367c08 …

Precise Identification of C difficile Transmission

Posted on by

A recent study uncovers some useful information about C difficile by using whole-genome sequencing on 1250 separate C difficile cases (NEJM 2013; 369: 1195-205).

Between 2007-2011, the authors used genetic sequencing to determine the similarity of C difficile cases.  They were able to successfully sequence 1223 (98%) of the identified cases.  Of these isolates, 71% were from inpatients, 25% from outpatients, and 4% from patients at other hospitals. To determine similarity, they compared single-nucleotide variants (SNVs) between the isolates.  If isolates were related, it was anticipated that there would be 0 to 2 SNVs between transmitted isolates (95% prediction if less than 124 days apart).

This study was from the Oxford University Hospitals which provide all acute care and 90% of hospital services in Oxfordshire, United Kingdom (~600,000 population).

Results:

  • Only 35% of cases were genetically related to at least one previous case.
  • Of the 333 (35%) with ≤2 SNVs (consistent with transmission), and 126 (38%) had close hospital contact with another patient, 120 (36%) had no hospital or community contact with another patient.
  • 13% of cases were genetically related (≤2 SNVs) but without any evidence of plausible contact.
  • 45% of C difficile cases were genetically distinct (>10 SNVs from any previous case) from all previous cases.  This indicates that the source of the infection was not from another symptomatic case; most likely these cases were acquired from asymptomatic persons or an environmental reservoir.
  • There were reductions in the rate of C difficile infection during the 4-year study.  The authors relate this to changes in antibiotic prescribing behavior, specifically the restriction of fluoroquinolones and cephalosporins.

Aspects of the setting may limit some of the conclusions.  For example, the study was conducted in a nonoutbreak setting and the hospitals had established measures to limit transmission from symptomatic patients.  These included the following:

  • isolation of patients with suspected C difficile
  • daily hypochlorite disinfection
  • monitoring of compliance

These measures will decrease nosocomial transmission.  However, at the same time, some of the genetically distinct cases could still have been acquired in the hospital setting from asymptomatic hospital sources. While the authors concede a number of limitations, this study is quite helpful in understanding the role of hospitals in controlling C difficile infection.

Take-home message: the fact that only 35% of cases were related to other symptomatic cases indicates that hospital control measures by themselves will not be effective.  The most important aspect in reducing C difficile infection will be optimizing antibiotic usage.

Related news media: On the same day of that I read this study, there was an article in the Atlanta Journal Constitution (“PLEASE wash your hands … Please.”) which describes a first-hand account of C difficile infection which contributed to a slow recovery from intestinal surgery.  The article contained some questionable assertions including that C difficile was “impossible to eradicate” and that her immune system trapped C difficile in peritoneal abscesses which required drainage (these abscesses were more likely related to the initial operation). However, the article is a stark reminder that many hospital staff do not follow basic hand washing recommendations.  The article is really bad PR for the named hospital.

Related blog posts:

Reference for Mitochondrial Hepatopathies

Posted on by

This morning’s blog discussed mitochondrial liver disease.

Another useful reference:

The Journal of Pediatrics Volume 163, Issue 4 , Pages 942-948, October 2013  Mitochondrial Hepatopathies: Advances in Genetics, Therapeutic Approaches, and Outcomes  Way Seah Lee, MD and Ronald J. Sokol, MD

Mitochondrial Liver Disease

Posted on by

A recent review provides advice for the evaluation of the child with suspected mitochondrial liver disease (JPGN 2013; 57: 269-79).

Clinical presentations:

  • Acute in a child with no history of hepatic dysfunction
  • Chronic liver and CNS dysfunction
  • Onset of liver disease in patient with known CNS disorder

Suggested Tiered Diagnostic Evaluation: Table 1 provides extensive suggestions.

  • 1st tier: CMP, INR, AFP, CPK, Phos, CBC/d, ammonia, Lactate/pyruvate (preferably 1 hour after feeding), serum ketone bodies, serum acylcarnitine profile, carnitine profile, urine organic acids, serum amino acids, urine acylglycines and 2-ethylmalonic acid quantification, plasma thymidine (especially if intestinal dysmotility), quantitative serum methylmalonic acid, CSF analysis (lactate and pyruvate, amino acids, protein)
  • 2nd tier: genotyping for more common genes (eg. panel with POLG1, DGUOK, MPV17), other genetic tests based on tier 1 testing (see table for details)
  • 3rd tier: liver biopsy, skin biopsy, and muscle biopsy (see table for details)
  • 4th tier: additional genetic tests based on 1st three tiers

Table 2 describes potential evaluations in other organs.  For example, for brain, MRI, EEG and CSF.

