Understanding Reflux/Airway Disease and Potential Role of Airway Impedance

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A recent blog post, Airway Impedance to Objectively Assess Airway Mucosal Integrity, reviewed a study by Rosen et al (R Rosen et al. J Pediatr 2023; 256: 5-10) which used a novel approach in assessing airway disease using airway impedance.

This month’s Journal of Pediatrics provides a terrific commentary by my partner, Jose Garza. Open Access: Airway Impedance: In Search of a New Tool (DOI:https://doi.org/10.1016/j.jpeds.2023.01.007).

The article first describes the history of identifying gastroesophageal reflux: “the first attempt to detect GER was in 1884 by Reichman, who lowered a sponge into the esophagus of a patient with heartburn and showed that it contained acid when retrieved. He found that fluid expressed from the sponge was acidic in persons with heartburn and alkaline in normal controls. The first in situ measurement of acid reflux in the esophagus is credited to Tuttle and Grossman 2 in 1958.”

With the development of multi-channel impedance, the concept of reflux has shifted in young children: “non-acid reflux events are more important to the development of symptoms than acid events.”

With regard to Rosen et al, the commentary reiterates that “measuring laryngeal mucosal integrity [using impedance] is safe and feasible in children with extraesophageal symptoms.” The study showed “no correlation between otolaryngology airway inflammation scores with airway impedance, further emphasizing the fact that we need to move away from these scores, as they have failed to show correlation with GERD and with laryngeal mucosal integrity.”

“The authors did find a decrease in airway impedance in patients with history of aspiration; those who aspirated more textures had lower median airway impedance. Therefore, not all airway inflammation is the result of reflux and oropharyngeal dysphagia–associated aspiration can cause GER-like symptoms and airway inflammation. Aspiration can be silent, and if we do not look for it, we are not going to find it.”

“Another group of patients with low airway impedance comprised patients receiving PPIs, which makes it clear that acid is not what is affecting the airway. Otherwise, PPIs would improve airway impedance.” 

My take (borrowed from author): “It is not yet clear whether measuring airway impedance will eventually become a widespread test with clinical applicability. However, the concepts advanced in this report are clearly a step in the right direction.”

Place Massena, Nice, France

Understanding Racial Differences in Response to IBD Treatment — Golimumab in Ulcerative Colitis

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R Greywoode et al. Inflamm Bowel Dis 2023; 29: 843-849. Open Access! Racial Difference in Efficacy of Golimumab in Ulcerative Colitis

The authors analyzed pooled individual-level data (n=1066) from induction and maintenance trials of golimumab in adults with moderate-to-severe UC. Key findings:

  • Compared with White participants, participants from racial minority groups had significantly lower clinical response (adjusted odds ratio [aOR], 0.43), clinical remission (aOR, 0.41), and endoscopic healing (aOR, 0.48) at week 6.
  • Participants from racial minority groups also had significantly lower clinical remission (aOR, 0.46) and endoscopic healing (aOR, 0.63) at week 30.
  • There were no racial differences in placebo response rates.

Discussion:

This is a fascinating study. Most of the differences in response to IBD treatment have been attributed to social determinants of health including access to care (geography, insurance), and adherence to medical care. This study implicates biological factors rather than social factors for driving the difference in response. “There is also a growing body of research uncovering differences in the frequencies of genetic variants in diseases, which may contribute to differences in observed health outcomes among divergent ancestral populations.32,33“

“One of the challenges in further understanding how race may affect response to IBD biologic drugs is the relatively small number of participants from racial minority groups included in clinical trials. There is a longstanding disparity in clinical trial participation in the United States, whereby racial and ethnic minority groups have disproportionately low representation.34-37“

While the differences in the disease phenotype may account for the response to treatment, there may be other factors as well. With hepatitis C infection, those of us who remember the frequent use of Peg-interferon therapy will recollect that specific mutations in Interleukin-28B (IL28B) gene predicted lower response rates in African-American populations (related post: Understanding IL28B).

My take: Most of the changes in outcomes to treatment are likely driven by socioeconomic factors. This study is a good reminder that biological factors play a big role as well.

This figure shows the treatment responses compared to 1.00 (white population)

You No Longer Have Fatty Liver Disease-You Have Steatotic Liver Disease!

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A total of 236 panelists from 56 countries participated in four online surveys and two hybrid meetings.

