Gastroesophageal Reflux Phenotypes and “Where Rome, Lyon, and Montreal Meet”

A useful review (DA Katzka et al. Clin Gastroenterol Hepatol 2020; 18: 767-76) discusses the phenotypes of gastroesophageal reflux and related disorders.   The authors note that consensus initiatives (Montreal, Rome, and Lyon) have looked at these disorders from different perspectives and their goal was to merge their perspectives.

Table 1 lists the major phenotypes:

  • Nonerosive reflux disease
  • Reflux hypersensitivity
  • Functional heartburn
  • Erosive esophagitis (low grade and high grade).  LA grade A esophagitis “can be found in approximately 6% of asymptomatic controls”
  • Barrett’s esophagus
  • Reflux chest pain syndrome
  • Regurgitation-dominant reflux disease: “need to differentiate from rumination and achalasia”
  • Laryngopharyngeal reflux
  • Chronic cough  “although reflux may contribute, it is rarely the dominant pathophysiology… more amenable to GERD therapy when accompanied by typical reflux symptoms”

Figure 1 provides a model for the pathogenesis of GERD. Figure 2 describes the relationship between reflux phenotypes and PPI responsiveness:

In those with typical reflux symptoms: 

  • esophagitis healing 84% with PPI Rx compared to 28% with placebo (NNT =1.8)
  • heartburn relief (with and without esophagitis) 56% with PPI Rx compared to 16% with placebo (NNT =4.4)
  • heartburn relief without esophagitis 40% with PPI Rx compared to 13% with placebo (NNT =3.7)
  • regurgitation relief (with and without esophagitis) 47% with PPI Rx compared to 30% with placebo (NNT =5.9)

In those with atypical reflux symptoms:

  • chest pain relief with objective GERD 74% with PPI Rx compared to 20% with placebo (NNT =1.6) (Studies used a 50% reduction in pain as opposed to complete elimination…opens the door for a greater placebo response)
  • chest pain relief without objective GERD 29% with PPI Rx compared to 23% with placebo (NNT =16.7) (Studies used a 50% reduction in pain as opposed to complete elimination…opens the door for a greater placebo response)
  • chronic cough with objective GERD 33% with PPI Rx compared to 9% with placebo (NNT =4.2)
  • chronic cough without objective GERD 31% with PPI Rx compared to 27% with placebo (NNT =25)
  • reflux laryngitis (without heartburn, complete resolution) 15% with PPI Rx compared to 16% with placebo
  • poorly-controlled asthma (without heartburn)-exacerbations per year: 2.5 with PPI Rx compared to 2.3 with placebo 
  • *references for this figure provided

Other useful points:

  • “An exception to the de-emphasizing the relationship of GERD to an extraesophageal syndrome is with lung transplantation, which …has unique considerations…the sequelae of untreated GERD …may lead to accelerated mortality from allograft injury…data have suggested that PPIs may be effective at prolonging allograft survival.”
  • The authors state that escalating PPI/antisecretory treatments for esophagitis is often effective but this approach has limited applicability for other indications and can result in overuse. “Similarly, failing to recognize the modulating effects of anxiety, hypervigilance, and visceral and central hypersensitivity on symptom severity has greatly oversimplified the problem.”

My take (borrowed in part from authors): PPIs work well for esophagitis and documented reflux; “the broad spectrum of syndromes [are] much less amenable to PPI therapy in any dose.”

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Curbside Humor

 

Do Acid Blockers Given to Infants Increase the Risk of Allergic Disease?

A recent retrospective study (Mitre E, et al. JAMA Pediatr. 2018;doi:10.1001/jamapediatrics.2018.0315) suggests that acid blockers, both histamine receptor antagonists and proton pump inhibitors increase the risk of developing allergic disease.  Since this is a retrospective study, this association with allergic diseases has NOT been proven to have a causal relationship; thus, an alternative explanation would be that infants who are likely to develop allergic diseases could be prescribed these agents more frequently due to symptoms attributed to reflux.

Here is an excerpt from a summary of this study (from Healio):  Acid-suppressor, antibiotic use in infancy tied to later allergic disease

Of the 792,130 children included in the study (49.9% female), 7.6% were prescribed a histamine-2 receptor antagonist (H2RA) and 1.7% were prescribed a proton pump inhibitor (PPI) within the first 6 months of life. Antibiotics also were prescribed for 16.6% of infants included in the study during this time. Mitre and colleagues noted that data continued to be collected on these infants for a median of 4.6 years…

When children were prescribed an H2RA, the researchers noted adjusted HRs of 2.18 (95% CI, 2.04-2.33) for food allergy, 1.70 (95% CI, 1.60-1.80) for medication allergy, 1.51 (95% CI, 1.38-1.66) for anaphylaxis, 1.50 (95% CI, 1.46-1.54) for allergic rhinitis and 1.25 (95% CI, 1.21-1.29) for asthma.

Infants who were prescribed PPIs had comparable aHRs, which the researchers observed at 2.59 (95% CI, 2.25-3.00) for food allergy, 1.84 (95% CI, 1.56-2.17) for medication allergy, 1.45 (95% CI, 1.22-1.73) for anaphylaxis and 1.44 (95% CI, 1.36-1.52) for asthma.

Mitre and colleagues also calculated the aHRs related to later allergic disease in children who were prescribed antibiotics within the first 6 months of life. They observed these rates at 2.09 (95% CI, 2.05-2.13) for asthma, 1.75 (95% CI, 1.72-1.78) for allergic rhinitis, 1.51 (95% CI, 1.38-1.66) for anaphylaxis and 1.42 (95% CI, 1.34-1.50) for allergic conjunctivitis.

My take: This study is another reminder that these agents may be more detrimental than beneficial in the vast majority of infants.

Related blog post:

Infant Feeding, Opportunity, and Asthma

A recent study (A Kloop et al. J Pediatr 2017; 190: 192-9) examined the relationship between mode of infant feeding and the development of asthma.  The authors used prospective data from 3296 Canadian children in the Canadian Healthy Infant Longitudinal Development (“CHILD” study) cohort.

Key finding:

  • “Compared with infants who received direct breast milk only [at 3 months of age], those who received some expressed milk had a 43% increased odds [of asthma at 3 years of life] …and those who received only formula had a 79% increased odds.”

The authors speculate that the direct breastfeeding may offer some advantages over expressed breast milk:

  • There may be alteration in breast milk components with storage
  • A nursing infant may trigger an increased immune response and be directly exposed to some beneficial commensal bacteria

Since this is an observational study and patients were not randomized there may be other unrecognized confounding variables.

Another study in the same issue (AF Beck et al. J Pediatr 2017; 190: 200-6) assessed whether the Child Opportunity Index (COI) was associated with asthma outcomes in a retrospective cohort of 5462 children in Hamilton County, Ohio.  The COI (see below for the measures in this index) has previously been linked to life expectancy, low birth weight, and prematurity.  Interestingly, one can go to diversitydatakids.org to see how this affects your location (here is the link for a heat map of this index in the Atlanta area: Atlanta COI)

Key finding:

  • Median hospitalization rates varied based on COI –those with very high opportunity had a rate of 1.8 per 1000.  The other quintiles of COI were the following: high opportunity 2.1, moderate opportunity 4.6, low opportunity 7.6, and very low 9.1

My take: The first study indicates that direct breastfeeding is associated with lower rates of asthma.  The second study shows that issues related to education, environment, and social/poverty have an enormous impact on need for asthma-related hospitalization.

 

 

Update on Chronic Cough

It is not uncommon for a pediatric gastroenterologist to see a patient with a chronic cough due to concerns about potential gastroesophageal reflux disease (GERD).  As such, a recent clinical practice article (JA Smith, A Woodcock. NEJM 2016; 375: 1544-51) by lung specialists was of interest, even though this article was not targeted to the pediatric population.

Key points:

  • The authors define a chronic cough as lasting more than 8 weeks and note that it common with respiratory conditions (eg. chronic obstructive pulmonary disease, asthma, and bronchiectasis) and some non-respiratory conditions (eg. gastroesophageal reflux and rhinosinusitis).  Medications, particularly ACE inhibitors, can trigger a chronic cough as well.
  • Steps in evaluation: 1. H&P, CXR, spirometry. 2. Consider metacholine challenge, ENT evaluation, consider empiric treatment (eg. inhaled glucocorticoids, PPI), and consider GERD evaluation. 3. High-resolution CT and bronchoscopy.
  • For many patients, there is likely to be an abnormality in neuronal pathways controlling cough and the term “cough hypersensitivity syndrome” has been coined.  Figure 2 (below) illustrates the neuronal pathways.
  • For refractory patients, potential therapies would include low-dose morphine, gabapentin or pregabalin, and speech language therapy.

screen-shot-2016-10-26-at-8-24-57-pm

GERD:

  • Guidelines “suggest a trial of treatment with acid-suppression therapy” (eg. twice-daily PPIs for up to 3 months).
  • “Most randomized, controlled trials of reflux treatment for cough have not shown a significant improvement in association with this type of treatment.”
  • Subgroups of patients with heartburn, regurgitation, or excessive acid reflux on esophageal pH monitoring “appeared marginally more likely to have a response to PPI treatment.”  pH or impedance tests “are poorly predictive of a response of cough to acid suppression.”

My take: In the absence of clinical reflux, reflux therapy is unlikely to help with chronic cough.  However, in patients with an adequate workup, an empiric course of a PPI is likely more preferable than empiric morphine or gabapentin.

Related blog posts:

 

screen-shot-2016-10-22-at-4-01-47-pm

Why Asthma Study is Important: Hygiene Theory

In my view, one of the most important pediatric studies this year was just published (reference below).  For a long time, it has been recognized that growing up on farms can reduce the likelihood of developing conditions like asthma, as well as inflammatory bowel disease (Related post: NYT: Educate Your Immune System | gutsandgrowth).  This study: Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children provides an in depth assessment of 60 children and helps uncover the reason for these epidemiologic results.

Here’s the quick 2 minute summary: Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children

Screen Shot 2016-08-05 at 9.13.14 AM

 

Understanding Single-Payer Health Care: “Medicare for All”

A recent commentary (J Oberlander. NEJM 2016; 374: 1401-3) explains the “virtues and vices of single-payer health care.”

“In a country where nearly 30 million persons remain uninsured, even insured patients face staggering bills, and more money is spent on administration than on heart disease and cancer, it’s no surprise to hear calls for sweeping change.”

Virtues of Single-Payer System:

  • Based on Canadian experience, single-payer greatly reduces administrative costs and complexity.
  • Concentration of purchasing power
  • Guarantee that all residents receive care
  • The problems of a single-payer system “pale in comparison” to the current U.S. system

Vices of Single-Payer System:

  • Wait lists for some services
  • Public dissatisfaction
  • Would require increased taxes (though may improve overall finances for most)

It Does Not Matter if Single-Payer is Better:

It would face intense opposition from insurers, medical industry, and would not be adopted by Congress. “In short, single payer has no realistic path to enactment in the foreseeable future.”

My take (in agreement with author): “Preserving and strengthening the ACA [affordable care act] as well as Medicare, and addressing underinsurance and affordability of private coverage is a less utopian cause than single payer. I believe it’s also the best way forward now for U.S. medical care.”

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Graphic showing association between obesity and asthma

Graphic showing association between obesity and asthma

 

Helicobacter Pylori: Relationship to Cancer and Dubious Beneficial Claims

I found a recent review (Gastroenterol 2015; 148: 719-31) regarding Helicobacter pylori (HP) of interest.  David Graham explores the issue of HP eradication with regard to cancer and whether there are benefits to the infection that result in detrimental effects with HP eradication.

The potential mechanisms in which HP infection can increase the risk of gastric cancer are depicted in Figure 2; the most important:

  • Inflammation induced by infection
  • Genetic/epigenetic changes –> genetic instability in gastric epithelial cells

Lessons regarding eradication therapy:

  • Sequential therapy has been shown in some studies to be effective/superior (in Italy) yet inferior in others (eg. Korea).  “The results are explained entirely by differences in patterns of drug resistance, which typically were not assessed before studies were initiated.”
  • Findings from many studies cannot be applied to other populations without resistance data.

Does HP infection reduce the risk of obesity or childhood asthma?  Probably not.

  • “Any claim that a major human pathogen also might provide a meaningful health benefit, and that plans to eradicate it should be reconsidered, is guaranteed to elicit interest from the press.”
  • As a counter example, Dr. Graham notes “because 2 events are associated does not mean that one causes the other. For example, one study reported a correlation between the number of storks in Brandenburg, Germany, and the birth rate in Berlin.” [Backen MB. Harm. In: Bracken MB. Risk, chance, and causation. New Haven: Yale University Press, 2013; 108-09.]
  • He notes that HP can both promote or inhibit acid secretion/acid reflux.  Increased acid secretion with resultant esophageal disease could increase the risk of adenocarcinoma of the esophagus; however, “the risk of developing adenocarcinoma of the stomach remains higher than the risk of adenocarcinoma of the esophagus.”  This indicates that if there is an increased esophageal cancer risk, eradication would still be favorable by lowering gastric cancer risk.
  • Asthma: “overall, the studies do not support the hypotheses that increases in childhood asthma were related to the absence of H pylori.”
  • Obesity: “A meaningful causative association between H pylori and obesity is unlikely.”
Screen Shot

Screen Shot

Take-home message: H pylori is a pathogen and should be treated as such.

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University of Chicago

University of Chicago

Can Apple Make Research Cool?

For anyone who has looked at Apple’s March presentation, there is big news with regard to research (thanks to Seth for this information).  Here’s a link to the March announcement –around minute 16 there is the research presentation: Apple March Event

Screenshot: Rationale for Apple iPhone for Research -Large Research Pool

Screenshot: Rationale for Apple iPhone for Research -Large Research Pool

The presentation makes it clear that Apple wants to dramatically increase the participation in research studies by leveraging 700 million iPhone users.  Using an app called, “ResearchKit”, Apple has partnered with leading academic centers to help study Parkinson’s, Diabetes, Asthma, Cardiovascular disease, and Breast Cancer.  For the GI community, I hope that someone will work collaboratively to add inflammatory bowel disease to the list.

Besides increased participation, iPhone-based research has the ability to lower research costs, collect data at frequent intervals, and allow a wider demographic representation.

A shorter ~4 minute video on a separate area of the website explains ResearchKit: ResearchKit video

 Screenshot: Research Kit


Screenshot: ResearchKit

NBC News provides a condensed summary along with the caveat that there will be concerns about accuracy of data collected with ResearchKit.  That being said, most critics have not always appreciated the impact of previous Apple innovations.

Has someone from our national organization (NASPGHAN) or from ImproveCareNow started working with Apple? If not, this looks like a great opportunity.

Probiotics, Atopy, and Asthma

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.

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Lessons on Stature from Asthma Treated with Steroids

A study of the effects of budesonide for the treatment of asthma should be carefully considered by those of us who treat eosinophilic esophagitis with “topical” steroids; also, this study has applicability to Crohn’s disease patients receiving chronic glucocorticoids.  Mean adult height was 1.2 cm lower in the budesonide-treated asthmatics than in the placebo group (NEJM 2012; 367: 904-12).

This was the main finding at the end of the Childhood Asthma Management Program (CAMP) clinical trial.  This report examined 943 of 1041 (90.6%) participants  who had received either 0.4 mg of budesonide, 16 mg of nedocromil or placebo daily for 4 to 6 years.  Treatment with these agents began between ages 5 to 13.

The reduction in adult height was to similar in adulthood as it was after 2 years of treatment; there was not catch up growth.  With regard to the adult measurements, 96.8% of the adult women were at least 18 years and the adult men were at least 20 years of age.

Other findings:

  • Larger daily dose: each microgram per kilogram was associated with -0.1 cm drop
  • Other risk groups: Hispanic ethnic group, female sex, greater body mass index, longer duration of asthma, and higher Tanner stage at initiation

The authors note that 0.2 mg dosage of budesonide has been shown to be effective to control asthma symptoms in children 5-11 years.  The “lowest effective dose” should be used; “the effect on adult height must be balance against the large and well-established benefit of these drugs in controlling persistent asthma.”

Related links:

Looking better or feeling better in EoE?

Guidelines for Eosinophilic Esophagitis

Choosing topical therapy for EoE

The undiscovered country