Table 3 lists ~27 mutation/syndromes and clinical features.

The last three words from the conclusion of the publication are not supported by the review.  The authors state that this systematic approach “can aid in making a timely, accurate, and cost-effective diagnosis.”  While the authors do not provide estimates of the expense of these tests, they are probably very expensive, though less costly than a failed liver transplantation.

Bottomline: “Available technology to aid in diagnosis has improved substantially.  Nonetheless, diagnosis of suspected mitochondrial disease in children is complicated.”

Related blog post:

Proven treatments for mitochondrial disorders | gutsandgrowth

Challenging assumptions

Posted on by

While this topic is not directly related to pediatrics or pediatric gastroenterology, I found a recent article regarding the treatment of back pain with steroids interesting.  This study challenges a treatment algorithm of using steroids to relieve inflammation triggering back pain.  The investigators showed that steroids per se are not more beneficial then saline in improving back pain.  Here is an excerpt from the NY Times, http://t.co/RF5O78odWe:

Questioning Steroid Shots for Back Pain

By NICHOLAS BAKALAR

Injecting steroids into the area around the spinal cord, known as an epidural, is the most commonly used treatment for back pain, but a new review of studies suggests that injecting any liquid, even plain saline solution, works just as well.

Researchers pooled the results of 43 studies involving more than 3,600 patients who got various kinds of injections for back pain. As they expected, they found some evidence that epidural steroid injections provided more relief than steroid injections into the muscles.

But the study, published online in Anesthesiology, also found that there was little difference between the amount of relief provided by steroidal and nonsteroidal epidural injections.

The researchers suggest that any liquid injected epidurally can help reduce inflammation, enhance blood flow to the nerves and clean out scar tissue.

Comment: There are inherently many limitations in pooling 43 studies and trying to reach a definitive conclusion.  Nevertheless, this study challenges some long-term treatment approaches.

Breakfast: a marker for heart-healthy habits

Posted on by

Summary of study (Circulation 2013; 128: 337-343) from Epocrates (emphasis in blue by blog):

Study Question:
Is eating breakfast or not associated with risk for coronary heart disease (CHD) among men residing in the United States?
Methods:
Data for this analysis were from the Health Professionals Follow-up Study, an ongoing prospective study of male health professionals. Approximately 97% of participants were of white European descent. Eating habits, including breakfast eating, were assessed in 1992 in 26,902 American men, ages 45-82 years, who were free of cardiovascular disease and cancer. Participants were followed through mailed biennial questionnaires that ascertained medical history, lifestyle, and health-related behaviors. Cox proportional hazards models were used to estimate relative risks and 95% confidence intervals for CHD, adjusted for demographic, diet, lifestyle, and other CHD risk factors.
Results:
Participants who did not report eating breakfast were younger than those who did, and were more likely to be smokers, to work full-time, to be unmarried, to be less physically active, and to drink more alcohol. Men who reported that they ate late at night were more likely to smoke, to sleep <7 hours a night, or to have baseline hypertension compared with men who did not eat late at night. The late-night eating abstainers were more likely to be married and to work full-time, and ate on average one time less per day than the late-night eaters. The mean diet quality of the participants was high among participants, regardless of their breakfast or late-night eating status. During 16 years of follow-up, 1,527 incident CHD cases were diagnosed. Men who skipped breakfast had a 27% higher risk of CHD compared with men who did not (relative risk, 1.27; 95% confidence interval, 1.06-1.53). Compared with men who did not eat late at night, those who ate late at night had a 55% higher CHD risk (relative risk, 1.55; 95% confidence interval, 1.05-2.29). These associations were mediated by body mass index, hypertension, hypercholesterolemia, and diabetes mellitus. No association was observed between eating frequency (times per day) and risk of CHD.
Conclusions:
The investigators concluded that eating breakfast was associated with significantly lower CHD risk in this cohort of male health professionals.
Perspective:
These data suggest that time of meals is associated with other lifestyle behaviors. Adjustment for body mass index, hypercholesterolemia, hypertension, and diabetes [resulted in the relationship between breakfast (and late-night meals) and CHD no longer being significant.] Physicians may use this information to assist in the identification of those who may be at risk and need to improve lifestyle habits. However, it is unlikely that eating breakfast by itself would confer significant protection against heart disease.

Full text available at http://circ.ahajournals.org/content/128/4/337

Related blog post:

Skipping breakfast –boomerang effect for obesity | gutsandgrowth