Key points:

  • Steatotic liver disease (SLD) was chosen as an overarching term to encompass the various “aetiologies” of steatosis.
  • The name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). There was consensus to change the definition to include the presence of at least one of five cardiometabolic risk factors (see 2nd figure).
  • The term steatohepatitis was felt to be an important pathophysiological concept that should be retained. Metabolic dysfunction-associated steatohepatitis (MASH) is the replacement term for NASH.
  • Those with no metabolic parameters and no known cause were deemed to have cryptogenic SLD.
  • A new category, outside pure MASLD, termed MetALD was selected to describe those with MASLD who consume greater amounts of alcohol per week (140 to 350 g/week and 210 to 420 g/week for females and males respectively). 

AASLD News Digest: “MASLD, formerly known as NAFLD, is the most common chronic liver disease around the world, affecting more than 30% of global population. This was why it was vital that the global liver community coalesce around an affirmative, non-stigmatizing name and diagnosis. Ultimately, the global members of the Nomenclature Development Initiative were focused on ensuring the global community had better nomenclature that could be used around the world so that the research and funding could be better directed to save more people’s lives.”

My take: NAFLD is now MASLD –time to update patient handouts (hopefully someone at GIKids.org is on top of this). Aslo, if you have really bad disease, should it be called the ‘monster MASH’ ?

Oral GLP-1 Receptor Agonist for Obesity: Orforglipron

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S Wharton et al. NEJM 2023; DOI: 10.1056/NEJMoa2302392. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity

In this phase 2 randomized, double-blind trial with 272 adults with obesity (mean weight at baseline 108 kg), participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. “The pharmacokinetic profile of orforglipron, with a half-life of 29 to 49 hours, supports once-daily oral administration.”

Key findings:

  • At week 36, the mean change ranged from −9.4% to −14.7% with orforglipron and was −2.3% with placebo.
  • A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo.
  • Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists.

Weight reduction of at least 10% at week 36:

My take: This is an exciting time for drug development for obesity. Given the low success rates of traditional ‘lifestyle’ management approaches, these medications have the potential to reduce a great deal of morbidity. Oral agents, rather than injections, would hasten the use of these agents more broadly. Long term outcomes are still unclear.

Related blog posts:

Another Promising Medication (Retatrutide) for Obesity

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AM Jastreboff et al. NEJM 2023; DOI: 10.1056/NEJMoa2301972. Triple–Hormone-Receptor Agonist Retatrutide for Obesity  — A Phase 2 Trial.

Background: Retatrutide (LY3437943) is an agonist of the glucose-dependent insulinotropic polypeptide, glucagon-like peptide 1, and glucagon receptors.

Methods: This study enrolled 338 with BMI of at least 27 in a a phase 2, double-blind, randomized, placebo-controlled trial with once-weekly injections of retatrutide.

Key Findings:

The number who achieved at least a 10% weight loss:

“The safety profile of retatrutide was consistent with reported phase 1 findings in persons with type 2 diabetes13 and similar to those of therapies based on GLP-1 or GIP–GLP-1 for the treatment of type 2 diabetes or obesity”

My take: There are a number of effective agents for obesity that have been developed very recently. Long term efficacy and safety are still not well-understood.

Related blog posts:

When to Use Dupilumab for Eosinophilic Esophagitis: Multispecialty Guidelines

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SS Aceves et al. Annals of Allergy, Asthma, and Immunology. 2023; 130: 371-378. Open Access! Clinical guidance for the use of dupilumab in eosinophilic esophagitis

This article summarizes updated recommendations for eosinophilic esophagitis from the Joint Task Force for the American Academy of Allergy Asthma Immunology and American College of Allergy Asthma Immunology and the American Gastroenterology Association (JTF-AGA). It offers a good number of recommendations regarding when using dupilumab should be considered.

Other Key Points:

  • “Dupilumab can be considered as first-line therapy in patients presenting with severe EoE”and in patients with multiple atopic diseases.
  • In addition, it recommends “performing a repeat EGD, along with obtaining biopsies, 5 to 6 months after either starting dupilumab therapy or whenever adjusting the dupilumab dose.” In some cases, like stricture dilatation, the authors indicate that earlier EGD may be appropriate.
  • The advantages/disadvantages of current treatment options are summarized in Table 3. For dupiliumab, the disadvantages include its high price of dupilumab and weekly injections. Conjunctivitis has been an adverse effect identified in its usage with other indications.

My take: Dupilumab is a major advance for patients with EoE. Due to the need for weekly injections and its costs, it is likely a 2nd line agent for most kids with EoE.

