Category Archives: Uncategorized

Origins of Hygiene Hypothesis

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A recent NY Times article explains the background of the ‘hygiene hypothesis’ and how it has held up remarkably well as a likely factor in the rising number of allergic and immune-mediated diseases.

Link: Your Environment is Cleaner. Your Immune System Has Never Been So Unprepared

An excerpt:

The British Journal of Homeopathy, volume 29, published in 1872, included a startlingly prescient observation: “Hay fever is said to be an aristocratic disease, and there can be no doubt that, if it is not almost wholly confined to the upper classes of society, it is rarely, if ever, met with but among the educated.”..

In November 1989, another highly influential paper was published on the subject of hay fever. The paper was short, less than two pages, in BMJ, titled “Hay Fever, Hygiene, and Household Size.”

The author looked at the prevalence of hay fever among 17,414 children born in March 1958. Of 16 variables the scientist explored, he described as “most striking” an association between the likelihood that a child would get hay fever allergy and the number of his or her siblings.

It was an inverse relationship, meaning the more siblings the child had, the less likely it was that he or she would get the allergy…The paper hypothesized that “allergic diseases were prevented by infection in early childhood, transmitted by unhygienic contact with older siblings, or acquired prenatally from a mother infected by contact with her older children…

[To avoid disease] we started washing our hands and took care to avoid certain foods that experience showed could be dangerous or deadly…Particularly in the wealthier areas of the world, we purified our water, and developed plumbing and waste treatment plants; we isolated and killed bacteria and other germs…

What does the immune system do when it’s not properly trained?

It can overreact. It becomes aggrieved by things like dust mites or pollen. It develops what we called allergies, chronic immune system attacks — inflammation — in a way that is counterproductive, irritating, even dangerous.

The percentage of children in the United States with a food allergy rose 50 percent between 1997–1999 and 2009–2011, according to the Centers for Disease Control and Prevention…

There are related trends in inflammatory bowel disease, lupus, rheumatic conditions and, in particular, celiac disease. The last results from the immune’s system overreacting to gluten..

And even doctors have been wrong….They have vastly overprescribed antibiotics. These may be a huge boon to an immune system faced with an otherwise deadly infection. But when used without good reason, the drugs can wipe out healthy microbes in our gut.

My take: With the increasing frequency of many diseases, there has to be environmental influences since our population genetic makeup does not change rapidly. Thus factors like infections, microbiome and exposure to antibiotics are likely important in the changing epidemiology.

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Mortality After Feeding Tube Placement in Children with Neurologic Impairment

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A population-based study (KE Nelson et al. Pediatrics 2019; 143: e20182863) used an administrative data based from Ontario, Canada to examine the mortality rates among children with a diagnosis of neurologic impairment who underwent either gastrostomy placement or gastrojejunal placement between 1993-2015.

Key findings:

  • Two-year survival after feeding tube placement was 87.4% and 5-year survival was 75.8%
  • Unplanned hospital days, emergency room visits and outpatient visits were not significantly different after tube placement compared to pre-tube placement.

The authors interpret their findings as showing a high mortality which is likely due to medical fragility as there was “stability of health care use before and after the procedure.”

In the associated commentary (by KJ Lee and TE Corden, e20183623) the authors note the placement of a Gtube often took place after an increase in health care in the weeks prior.  They recommended engaging in shared-decision making regarding Gtube placement prior to crisis.

My take: There have been a number of studies, particularly in adults, that have shown that Gtubes may not prolong survival in many conditions.  However, they have been shown to improve nutritional status, simplify care, and improve quality of life.

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Joshua Tree National Park

 

Can We Ignore Laryngeal Penetration?

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A recent retrospective study (DR Duncan et al. JPGN 2019; 68: 218-24) makes it clear that laryngeal penetration is an important finding when identified on a swallow study. The authors reviewed charts from 137 subjects (mean age 9 months) who had laryngeal penetration but not aspiration with a video swallow study (VSS).

Key findings:

  • 40% of patients with laryngeal penetration receiving thickening of feeds as treatment, 15% had a change in flow rate.  60% were maintained on thin liquids.
  • Thickening feeds was significantly associated with improvement in symptoms with OR 41.8.  91% of subjects with thickening had symptom improvement compared to 19% among group with no feeding intervention.
  • Subjects receiving a feeding intervention (thickening or change in flow rate) had decreased total  and pulmonary hospitalizations.  In contrast, in patients who did not have a feeding intervention, no significant decrease in hospitalization was noted. These data are tabulated in Table 3.  It is worth noting that those who had feeding intervention had higher risk of admission prior to feeding intervention, 0.69 compared to 0.53 for non-intervention group. Afterwards, the feeding intervention group  risk was  0.40 compared to 0.45 for the non-intervention group.
  • On followup VSS, 26% had evidence of aspiration.

One key point is that those with deep penetration were much more likely to have their feeds thickened/adjusted.

My take: This study makes it clear that all symptomatic children with laryngeal penetration should have adjustment in their feedings, most often thickening of their feeds.   These interventions appear to lower hospitalizations and are needed because in many cases the swallow dysfunction does not resolve or worsens.

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Georgia Aquarium

Clostridium difficile and Cannabis

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Briefly noted:

W El-Matary et al. J Pediatr 2019; 206: 20-5.  This study from Manitoba using electronic database found that the incidence rate of C difficile was stable from 2005-2015, with an overall rate of 7.8 per 100,000 person-years.  Children with Hirschsprung’s and inflammatory bowel disease had increased prevalence rates.

JL O’Loughlin et al. J Pediatr 2019; 206: 142-7. Using data from two longitudinal studies in Montreal (Cannabis is legal for adults in Canada since 2018), the authors examined the rate of cannabis initiation starting in 6th grade through 11th grade. Key finding was that cannabis use was 1.8 time more likely among children whose parents used cannabis.  Overall, cannabis use increased from 3.1% in grade 6 to 25.7% in grade 11.

What is erythromelagia?  This term was noted in the title of a recent report (J Pediatr 2019; 206: 217-24) and refers to bilateral episodic pain and redness that occurs in feet, hands and occasionally the ears.  In some case, symptoms progress proximally to involve the legs, arms, and rarely the face.

 

AGA Guidelines on the Management of Mild-to-Moderate Ulcerative Colitis

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A recent AGA Clinical Practice Guideline on the Management of Mild-to-Moderate Ulcerative Colitis was published along with patient guide (pg 766-67), a brief summary (pg 768) (“spotlight”) and technical review.

  • CW Ko et al. Gastroenterol 2019; 156: 748-64.
  • S Singh, JD Feuerstein et al. Gastroenterol 2019; 156: 769-808.

Summary of Recommendations for the medical management of mild-to-moderate ulcerative colitis: (available from AGA Website, my comments in blue & I bolded some of the recommendations):

1.    Use either standard dose mesalamine (2-3 grams/day) or diazo-bonded 5-ASA [Balsalazide or Olsalazine] rather than low dose mesalamine, sulfasalazine or no treatment in patients with extensive mild-moderate UC. (Strong recommendation, moderate quality evidence) [The article notes several potential exceptions for sulfasalazine: doing well on current treatment, prominent arthritic symptoms, or cost]

2.    In patients with extensive or left-sided mild-moderate UC, add rectal mesalamine to oral 5-ASA. (Conditional recommendation, moderate quality evidence)

3.    In patients with mild–moderate UC with suboptimal response to standard-dose mesalamine or diazo-bonded 5-ASA or with moderate disease activity, use high-dose mesalamine (>3 g/d) with rectal mesalamine. (Conditional recommendation, moderate-quality evidence [induction of remission], low-quality evidence [maintenance of remission])

4.    In patients with mild–moderate UC being treated with oral mesalamine, use once-daily dosing rather than multiple times per day dosing. (Conditional recommendation, moderate quality evidence) [In the commentary, the authors note that 4 RCTs have shown no differences when using equivalent dose once a day compared to divided dose and that once a day promotes adherence]

5.    In patients with mild–moderate UC, use standard-dose oral mesalamine or diazo-bonded 5-ASA, rather than budesonide MMX or controlled ileal-release budesonide for induction of remission. (Conditional recommendation, low quality of evidence)

6.    In patients with mild–moderate ulcerative proctosigmoiditis or proctitis, use mesalamine enemas (or suppositories) rather than oral mesalamine. (Conditional recommendation, very-low-quality evidence) [In commentary, the authors note that oral mesalamine can be given based on patient preference, but that for distal disease there is likely a higher response with topical therapy]

7.    In patients with mild–moderate ulcerative proctosigmoiditis who choose rectal therapy over oral therapy, use mesalamine enemas rather than rectal corticosteroids.(Conditional recommendation, moderate-quality evidence)

8.    In patients with mild–moderate ulcerative proctitis who choose rectal therapy over oral therapy, use mesalamine suppositories. (Strong recommendation, moderate-quality evidence)

9.    In patients with mild–moderate ulcerative proctosigmoiditis or proctitis being treated with rectal therapy who are intolerant of or refractory to mesalamine suppositories, use rectal corticosteroid therapy rather than no therapy for induction of remission. (Conditional recommendation, low-quality evidence)

10.    In patients with mild–moderate UC refractory to optimized oral and rectal 5-ASA, regardless of disease extent, add either oral prednisone or budesonide MMX. (Conditional recommendation, low-quality evidence)

11.    In patients with mild–moderate UC , AGA makes no recommendation for use of probiotics. (No recommendation, knowledge gap)

12.    In patients with mild–moderate UC despite 5-ASA therapy, AGA makes no recommendation for use of curcumin. (No recommendation, knowledge gap)

13.    In patients with mild–moderate UC without Clostridium difficile infection, AGA recommends fecal microbiota transplantation be performed only in the context of a clinical trial. (No recommendation for treatment of ulcerative colitis, knowledge gap)

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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist.  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

Joshua Tree National Park, Hike to Warren Peak

A Role for Thiopurine Therapy

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In high school, the usual advice on multiple choice questions was to avoid picking “always” and “never” on multiple choice questions.

A recent commentary (KH de Boer et al.”Thiopurine Therapy in Inflammatory Bowel Diseases: Making New Friends Should Not Mean Losing Old Ones”Gastroenterol 2019; 156: 11-4) makes the point that “never” is probably the wrong answer with regard to thiopurine usage.

Key points:

  • “Thiopurine therapy has proven its value in maintenance of remission, decreased need for surgery, lowered colorectal cancer risk, less phenotypic disease progression, and synergistic effects when used with infliximab therapy, including increased biologic drug levels and less antibody formation.”
  • “Notwithstanding the extensive experience by many physicians, the clinical use of conventional immunosuppressive therapies has been questioned in recent years.”
  • “In this issue of Gastroenterology, Hanauer et al share their expert opinion on the evolving use of thiopurines and methotrexate in daily practice. In their literature review, the importance of assessing the risks (infections and cancer risk) and benefits (maintenance of remission) of thiopurine therapy is highlighted”
  • Lymphoma risk: “The recent nationwide cohort study based on French National Health Insurance databases is illustrative. Including 189,289 patients, it was demonstrated that both thiopurine (adjusted hazard ratio of 2.6) and anti-TNF monotherapy (adjusted hazard ratio of 2.4) were associated with a similar small but statistically significant increased risk of lymphoma. Furthermore, combination therapy of thiopurine and anti-TNF was associated with a higher chance of developing a lymphoma (adjusted hazard ratio of 6.1).”
  • “The individual absolute risk remains low, especially in patients without additional risk factors such as a young age in male patients and negative Epstein-Barr virus serology.”

The author’s conclusion: “The thiopurines are not perfect regarding both efficacy and toxicity, but in recent years they may have been portrayed in a worse light than they deserved. No doubt, the thiopurines will be surpassed eventually by newer safe and economical (oral) therapies, but it is too early to discard these old friends.”

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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.

Monticello

 

Mortality Risk from Childhood Inflammatory Bowel Disease

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A recent study (O Olen et al. Gastroenterol 2019; 156: 614-22) was summarized quite succinctly by NEJM journal watch:

Using the Swedish National Patient Registry data, investigators identified 9442 incident cases of IBD diagnosed in patients under age 18 years from 1964 through 2014. Based on 139,000 person-years of follow-up, results were as follows:

  • There were 259 deaths among people with IBD (133 were from cancer and 54 from digestive disease).
  • The all-cause mortality rate in these patients was 2.1/1000 person-years, compared with 0.7 in matched reference individuals from the general population.
  • The average age at death was 61.7 compared with 63.9 years in the reference group.
  • The hazard ratio for death was 3.2 and was higher in those with ulcerative colitis (HR, 4.0), especially if they had concomitant primary sclerosing cholangitis (HR, 12.2), a first-degree relative with ulcerative colitis (HR, 8.3), or a history of surgery (HR, 4.6).
  • Mortality risks were similar when limited to the period after the introduction of biologics (2002–2014).

My take: This study found that having IBD diagnosed in childhood increased the risk of mortality (~1 extra death for every 700 patients followed for 1 year) especially in patients with concomitant PSC and in patients with severe ulcerative colitis.  The study did not see an effect of the newest therapies but was underpowered to directly assess this effect.

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Chattahoochee River, near Azalea Drive

 

Safety of Senna-Based Laxatives

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A recent study  (Vilanova-Sanchez A, et al. J Pediatr Surg 2018; 53: 722-7) provides reassurance regarding the safety of senna-based laxatives in kids.

The authors performed a literature review and reviewed their personal experience (2014 to 2017) of prescribing Senna in 640 patients. In this cohort, 230 (36%) had functional constipation.

Key findings:

  • Besides abdominal cramping or diarrhea during the first weeks of administration, there were no other long-term side effects from Senna found in the pediatric literature with long-term treatment
  • At their institution, 83 (13%) patients presented minor side effects such as abdominal cramping, vomiting or diarrhea, almost half (48%) of which resolved spontaneously within two weeks.
  • “We did not see any side effects in 540 (84.3%) patients.”  The median length of treatment was 338 days and median dose was 17.5 mg.  “430 (80%) of them are currently taking Senna.”
  • 17 patients (2.2%) developed blisters during their treatment. Patients who developed blisters had higher doses 60 mg/day; 60 [12–100] vs. 17.5 [1.7–150] (p < 0.001). All of the blistering episodes were related to night-time accidents, with a long period of stool to skin contact.

In their discussion, the authors note that senna and other anthranoid glycosides are not absorbed in the small intestine.  They are maintained as prodrugs until they reach the large intestine where they are metabolized to the active form. In addition, “despite an extensive search of both the medical and lay literature we did not find any reference to long term tolerance due to treatment which we find is a frequently mentioned concern by families and clinicians”

The authors comments on the study from Nationwide Children’s Hospital website:

  • “The safety profile of senna is as good as or better than many common medications a person would be on, including over-the-counter medications routinely given to very young children, and tolerance does not appear to be a concern,” says Dr. Levitt, who is also a professor of Surgery at The Ohio State University College of Medicine. “We hope this paper will make physicians more comfortable in using senna-based laxatives, and that they will be more widely used.”
  • Senna is often more effective than polyethylene glycol. This study shows that it is safe as well.  “A physician should consider senna as the first line medication,” says Dr. Levitt.

My take: Many patients who come to pediatric gastroenterologists have not responded to polyethylene glycol.  Senna has been effective in many of these patients as part of a bowel regimen which usually includes behavior modification and diet.

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Pictures from Joshua Tree National Park

NY Times: The Battle Over Fecal Transplantation

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NY Times: Drug Companies and Doctors Battle Over the Future of Fecal Transplants

This article highlights a concern that pharmaceutical companies may persuade the FDA to regulate fecal transplants similar to medications.  This will exponentially increase the cost and limit the access to beneficial human excrement. Thanks to one of my sons for pointing out this commentary to me.

An excerpt:

As pharmaceutical companies seek to profit from the curative wonders of human feces, doctors worry about new regulations, higher prices and patients attempting DIY cures…

The clash is over the future of fecal microbiota transplants, or F.M.T., a revolutionary treatment that has proved remarkably effective in treating Clostridioides difficile, a debilitating bacterial infection that strikes 500,000 Americans a year and kills 30,000…

At the heart of the controversy is a question of classification: Are the fecal microbiota that cure C. diff a drug, or are they more akin to organs, tissues and blood products that are transferred from the healthy to treat the sick? The answer will determine how the Food and Drug Administration regulates the procedure, how much it costs and who gets to profit…

Human feces, it turns out, are a potential gold mine, for both medical researchers and drug makers…

Inspired by the success of fecal transplants for C. diff, scientists are racing to develop similar treatments for an array of ailments and disorders, among them obesity, autism, ulcerative colitis, and Alzheimer’s and Parkinson’s diseases…

For now, most of the material used in fecal transplants comes from OpenBiome, the public stool bank in Cambridge …The material comes from donors who earn $40 a pop and must pass intensive screenings and regular medical checkups. “It’s harder to become a stool donor than it is to get into M.I.T.,” said Carolyn Edelstein, who runs the organization…The F.D.A. has ramped up oversight of OpenBiome’s production, leading to more rigorous testing and higher prices, which will double to $1,600 this month.

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From NY Times Twitter Feed