Related blog posts:

Mel Heyman: Past, Present and Future of ARFID

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Recently, at the Georgia AAP Pediatrics by the Sea meeting, Mel Heyman presented a terrific lecture reviewing ARFID. This lecture delved into the historical backgrounds of eating disorders and described the subtypes of ARFID along with evaluation/management. This lecture was presented in honor of Stan Cohen who recently retired from our group. Here are many of the slides:

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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.

The Expanding Adalimumab Options

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S White, R Morrow, I Pan, EF de Zoeten. JPGN 2023; 76: 701-703.
Riding the Wave of Adalimumab Biosimilars: Considerations for Pediatric Gastroenterologists

This article is a very handy update on approved adalimumab biosimilars, though even more biosimilars are expected to become available soon. The table below which is similar to a table in the article outlines the similarities and differences in these products compared to the reference product.

These biosimilars are FDA-approved for the treatment of adult and pediatric patients aged 6 and older with Crohn disease. “However, the biosimilar products are only approved for treatment of adult patients” (18 and older) with ulcerative colitis. “This may be due to the recent change in pediatric ulcerative colitis Humira FDA-approved dosing.”

My take (borrowed in part from authors): Insurance coverage decisions are likely to overlook some of these factors which are very important for pediatric patients. “The adalimumab biosimilars will likely provide a clinically effective, cost saving option for our patients, but consideration of a number of factors will be key when selecting between” them.

Related posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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.

AGA Guidance on Extraesophageal Gastroesophageal Reflux

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JW Chen et al. Clin Gastroenterol Hepatol 2023; 21: 1414-1421. Open Access! AGA Clinical Practice Update on the Diagnosis and Management of Extraesophageal Gastroesophageal Reflux Disease: Expert Review

Some the “best practice advice:”

  • #3 Currently, there is no single diagnostic tool that can conclusively identify GER as the cause of EER symptoms. Determination of the contribution of GER to EER symptoms should be based on the global clinical impression derived from patients’ symptoms, response to GER therapy, and results of endoscopy and reflux testing.
  • #4 Consideration should be given toward diagnostic testing for reflux before initiation of proton pump inhibitor (PPI) therapy in patients with potential extraesophageal manifestations of GERD, but without typical GERD symptoms. Initial single-dose PPI trial, titrating up to twice daily in those with typical GERD symptoms, is reasonable.
  • #6 In patients with suspected extraesophageal manifestation of GERD who have failed one trial (up to 12 weeks) of PPI therapy, one should consider objective testing for pathologic GER, because additional trials of different PPIs are low yield.
Proposed Diagnostic Algorithm by Authors

Related commentary: R Yadlapati, WW Chan. Clin Gastroenterol Hepatol 2023; 21: 1395-1398. Modern Day Approach to Extraesophageal Reflux: Clearing the Murky Lens

This commentary identifies huge gaps in our understanding of extraesophageal reflux (EER):

  • Clinical value of upper GI endoscopy
  • Diagnostic thresholds of reflux monitoring to use for EER (Is it the same as GERD?)
  • Significance of nonacidic or weakly acidic reflux
  • Whether focus should remain on distal esophageal reflux or proximal reflux

My take: If a patient has normal amounts of reflux, can they still have extraesophageal reflux symptoms? If so, how does one objectively gauge success?

Related blog posts:

Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician.  Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure.  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.

Favorable Phase II Study of Cilofexor for Patients with PSC

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M Trauner et al. Clin Gastroenterol Hepatol 2023; 21: 1552-1560. Open Access! Safety and Sustained Efficacy of the Farnesoid X Receptor (FXR) Agonist Cilofexor Over a 96-Week Open-label Extension in Patients With PSC

Study: There were 52 subjects enrolled in the phase II study, 47 (90%) continued in the open-label extension phase. Key findings:

  • At week 96, reductions in serum alkaline phosphatase (median, −8.3%), gamma-glutamyl transferase (−29.8%), alanine aminotransaminase (−29.8%), and aspartate aminotransaminase (−16.7%) occurred, and rebounded after 4 weeks of untreated follow-up. Serum cytokeratin 18 M30 and M65 (which are markers of apotopsis and necrosis)were also reduced in the OLE

My take (from authors): “Whether cilofexor impacts clinically relevant endpoints associated with PSC await the results from the placebo-controlled, phase III PRIMIS study.”

Longitudinal relative change in serum ALP, GGT, and ALT from OLE baseline to week 96
and then 4-week, untreated follow up (F/U).

Related blog posts: