Gastroenterology and Endoscopy News Special Edition - October 2021 by McMahon Group

gastroendonews.com Annual Supplement to Gastroenterology & Endoscopy News • 2021

FROM THE NEWS:

Eosinophilic Disorders Ancillary Services and Practice Management C. difﬁcile Infection Artiﬁcial Intelligence In Gastroenterology

Pancreatic Cystic Lesions: A Case-Based Approach

Probiotics: A Review for Clinical Use

Diagnosis of Esophageal Motor Disorders Bowel Preparation Quality:

Endoscopy-Associated Infections Upper GI Ailments Inﬂammatory Bowel Disease

How to Get Perfect Bowel Preparation for Every Patient

Investigate all 3 domains together to uncover the hidden signs of chronic inflammation in EoE.1-4

Symptoms, such as dysphagia, may be masked by adaptive

behaviors that patients unknowingly develop1,5

Endoscopy can miss complications such as strictures caused by

ǉǦȖȅǿǩǉ ǩǿМ ƺǾǾƺȠǩȅǿ ǩǿ ȅ ǏȣǓ Ƞȅ ȠǦǓ ǏǩșǓƺșǓঢ়ș ȒƺȠǉǦΡ ǿƺȠȣȖǓ 1-4,6,7

Histopathology may help confirm a suspected diagnosis, but esophageal eosinophilia with ≥15 eos/hpf can be a sign of various ǓșȅȒǦƺǠǓƺǹ ǏǩșǓƺșǓș ǈǓșǩǏǓș ȅ 2,3

Learn more at revealEoE.com

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gastroendonews.com

Annual Supplement to Gastroenterology & Endoscopy News • 2021

Pancreatic Cystic Lesions: A Case-Based Approach

Probiotics: A Review for Clinical Use

Diagnosis of Esophageal Motor Disorders

Bowel Preparation Quality: How to Get Perfect Bowel Preparation For Every Patient

FROM THE NEWS:

Eosinophilic Disorders

13 Ancillary Services and Practice Management 53 C. difficile Infection 57 Artificial Intelligence in Gastroenterology 67 Endoscopy-Associated Infections 75 Upper GI Ailments 93 Inflammatory Bowel Disease

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EDITORIAL A DV I S O RY B OA R D

EDITORIAL S TA F F

ART AND PRODUCTION

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ALAN F. CUTLER, MD Farmington Hills, Michigan RONNIE FASS, MD, MACG Cleveland, Ohio HARISH K. GAGNEJA, MD Austin, Texas FRANK G. GRESS, MD New York, New York VIVEK KAUL, MD, FACG, FASGE, AGAF Rochester, New York GARY R. LICHTENSTEIN, MD Philadelphia, Pennsylvania JENIFER R. LIGHTDALE, MD, MPH Worcester, Massachusetts DANA J. LUKIN, MD, PH D, FACG New York, New York PETER R. MCNALLY, DO Fort Carson, Colorado KLAUS MERGENER, MD, PH D, MBA Tacoma, Washington SATISH RAO, MD, PH D Augusta, Georgia

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MCMAHON PUBLISHING VAN VELLE President, Partner MATTHEW MCMAHON General Manager, Partner LAUREN SMITH MICHAEL P. MCMAHON MICHELE MCMAHON VELLE ROSANNE C. MCMAHON Partners RAY AND ROSANNE MCMAHON Co-founders

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JOEL E. RICHTER, MD Tampa, Florida DAVID ROBBINS, MD New York, New York ELLEN J. SCHERL, MD New York, New York

DISCLAIMER—The reviews in this issue are designed to be a summary of information, and they represent the opinions of the authors. Although detailed, the reviews are not exhaustive.

PRATEEK SHARMA, MD Kansas City, Kansas

Readers are strongly urged to consult any relevant primary literature, the complete prescrib-

JEROME H. SIEGEL, MD New York, New York

protocols. No liability will be assumed for the use of these reviews, and the absence of typo-

ASHWANI K. SINGAL, MD, MS Sioux Falls, South Dakota

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ing information available in the package insert of each drug, and the appropriate clinical

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Untreated Eosinophilic Esophagitis Is a Progressive Disorder

ew data indicate that, without treatment, eosinophilic

esophagitis is a progressive disorder in some patients.

Prevalence of strictures, %

100

P<0.05 for trend

0 ≥2 and <4 (n=44)

≥4 and <6 (n=24)

≥6 and <8 (n=18)

≥8 (n=8)

Length of gap, years

Figure. As treatment gap grows for patients with eosinophilic esophagitis, esophageal strictures are more common.

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The findings, from a study of patients followed for “There are no guidelines for follow-up, meaning that at least two years after a diagnosis of EoE, “serve individual clinicians set their own intervals for ongoing as a call for regular monitoring and maintenance” of care, and these can often vary substantially,” Dr. Dellon patients with the condition, said Evan S. Dellon, MD, said. Patients in his own clinic are typically asked to a professor of medicine in return for reevaluation the Division of Gastroenafter changes in treatment, terology and Hepatology when it is time to renew at the University of North medications, or to reas‘There are no guidelines for follow-up, sess or re-treat a previously Carolina at Chapel Hill, who helped conduct the noted esophageal stricture. meaning that individual clinicians set research. But Dr. Dellon said no sysDrawn from a larger tematic approach exists to their own intervals for ongoing care, group of 705 patients diagensuring patients receive nosed with EoE in the same care. and these can often vary substantially.’ period of time, the focus of “This lack of consensus the new study was a subon the appropriate inter—Evan S. Dellon, MD, University of group of 95 patients who vals for follow-up visits is had a lengthy gap in care. something that should be North Carolina at Chapel Hil A gap was defined as two addressed, and there are years or more without care ongoing efforts to do so,” specifically related to EoE. he said. “The implication of All 95 patients had EoE confirmed on endoscopy prior these data is that two years to go without follow-up to the treatment gap. and treatment may be too long.” Over time, there was a significant trend EoE was first described in the 1990s. After some (P<0.05) for development of fibrosis, according to debate about the underlying pathophysiology and the Dr. Dellon’s group, who presented their findings at the optimal treatments, experts now tend to agree about 2021 virtual Digestive Disease Week (abstract Fr184). the need and strategies for control of the condition. “Each additional year of gap time increased the However, how quickly nonspecialists seek this diagnoadjusted odds of stricture by 26% [adjusted odds sis in patients presenting with upper GI symptoms is ratio, 1.26; 95% CI, 1.03-1.55],” reported Nicole Chang, unclear, Dr. Dellon said. These follow-up data contriba fourth-year medical student and collaborator on the ute evidence for prompt intervention. research. Ms. Chang said care gaps were also associ“Those of us who have been following this more ated with greater likelihood of food impactions and closely have seen a rapid increase in the number of worsening endoscopic assessments. patients diagnosed with EoE, but longer-term moniRelative to the pretreatment gap assessment, mean toring strategies—both among specialists and nonspeEndoscopic Reference Scores climbed (1.5-2.5; P<0.01) cialists—need to be better understood,” Dr. Dellon said. and mean esophageal diameters narrowed (12.7-11.0 mm; David A. Katzka, MD, of the Department of GastroP=0.04). Of the 67 patients without fibrotic features enterology and Hepatology at Mayo Clinic in Rochprior to the treatment gap, 25 (37%) had developed ester, Minn., called the new data “important” for their at least one, such as stricture or narrowing, after the value in better characterizing how EoE progresses. gap (Figure). “As opposed to prior data which studied progression When compared, “patients who progressed to fibrobefore treatment, this study expands our knowledge sis had longer gaps than nonprogressors [mean, 5.4 vs. by demonstrating the same phenomenon in patients 2.2 years; P=0.03],” Ms. Chang reported. who underwent initial treatment but then have periods From the time of diagnosis, the mean interval to the with lack of treatment,” Dr. Katzka said. “It emphasizes start of a gap in care was one year. The mean gap in the importance of ongoing monitoring and treatment care was 4.8 years. The reasons for the gap varied but of patients with EoE.” appeared to be due to typical causes, such as insufficient symptoms to motivate a return visit or a loss of —Ted Bosworth insurance coverage, according to Dr. Dellon. However, Dr. Dellon reported ﬁnancial relationships with Adare, he questioned whether inconsistent follow-up recomAlivio, Allakos, AstraZeneca, Banner, Calypso, Enumeral, EsoCap, Celgene, GlaxoSmithKline, Regeneron, Robarts and Shire. mendations from treating clinicians might have made Dr. Katzka reported ﬁnancial relationships with Mallinckrodt, a contribution. Medtronic, Merck and Tetraphase.

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 02 1

Dr. Sharma’s Endoscopy Insights: EoE a Family Affair, and More Prateek Sharma, MD Professor of medicine at the University of Kansas School of Medicine, in Kansas City

or this installment, I’ve chosen three studies that highlight how we can optimize the diagnosis and management of eosinophilic esophagitis (EoE). The first study emphasizes the importance of careful examination and systematic biopsy akin to Barrett’s esophagus. It suggests a new protocol for sampling and obtaining an adequate number of biopsies in EoE. Current guidelines state that we should obtain at least six biopsies from the distal and proximal esophagus in patients with suspected EoE.

The second study describes a high prevalence of EoE in first-degree relatives (FDRs) of patients with this condition, particularly when these relatives have allergy symptoms. The results highlight the importance of obtaining a good family and personal history from patients with EoE, and they encourage family members with symptoms of allergies to discuss diagnostic considerations of EoE with their providers. The findings also point to the need to explore genetic associations in the pathogenesis of this condition.

The last study looked at the use of esophageal dilation alone as a long-term treatment for difficultto-treat EoE. Right now, fewer than 20% to 30% of patients are treated with dilation alone, but these results demonstrate the therapy can be considered a long-term strategy with fair success and minimal complications. This salvage option in patients who are otherwise nonresponsive to other therapies will need to be studied in prospective trials to more fully delineate its risks and benefits.

In Denmark, Adequate Number Of Biopsies Increase EoE Diagnoses 50-Fold (Endoscopy 2021;53[1]:15-24) After finding very few cases of EoE diagnosed in the North Denmark Region between 1999 and 2010, experts there developed a consensus biopsy protocol to ensure appropriate diagnosis of the condition in patients with dysphagia. The protocol recommends that four biopsies be taken at 4 and 14 cm above the esophagogastric junction in these patients—the so-called 4-14-4 rule—and encourages clinicians to consider a diagnosis of EoE if histology reveals 15 or more eosinophils per high-power field. The impact of the new protocol has been profound, as the researchers report. The number of patients diagnosed with EoE increased from a median of one per year between 2007 and 2011 to a median of 52 annually after the protocol was implemented (P<0.001). During the same period, clinicians doubled

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the number of biopsies obtained per patient, from a median of four in 2007 to a median of eight in 2017 (P<0.04).

Don’t Forget FDRs of EoE Patients (Clin Gastroenterol Hepatol 2020 Nov 18. [Epub ahead of print]) Researchers in Salt Lake City enrolled 239 adult FDRs of 37 patients with EoE. They examined their medical records; administered questionnaires about reflux, dysphagia, and allergy and atopy symptoms; and performed endoscopies in 71 patients.

Roughly 15% of all FDRs had EoE, found either through endoscopic examination or medical record analysis. Hay fever, allergic eye symptoms and reported food allergy symptoms were significantly more common in FDRs with EoE than in those without. Allergic rhinitis and asthma were not associated with a higher likelihood of EoE. Other significant risk factors for EoE in FDRs included male sex, younger age and higher serum eosinophils.

Esophageal Dilation as Stand-Alone Long-Term Treatment (American College Of Gastroenterology 2020 annual meeting; poster 0834) Researchers at the University of North Carolina at Chapel Hill reviewed medical records from 205 patients with EoE who underwent esophageal dilation. Of those, 26% received at least three dilations as either sole treatment for EoE or histologically refractory disease, undergoing a total of 408 dilations. They had previously failed to respond to proton pump inhibitors or steroids (75%), or had poor adherence to medication (40%) or preferred dilation (23%).

Compared with the routine-care group, who received two or fewer dilations or had histologic response to other treatments, patients in the dilation-only group were younger (41 vs. 33 years; P=0.003), had a smaller mean baseline esophageal diameter (11.5 vs. 9.8 mm; P=0.005) and underwent more dilations on average (3.4 vs. 7.7; P<0.001). They achieved a smaller final esophageal diameter (16.7 vs. 15.7 mm; P=0.01). Fifty-seven percent of those undergoing dilation alone reported symptom response. The researchers observed no deaths or perforations resulting directly from dilations, but seven patients required hospitalization during followup for chest pain, inability to tolerate oral food or drink, or food impaction.

—Compiled and written by David Wild

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 02 1

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‘Winter Is Here’: How to See More Patients And Earn More Revenue

ow you saw medicine as a profession—at least in terms of a business model—is likely much different from the realities of today. I know what I saw in the past is not the case anymore, and that was before COVID-19.

BRIAN S. DOORECK, MD Dr. Dooreck is a gastroenterologist in Pembroke Pines, Fla. G AST R O E N T E R O LO GY & E N D O S CO PY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 02 1

I give this card to all my patients.

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If you watched “Game of Thrones,” you will understand that “winter is coming” has become “winter is here.” What does “winter” mean? “Winter” is used to describe warning, intimidation and constant vigilance. Physicians in private practice experienced that alarm due to the COVID-19 pandemic. How do I know it? I will explain more below. But I am with you. What I have learned in more than 15 years in private practice as a gastroenterologist is how to generate more patients and more revenue, on my terms, at minimal cost and under my own direction—with autonomy, ownership and ongoing exciting engagement in the process. The world has changed. Here are some facts that drive patients and revenue, to you or away from you: • 75% of respondents are influenced by online rating and review sites when selecting a provider.1 • 91% of patients will choose one doctor over another based on positive reviews.2 I chose a career in medicine for many reasons and I still love what I do. I did not choose a career in medicine to feel the financial burdens we all feel—to be an employee, nor have my fiscal future dictated to me. Consider the following: • Total annual health care spending in the United States exceeds $3.6 trillion annually.3 • Spending on health care administration is 34% of that figure.4 • Spending on physician salaries is 8.6% of the total.5 Let’s break it down. According to The New York Times, “Anthem’s net income soared to $2.3 billion for the second quarter [in 2020], from $1.1 billion in 2019, while UnitedHealth reported net earnings of $6.7 billion, compared to $3.4 billion for the same three months last year.”6 Humana’s CEO took home nearly $20 million in 2019. Aetna paid $18.8 million to its top executive, while HCA Healthcare paid $17.3 million. They are far from alone on the list of vastly overpaid executives in the industry. Where are you financially from your professional income? You’re likely not where you want to be. I will share with you how to start now getting more patients and earning more revenue, on your terms. I am not a marketing executive, but I grew my practice billing by 58% since I joined our small group. I am not an expert in search engine optimization (SEO), but I have 132% more Google reviews than the next specialist in my field locally. I do not have a degree in marketing or advertising, yet I generated 78% more Google reviews for our practice from our patients, over the past two months compared with early 2020—despite COVID-19—at a cost of $0. How can you succeed in the digital age? The first step is to acknowledge the facts. Here are a few: • 60% of consumers check the ratings and reviews of

So, how do you get Google reviews? My advice: Ask. Yes, it can be uncomfortable at first. Yes, it may feel strange and off-putting. But try. Although you might find your own system, here’s what works for me and my practice:

I ask patients, usually post-procedure or at the end of the visit. Find the time of “peak satisfaction” with you or your office. My wording is always changing and evolving. Now I ask: “Look me up online. Can you please Google me and write a review online? It helps reassure patients to see doctors even with COVID. It helps them get the care they need now. Many people are not going to the doctors as they should.”

2. 3.

I provide printed cards to remind patients to “Google me” and review me or my practice. I have orders in our electronic health record system directing patients to write reviews.

a provider, even when referred by another provider, which is up 44% since 2018. • Only 9% of respondents in 2019 selected they “do not use any websites or online platforms” when choosing a provider, showing an 80% increase in Americans using some form of online resource to choose a provider. To reiterate, the number of Americans who say they use some form of online website or platform to choose a provider has risen by 80% in recent years. That means a significant percentage of the new patients you see used a website or an online platform to choose you. Ask yourself: How many potential new patients are you missing out on seeing? How many are finding the provider down the street, in a neighboring town or next door? If you are not growing your online presence, you are going to get crushed over time. Why? Because we know that more and more patients rely on social media when choosing a doctor. We know this is here to stay. We know that if you want more patients and more revenue, you need to constantly be feeding Google and some other selected websites, real online reviews and your timely, appropriate responses to them. And yes, your responses matter to all reviews, including “the good, the bad and the ugly.” You may ask, “How do I know if someone submits a review?” That takes a basic setup of your online profiles. You can pay a third party to manage this for you, but I prefer to handle it myself. I want oversight of my

I use a Google Voice number to text patients with my review page links and with reminders that follow. Note that nothing is automated; it’s all done manually. It takes a few minutes, but the return on investment is massive. This is a “conversation, not automation.”

5. 6.

I have my staff encourage reviews from patients. It is a simple formula: More patients + more revenue = more job security for everyone. I also actively encourage reviews on Facebook, Healthgrades, Vitals, Yelp and CareDash. I will share more on that over the coming months.

name, of my digital reputation. Once you’ve been reviewed online, what’s next? Simple: Respond. I’ll discuss responses, and how to handle negative reviews, in a future column. This is what I did for myself and my practice in one month with COVID-19. Our cost: $0.00. Look at what you, too, can do in 30, 60 and 90 days at no cost. You can connect with Dr. Dooreck on LinkedIn at http://linkedin.com/in/drdooreck and on Twitter @drdooreck. Need help now? Email Dr. Dooreck anytime at help@browardgi.com.

References 1.

2. 3.

4. 5. 6.

https://www.binaryfountain.com/news/ binary-fountain-unveils-results-of-third-annual-healthcare-consumer-insight-digital-engagement-survey/ Software Advice. How patients use online reviews. https://www. softwareadvice.com/resources/how-patients-use-online-reviews/ https://www.cms.gov/Research-Statistics-Data-and-Systems/ Statistics-Trends-and-Reports/NationalHealthExpendData/ NationalHealthAccountsHistorical https://www.acpjournals.org/doi/10.7326/M19-2818 https://www.beckershospitalreview.com/compensation-issues/ physician-pay-accounts-for-86-of-total-healthcare-expenses.html https://www.nytimes.com/2020/08/05/health/covid-insuranceprofits.html

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 02 1

Google My Business BRIAN DOORECK, MD Dr. Dooreck is a gastroenterologist in Pembroke Pines, Fla.

he way I see it, you have three options in today’s practice environment, the first two of which are suboptimal: Do nothing or pay someone a lot of money to do something for you. Or you can become engaged in your digital “reputation.” That reputation is now the most important factor that determines the success of your medical practice—as a business, a source of income, and a financial reward for the years invested and work that you do.

Let’s quickly review the key facts: • 75% of respondents are influenced by the online rating and review sites when selecting a provider.1 • 91% of patients will choose one doctor over another based on positive reviews.2 The first article in this series (see page 13) looked at how to generate reviews, how to respond to them and how to dominate your local area or market. Now let’s talk about one of the cornerstones of where reviews come from: your local online presence or local search engine optimization (SEO). I am not going into details on SEO; that’s not what I do. I am a gastroenterologist and physician, like you, but I do know very well how to optimize your website and online presence in a local search environment. Why does this matter? It’s important because reviews are looked at with greater weight in the health care industry than any other industry now—and that is the industry you and I are in. NRC Health’s research found that 92.4% of consumers use online reviews to guide most of their ordinary purchasing decisions. Similarly, more than one-third (34.7%) of patients say their doctors’ online reputation is very important—a higher percentage than in any other industry.3

Google My Business Page Key Information Fields Business Name* Website Url* Tags/Keywords* Description* Street Address* City, State and Zip code* Owner Name Phone* Business Email Fax Social Links Logo/Images Hours

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Here are some basic first steps to take charge now of your Google My Business page and how to optimize it for your digital presence:

Here are a few more facts: • 60% of consumers check the ratings and reviews of a provider, even when referred by another provider, which is up 44% since 2018. • Only 9% of respondents in 2019 selected they “do not use any websites or online platforms” when choosing a provider, showing an 80% increase in Americans using some form of online resource to choose a provider. To reiterate, the number of Americans who say they use some form of online website or platform to choose a provider has risen by 80% in recent years. Yes, you need a website and SEO behind it. But the critical element, in my opinion, is people finding you online first. Google My Business is the force that drives patients to you more and more in the current world we are in. Think: How far will your patients drive to see you? Most will drive less than 30 minutes, and most will be in a 10- to 20-mile radius of your office. So, you need to think local. You need to position yourself, your practice, your website, in essence your online digital presence to target a local search environment. From my experience and from the documented industry trends, it has become clear that Google My Business is vital to your success. It may be more important than your website, the links to it, even your online reviews. Ask yourself: Do you have a Google My Business page for your practice? For yourself? For your group? For your surgery or endoscopy center? Have you ever looked at it? Do you or someone you trust have ownership of it? Do you update it? Do you post weekly updates to it? Do you post COVID-19 updates to it? Do you manage your reviews on it? If you answered no or are vague on any of these questions, go back to the options I suggested before: Do nothing, pass it off on someone else, or get engaged in managing your digital reputation. I chose the latter course many years ago and embrace that choice more and more every day. I suggest you join me on that path. It works. I love Simon Sinek’s approach to this addressing your “why” when looking how to describe what you do to your online profile. Watch his TED talk on this point: https://www.ted.com/talks/ simon_sinek_how_great_leaders_inspire_action. Your location and contact details need to match your website. You want everything to match your Google My Business information. Why? It’s because discrepancies and differences decrease your validity of a business in the eyes of the Google algorithm. That is another conversation on local citations, but think YellowPages.com

Google yourself and find your Google My Business page. • Claim it as the owner. • Get verified by Google. • Make sure your business name is correct. • Make sure your business website URL address is correct. Add the tag/keywords that should be specific to what you do. • The “Primary category” for me is “Gastroenterologist.” • “Additional categories” are Doctor, Endoscopies, Medical office, etc. Create a business description that shares with the viewer who you are, what you do and where you do it. Add why they should feel confidence in you. Add your social media links (e.g., Facebook, Instagram, YouTube, Twitter, etc.). Add your logo with clean and professional images (photos). Add your hours of operation.

and the hundreds of other sites online that list you and your business. Hundreds of them at a minimum are now active on the internet. All of those sites need the same information as your Google My Business page. It adds validity and helps your website rank higher. There is only one way to get control of this, and you have control over this. I suggest you start now. Your Google My Business page is there for you and there to share with your patients, and potential patients. It is there for them to review you publicly and share their experiences with you and your practice—openly and with Google. Don’t look at this as something overwhelming or hard to do. Seeing patients who found you on Google— based on the steps above—is rewarding. Need help? Ask me. If we are not helping one another now, then when? #DoctorsForDoctors You can connect with Dr. Dooreck on LinkedIn at http://linkedin.com/in/drdooreck, and on Twitter @drdooreck. Need help now? Email Dr. Dooreck anytime at help@browardgi.com.

References 1.

https://www.binaryfountain.com/news/ binary-fountain-unveils-results-of-third-annual- healthcare-consumer-insight-digital-engagement-survey/

Software Advice. How patients use online reviews. https://www.softwareadvice.com/ resources/ how-patients-use-online-reviews/

https://nrchealth.com/patients-trust-online-reviews/

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Referrals Are the Lifeblood Of Your Practice—Here’s How to Earn Them

n earlier parts of this series of columns on how to grow your practice, we looked at building your online digital presence and discussed why your Google My Business page matters so much—now more than ever (see pages 13 and 16). For this part, let’s go back to the basics: referrals. Yes, basic primary care referrals.

We all know that referrals drive a lot of business and will remain the mainstay for many physicians and subspecialty practictioners such as gastroenterologists. That’s true for my practice and is likely the same for yours. We also know reviews drive many new patients to doctors these days. We know that they cannot be ignored and must be embraced if you want to be active in the patient—read, consumer—marketplace. They are essential if you want to be ahead of the local market. They don’t matter if you do not want to grow your practice. I choose the first option. But referrals matter, too. They matter a lot. The reality is that both referrals and reviews work hand-in-hand. They support each other and also can break each other. As the first column discussed:

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•

75% of respondents are influenced by online rating and review sites when selecting a provider1; • 91% of patients will choose one doctor over another based on positive reviews2; and • 60% of consumers check the ratings and reviews of a provider, even when referred by another provider, which is up 44% since 2018. So, even if you have the strongest of referral patterns and consistent referrals from a primary care provider, these can be eroded by bad online reviews or unmonitored reviews without your response. Maybe you choose to ignore them or you simply don’t know they exist. Either way, you must be aware that you have an online digital presence in 2021—like it or not. It is your choice how you handle it. I know how I am choosing to handle mine. Patients will Google you even if the referral order is

Sample image from a fax to referral coordinators and office managers.

telling them to see you. So, ask yourself: How many good reviews do you need to bury that one bad one, even if you feel it was not justified? How many would you want to see if you were searching online for a physician? Here is my learned methodology of building a good referral network, a strategy that will support your good reviews and help minimize the negative ones. You have to truly care, provide excellence in services, and communicate with the patients and the referring provider. Remember that all of this—all of what we do—is a conversation. If you forget that, then you are losing ground in your practice growth every day, not to mention other areas of your professional fulfillment, at least in my opinion. How did I grow my referral base? My secret, learned years ago, was not to focus solely on the doctor, the primary care provider or the provider. I targeted the true source of referrals: the referral desk, the office manager, the staff, the medical assistants or anyone who engages with the patient during their primary care encounters. That has resulted in the highest yield by far. It takes work. Calling, visiting, calling, emailing, faxing, calling. How many doctors actually call the referral coordinators or referral desk to introduce themselves? How many ask, “How are you doing?” or “What can we do to make the process easier for you and your patients?” Remember, most people want things to be easy. Is there any way you can make your process easier for the referral desk or a referring provider? One idea is to create fax forms and systems for them. Can you think of a way to make the referral coordinator feel special? Try remembering his or her name. Keep notes in your contacts of people’s roles and update it every six months, if not more frequently. Try asking how they are doing. Engage them in conversation. The business cards and marketing materials all follow the conversation. The “ask” follows the “give.” Remember, this is a conversation. So, listen, too. You can connect with Dr. Dooreck on LinkedIn at http://linkedin.com/in/drdooreck and on Twitter @drdooreck. Need help now? Email Dr. Dooreck anytime at help@browardgi.com.

References

Sample image from an email to referral coordinators and office managers.

Binary Fountain unveils results of third annual “Healthcare Consumer Insight & Digital Engagement” survey. Binary Fountain; September 4, 2019. https://www.binaryfountain.com/news/ binary-fountain-unveils-results-of-third-annual-healthcare-consumer-insight-digital-engagement-survey/

Hedges L, Couey C. How patients use online reviews. Software Advice. April 3, 2020. https://www.softwareadvice.com/resources/ how-patients-use-online-reviews/

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Pancreatic Cystic Lesions: A Case-Based Approach VANESSA M. SHAMI, MD

AMIR RUMMAN, MD

Professor of Medicine Director of Endoscopic Ultrasound Division of Gastroenterology and Hepatology University of Virginia Medical Center Charlottesville, Virginia

Assistant Professor of Medicine Section of Digestive Diseases and Nutrition Department of Medicine University of Oklahoma Oklahoma City, Oklahoma

ancreatic cysts are a biologically diverse group of lesions that have varying degrees of malignant potential. Due to the widespread use of cross-sectional imaging, these

lesions are increasingly being detected incidentally.

a careful review of cross-sectional imaging and occasionally requires the use of additional testing, such as endoscopic ultrasound (EUS), with or without fine needle aspiration (FNA) for fluid analysis and/or cytology.

Classifying Pancreatic Cysts Despite our growing armamentarium of tests, there is no perfect test for quantifying the malignant potential of pancreatic cysts. This creates challenges for clinicians and patients alike and underscores the importance of a multidisciplinary approach to pancreatic cysts. It is estimated that pancreatic cysts are identified in approximately 3% of patients who undergo CT and up to 13.5% in older patients undergoing MRI.1,2 The management of pancreatic cysts requires accurate risk stratification for malignant potential based on the presence or absence of symptoms and high-risk features on imaging. This process of risk stratification often begins with

Multiple classification schemes have been proposed to describe pancreatic cysts. Perhaps the most clinically relevant classification involves grouping cysts based on their malignant potential (Table 1). This classification creates 2 groups of cysts: inflammatory fluid collections and pancreatic cystic neoplasms (PCNs). Pancreatic inflammatory fluid collections are not lined by an epithelium and are a result of local complications of acute pancreatitis. These are classified according to revised Atlanta classification and include acute peripancreatic fluid collections (APFCs), pancreatic pseudocysts, acute necrotic collections, and walled-off

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Table 1. Pancreatic Cysts Classified by Malignant Potential Cyst Type

Epidemiology Morphology and Location

PD Communication

Cyst Aspirate

Additional Clues

Benign Cysts Pseudocyst

• M>F • Age variable

• Unilocular cyst with thin or thick wall • Anywhere in pancreas

+ or –

• Brownish, thin • CEA low, amylase high • Inflammatory cells, cyst debris

History of pancreatitis

SCA

• F>M • Mean age, 60 y

• Microcystic/honeycomb (80%) • Macrocystic (20%) • Central/stellate scar (20%-30%) • Anywhere in pancreas

–

• Clear, thin • CEA low, amylase low • Serous glycogen-rich cuboidal cells, stain for alpha-inhibin

VHL mutation

Cysts With Malignant Potential MCN

• Almost exclusively F • Mean age, 40 y

• Well-circumscribed macrocystic lesion • Usually in body or tail

–

• Clear, viscous • CEA high, amylase variable • Columnar/cuboidal mucinous cells

KRAS mutation GNAS intact

IPMN

• M=F • Mean age, 65 y

• Dilated MPD and/or branch ducts • Unilocular or septated • Fish-mouth papilla • Usually in the head or uncinate

• Clear, viscous • CEA usually high, amylase high • Columnar papillary mucinous cells

KRAS and GNAS mutations in >90%

Malignant Cysts SPN

• Almost exclusively F • Mean age, 30 y

• Mixed solid and cystic • Usually body or tail

–

• Bloody, thin • CEA low, amylase low • Stain for vimentin, alpha1-antitrypsin, beta-catenin

Risk for metastases at diagnosis up to 10%

PNET

• M=F • Mean age, 50 y

• Cystic lesion with solid mass • Anywhere in pancreas

–

• Thin • CEA low, amylase low • Endocrine cells, stain for synaptophysin, chromogranin

Associated with MEN syndrome type 1

CEA, carcinoembryonic antigen; F, female; IPMN, intraductal papillary mucinous neoplasm; M, male; MCN, mucinous cyts neoplasms; MEN, multiple endocrine neoplasia; MPD, main pancreatic duct; PD, pancreatic duct; PNET, pancreatic neuroendocrine tumor; SCA, serous cystadenoma; SPN, solid pseudopapillary neoplasm

Figure 1. When aspirated, mucinous pancreatic cystic neoplasms have a positive string sign.

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pancreatic necrosis.3 APFCs occur within 4 weeks of the onset of acute interstitial pancreatitis and do not have a definable wall. Pseudocysts are mature fluid collections that occur 4 weeks after the onset of interstitial pancreatitis and can be challenging to distinguish from PCNs. PCNs, according to the World Health Organization histologic classification, are divided into 2 categories: serous (nonmucinous) and mucinous. Serous cystadenomas (SCAs) are the most common serous PCNs. These are benign cysts lined by glycogen-rich cuboidal cells that originate from pancreatic acinar cells. Other serous PCNs include solid serous adenoma, von Hippel-Lindau (VHL) syndrome–associated serous cystic neoplasm, and mixed serous-neuroendocrine neoplasm. Mucinous PCNs include mucinous cystic neoplasms (MCNs), intraductal papillary mucinous neoplasms (IPMNs), and solid pseudopapillary neoplasms (SPNs). Determining whether a PCN is serous/nonmucinous or mucinous usually is the first step in risk stratification because mucinous cysts are considered premalignant. Mucinous cysts are lined by a columnar epithelium capable of producing mucus.4 When aspirated, these lesions will have viscous contents with a positive “string sign” (Figure 1), which has a specificity of 95%.5 In addition, fluid carcinoembryonic antigen (CEA) levels can be helpful in distinguishing mucinous and nonmucinous PCNs. CEA is secreted from columnar epithelial cells that are derived from the endoderm and line mucinous PCNs.6 The Cooperative Pancreatic Cyst study revealed that a CEA level cutoff of 192 ng/mL was the most accurate in differentiating mucinous from nonmucinous cysts.7 Therefore, the majority of guidelines use a cyst fluid CEA level of 192 ng/mL as a cutoff value, above which CEA is considered elevated, indicating the PCN is a mucinous lesion. Finally, an elevated pancreatic cyst fluid amylase level indicates a connection with the pancreatic duct and typically is noted in IPMNs and pseudocysts.

Case 1 A 38-year-old woman with a history of alcoholrelated pancreatitis presents with postprandial abdominal pain, early satiety, and emesis. A CT scan revealed a 65- × 65-mm unilocular cystic structure at the level of the pancreatic head (Figure 2A). EUS confirmed a unilocular cyst at the pancreatic head (Figure 2B). The cyst had a mature wall and no internal debris or mass. There was clear communication with the pancreatic duct. FNA revealed thin brown fluid with an amylase level greater than 15,000 U/L and a CEA level less than 5 ng/mL. Cystoduodenostomy was performed, with complete resolution of the patient’s symptoms.

Case 1 Answer: Pancreatic Pseudocyst Pseudocysts occur in the setting of pancreatitis. Clues on history include a discrete episode of pancreatitis (acute epigastric pain associated with nausea and vomiting, lipase or amylase levels 3 times the upper limit of normal, and imaging evidence of pancreatitis) and risk factors of pancreatitis (heavy alcohol use, gallstones, hypertriglyceridemia). Pseudocysts occur more than 4 weeks after the onset of interstitial pancreatitis. On imaging, they appear as an encapsulated unilocular collection of fluid with a well-defined inflammatory wall usually outside the pancreas, with minimal or no necrosis. Communication with the pancreatic duct usually is demonstrated. Although pseudocysts have no malignant potential, pancreatic cancer sometimes can present as acute pancreatitis, and a pseudocyst may develop in that setting. Therefore, EUS is recommended for patients over 40 years of age with acute pancreatitis without a clear cause.8 In cases of diagnostic uncertainty, EUS-FNA is useful. Fluid from pseudocysts is dark yellow or brown and has an elevated amylase level (>250 U/L) and a low CEA level (<5 ng/mL). Pseudocysts do not require surveillance but require drainage if they are symptomatic.

Figure 2. A) CT scan reveals unilocular cystic structure at the level of the pancreatic head (yellow arrow). B) EUS confirms a unilocular head of pancreatic cyst. EUS, endoscopic ultrasound

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Case 2 A 74-year-old woman underwent CT for intermittent right upper quadrant discomfort. This revealed a 21- × 16- × 21-mm round cystic density in the body of the pancreas (Figure 3A). EUS revealed a 17- × 17-mm cystic lesion in the pancreatic body, which appeared microcystic in a honeycomb pattern (Figure 3B). FNA revealed rare clusters of bland epithelium. No mucin was seen.

Case 2 Answer: Serous Cystadenoma SCAs have an exceedingly low (approximately 0.1%) likelihood of malignant transformation.9 These lesions are almost always asymptomatic and detected incidentally

on imaging. They occur in the fifth to seventh decades of life and are more common in women. Rarely, larger SCAs can cause abdominal pain, pancreatitis, and bile duct and/or gastric outlet obstruction.10 On imaging, a classic SCA appears as a solitary, well-demarcated microcystic lesion with a honeycomb appearance. A central scar or “sunburst” calcified center is considered pathognomonic for SCA but is seen only in 20% to 30% of lesions. A macrocystic variant exists less commonly, and this can be difficult to distinguish from mucinous cystic lesions. Multifocal SCAs are associated with VHL syndrome and may include a neuroendocrine component. Pancreatic ductal communication is absent. SCAs usually can be diagnosed based on radiographic findings; however, EUS occasionally is needed if there is diagnostic uncertainty. The cyst aspirate is thin or serous (nonmucinous) and typically shows a low level of CEA (<5 ng/mL).11

Case 3 A 38-year-old woman with intermittent left upper quadrant discomfort and 1 episode of idiopathic acute pancreatitis is referred for assessment. She underwent MRI, which revealed a unilocular cyst at the level of the pancreatic tail (Figure 4A). EUS revealed a unilocular 48-mm cyst with a thick wall and floating mucin ball (Figure 4B). There was no communication with the main pancreatic duct. FNA revealed clear mucinous cyst fluid. The CEA level was 355 ng/mL and the amylase level was 25 U/L. Cytology revealed cuboidal mucinous cells without dysplasia. Molecular testing revealed mutated KRAS and wild-type GNAS. The patient was referred for distal pancreatectomy. Pathology revealed an MCN with extensive enzymatic fat necrosis but without dysplasia.

Case 3 Answer: MCN

Figure 3. A) CT scan reveals round cystic density in the body of the pancreas (yellow arrow). B) EUS shows a microcystic lesion appeared in a honeycomb pattern in the pancreatic body (yellow arrow). EUS, endoscopic ultrasound

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MCNs present almost exclusively in women between 40 and 60 years of age. Radiographically, they usually appear as a septated cystic lesion in the body or tail of the pancreas, although unilocular lesions also are possible. Communication with the main pancreatic duct is absent. Eccentric calcifications may be present in 15% of cases.12 Fluid aspiration reveals viscous or mucinous fluid with a high level of CEA (>192 ng/mL). The risk for invasive cancer in patients with MCNs depends on the presence of concerning features on preoperative imaging. These include large size (>5 cm), a thickened or irregular cyst wall, an internal nodule or mass, and the presence of a calcified cyst wall. In a meta-analysis, small (<4 cm) asymptomatic MCNs without worrisome features on imaging were found to have a small (approximately 0.03%) risk for harboring invasive cancer.13 The management of MCNs requires a multidisciplinary approach. Surgical resection should be considered in large MCNs with high-risk features on imaging. Surveillance may be appropriate for smaller lesions without high-risk features. If resection is offered and the lesion is completely resected on pathology, postoperative surveillance usually is not required.

Figure 4. A) MRI shows a unilocular cyst at the level of the pancreatic tail (yellow arrow). B) EUS reveals a unilocular cyst with a thick wall and floating mucin ball. EUS, endoscopic ultrasound

Case 4 A 61-year-old man with a history of hypertension and dyslipidemia undergoes a CT scan for workup of suspected nephrolithiasis. An incidental multilocular cystic lesion is noted at the level of the pancreatic head (Figure 5A). There is a suspected mural nodule/mass within the cyst. The main pancreatic duct is dilated to 12 mm. EUS is performed and confirms a multilocular cystic lesion at the level of the pancreatic head. The lesion communicates with the dilated main pancreatic duct. There is a focal mural nodule measuring 6 mm (Figure 5B). EUS-guided microforceps biopsy of the mural nodule was performed, revealing superficial

fragments of intestinal-type papillary neoplasia with at least high-grade dysplasia. The patient was referred for surgical resection.

Case 4 Answer: IPMNs The most common pancreatic cysts, IPMNs occur in men and women equally, typically presenting in patients over 60 years of age. IPMNs may involve the main duct (MD-IPMN), the branch ducts (BD-IPMN), or both (mixed-type IPMNs). MD-IPMNs appear radiographically as a diffusely or partially dilated main pancreatic duct filled with mucin. They are found predominantly in the pancreatic head but can involve any part of the pancreas. BD-IPMNs are characterized by dilation of side

Figure 5. A) CT scan shows multilocular cystic lesion at the level of the pancreatic head (yellow arrow). B) A focal mural nodule is evident (yellow arrow). EUS, endoscopic ultrasound

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Table 2. Alarm Features For IPMNs Clinical • Jaundice • Acute pancreatitis • Elevated CA 19-9 Radiographic • Cyst >3 cm • Enhancing mural nodule or mass or solid component within the cyst >5 mm • Thickened/enhancing cyst walls • Dilation of the pancreatic duct >5 mm • Focal dilation of the pancreatic duct or abrupt change in the pancreatic duct caliber with distal pancreatic atrophy • Lymphadenopathy • Cyst growth rate >5 mm in 2 y CA 19-9, cancer antigen 19-9; IPMN, intraductal papillary mucinous neoplasms

branches of the pancreatic duct. They often are seen in the pancreatic head or uncinate process.14 Cyst aspirate reveals mucinous fluid, and the CEA level is typically elevated (>192 ng/mL). The risk for malignancy associated with IPMNs depends on the type. MD-IPMNs and mixed-type IPMNs have a higher risk for malignancy compared with BDIPMNs; the elevated risk was up to 60% in surgical series of resected lesions, but selection bias is a significant limitation of these data.15 The risk for malignant transformation of BD-IPMNs is much lower. In a study of 1,404 consecutive patients with BD-IPMNs, the overall incidence rate of pancreatic carcinoma 5, 10, and 15 years after IPMN diagnosis was 3.3%, 6.6%, and 15%, respectively.16 Prospective studies are needed to define the malignant risk of these lesions more accurately. Available guidelines recommend some form of longterm surveillance of patients with IPMNs.8,15,17,18 There are differences in surveillance intervals between the various guidelines, but most guidelines suggest that small cysts (<3 cm) in asymptomatic patients without any suspicious features may be observed with serial imaging because the risk for malignancy is low. The surveillance interval is based on the size of the cyst and varies between guidelines but generally is every 2 years for cysts under 1 cm, every year for cysts between 1 and 2 cm, and every 6 months for cysts between 2 and 3 cm. Patients with worrisome features (Table 2) should be referred to a multidisciplinary group for further evaluation and consideration of surgical resection. If surgical resection is offered, surveillance is required after resection because additional IPMNs may develop.

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Figure 6. A) CT scan shows an incidental unilocular cyst in the body of the pancreatic cyst, with a thick wall and internal septations (yellow arrow). B) EUS reveals a hypoechoic lesion with distinct borders. C) Cytology reveals small blue cells on Diff-Quik stain. D) Immunohistochemistry is positive for chromogranin, confirming a PNET. EUS, endoscopic ultrasound; PNET, pancreatic neuroendocrine tumor

Case 5

Case 6

A 55-year-old man with a history of diabetes and hypertension undergoes CT after being involved in a motor vehicle collision. This reveals an incidental unilocular cyst in the body of the pancreas cyst, with a thick wall and internal septations measuring 17 mm (Figure 6A). EUS reveals a hypoechoic lesion with distinct borders (Figure 6B). Cytology reveals small blue cells on Diff-Quik stain (Figure 6C). Immunohistochemistry is positive for chromogranin, which confirms the diagnosis of pancreatic neuroendocrine tumor (PNET) (Figure 6D). The patient underwent distal pancreatectomy.

Case 5 Answer: PNET With Cystic Degeneration PNETs are rare lesions, with an incidence of fewer than 1 case per 100,000 individuals per year.19 Most PNETs are sporadic, but they can be associated with hereditary endocrinopathies, including multiple endocrine neoplasia type 1, VHL syndrome, neurofibromatosis type 1, and tuberous sclerosis. PNETs occasionally undergo cystic degeneration. They usually present as a unilocular cyst with a prominent wall that is hyperenhancing on contrast CT. Cyst aspirate usually reveals blood-tinged fluid and fluid CEA is low. Surgical resection is offered for functional (hormonesecreting) PNETs and PNETs larger than 2 cm. PNETs smaller than 1 cm generally can be followed radiographically. There is debate in the literature about the optimal management of PNETs measuring between 1 and 2 cm, and multidisciplinary discussion is advised in these cases.

A 31-year-old woman without a significant medical history is evaluated for worsening postprandial left upper quadrant pain associated with early satiety. Ultrasounds showed an ill-defined cyst in the pancreas body, and an MRI revealed a heterogeneous lesion measuring 70 mm in diameter arising from the body of the pancreas, with both cystic and solid components (Figure 7A). Microcalcifications were present. EUS revealed a mixed solid/cystic lesion (Figure 7B), and EUS-FNA revealed thin, bloody aspirate. Immunohistochemistry stains for vimentin, alpha1-antitrypsin, and beta-catenin were positive. The patient was referred for distal pancreatectomy, and the final pathology confirmed an SPN without dysplasia.

Case 6 Answer: SPN SPNs occur almost exclusively in women and usually present in the second to third decade. Radiographically, they appear as a solitary lesion with cystic and solid components. They can be located anywhere in the pancreas. Occasionally, calcifications are present. Historically, the majority of patients with SPNs were symptomatic. However, incidental detection of SPNs is becoming more common with widespread use of crosssectional imaging and now accounts for up to 50% of cases. Reported symptoms, in order of increasing frequency, are abdominal pain, nausea/vomiting, and weight loss. Other symptoms that occur less frequently include bowel obstruction, anemia, jaundice due to bile duct obstruction, and pancreatitis. Patients also may have a palpable mass, which is the most common presentation in children.20

Figure 7. A) MRI reveals a heterogeneous lesion arising from the pancreatic body, with both cystic and solid components (yellow arrow). B) EUS confirms a mixed solid/cystic lesion. EUS, endoscopic ultrasound

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The risk for malignancy in SPNs in estimated to be around 15%, based on data from 2 surgical series.20,21 Tumor size of at least 5 cm was associated with an increased risk for high-grade malignancy.20 Given that these lesions occur in younger individuals and have a malignant potential, surgical resection generally is offered.

Emerging Technologies In recent years, new markers from EUS-guided fluid samples from PCNs and new technical modalities of tissue acquisition and assessment have emerged that could improve our ability to accurately diagnosis PCNs and understand their risk for malignant transformation. However, these are not currently recommended by any of the guidelines, so we discuss them only briefly. Next-generation sequencing of PCN fluid: Newer DNA-based molecular analysis using next-generation sequencing has allowed for the identification of specific markers for PCNs. The technology of next-generation sequencing allows for parallel sequencing of millions or billions of DNA strands, which has enabled the rapid sequencing of entire genomes and exomes, including targeted sequencing studies. In a single-center prospective study, next-generation sequencing was used for to differentiate 102 surgically resected PCNs.22 The sensitivity and specificity of KRAS and/or GNAS mutations to differentiate mucinous from nonmucinous PCNs were 89% and 100%, respectively. Advanced neoplasia was identified by the additional mutation of TP53/ PIK3CA/PTEN, with 79% sensitivity and 96% specificity. Cyst fluid glucose level: Studies have shown pancreatic cyst fluid glucose levels to be lower in mucinous PCNs than in nonmucinous ones.23,24 A meta-analysis of 8 studies including 609 PCNs found that when comparing PCN fluid glucose with PCN fluid CEA, glucose had a

higher sensitivity (91% vs 56%) and diagnostic accuracy (94% vs 85%) for detecting mucinous lesions, and there was no difference in specificity between the tests.25 Microbiopsy: Recently, a through-the-needle microforceps device (Moray micro forceps, US Endoscopy) was introduced for EUS-guided tissue sampling in PCNs. This single-use microforceps can be passed through the lumen of a standard 19-gauge EUS-FNA needle, allowing through-the-needle tissue biopsy for histologic sampling of PCNs. Use of microbiopsy forceps may increase the diagnosis yield, help differentiate nonmucinous from mucinous PCNs, and improve presurgical assessment of risk for malignancy.26-28 Needle-based confocal laser endomicroscopy: Needle-based confocal laser endomicroscopy (nCLE) enables the observation of the inner wall of the pancreatic cyst using EUS-FNA. A confocal laser endomicroscope is inserted through a 19-gauge EUS-guided needle. Intravenous injection of fluorescein is performed 30 seconds to 2 minutes before nCLE. A low-power laser scans and illuminates tissue within a pancreatic cyst in a single focal plane, allowing microscopic detail of the surface epithelium to be examined for characteristics distinguishing various pancreatic cyst types. The use of nCLE has been shown to increase accuracy of differentiation of PCNs.29

Conclusion Although pancreatic cysts present a clinical challenge, familiarity with the different types of cysts and the ability to identify those with malignant potential are important. Pattern recognition taking into account demographics, imaging characteristics, and cyst content analysis is helpful. Although emerging technologies are promising to identify different cyst types, we are still far from having the perfect test.

References 1.

Laffan TA, et al. AJR Am J Roentgenol. 2008;191(3):802-807.

16.

Lee KS, et al. Am J Gastroenterol. 2010;105(9):2079-2084.

17.

Vege SS, et al. Gastroenterology. 2015;148(4):819-822.

Banks PA, et al. Gut. 2013;62(1):102-111.

18.

van Huijgevoort NCM, et al. Nat Rev Gastroenterol Hepatol. 2019;16(11):676-689.

European Study Group on Cystic Tumours of the Pancreas. Gut. 2018;67(5):789-804.

19.

Hallet J, et al. Cancer. 2015;121(4):589-597.

Bick BL, et al. Endoscopy. 2015;47(7):626-631.

20.

Kim MJ, et al. Br J Surg. 2014;101(10):1266-1271.

Oh SH, et al. Gut Liver. 2017;11(2):283-289.

21.

Lee SE, et al. Arch Surg. 2008;143(12):1218-1221.

Brugge WR, et al. Gastroenterology. 2004;126(5):1330-1336.

22.

Singhi AD, et al. Gut. 2018;67(12):2131-2141.

Elta GH, et al. Am J Gastroenterol. 2018;113(4):464-479.

23.

Lopes CV. World J Gastroenterol. 2019;25(19):2271-2278.

Jais B, et al. Gut. 2016;65(2):305-312.

24.

Park WG, et al. Gastrointest Endosc. 2013;78(2):295-302.e2.

10.

Tseng JF, et al. Ann Surg. 2005;242(3):413-419; discussion 419-421.

25.

McCarty TR, et al. Gastrointest Endosc. 2021;94(4):698-712.e6.

26.

Kovacevic B, et al. Endosc Ultrasound. 2020;9(4):220-224.

11.

van der Waaij LA, et al. Gastrointest Endosc. 2005;62(3):383-389.

27.

12.

Gress F, et al. Am J Gastroenterol. 2000;95(4):961-965.

Hashimoto R, et al. World J Gastrointest Endosc. 2019;11(11):531-540.

13.

Nilsson LN, et al. Pancreatology. 2016;16(6):1028-1036.

28.

Yang D, et al. Clin Gastroenterol Hepatol. 2019;17(8):1587-1596.

14.

Machado NO, et al. N Am J Med Sci. 2015;7(5):160-175.

29.

15.

Tanaka M, et al. Pancreatology. 2017;17(5):738-753.

Krishna SG, et al. Clin Gastroenterol Hepatol. 2020;18(2): 432-440.e6.

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Oyama H, et al. Gastroenterology. 2020;158(1):226-237.e5.

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Koning et al. The effect of a multispecies probiotic on the intestinal microbiota and bowel movements in healthy volunteers taking the antibiotic amoxycillin. Am J Gastroenterol. 2008;103(1):178-89.

M. Hell et al, Probiotics in Clostridium difficile infection: reviewing the need for a multistrain probiotic, Beneficial Microbes. 2013; 4(1):39-51.

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Probiotics: A Review for Clinical Use ELENA A. IVANINA, DO, MPH

DANIEL E. HOGAN JR, DO

DAVID H. ROBBINS, MD, MSC

Lenox Hill Hospital/ Northwell Gastroenterology New York, New York

Lenox Hill Hospital/ Northwell Internal Medicine New York, New York

Lenox Hill Hospital/ Northwell Gastroenterology New York, New York

nterest in modifying the gut flora by consuming foods or microbes that may improve overall health

dates back to the early 1900s, when it was theorized that certain milks and yogurts may provide a health benefit to the populations consuming them.1

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Just how probiotics may affect various conditions is not completely understood, but several mechanisms have been proposed. One is that the gut microbiome influences visceral hypersensitivity and pain and that Lactobacillus-induced expression of mu-opioid and cannabinoid receptors in the intestinal epithelium may be able to mediate pain in a manner similar to that of opioids.2 Another proposed mechanism is modulation of the immune system. Several studies have found that probiotics or their products suppress inflammatory cytokines and stimulate protective cytokines, mostly in models of inflammatory bowel disease (IBD).3-5 Finally, probiotics may promote integrity of the intestinal epithelium, protecting intestinal epithelial tight junctions and barrier function, and create biofilms that secrete factors that can inhibit pathogen invasion.6,7 As understanding of the gut microbiota and complex interactions involved in inflammation, gut permeability, and dysbiosis advances, the potential of probiotics is appealing to clinicians and patients alike. However, while enthusiasm for probiotics has skyrocketed—particularly alongside other heavily promoted nutritional supplements—scant data support their use. Perhaps more importantly, the gastrointestinal diseases for which they have benefits and the species that confer these benefits remain unclear, resulting in confusion among clinicians and the general public. This evidence-based review is an update of a 2018 review meant to guide the choice of a probiotic regimen where data appear strong and highlights areas where more research is needed before more conclusive recommendations can be made.

Evidence Search The methods used for finding the recommendations involved searches via PubMed, OVID, and the Cochrane Review Library for the terms “probiotics,” “indications,” “dosing,” “pouchitis,” “infectious diarrhea,” “antibioticassociated diarrhea,” “constipation,” “irritable bowel syndrome,” “hepatic encephalopathy,” “ulcerative colitis,” “Crohn’s disease,” and “Clostridioides.” Results were further narrowed into randomized controlled trials (RCTs), meta-analyses, and review articles in which information about specific strains and dosing could be found. Recommendations were selected based on the relative robustness of the relevant data.

Pouchitis One of the best supported indications for the use of probiotics is pouchitis. In severe ulcerative colitis (UC) and familial adenomatous polyposis for which a total colectomy is required, the appropriate procedure is a proctocolectomy with ileal pouch–anal anastomosis. The most frequent long-term complication of this surgical correction is acute or chronic inflammation of the S- or J-shaped ileal pouch.8 Symptoms of pouchitis include abdominal pain, fever, hematochezia, urgency, and increased stool frequency. Patients with pouchitis

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have distinct microbial patterns that likely are due to fecal stasis and colonic metaplasia from the original ileal mucosa, creating an inflammatory milieu associated with bacterial species such as Bacteroidaceae and Clostridiaceae species.8 Enterococcaceae may have a role in maintaining immunologic homeostasis in the mucosa.9 A probiotic containing Bifidobacterium breve, B. longum, B. infantis, Lactobacillus acidophilus, L. plantarum, L. paracasei, L. bulgaricus, and Streptococcus thermophilus—has been found to be effective in randomized, placebo-controlled trials in both primary and secondary prophylaxis.10,11 This probiotic appears to work by decreasing tumor necrosis factor (TNF)-alpha, interferon-gamma, and matrix metalloproteinases 2 and 9. Primary prophylaxis has been studied at a dosage of 3 g per day for 12 months.12 Secondary prophylaxis of relapsing pouchitis has been studied at a dosage of 6 g per day for 9 months to 1 year.10 Although antibiotics remain the drug of choice for periods of inflammation, high-dose VSL#3 (the original De Simone formulation) at a dosage of 2 sachets twice daily (3,600 billion bacteria/day) for 4 weeks has been found to be effective for the treatment of mild pouchitis (between 7 and 12 on the Pouchitis Disease Activity Index).13 The American Gastroenterological Association (AGA) probiotic guidelines note that if the feasibility and cost of this combination of bacterial strains are problematic, one may reasonably not prescribe probiotics.14

Infectious Diarrhea Infectious Gastroenteritis The role of probiotics in treating acute infectious diarrhea in adults and children has been scrutinized. The AGA released guidelines recommending against the use of probiotics in children with acute infectious gastroenteritis since most studies were performed outside the United States and, therefore, differences in host genetics, diet, sanitation, and endemic enteropathogens preclude generalization of the outcomes to the United States.14 Probiotic use in adults with acute infectious gastroenteritis is unproven. A 2010 metaanalysis that included 63 RCTs—using different probiotic preparations but most commonly Lactobacillus GG and Saccharomyces boulardii—in adults and children found that probiotics reduced the overall risk for diarrhea lasting 4 or more days by 59% (relative risk, 0.41; 95% CI, 0.32-0.53) and the mean duration of diarrhea by 25 hours (95% CI, 16-34 hours).15

Travelers’ Diarrhea The use of probiotics also has been studied for the prevention of travelers’ diarrhea. Specifically, Lactobacillus GG has been shown to be effective because it is resistant to acid and bile, adheres to ileal cells, and produces an antimicrobial substance. In a double-blind, placebo-controlled study from

Table. Selected Probiotic Regimens Indications

Probiotic Regimen

Pouchitis

Primary prophylaxis: VSL#3 3 g/d for 12 mo

Infectious diarrhea

Lactobacillus casei GG 6×109 CFU twice per day for 5 d

Clostridioides difficile–associated diarrhea

L. acidophilus 25×109 CFU/d for 2 d, then 50×109 CFU/d for the duration of antibiotics OR L. casei 19×109 CFU/d, L. bulgaris 1.9×109 CFU/d, and Streptococcus thermophilus 19×109 CFU/d, all starting within 48 h of antibiotics and continued for 7 d after antibiotics

Helicobacter pylori infection

Prophylaxis of treatment associated diarrhea: Lactobacillus GG twice daily for the duration of treatment and for 7 d thereafter

Constipation

L. casei Shirota 6.5×109 CFU/d for 4 wk OR E. coli Nissle 1917 25×109 CFU/d for 8 wk

Irritable bowel syndrome

Bifidobacterium infantis 35624 1×109 CFU/d for 4 wk OR B. bifidum MMBb 75 1×109 CFU/d for 4 wk

Hepatic encephalopathy

No recommended regimen

Crohn’s disease

No recommended regimen

Ulcerative colitis

Escherichia coli Nissle 1917 200 mg/d for maintenance of remission

Finland, Lactobacillus GG was used to prevent travelers’ diarrhea, with protection rates of 1.8% to 39.5%.16 Another study found that taking Lactobacillus GG capsules at a dose of 2×109 bacteria starting 2 days before departure and continuing throughout the trip reduced the risk for diarrhea from 7.4% to 3.9% per day.17 Of note, a 2018 report in the Journal of Travel Medicine found that the data for probiotics were too weak to recommend use to prevent travelers’ diarrhea but that there was promising evidence for the prebiotic bifidobacterial-galacto-oligosaccharides (B-GOS).18 In trials, B-GOS strongly inhibited the attachment and colonization of the gut pathogens Escherichia coli and Salmonella typhi. A double-blind, placebo-controlled study concluded that the group given the B-GOS mixture reported a statistically significant reduction in reported diarrhea compared with a placebo group (P<0.05). Combining prebiotics and probiotics into a single formulation (synbiotic) did not reduce the risk for developing travelers’ diarrhea. We do not believe there

is sufficient evidence yet to warrant prophylactic probiotics for travelers’ diarrhea.

Antibiotic-Associated Diarrhea The most common form of infectious diarrhea related to the use of antibiotics is caused by Clostridioides difficile and is referred to as C. difficile–associated diarrhea (CDAD). Probiotics have a defined role in its prevention. The mechanism of action includes alteration of intestinal flora, antimicrobial activity, intestinal barrier protection, and immunomodulation. A systematic review of probiotic use to prevent C. difficile infection in hospitalized patients found that probiotics reduced the risk for CDAD by more than 50% when they were taken within 2 days of the first antibiotic dose, with no evident increase in adverse events (AEs).19 There are 4 recommended probiotic regimens for the prevention of C. difficile infection. In adults and children on antibiotic treatment, the recommended regimens for preventing C. difficile infection include

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■ BioKult ■ Placebo

Baseline Month 1 (P=0.002)

Month 2 (P<0.001)

Month 3 (P<0.001)

Month 4 (P<0.001)

Follow-up (P<0.001)

Figure. IBS-SSS abdominal pain ratings with probiotic or placebo (16 weeks’ treatment and 1-month follow-up). IBS-SSS, Irritable Bowel Syndrome Symptom Severity Score; NS, not significant From Ishaque SM, Khosruzzama SM, Ahmed DS, et al. A randomised placebo-controlled trial of a multi-strain probiotic formulation (Bio-Kult) in the management of diarrhea-predominant irritable bowel syndrome, Digestive Disease Week 2018, abstract Tu2015.

S. boulardii; a 2-strain combination of L. acidophilus CL1285 and L. casei LBC80R; a 3-strain combination of L. acidophilus, L. delbrueckii subspecies bulgaricus, and Bifidobacterium bifidum; or the 4-strain combination of L. acidophilus, L. delbrueckii subspecies bulgaricus, B. bifidum, and Streptococcus salivarius subspecies thermophilus.14 The beneficial effect of probiotics was seen mainly in patients with a very high risk for developing C. difficile infection (>15% baseline risk). There is, however, insufficient evidence to recommend probiotics for treatment of active CDAD.

Helicobacter pylori Infection Another antibiotic-associated indication for probiotics is for patients undergoing therapy to eradicate Helicobacter pylori. In an updated, evidence-based international consensus, experts concluded that probiotics are helpful as adjuvant therapy to prevent or reduce the duration or intensity of AEs to H. pylori eradication therapy and improve compliance with treatment.20 In a randomized, placebo-controlled study, patients

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taking a standard H. pylori regimen supplemented with probiotics reported a lower incidence of AEs, including diarrhea, and overall treatment tolerability was improved.21 The probiotic was given during and for 7 days after H. pylori therapy; patients received one of several effective regimens, including Lactobacillus GG administered twice daily, S. boulardii given twice daily, or a combination of Lactobacillus and Bifidobacterium administered twice daily. A meta-analysis of 10 clinical trials of adjuvant probiotics in patients with H. pylori infection demonstrated increased cure rates with probiotic supplementation (pooled odds ratio [OR], 2.07; 95% CI, 1.40-3.06) and reduced the incidence of total antibiotic-related AEs (pooled OR, 0.31; 95% CI, 0.12-0.79).22

Constipation Using probiotics in patients who have nonsevere chronic constipation and do not have irritable bowel syndrome (IBS) also has been studied, and the results remain unconvincing. A randomized, double-blind,

placebo-controlled study showed that a probiotic beverage containing L. casei Shirota at a dosage of 6.5×109 colony-forming units (CFU) or 65 mL per day for 4 weeks resulted in a significant improvement in both stool frequency and consistency starting in the second week of intervention.23 In another RCT, E. coli Nissle 1917 at a dosage of 25×109 CFU for 8 weeks increased stool frequency.24 Although small studies have suggested an improvement in bowel movements, including frequency, stool consistency, and intestinal transit time with Bifidobacterium lactis DN-173 010, B. lactis BB12, L. casei Shirota, L. reuteri DSM 19738, and E. coli Nissle 1917, there was marked heterogeneity in study design and results, as well as publication bias.

Irritable Bowel Syndrome Although data supporting probiotics for general IBS are limited largely by methodological shortcomings, there is some support for their use for the diarrhea variant (IBS-D). Controlled trials have shown that B. infantis 35624 at a dosage of 1×108 CFU per day for 4 weeks can improve abdominal pain, bloating, bowel dysfunction, incomplete evacuation, straining, and the passage of gas.25 One capsule of B. bifidum MIMBb75 dosed at 1×109 CFU over 4 weeks effectively alleviates global IBS and improves IBS symptoms simultaneously, with a subjectively reported improvement in quality of life.26 Studies examining a number of Lactobacillus species, including L. salivarius UCC4331, L. plantarum DSM9843, L. plantarum LPO1, and L. plantarum 299V, as well as B. bifidum MIMBb75, B. breve BR, and VSL#3, also have shown improvement in patient-reported symptoms, including flatulence and bloating, but have shown no overall effect on stool quality or frequency. The ACG Monograph on Management of Irritable Bowel Syndrome, published in 2018, suggested probiotics can be taken to improve global symptoms as well as bloating and flatulence in patients with IBS.27 The authors reviewed 53 RCTs involving 5,545 patients and found that probiotics were statistically superior to placebo, with a number needed to treat of 71. In general, probiotics appeared to have beneficial effects on global IBS symptom scores or abdominal pain scores, bloating scores, and flatulence scores. In all 36 studies reviewed, involving 4,183 patients, there was no increased risk for AEs. A more targeted microbiome approach is evolving. A systematic review of gut microbiota in IBS has described a decrease in the genus Bifidobacterium.28 To address this specific dysbiosis seen in IBS, a randomized, double-blind, placebo-controlled study explored human milk oligosaccharides (HMO), specifically a 4:1 mix of 2’-O-fucosyllactose and lacto-Nneotetraose and found that it increased the abundance of Bifidobacterium species in IBS patients.29 In an abstract, symptoms associated with moderate or severe IBS improved significantly at 12 weeks in adults who

consumed a supplement containing HMO, with overall IBS severity score decreasing by 55%.30 This type of precision microbiome-tailored therapy will evolve in the coming years.

Hepatic Encephalopathy In various forms of chronic liver disease, the liver— secondary to damage and diverted blood flow—loses the ability to clear ammonia from the body. The increasing levels of ammonia lead to a reversible encephalopathy known as hepatic encephalopathy. Treatment is aimed at either increasing the excretion of or decreasing the production of ammonia. Lactulose, a prebiotic, works via ion-trapping coupled with a potent laxative effect. Rifaximin (Xifaxan, Salix) works by decreasing the population of urease-producing bacteria. Probiotics are theorized to work by making the gut environment more favorable for non–urease-producing bacterial species or modifying the pH of the gut lumen, thereby decreasing the production of ammonia and preventing or reversing hepatic encephalopathy.31 An RCT has shown that a dose of 3 capsules per day containing 112.5 billion viable lyophilized bacteria per capsule, each containing 4 strains of Lactobacillus (L. casei, L. plantarum, L. acidophilus, and L. delbrueckii subspecies bulgaricus), 3 strains of Bifidobacterium (B. longum, B. breve, and B. infantis), and 1 strain of Streptococcus salivarius (subspecies thermophilus), was more effective than no treatment for secondary prophylaxis of clinical hepatic encephalopathy, and was as effective as standard lactulose therapy.32 Overall, however, no mortality benefit has been identified to support the use of probiotics alone in the treatment of hepatic encephalopathy.33 Recently, the focus has shifted to analyzing the effect of fecal microbiota transplantation (FMT) in patients with hepatic encephalopathy.34 A study published in Hepatology found that FMT reduced hospitalizations and improved cognition and dysbiosis in cirrhosis with recurrent hepatic encephalopathy.35 In addition, FMT capsules were found to be safe and associated with improved duodenal mucosal diversity, dysbiosis, reduced lipopolysaccharide-binding protein, and improved EncephalApp performance. More research is needed to determine the best technique to target the microbiome to improve hepatic encephalopathy.

Crohn’s Disease and UC Alterations in gut microbiota have been shown to play a role in the pathogenesis of Crohn’s disease (CD) and UC. As for many of the other indications discussed, strong evidence is lacking in IBD because of small sample sizes, variations in probiotic regimens, or variations in dosing. VSL#3, however, has shown some efficacy in inducing remission in mild to moderate UC. In an RCT (N=147), more patients with active mild to moderate UC taking VSL#3 (900 billion bacteria/day) had 50% improvement in the Ulcerative Colitis Disease

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Activity Index compared with those receiving placebo at 6 weeks (32.5% vs 10.0%; P=0.001).36 At week 12, 42.9% of patients taking VSL#3 achieved remission versus 15.7% of placebo-treated patients (P<0.001). A metaanalysis found that VSL#3, when added to conventional therapy at a dose of 3.6×1012 CFU/day, is safe and more effective than conventional therapy alone in achieving higher rates of response and remission in patients with mild to moderate UC.37 The literature also suggests that VSL#3 may reduce rates of relapse in quiescent UC. One RCT looked at the add-on use of VSL#3 (weight-based 450-1,800 billion bacteria/day) to a 5-aminosalicylate in the maintenance of remission in a small pediatric cohort with mild to moderate UC (N=29).38 Fewer patients treated with VSL#3 relapsed within 1 year of follow-up (21.4% vs 73.3%). At 6 months, 12 months, and time of relapse, endoscopic and histologic scores were lower in the VSL#3 group. In addition, in 2 RCTs, E. coli Nissle 1917 given at a dose of 200 mg per day (2.5-25×109 viable bacteria per capsule) for 12 months was found to be at least as effective as mesalamine in the prevention of relapse of UC during symptom-free periods in patients followed over 1 year.31,39,40 Furthermore, there were no significant differences between mesalamine and E. coli Nissle 1917 in safety and tolerability measures in UC patients. The AGA recommends the use of probiotics in UC only in the context of a clinical trial due to the lack of large RCTs and the cost of VSL#3.14 In CD, the data, again, are minimal and show either no significant difference between any studied probiotic strain alone and placebo or, less optimistically, show worse outcomes compared with standard medical therapies. In a small RCT, a dose of 2×1011 CFU of freeze-dried viable B. longum in a gelatin capsule, and a sachet containing 6 g of Synergy I (Orafti), given twice daily for 6 months, resulted in improvement in endoscopic and histologic scoring of CD compared with placebo alone.41 This intervention, however, did not lead to improvement in patient-reported symptoms. At the time of this writing, there were no data recommending the use of probiotics alone in the maintenance or induction of remission in CD, and the AGA recommends only to use probiotics in CD in the context of a clinical trial.14,42,43 Another approach to modulating the microbiome in CD is diet-based therapy. A multinational head-to-head RCT looked at a whole-food oral diet with partial enteral nutrition (EN) compared with standard-of-care exclusive EN in pediatric patients with mild to moderate CD.44 Both diets were effective in inducing remission by week 6, and the combination CD exclusion diet plus partial EN induced sustained remission in a significantly higher proportion of patients than exclusive EN; the combination also produced changes in the fecal microbiome associated with remission (decreases in Haemophilus, Veillonella, Anaerostipes, and Prevotella, and increases in Roseburia and Oscillibacter).

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Preterm Low–Birth-Weight Babies One of the most compelling indications for probiotics is to prevent necrotizing enterocolitis (NEC) in at-risk preterm (<37 weeks’ gestational age) low–birthweight infants.14,21 NEC, an emergent condition associated with intestinal necrosis, can lead to short bowel syndrome and impaired neurodevelopment. The microbiome composition is different in infants with NEC compared with healthy infants, providing a possible therapeutic intervention with probiotics. The recommended combinations include Lactobacillus species and Bifidobacterium species (L. rhamnosus ATCC 53103 and B. longum subspecies infantis; L. casei and B. breve; L. rhamnosus, L. acidophilus, L. casei, B. longum subspecies infantis, B. bifidum, and B. longum subspecies longum; L. acidophilus and B. longum subspecies infantis; L. acidophilus and B. bifidum; L. rhamnosus ATCC 53103 and B. longum Reuter ATCC BAA-999; L. acidophilus, B. bifidum, B. animalis subspecies lactis, and B. longum subspecies longum; B. animalis subspecies lactis [including DSM 15954]; L. reuteri [DSM 17938 or ATCC 55730]; or L. rhamnosus [ATCC 53103 or ATC A07FA, or LCR 35]). These regimens were found to reduce all-cause mortality compared with placebo.

Cautions and Considerations It is imperative that clinicians consider and discuss contraindications and risks when recommending and prescribing probiotics for patients. Hypothetically, probiotics may translocate, causing bacteremia or fungemia, as well as contamination of the product, and caution is advised when they are used in immunocompromised, hospitalized, or postoperative patients.45,46 In addition, commercially available probiotics may be contaminated with allergens, such as cow’s milk protein, and should be avoided in patients with severe allergies.47 An abstract from the Celiac Disease Center presented at the 2018 Digestive Disease Week found that there is significant contamination of probiotics with gluten; celiac patients should be cautious when using these products.48 In addition, there are not enough safety data on the use of probiotics during pregnancy, although published studies thus far have not found any AEs.49 Pregnant women also should avoid any unpasteurized products. Another important consideration when counseling patients about probiotics is the utility of eating yogurt as a source of probiotics. Some yogurts made in the United States are pasteurized, a process that kills live bacterial cultures. In addition, studies have shown that live cultures in yogurt may not survive in the low pH of the product, they may not persist during prolonged shelf time or transit through the acidic stomach, and they may not resist degradation in the small intestine by hydrolytic enzymes and bile salts.50 It is not known how much of the live cultures reach the distal gut and colonize the microbiota after the aforementioned processes, leading to questions about the clinical utility of

ingesting yogurt for the probiotic content. Other foods to consider that contain live cultures include kimchi (a Korean fermented cabbage dish), sauerkraut (fermented cabbage), miso (a fermented soybean-based paste), pickles, kombucha (a fermented tea), and apple cider vinegar (made from fermented apple sugars).

Conclusion The data remain strongest for the use of probiotics in pouchitis at a dosage of 3 g per day of VSL#3 for primary prophylaxis, and 6 g per day for secondary prophylaxis. There is not enough evidence to use probiotics to treat C. difficile infection, but there are probiotic regimens that are effective as a preventive measure in patients while they are receiving antibiotic therapy. The evidence for microbiome-manipulating therapy in IBS and hepatic encephalopathy is promising. In IBD, probiotics can be considered for the induction of remission and maintenance in mild to moderate UC. Although the proposed health benefits of probiotics continue to trend on social media and remain an area

of active clinical research, it is clear that there is a shift toward other modalities of microbiome-based therapy. With confounding variables such as heterogeneity in study design, many researchers have started focusing on the other ways to induce changes in the microbiome, including diet, prebiotics, and FMT. In the near future, microbiome therapy will become more targeted and individualized, and precision microbiome manipulation will become a reality. Patients will continue to ask about probiotics. When discussing probiotic use with patients, ensure to review the risks, benefits, and contraindications of their use. Consider concentrated, rigorously tested probiotic strains, in addition to foods that are able to deliver live bacterial cultures past the initial stages of digestion. Ensure patients are taking the correct regimen for the appropriate indication, and caution them that the data for other diseases are preliminary and likely will advance in the coming years. And stay tuned—the recommendations on probiotic strains and dosing will change as research continues in this rapidly evolving field.

References 1.

Brown AC, Valiere A. Probiotics and medical nutrition therapy. Nutr Clin Care. 2004;7(2):56-68. 2. Rousseaux C, Thuru X, Gelot A, et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med. 2007;13(1):35-37. 3. Sokol H, Pigneur B, Watterlot L, et al. Faecalibacterium prausnitzii is an anti-inflammatory commensal bacterium identified by gut microbiota analysis of Crohn disease patients. Proc Natl Acad Sci U S A. 2008;105(43):16731-16736. 4. McCarthy J, O’Mahony L, O’Callaghan L, et al. Double blind, placebo-controlled trial of two probiotic strains in interleukin 10 knockout mice and mechanistic link with cytokine balance. Gut. 2003;52(7):975-980. 5. Lin YP, Thibodeaux CH, Pena JA, et al. Probiotic Lactobacillus reuteri suppress proinflammatory cytokines via c-Jun. Inflamm Bowel Dis. 2008;14(8):1068-1083. 6. Seth A, Yan F, Polk DB, et al. Probiotics ameliorate the hydrogen peroxide-induced epithelial barrier disruption by a PKC- and MAP kinase-dependent mechanism. Am J Physiol Gastrointest Liver Physiol. 2008;294(4):G1060-G1069. 7. Jones SE, Versalovic J. Probiotic Lactobacillus reuteri biofilms produce antimicrobial and anti-inflammatory factors. BMC Microbiol. 2009;9:35. 8. Shen B. Pouchitis: what every gastroenterologist needs to know. Clin Gastroenterol Hepatol. 2013; 11(12):1538-1549. 9. Scarpa M, Grillo A, Faggian D, et al. Relationship between mucosa-associated microbiota and inflammatory parameters in the ileal pouch after restorative proctocolectomy for ulcerative colitis. Surgery. 2011;150(1):56-67. 10. Gionchetti P, Rizzello F, Venturi A, et al. Oral bacteriotherapy as maintenance treatment in patients with chronic pouchitis: a double-blind, placebo-controlled trial. Gastroenterology. 2000;119(2):305-309. 11. Komanduri S, Gillevet PM, Sikaroodi M, et al. Dysbiosis in pouchitis: evidence of unique microfloral patterns

in pouch inflammation. Clin Gastroenterol Hepatol. 2007;5(3):352-360. 12. Gionchetti P, Rizzello F, Helwig U, et al. Prophylaxis of pouchitis onset with probiotic therapy: a doubleblind, placebo-controlled trial. Gastroenterology. 2003;124(5):1202-1209. 13. Gionchetti P, Rizzello F, Morselli C, et al. High-dose probiotics for the treatment of active pouchitis. Dis Colon Rectum. 2007;50(12):2075-2082; discussion 2082-2084. 14. Su GL, Ko CW, Bercik P, et al. AGA Clinical Practice Guidelines on the Role of Probiotics in the Management of Gastrointestinal Disorders. Gastroenterology. 2020;159:697-705. 15. Allen SJ, Martinez EG, Gregorio GV, et al. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev. 2010;(11):CD003048. 16. Oksanen PJ, Salminen S, Saxelin M, et al. Prevention of travellers’ diarrhoea by Lactobacillus GG. Ann Med. 1990;22(1):53-56. 17. Hilton E, Kolakowski P, Singer C, et al. Efficacy of Lactobacillus GG as a diarrheal preventive in travelers. J Travel Med. 1997;4(1):41-43. 18. Evans DP. Non-pharmacotherapeutic interventions in travellers diarrhoea (TD). J Travel Med. 2019;25(suppl 1): S38-S45. 19. Shen NT, Maw A, Tmanova LL, et al. Timely use of probiotics in hospitalized adults prevents Clostridium difficile infection: a systematic review with meta-regression analysis. Gastroenterology. 2017;152(8):1889-1900.e9. 20. Cremonini F, Di Caro S, Covino M, et al. Effect of different probiotic preparations on anti-helicobacter pylori therapy-related side effects: a parallel group, triple blind, placebo-controlled study. Am J Gastroenterol. 2002;97(11):2744-2749. 21. Koebnick C, Wagner I, Leitzmann P, et al. Probiotic beverage containing Lactobacillus casei Shirota improves gastrointestinal symptoms in patients with chronic constipation. Can J Gastroenterol. 2003;17(11):655-659.

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22. Wang ZH, Gao QY, Fang JY. Meta-analysis of the efficacy and safety of Lactobacillus-containing and Bifidobacterium-containing probiotic compound 23. preparation in Helicobacter pylori eradication therapy. J Clin Gastroenterol. 2013;47(1):25-32. 24. Tilley L, Keppens K, Kushiro A, et al. A probiotic fermented milk drink containing Lactobacillus casei strain Shirota improves stool consistency of subjects with hard stools. Int J Probiotics Prebiotics. 2014;9(1-2):23-29. 25. Mollenbrink M, Bruckschen E. [Treatment of chronic constipation with physiologic Escherichia coli bacteria. Results of a clinical study of the effectiveness and tolerance of microbiological therapy with the E. coli Nissle 1917 strain (Mutaflor)] [In German]. Med Klin (Munich). 1994;89(11):587-593. 26. Whorwell PJ, Altringer L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol. 2006;101(7):1581-1590. 27. Guglielmetti S, Mora D, Gschwender M, et al. Randomised clinical trial: Bifidobacterium bifidum MIMBb75 significantly alleviates irritable bowel syndrome and improves quality of life—a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 2011;33(10):1123-1132. 28. Ford AC, Moayyedi P, Chey WD, et al. American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome. Am J Gastroenterol. 2018;113(suppl 2):1-18. 29. Pittayanon R, Lau JT, Yuan Y, et al. Gut microbiota in patients with irritable bowel syndrome—a systematic review. Gastroenterology. 2019;157(1):97-108. 30. Iribarren C, Törnblom H, Aziz I, et al. Human milk oligosaccharide supplementation in irritable bowel syndrome patients: a parallel, randomized, double-blind, placebo-controlled study. Neurogastroenterol Motil. 2020;32(10):e13920. 31. Palsson OS, Peery A, Seitzberg D, et al. Human milk oligosaccharides improve all the central symptoms of irritable bowel syndrome: a multicenter, open-label trial. Am J Gastroenterol. 2019;114(suppl):abstract 467. 32. Dalal R, McGee RG, Riordan SM, et al. Probiotics for people with hepatic encephalopathy. Cochrane Database Syst Rev. 2017;2:CD008716. 33. Agrawal A, Sharma BC, Sharma P, et al. Secondary prophylaxis of hepatic encephalopathy in cirrhosis: an open-label, randomized controlled trial of lactulose, probiotics, and no therapy. Am J Gastroenterol. 2012;107(7):1043-1050. 34. Khungar V, Poordad F. Hepatic encephalopathy. Clin Liver Dis. 2012;16(2):301-320. 35. Bajaj JS, Kassam Z, Fagan A, et al. Fecal microbiota transplant from a rational stool donor improves hepatic encephalopathy: a randomized clinical trial. Hepatology. 2017;66(6):1727-1738. 36. Bajaj JS, Salzman NH, Acharya C, et al. Fecal microbial transplant capsules are safe in hepatic encephalopathy: a phase 1, randomized, placebo-controlled trial. Hepatology. 2019;70(5):1690-1703.

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37. Sood A, Midha V, Makharia GK, et al. The probiotic preparation, VSL#3 induces remission in patients with mild-to-moderately active ulcerative colitis. Clin Gastroenterol Hepatol. 2009;7(11):1202-1209, 1209.e1. 38. Mardini HE, Grigorian AY. Probiotic mix VSL#3 is effective adjunctive therapy for mild to moderately active ulcerative colitis: a meta-analysis. Inflamm Bowel Dis. 2014;20(9):1562-1567. 39. Miele E, Pascarella F, Giannetti E, et al. Effect of a probiotic preparation (VSL#3) on induction and maintenance of remission in children with ulcerative colitis. Am J Gastroenterol. 2009;104(2):437-443. 40. Kruis W, Fric P, Pokrotnieks J, et al. Maintaining remission of ulcerative colitis with the probiotic Escherichia coli Nissle 1917 is as effective as with standard mesalazine. Gut. 2004;53(11):1617-1623. 41. Rembacken BJ, Snelling AM, Hawkey PM, et al. Nonpathogenic Escherichia coli versus mesalazine for the treatment of ulcerative colitis: a randomised trial. Lancet. 1999;354(9179):635-639. 42. Steed H, Macfarlane GT, Blackett KL, et al. Clinical trial: the microbiological and immunological effects of synbiotic consumption – a randomized double-blind placebo-controlled study in active Crohn’s disease. Aliment Pharmacol Ther. 2010;32(7):872-883. 43. Lichtenstein L, Avni-Biron I, Ben-Bassat O. Probiotics and prebiotics in Crohn’s disease therapies. Best Pract Res Clin Gastroenterol. 2016;30(1):81-88. 44. Rolfe VE, Fortun PJ, Hawkey CJ, et al. Probiotics for maintenance of remission in Crohn’s disease. Cochrane Database Syst Rev. 2006;(4):CD004826. 45. Levine A, Wine E, Assa A, et al. Crohn’s disease exclusion diet plus partial enteral nutrition tnduces sustained remission in a randomized controlled trial. Gastroenterology. 2019;157(2):440-450.e8. 46. Borriello SP, Hammes WP, Holzapfel W, et al. Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis. 2003;36(6):775-780. 47. Liong MT. Safety of probiotics: translocation and infection. Nutr Rev. 2008;66(4):192-202. 48. Bruni FM, Piacentini GL, Peroni DG, et al. Cow’s milk allergic children can present sensitisation to probiotics. Acta Paediatr. 2009;98(2):321-323. 49. Nazareth S, Lebwohl B, Voyksner JS, et al. Widespread contamination of probiotics with gluten, detected by liquid chromatography-mass spectrometry. Gastroenterology. 2015;148(4):S-28. 50. Dugoua JJ, Machado M, Zhu X, et al. Probiotic safety in pregnancy: a systematic review and meta-analysis of randomized controlled trials of Lactobacillus, Bifidobacterium, and Saccharomyces spp. J Obstet Gynaecol Can. 2009;31(6):542-552. 51. Kailasapathy K, Chin J. Survival and therapeutic potential of probiotic organisms with reference to Lactobacillus acidophilus and Bifidobacterium spp. Immunol Cell Biol. 2000;78(1):80-88. Editor’s note: Readers should be aware that the probiotic VSL#3 described in the referenced studies is the original formulation (the “De Simone Formulation”) that currently is being sold exclusively as Visbiome by ExeGi.

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PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

Diagnosis of Esophageal Motor Disorders OFER Z. FASS, MD, MACG Division of Gastroenterology and Hepatology Stanford University School of Medicine Redwood City, California

RONNIE FASS, MD Esophageal and Swallowing Center Division of Gastroenterology and Hepatology MetroHealth Medical System Case Western Reserve University Cleveland, Ohio

sophageal motor disorders comprise a diverse group of diagnoses defined by an altered pattern and vigor of contractions and sphincter dysfunction. They commonly present with dysphagia or chest pain but also may be associated

with heartburn, regurgitation, and globus sensation. The diagnosis of nonachalasic esophageal motor disorders requires normal endoscopy and esophageal biopsies followed by esophageal manometry.

Manometric testing previously lacked standardization, with variability between devices and protocols. The introduction of the Chicago Classification version 4.0 (CCv4.0), an international consensus, helped to improve the reproducibility of testing and establish diagnostic criteria for esophageal motility disorders identified on high-resolution manometry (HRM).1 Although HRM is considered the gold standard for diagnosing esophageal motor disorders, other tests— including upper endoscopy, barium swallow, barium swallow with a tablet, timed barium esophagram (TBE), fluoroscopy, and endoscopic ultrasound—commonly are used for diagnostic support. Newly developed diagnostic tools, such as combined impedance/ HRM and functional lumen imaging probe (FLIP) planimetry, allow for better assessment of esophageal body and sphincter function. New maneuvers that have been incorporated into the HRM protocol offer better diagnostic and prognostic information. Diagnostic testing for esophageal motor disorders remains an area of intense research due to the continued need for more accurate and simplified tools.

Basics of Esophageal Manometry Manometric testing should be considered for any patient presenting with either dysphagia or chest pain and normal endoscopy (ie, the absence of ulceration, obstruction, or inflammation) and with unremarkable esophageal biopsies. When available, HRM is preferred over other diagnostic tests.1 HRM is performed using an array of pressure sensors spaced approximately 1 to 2 cm apart. This approach allows for real-time, simultaneous measurements of pressures spanning the entire esophageal lumen and both sphincters. Older arrays used sensors spaced out at greater than 3-cm intervals, resulting in lower resolution and reduced diagnostic accuracy. HRM pressure tracings are visualized using esophageal pressure topography, in which time is plotted in seconds along the x-axis and location within the esophagus is plotted in centimeters along the y-axis. Pressure is represented as a continuous color scale along the Cartesian coordinate system, with blue (“cool”) colors representing lower pressures and red (“hot”) colors higher pressures. New to CCv4.0 is an updated standardized protocol

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for performing esophageal manometry. Patients should fast for at least 4 hours before testing, although small volumes of clear liquids are acceptable. The HRM catheter is placed into the esophageal lumen via nasal intubation, and testing is started with the patient in the supine position. On placement of the catheter, the patient is allowed 60 seconds for adaptation, after which the patient takes at least 3 deep inspirations to confirm catheter positioning. Baseline measurements are recorded for 30 seconds followed by 10 swallows of 5 mL of fluid (room temperature water, or saline if impedance measurements also are being performed). Swallows should be at least 30 seconds apart to prevent deglutitive inhibition. Supine testing concludes with a multiple rapid swallow (MRS) sequence of 5 liquid swallows, 2 mL each, administered using a 10-mL syringe, 2 to 3 seconds apart.2,3 The protocol is repeated with the patient in the upright position, with 5 or more wet swallows followed by a rapid drink challenge (RDC) that involves swallowing 200 mL of fluid as quickly as possible through a straw instead of an MRS sequence.4 Diagnoses are based on manometric results from the 10 wet swallows in the primary testing position. The secondary testing position and provocative maneuvers are used to support or exclude the suspected diagnosis. If results from the secondary position differ from those obtained in the primary position, additional testing, such as a solid test meal (STM), pharmacologic provocation, TBE, or endoluminal FLIP, may be required.5,6 Key manometric measures include integrated relaxation pressure (IRP), distal contractile integral (DCI), and distal latency. These metrics form the basis of the diagnostic criteria for esophageal motor disorders. IRP reflects the adequacy of esophagogastric junction (EGJ) relaxation in response to swallowing. It is calculated by averaging the minimum EGJ pressure over 4 seconds of relaxation within 10 seconds of upper esophageal relaxation. The upper limit of normal IRP depends on patient positioning and which equipment is used. In the supine position, an abnormal IRP is at least 15 mm Hg (Medtronic) or at least 22 mm Hg (Laborie/ Diversatek).7 In the upright position, an abnormal IRP is at least 12 mm Hg (Medtronic) or at least 15 mm Hg (Laborie/Diversatek). DCI, a measure of esophageal contractile vigor, is an integrated value of the mean contractile amplitude, length, and time within the distal esophagus.8,9 A normal DCI value is between 450 and 8,000 mm Hg•s•cm. Ineffective swallows include weak (100-450 mm Hg•s•cm), failed (<100 mm Hg•s•cm), and fragmented contractions. Fragmented contractions are represented by a break within the 20-mm Hg isobaric contour that is greater than 5 cm with a normal DCI.1 A swallow is defined as hypercontractile if the DCI exceeds 8,000 mm Hg•s•cm.1 Distal latency is measured as the time from upper esophageal sphincter relaxation to the contractile deceleration point (CDP), the transition point from the proximal rapid to distal slow esophageal contraction. This correlates anatomically with the beginning

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of the globular phrenic ampulla, a temporary structure formed by the elongated and elevated lower esophageal sphincter (LES).10 Physiologically, this represents the transition from peristaltic transport to ampullary emptying. Identifying the CDP can be challenging, but it can be pinpointed using the 30-mm Hg isobaric contour on esophageal pressure topographic plots. Two tangent lines are drawn: one along the slope of the initial, rapid contraction, and another extending proximally from EGJ along the slow contraction wave front. The intersection point of the 2 lines represents the CDP. Criteria dictate that the CDP should be within 3 cm of the EGJ proximal border.11 The lower limit of normal for distal latency is 4.5 seconds, and in the setting of a normal DCI, distal latency less than 4.5 seconds is considered a premature contraction.9

Diagnosis of Esophageal Motor Disorders HRM is considered the gold standard for the diagnosis of esophageal motor disorders. Before HRM is performed, endoscopy with possible esophageal biopsies should be considered to exclude any mechanical obstruction, mucosal ulceration, or inflammation that may otherwise explain a patient’s symptoms. In patients with suspected achalasia and those with esophageal dysphagia with a history of radiotherapy, caustic ingestion, or laryngeal surgery, barium swallow may be offered first. Esophageal motor disorders are divided into 2 categories based on IRP: EGJ outflow abnormalities, suggested by an elevated median IRP, and peristaltic disorders, indicated by a normal IRP. Occasionally, HRM testing is inconclusive, with borderline measurements. A definitive diagnosis may require supportive testing in the form of pharmacologic provocation, TBE, or FLIP. Figure 1 demonstrates a diagnostic algorithm for esophageal motor disorders.

EGJ Outflow Abnormalities The presence of an elevated median IRP suggests an EGJ outflow abnormality. Disorders of elevated IRP include achalasia and EGJ outflow obstruction (EGJOO). During HRM, an elevated median IRP should be observed in both the supine and upright positions.1 Achalasia is classified into 3 subtypes, all of which are characterized by an elevated median IRP and the complete absence/failure of peristalsis. Type I achalasia (classic) is defined by an abnormal median IRP and absent contractility.12-15 Type II achalasia has similar diagnostic requirements (increased IRP and 100% lack of peristalsis) but is distinguished by the presence of panesophageal pressurization in at least 20% of observed swallows.12-15 Type III achalasia (spastic) is differentiated by the presence of esophageal spasm in at least 20% of swallows.12-15 Type III achalasia has been shown to be associated with chronic opioid use; given this, testing should be performed with opioids held if possible.16 When the diagnosis for any type of achalasia

Step 1: Perform 10 wet swallows (primary position)

Disorders of EGJ Outflow

Disorders of Peristalsis

Abnormal median IRP Achalasia I

Yes

Achalasia II

Yes

Achalasia III

Yes

100% failed peristalsis without PEP

Yes

100% failed peristalsis with PEP in ≥20% swallows

Yes

100% absent peristalsis; all swallows are either failed or prematurea No

≥20% swallows with premature contractions; failed peristalsis ± PEP may be present

Yes

Abnormal TBE or FLIP

Elevated LES IRP in varying positions ± elevated IBP/PEP No Yes

Absent contractility

Yes

Distal esophageal spasmb

Yes

Hypercontractile esophagusb

>70% ineffective or Yes ≥50% failed swallows

Ineffective esophageal motility

No ≥20% swallows with premature contractions No ≥20% swallows with hypercontractility No No

No evidence of EGJ outflow obstruction

Yes

EGJOOb,d

Yes

100% failed peristalsis

Step 2 (if not done previously): Wet swallows in secondary position + MRS/RDC

Elevated LES IRP persists in varying positions + elevated IBP/ PEPc

Step 2: Wet swallows in secondary position + MRS/RDC

No evidence of disorder of peristalsis Consider meal challenges based on symptomse

Figure 1. Diagnostic algorithm for esophageal motor disorders. CCv4.0 Hierarchical Classification Scheme that defines the flow process of how the CCv4.0 diagnosis is generated within the constructs of the various phases of the protocol. In this conceptual model, the current protocol allows for some flexibility if the diagnosis is conclusive with 10 swallows in either the primary supine or upright position and allows for a sequenced progression of the protocol to help confirm or rule out the diagnosis. The flow diagram represents the optimal flow process, but exceptions will exist based on the fact that some cutoffs are arbitrary and the model assumes that a motility expert or a highly qualified motility technician or nurse is performing the protocol and analysis. a

Patients previously defined absent contractility based on 10 swallows in the primary position may have achalasia if IRP is elevated in an alternate position with RDC and/or MRS. These cases should be considered inconclusive for type 1 or II achalasia as appropriate and evaluated further with TBE/FLIP. b Denote manometric patterns of unclear clinical relevance. A clinically relevant conclusive diagnosis requires additional information, which may include clinically relevant symptoms and/or supportive testing. c RDC, solid test swallows, and/or pharmacologic provocation can be instituted to assess for obstruction. d Patients with EGJ obstruction and peristaltic swallows would fulfill strict criteria for EGJOO and may have features suggestive of achalasia or other patterns of peristalsis. e If no evidence of a disorder of peristalsis or EGJ outflow in patients with high probability of missed EGJOO, STM can be added to rule out obstructive pattern; if abnormal, the possibility of mechanical obstruction should be readdressed. In patients with regurgitation or belching, postprandial high-resolution impedance monitoring can be used to assess for rumination/belching disorder. DCI, distal contractile integral; EGJ, esophagogastric junction; EGJOO, esophagogastric outflow obstruction; FLIP, functional lumen imaging probe; IBP, Intrabolus pressurization; IRP, integrated relaxation pressure; LES, lower esophageal sphincter; MRS, multiple rapid swallow; PEP, panesophageal pressurization; RDC, rapid drink challenge; TBE, timed barium esophagram Adapted from reference 1 with permission.

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is inconclusive, especially when the IRP is borderline or within normal range, additional testing with TBE and/or FLIP often is required.5,6,17-20 In contrast to achalasia, EGJOO requires an abnormal median IRP in both the supine and upright positions. In addition, at least 20% of swallows should demonstrate elevated intrabolus pressures in the supine position with intact peristalsis.21-25 Unlike achalasia, EGJOO can be a manometric finding without clinical significance. In addition, the diagnosis of EGJOO may be erroneous, with manometric findings representing developing achalasia or mechanical obstruction. For EGJOO to be deemed clinically relevant, dysphagia or chest pain must accompany manometric findings.22,23,26,27 Further supportive testing, such as TBE or FLIP, also should be implemented to reinforce the presence of nonmechanical EGJ obstruction.5,6,17,21 Because EGJOO may be a

transient phenomenon, commonly due to medication use, some clinicians elect to repeat HRM after 6 months to ensure durability of the motility finding.28 The importance of performing HRM in both the supine and upright positions is demonstrated in Figure 2. A patient is shown to have an abnormally elevated IRP in the supine position, which resolves with upright swallows. Provocative testing and certain manometric observations can support the diagnosis of EGJOO. These include outflow obstruction and pressurization during RDC, outflow obstruction during STM swallow with accompanying clinical symptoms, and pharmacologic provocation with amyl nitrite revealing abnormal EGJ function.4,29-33 When a diagnosis of EGJOO is made, the accompanying contractile pattern—for example, EGJOO

Figure 2A. Abnormally elevated median IRP in the supine position during 10 wet swallows in a patient with dysphagia. Ten swallows in the supine position revealing an abnormally high IRP. CFV, contractile front velocity; DCI, distal contractile interval; IRP, integrated relaxation pressure; LES, lower esophageal sphincter; UES, upper esophageal sphincter

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with hypercontractility, EGJOO with absent peristalsis, EGJOO with normal peristalsis, or EGJOO with ineffective motility (IEM)—should be described because case series from various institutions have demonstrated that EGJOO can coexist with disorders of peristalsis.1 The accompanying contractile pattern may indicate the treatments to which a patient will likely respond.33

Peristaltic Disorders Esophageal motor abnormalities with a normal IRP are categorized as disorders of peristalsis. These include distal esophageal spasm (DES), hypercontractile esophagus, absent contractility, and IEM. Patients may have overlapping features of multiple peristaltic disorders. When this is the case, a diagnostic hierarchy should be applied in the order of DES, hypercontractile esophagus, and finally IEM.1

DES is defined as at least 20% of swallows with premature contractions in the context of normal IRP and DCI. Premature contractions are identified on HRM as a distal latency less than 4.5 seconds. Like EGJOO, DES can be observed on HRM but may lack clinical significance. Thus, for DES to be clinically relevant, manometric findings should correlate with symptoms of either chest pain or dysphagia.34 An inconclusive diagnosis of DES occurs when at least 20% of the swallows are premature, but the DCI is less than 450 mm Hg•s•cm. When an inconclusive diagnosis is encountered, supportive testing can be considered. MRS support the diagnosis of DES when the absence of deglutitive inhibition is noted.35 DES also should be suspected when barium esophagram reveals a corkscrew, or rosary bead–shaped esophagus.36,37 Finally, DES is considered when FLIP demonstrates persistent obstructing

Figure 2B. Normal IRP in upright position in same patient during a wet swallow. Representative of 1 of 5 upright wet swallows (all with normal IRP) and an upright swallow in the same patient demonstrating normal IRP. CFV, contractile front velocity; DCI, distal contractile interval; IRP, integrated relaxation pressure; LES, lower esophageal sphincter; UES, upper esophageal sphincter

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contractions or cyclic retrograde contractions in the esophageal body during esophageal distention.18 Per the hierarchal order, the next peristaltic disorder to consider is hypercontractile esophagus. This disorder is defined as at least 20% of swallows with a DCI greater than 8,000 mm Hg•s•cm.38-40 IRP must be normal and mechanical obstruction should be excluded via index endoscopy. The exclusion of mechanical obstruction is crucial, because obstruction may provoke a hypercontractile response. Similar to DES, one should distinguish between clinically relevant and irrelevant hypercontractile esophagus based on the presence of typical symptoms (chest pain and dysphagia).41,42 Hypercontractile esophagus is further divided into 3 subgroups: singlepeaked hypercontractile swallows, jackhammer with repetitive prolonged contractions, and hypercontractile swallows with vigorous LES after-contraction.43 Although differentiating between the hypercontractile subtypes is outside the scope of this review, jackhammer tends be of greater clinical interest because it is associated with higher DCI values and greater symptom severity.44 Absent contractility is defined as 100% failed peristalsis (DCI <100 mm Hg•s•cm) in the setting of a normal IRP in both the supine and upright positions.1 Ensuring a normal median IRP in both positions is crucial because it is the only feature differentiating hypercontractile esophagus from type I achalasia. If IRP values are borderline elevated and the predominant symptom is dysphagia, type I achalasia should be included in the differential diagnosis. Confirmatory testing with TBE and/or FLIP should be performed. The final diagnosis under peristaltic disorders is IEM. Previous versions of the Chicago Classification listed IEM and fragmented peristalsis as “minor disorders.” With CCv4.0, fragmented peristalsis has been incorporated into IEM, and the distinction between major and minor peristaltic disorders has been removed. The criterion for diagnosing IEM requires at least 70% ineffective swallows, defined as a DCI between 100 and 450 mm Hg•s•cm, or at least 50% failed swallows, defined as a DCI less than 100 mm Hg•s•cm.45-48

Supportive Testing Occasionally, manometric testing may return inconclusive or equivocal results, such as conflicting measurements in the supine versus seated positions, measurements inconsistent with clinical presentation, or indications of an EGJOO that does not fully meet the criteria for achalasia. Under these circumstances, supportive testing can assist with further delineation of esophageal motor patterns while supporting or challenging a specific diagnosis. Various HRM maneuvers and diagnostic tools have been proposed as supportive tests. A summary of supportive tests endorsed by CCv4.0 can be reviewed in Table 1.

Multiple Rapid Swallows MRS are included as part of the standardized HRM protocol. An MRS sequence is executed at the end

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of supine testing, with the patient asked to perform 5 liquid swallows of 2 mL each administered at 2- to 3-second intervals.2,3 A normal response is the absence of esophageal contractions (DCI <100 mm Hg•s•cm) and complete deglutitive inhibition of the LES during the MRS sequence, with an augmented peristaltic aftercontraction at the end of the sequence. The augmented contraction should have a DCI greater than the mean DCI of a single swallow.3,49-51 For MRS function to be normal, the inhibitory and excitatory neural pathways within the esophagus, as well as the integrity of the esophageal muscle, must be intact. Studies have demonstrated that MRS reflects the peristaltic motor reserve of patients with esophageal symptoms and hypotensive peristalsis.52 This has various applications, such as supporting the diagnosis of DES when deglutitive inhibition is absent.35 MRS also can suggest a diagnosis of EGJOO when an upright IRP greater than 12 mm Hg is observed during rapid swallows.51 Rapid swallows also can have prognostic utility; the absence of an augmented contraction at the end of an MRS sequence is predictive of late postoperative dysphagia after antireflux surgery.3 Finally, the vigor of the MRS after-contraction has been shown to be inversely correlated with acid exposure time in patients with nonerosive reflux disease or IEM.50,53 In light of the above-mentioned evidence, the lack of peristaltic reserve during MRS supports the diagnosis of IEM.1

Rapid Drink Challenge Like MRS, the RDC also is part of the standardized HRM protocol. It is performed at the end of upright testing and entails having the patient drink 200 mL of fluid quickly through a straw. A normal response is complete deglutitive inhibition of peristalsis (DCI <100 mm Hg•s•cm) and the LES during the RDC, without any significant motility abnormalities after completion.1 Unlike in MRS, during RDC an augmented after-contraction is less readily assessed and may be absent in healthy controls. However, a greater esophagogastric pressure gradient is generated, allowing for better evaluation of esophageal outflow resistance.49 Therefore, the focus of MRS is primarily the vigor of the after-contraction, whereas the focus of RDC is the IRP. RDC has been shown to act as a “stress test” for the EGJ. The mean IRP during an RDC is predictive of radiographically confirmed outflow obstruction (sensitivity of 100% and specificity of 85.5% in untreated patients) and correlates with the Eckardt symptom score in patients with achalasia.4,51 A study comparing healthy controls with patients with dysphagia and reflux symptoms established an elevated RDC-IRP as an accurate measure of outflow obstruction, with a sensitivity and specificity greater than 90%.54 In addition to IRP measurements, stereotypical pressurization patterns have been observed during RDC, which may help identify motor disorders in patients with otherwise normal manometry.55 More recently, RDC has been shown to be superior to standard 5-mL water swallows in

identifying patients with clinically relevant EGJOO who are likely to respond to therapy.29 Overall, an upright IRP greater than 12 mm Hg, or panesophageal pressurization greater than 20 mm Hg (measurement cutoffs based on Medtronic HRM catheter), during RDC support the presence of outflow obstruction.

Solid Test Swallows and Meals Solid test swallows and meals have been introduced as an adjunct to the fluid swallows in the standardized HRM protocol. Solid test swallows comprise 10 swallows of soft, solid foods, such as bread, boiled rice, or marshmallows, each approximately 1 cm3 in volume. An STM is analogous to an RDC, with the patient consuming 200 g of a soft, solid meal at a comfortable pace. The test is stopped once the patient has completed the meal or 8 minutes have elapsed, whichever comes first. A normal response for both solid test swallows and meal is greater than 20% pharyngeal swallows followed by an effective peristaltic contraction with DCI greater than 1,000 mm Hg•s•cm and no breaks within the 20-mm Hg isobaric contour greater than 5 cm. For the STM, any symptoms that arise should be recorded, and an inability to finish the meal in 8 minutes is considered abnormal and should be noted.1 Clinicians may elect to perform postprandial meal measurements, continuing manometric recording for at least 10 minutes after completion of an STM or other solid meal. A normal response is considered the absence of symptoms or abnormal motility. No more than 4 transient LES relaxations should be observed during the first 10 minutes, and no regurgitation or rumination should be seen.1 The use of postprandial HRM immediately after an STM is the best diagnostic approach to identify rumination or belching disorder. Solid test swallows, similar to RDC, were noted to be superior to water swallows in identifying patients with clinically relevant EGJOO who were likely to respond to therapy.29 The utility of STM in increasing the diagnostic sensitivity of HRM was established by a large cohort study of 750 patients presenting with esophageal symptoms. STM was found to identify esophageal motor disorders among patients with a primary complaint of dysphagia.30 Further evidence for the diagnostic utility of STM was demonstrated in a study evaluating HRM with STM results in healthy volunteers and patients with major motility disorders.31 Patients with motility disorders ate slower than healthy controls, and pathologic contractile patterns were reproduced readily. STM is considered a supportive test for the diagnosis of outflow obstruction by revealing an IRP greater than 25 mm Hg and/or panesophageal pressurization greater than 20 mm Hg (measurement cutoffs based on Medtronic HRM catheter).1

Esophageal Impedance Monitoring Impedance refers to the measurement of electrical resistance between closely arranged electrodes mounted on an intraluminal catheter. The directional movement of an intraluminal bolus and its contents can be determined

during impedance monitoring. Air has a high impedance, whereas liquid (swallowed or refluxed) has a low impedance. A limitation of impedance monitoring is the inability to determine the volume of an intraluminal bolus.56 Impedance monitoring has been shown to support the diagnosis of IEM. A study comparing 33 patients with IEM and 44 patients with normal motility testing demonstrated that a decreased bolus clearance percent is associated with IEM.57 The utility of impedance monitoring for identifying impaired bolus transit has been further supported by studies showing agreement between abnormal impedance and impaired clearance on barium swallow.58 Consequently, poor bolus transit observed during impedance monitoring supports the diagnosis of IEM.

Pharmacologic Provocation Pharmacologic provocation refers to the use of compounds to stimulate the esophagus during HRM. Commonly used agents include amyl nitrite and cholecystokinin. Amyl nitrite provocation is performed by having the patient inhale 0.3 mL of the compound in the recumbent position.59 A normal response is significant relaxation of the distal esophagus and LES. In a healthy individual, the IRP is comparable to the deglutitive IRP after amyl nitrite inhalation, but patients with outflow obstruction secondary to LES dysfunction experience a profound drop in the IRP compared with the deglutitive IRP, with a difference of 10 mm Hg or greater. Patients with mechanical obstruction or stricture experience an IRP difference less than 10 mm Hg.1 Cholecystokinin provocation is performed during HRM by infusing 40 ng/kg intravenously while the patient is in the recumbent position. A normal response is esophageal shortening followed by partial EGJ relaxation. In patients with achalasia and inhibitory dysfunction, cholecystokinin infusion results in a paradoxical contraction of the LES greater than 50 mm Hg.1 A proposed use of pharmacologic esophageal stimulation during HRM is to distinguish between opioidinduced type III achalasia and idiopathic type III achalasia. After amyl nitrite inhalation, patients with opioid-induced type III achalasia demonstrate diminished esophageal contraction pressures. When cholecystokinin is administered, patients with opioid-induced type III achalasia exhibit an attenuated paradoxical contraction of the EGJ. Furthermore, patients with opioid-induced type III achalasia have 100% relaxation during the second phase of cholecystokinin response, as opposed to 26% relaxation for patients with idiopathic type III achalasia.59 Another suggested use of pharmacologic provocation is to differentiate between absent contractility and type I achalasia among patients with borderline IRP measurements.60 The use of amyl nitrite inhalation also may provide useful prognostic information by identifying EGJOO patients who may respond to LES ablative therapies. A study of 49 patients with true EGJOO revealed that only half demonstrate impaired LES

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Table. Supportive Maneuvers and Testing to High-Resolution Esophageal Manometry in Patients Suspected of Esophageal Motor Abnormality Test

Description

Normal Response

Multiple rapid swallows

While supine, the patient performs 5 liquid swallows, 2 mL each, at 2- to 3-s intervals

Absent esophageal contractions and deglutitive inhibition of the LES, with an augmented peristaltic after-contraction at end of sequence

Rapid drink challenge

While upright, the patient drinks 200 mL of fluid quickly through a straw

Absent esophageal contractions and inhibition of the LES, without any significant motility abnormalities observed after completion; an augmented after-contraction does not need to be present

Solid test swallows

The patient performs 10 swallows of soft, solid foods (bread, boiled rice, marshmallows) each approximately 1 cubic cm in size

20% pharyngeal swallows followed by an effective peristaltic contraction (DCI >1,000 mm Hg•s•cm) and no breaks within the 20-mm Hg isobaric contour >5 cm

Solid test meals

The patient consumes 200 g of a soft, solid meal at a comfortable pace within 8 min

>20% pharyngeal swallows followed by an effective peristaltic contraction (DCI >1,000 mm Hg•s•cm) and no breaks within the 20-mm Hg isobaric contour >5 cm; patient should finish meal within 8 min

Postprandial meal

Continued manometric recording for at least 10 min after completion of a meal (solid test or otherwise)

≤4 transient LES relaxations during first 10 min and no regurgitation or rumination

While recumbent, the patient performs 4-5 sniffs of amyl nitrite

Significant relaxation of distal esophagus and LES; amyl nitrite–induced IRP should be similar to deglutitive IRP

Pharmacologic provocation

Amyl nitrite

Cholecystokinin While recumbent, patient receives a 40-ng/kg infusion

Esophageal shortening (typically <2 cm) after infusion, followed by partial EGJ relaxation

Timed barium esophagram

Patient swallows 100-250 mL of barium sulphate with radiographs obtained at times 1, 3, and 5 min; an optional barium tablet may be combined with the liquid barium.

Complete emptying of barium within 5 min

Functional luminal impedance

FLIP catheter is placed into the esophagus during endoscopy and a balloon inflated to measure esophageal compliance and distensibility

EGJ-DI >2.8 mm2/mm Hg, distensibility plateau >18 mm, and antegrade contractions in repetitive pattern

DCI, distal contractile integral; EGJ, esophagogastric junction; EGJ-DI, esophagogastric junction distensibility index; EGJOO, esophagogastric outflow obstruction; FLIP, functional lumen imaging probe; IRP, integrated relaxation pressure; LES, lower esophageal sphincter; RDC, rapid drink challenge Adapted from reference 1 with permission.

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relaxation during amyl nitrite inhalation. Patients with a drop in IRP that is greater than 10 mm Hg were hypothesized to respond better to LES-targeted therapies.32

Timed Barium Esophagram Utility Evaluates peristaltic reserve; predicts dysphagia in patients who have undergone antireflux surgery; diminished after-contraction supports diagnosis of ineffective motility Acts as a “stress test” of the EGJ; associated with outflow obstruction and may predict which patients with EGJOO will respond to therapy; elevated IRP or panesophageal pressurization during RDC supports the diagnosis of outflow obstruction May be superior to water swallows in identifying patients with clinically relevant EGJOO who will respond to therapy

Elevated IRP or panesophageal pressurization supports diagnosis of outflow obstruction

Identification of rumination or belching disorder

Can differentiate LES dysfunction from mechanical obstruction/stricture; also distinguishes opioid-induced type III achalasia from idiopathic etiologies; may identify EGJOO patients who may respond to LES ablative therapies; supports diagnosis of EGJOO Distinguishes between opioid-induced type III achalasia and idiopathic etiologies; can differentiate absent esophageal contractility from type I achalasia when IRP measurement is borderline abnormal; supports diagnosis of EGJOO Can assess response to therapy after pneumatic dilation in achalasia and idiopathic EGJOO; can differentiate EGJOO from type I achalasia; supportive test for diagnosing clinically relevant EGJOO

Reduced EGJ-DI, decreased maximal EGJ diameter, absent peristalsis during esophageal distension all support diagnosis of achalasia; can predict response to achalasia-type therapy in EGJOO patients; supportive test for diagnosing clinically relevant EGJOO

TBE can assist in identifying esophageal outlet obstruction. A patient swallows 100 to 250 mL of barium sulfate, and radiographs are obtained at set time intervals. The height and width of the retained barium column is measured to assess esophageal emptying.61 A small barium tablet (approximately 13 mm in diameter) sometimes is used in combination with liquid barium to better isolate delayed emptying and areas of retention.62 A healthy adult should show complete emptying of barium within 5 minutes. Another potential application of TBE is differentiating between achalasia and nonachalasia dysphagia. Barium height of greater than 2 cm at 5 minutes has a sensitivity of 85% and specificity of 86% for achalasia. Combining TBE with a radiopaque tablet increases diagnostic yield for achalasia to 100%.17 TBE also has been used to assess response to therapy, such as pneumatic dilation in achalasia and idiopathic EGJOO.63,64 In certain patients with clinical features of achalasia and normal IRP, impaired LES relaxation may be identified only during TBE.65 Despite its many uses, TBE is limited by its inability to distinguish between anatomic obstruction and functional EGJOO.5 TBE has been shown to support the diagnosis of both EGJOO and achalasia. Esophageal contrast retention or delayed tablet transit suggests achalasia. TBE also is recommended for supportive testing in patients who have an inconclusive diagnosis of achalasia and a primary symptom of dysphagia. Lastly, TBE (in addition to FLIP) is considered a supportive test for diagnosing clinically relevant EGJOO.1

Endoluminal FLIP FLIP is a newer technology that measures the mechanical forces of the esophagus by using impedance planimetry during controlled luminal distention. The resultant luminal cross-sectional area and pressure measurements can be used to assess various mechanical properties of the esophagus, including its compliance and distensibility. In addition to providing novel planimetric measurements, FLIP testing can be performed during the index esophageal endoscopy. Although the full application of FLIP continues to be explored, various uses have been investigated. A reduction in the EGJ distensibility index, decreased maximal EGJ diameter, and absence of peristalsis with esophageal distention all support the diagnosis of achalasia.18 Furthermore, FLIP can be used in patients with EGJOO to predict who may respond to achalasia-directed therapy. A low EGJ distensibility index predicts a better response to interventions used in achalasia, whereas patients with a normal EGJ distensibility index respond better to conservative management.6 Finally, FLIP has shown that a certain subset of patients with clinical and

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radiographic features of achalasia, but normal IRP on HRM and reduced EGJ distensibility index, are likely to respond positively to achalasia treatment.19 FLIP, as with TBE, is considered a supportive test for the diagnosis of achalasia and clinically relevant EGJOO.

Conclusion HRM is considered the main diagnostic tool for esophageal motor disorders, supported by tests such as TBE and FLIP. Novel diagnostic maneuvers have been incorporated into the current HRM protocol. These help to better identify esophageal motor abnormalities in symptomatic patients, primarily those with dysphagia and chest pain. In addition, they help to elicit motor abnormalities in symptomatic patients

who appear to have normal or nonspecific changes on HRM that do not explain their symptoms. The addition of new diagnostic maneuvers to the current protocol of HRM significantly prolongs the test, but they are essential for diagnostic accuracy and could prevent unnecessary treatment. It also is important to recognize that some of the diagnosed esophageal motor disorders are transient, commonly due to medication use, and thus repeat testing after several months may be needed to demonstrate durability. Furthermore, the importance of TBE and FLIP as supportive tests for establishing or ruling out the diagnosis of esophageal outlet obstruction has been recognized and incorporated into the diagnostic workup of esophageal motor disorders such as achalasia and EGJOO.

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Dr Ronnie Fass reported financial relationships with AstraZeneca, Clexio Biosciences, Daewoong, Diversitek, Eisai, GerdCare, Johnson & Johnson, Medtronic, Neurogastrx, Phathom and Takeda. Dr Ofer Fass reported no relevant financial disclosures.

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Studies Find Predictors Of FMT Failure, CDI Recurrence

esearchers have identified a number of risk factors for treatment failure after fecal

microbiota transplantation (FMT) for Clostridioides difficile infection (CDI), some of them modifiable. “Although [FMT] is a powerful therapy for individuals who develop recurrent CDI (rCDI), 10% to 15% of patients still fail to recover following FMT,” Alexa Weingarden, MD, PhD, a gastroenterology fellow at Stanford University School of Medicine, in California, and her co-investigators noted in an abstract presented at the virtual Digestive Disease Week 2021 (abstract Fr575). In an effort to identify predictors of FMT failure and rCDI after initial FMT success, they examined data from 65 patients who had undergone a total of 77 FMTs at their institution between 2015 and 2020. Nineteen procedures were performed in patients who had inflammatory bowel disease, 27 were performed in patients with functional gastrointestinal disorders, and 20 were performed in patients with compromised immune systems. Eight FMTs were administered through the upper gastrointestinal tract, and 29 involved the delivery of fecal matter to the terminal ileum. An analysis of clinical outcomes up to 60 days showed that 88.3% of patients experienced either no rCDI symptoms or CDI-like symptoms with a negative C. difficile stool test within two months of FMT. However, 23.5% of those who had an initial response experienced rCDI 60 or more days after the procedure, the researchers found. In univariate analyses, poor cleansing of the transverse colon (P=0.043) and narcotic use were significant predictors of rCDI after successful FMT (P=0.039). see FMT Failure, page 55

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Studies Look at Nonantibiotic Medications and C. difficile Link

wo recent studies have shed light on the impact of nonantibiotic medications on the risk for

Clostridioides difficile infection (CDI).

In one study, researchers found a twofold increased risk for CDI during proton pump inhibitor (PPI) use, with a lingering risk up to one year after PPI discontinuation, while a separate study found no association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and CDI. “Studies like these are important as we seek to understand environmental influences on gut microbiota which might increase risk for C. difficile infections,” commented CDI expert Colleen Kelly, MD, an associate professor of medicine in the Division of Gastroenterology at the Warren Alpert Medical School of Brown University, in Providence, R.I., who was not involved in the research.

Higher CDI Risk in PPI Users Malin Inghammar, MD, an associate professor of infection medicine at Lund University, in Sweden, and his co-investigators studied the link between community-acquired CDI and PPIs (Clin Infect Dis 2021;72[12]:e1084-e1089). They noted that prior observational studies have identified a link between PPI use and CDI risk, but that association has remained controversial “due to the absence of data from randomized controlled trials, considerable variability between studies, and insufficient adjustment for confounding in previous studies.” To address these shortcomings, the authors examined nationwide registry data in Denmark and found 3,583

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incident episodes of CDI that occurred between 2010 and 2013 in patients who were not hospitalized within 12 weeks before infection and who did not have a positive C. difficile test in the prior eight weeks. The CDI cases were identified through a positive culture, molecular assay or toxin test, and by definition. Their data set also included C. difficile test results in the Danish Microbiology Database, prescription information and patient characteristics, allowing them to perform analyses controlling for the effects of chronic disease, genetics, socioeconomic status, hospital stay, and antibiotic and corticosteroid use. The researchers reported that 964 cases of CDI were diagnosed in patients during PPI treatment; 324 occurred in patients who had discontinued treatment within the previous six months; and 123 occurred six to 12 months after PPI cessation. The remaining patients had not received a PPI during or the year before CDI. Dr. Inghammar and his colleagues found the risk for CDI was over twice as high among current PPI users than among individuals not receiving PPIs (adjusted incidence rate ratio [IRR], 2.03; 95% CI, 1.74-2.36). The PPI-CDI association persisted, with a 54% higher risk for CDI during the six months after PPI cessation (adjusted IRR, 1.54; 95% CI, 1.31-1.80) and a 24% higher risk in the six to 12 months after PPI cessation (adjusted IRR, 1.24; 95% CI, 1-1.53).

Sex, age and hospitalization one or more years before CDI did not affect the risk for infection in PPI users, the authors found. “This large study with thorough control for confounding significantly adds to the body of evidence that increased risk of CDI, even in the community setting, should be considered when prescribing PPIs,” the investigators noted. Although Dr. Kelly said these results confirm prior findings, the observational nature of the study is a limitation. She also said the observed increased risks for CDI with PPIs “are extremely small in comparison with known CDI risk factors, and discontinuing antisecretory therapy may leave patients at risk of harm by leaving acid-related conditions, such as peptic ulcer disease and reflux esophagitis, untreated.” Dr. Kelly emphasized that “when used for appropriate indications, the benefits of PPI are clear, and therapy should not be interrupted in patients being treated for CDI or at higher risk of this infection.”

No Link Between Nonaspirin NSAIDs and CDI In another study, Adam Ressler, MD, from the Department of Internal Medicine, Division of Infectious Disease, at the University of Michigan, in Ann Arbor, and his co-investigators identified 628 CDI cases from a previously published cohort of patients treated at Michigan Medicine and 628 controls who also were treated there for diarrhea suspicious for CDI but who were negative for CDI (Anaerobe 2021 Sep 8. https://doi.org/10.1016/j. anaerobe.2021.102444). They analyzed data for prescribed and over-thecounter nonaspirin NSAIDs within 30 days of CDI as

FMT Failure continued from page 53

In multivariate analyses, the presence of diabetes predicted initial FMT failure (odds ratio [OR], 0.03; 95% CI, 0.001-0.81), and failure to deliver transplanted stool to the terminal ileum predicted rCDI after initial success (OR, 0.81; 95% CI, 0.66-0.99). “Our data suggest that terminal ileum administration of stool may be an important independent factor in decreasing the risk of CDI recurrence following [FMT],” the authors concluded. “Future prospective studies are needed to confirm these findings and determine whether terminal ileum administration should be routinely attempted during [FMT].” In a separate study presented at DDW (abstract Fr556), Sachit Sharma, MD, a hospital medicine specialist at the University of Toledo Medical Center, in Ohio, and his co-investigators performed a metaanalysis of 18 studies published through October 2020. The studies had included multivariate analyses of risk factors for FMT failure in 3,819 patients

well comorbidities and baseline laboratory findings. Patients with CDI and NSAID use were closely matched with non-CDI NSAID users according to sex, presence of back pain and arthritis, baseline serum creatinine, serum albumin, and use of anticoagulants or antiplatelet medications. The investigators found that 22% to 26% of those with or without CDI had used nonaspirin NSAIDs during the previous month, with analyses confirming there was no elevated CDI risk among those receiving NSAIDs (odds ratio [OR], 0.97; 95% CI, 0.72-1.29; P=0.816). The only significant CDI risk factors they found were older age (OR, 1.09; CI, 1.01-1.17; P=0.02), scores on the weighted Elixhauser Comorbidity Index, a measure of comorbidity burden (OR, 0.98; 95% CI, 0.97-0.99) and prior CDI (OR, 2.64; 95% CI, 1.96-3.56). “Both on unadjusted and adjusted modeling, our findings do not support an association between NSAID use and an increased risk for CDI,” noted to the investigators. Prior research on the topic that has found an association between NSAID use and CDI “had two major limitations, [including] inadequate assessment of over-the-counter NSAID use and failure to account for treatment assignment bias,” the team wrote. “To our knowledge this is the first study of NSAID use as a risk factor for CDI to account for treatment assignment bias utilizing propensity score matching,” they added. “This is significant as it increases our confidence that our modeled risk of CDI is causally related to NSAID use itself, rather than the underlying indication for the NSAID use.” —David Wild

who had undergone the procedure and had recurrent, refractory or severe/complicated CDI. Followup ranged from 0.2 to 34.9 months. According to Dr. Sharma’s team, 15.6% of patients experienced complete FMT failure with no initial response. Of 26 different risk factors identified in the studies, the current meta-analysis identified inpatient FMT administration (OR, 5.2; 95% CI, 3-8.92), older age (OR, 1.05; 95% CI, 1.021-1.086) and the presence of IBD (OR, 5.2; 95% CI, 2.53-10.67) as predictors of failure. Other predictors of FMT failure included early antibiotic use after FMT (OR, 4.73; 95% CI, 1.77-12.65), immunosuppression (OR, 3.85; 95% CI, 1.85-8), higher Charlson Comorbidity Index scores (OR, 1.34; 95% CI, 1.1-2.87) and the presence of pseudomembranes at the time of FMT (OR, 4.681; 95% CI, 1.79-12.25). The authors noted that the findings “may help develop a risk stratification model for prediction of FMT failure in patients with recurrent CDI.” —David Wild

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The State of the Art Of Artificial Intelligence In Gastroenterology

he use of artificial intelligence in gastroenterology and endoscopy is a rapidly advancing frontier, predominantly in computer-aided detection (CADe) systems for identifying colorectal polyps. The first iterations of convoluted neural network systems were built on

While CADe systems detect, computer-aided diagnosis (CADx) systems are learning to differentiate details that characterize a polyp as an adenoma versus a nonneoplastic, hyperplastic polyp. However, these AI systems have fully utilized their potential to increase the quality of colonoscopy when they have been applied to real-time procedures with the goal of addressing the nearly 27% of missed adenomas and improving adenoma detection rates (ADRs). The move toward building and refining AI systems for this task was swift. Multiple systems for CADe polyp detection in live endoscopies have been shown to improve ADRs and decrease reaction time of endoscopists. In April 2021, the FDA approved the GI Genius (Medtronic) as the first CADe system for real-time detection of colorectal polyps to be marketed and used in clinical practice. This system showed an overall ADR of 54.8% versus 40.4% under standard white light colonoscopy in a multicenter randomized controlled trial, and more specifically, a significant difference in ADR for polyps smaller than 1 cm. The approval of this system brings the realistic prospect of change in endoscopy practices for colonoscopy today and other procedures in the near future. Looking ahead, the next step is to improve polyp characterization with CADx systems. Use of AI imaging on colonoscopy can improve detection and differentiation of neoplastic lesions. Several studies have shown that AI has high accuracy in histologic prediction (area under the receiver operating curve [AUROC], 0.96), which can be further improved with the addition of virtual chromoendoscopy to images (AUROC, 0.98). Some AI systems have performed significantly better than nonexpert endoscopists. In addition, several studies have found AI systems to have good accuracy when predicting adenomatous versus hyperplastic histology of endoscopic images, compared with the pathology-confirmed diagnoses. Although

Prateek Sharma, MD Professor of medicine at the University of Kansas School of Medicine, in Kansas City

endoscopy images and videos to teach systems to recognize patterns and complex relations within the data sets through layers of algorithms. The systems learn to predict outcomes, such as the identification of polyps from other mucosal abnormalities. these results are promising, these systems must prove themselves capable of real-time evaluation during live colonoscopy. The use of AI in colorectal cancer screening and surveillance holds tremendous promise. AI in inflammatory bowel disease also is making strides to diagnose patients with Crohn’s disease and ulcerative colitis, and also evaluate severity of illness and response to treatment. Systems are being developed to identify mucosal features of esophageal squamous cell carcinoma, Barrett’s-related neoplasia and gastric adenocarcinoma. However, as these innovative systems are developed, it is imperative to critically question their strength and clinical validity. Some important questions to ask are: What is the sample size of the training and validation data sets? Was the system trained and tested on images, postprocedural videos or live procedures? Is the system capable of real-time assessment with minimal lag time? What improvement does this system really offer and does it have clinical benefit, in the form of decreased reaction time, improved ADR, accuracy in the characterization of abnormalities for targeted biopsies, assessment of quality of endoscopic views and important anatomic landmarks? Was the system tested against expert endoscopists in validation? The beauty of AI systems is that they can be constantly trained and updated. Systems do not read a particular scenario and determine the outcome based on a previous instance with identical circumstances. Instead, convoluted neural networks learn from data and make predictions based on previous trends in intricate relationships between data points. As new trends and outcomes are learned, the system can be adjusted to its predictions. The more information we feed these systems and curate the data to help make accurate predictions, the better we will develop systems that move medicine forward and benefit patients in the real world ■ in a clinically significant way.

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An AI Solution to Volume Status in Cirrhotic Patients

new machine learning algorithm seems to be able to use pulse oximeter waveforms to estimate

volume status in patients with cirrhosis.

Researchers from the Northwestern University Feinberg School of Medicine, in Chicago, found that analysis of fingertip photoplethysmography waveforms during breath-holding estimates intravascular volume overload more accurately than measurements of serum brain natriuretic peptide (BNP). Nikhilesh R. Mazumder, MD, MPH, a transplant hepatology fellow at Northwestern, said inaccurate estimation of the intravascular space can lead to adverse events in patients with cirrhosis who are taking diuretics for volume overload. “Seeing all these patients in clinic can be challenging, so I was thinking about a way that we can quantify their physiology noninvasively from home,” Dr. Mazumder said. Although decreased pulse pressure at the end of breath holding represents normal physiology, its absence is a sign of volume overload, he added. His group presented the findings at the 2020 Liver Meeting (abstract 126). see Cirrhotic, page 63

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Once Trailing, Gastro Catching Up in AI Applications

rtificial intelligence entered the medical arena more than 30 years ago with systems designed to build on physician

expertise. Until recently, the development of AI has been fairly gradual, with forays into genomics, electronic health records and robot-assisted surgery.

But now, the overlapping disciplines of AI, machine learning (ML) and deep learning are rapidly forging ahead in drug development, preclinical research, personalized health care and in applications for different specialties. “There are a number of fields already ahead of the game in AI,” noted Prateek Sharma, MD, a professor of medicine at the University of Kansas School of Medicine in Kansas City. He cited several examples, such as the validation of a deep learning system to identify diabetic retinopathy in patients with diabetes, and the application of these systems to detect lymph node metastases in patients with breast cancer. “The deep learning algorithms were able to achieve a better diagnostic performance than a panel of expert pathologists,” he said. in a presentation at the 2020 annual meeting of the American College of Gastroenterology, Dr. Sharma discussed potential uses for AI in gastroenterology. “In gastroenterology,” he said, “could AI reduce delays in diagnosis? Automate tedious tasks? Expand access to medical services?”

AI in Endoscopy To understand how AI might foster better recognition and characterization of polyps, and with the demarcation of the extent of lesions using algorithms, having an idea of how ML develops in the field of endoscopy is helpful, Dr. Sharma said. “We use a ground truth or external standard to develop a training set, which leads to the development of algorithms. Then a different set of external standards is used to assess the accuracy of the algorithms developed from the training set,” Dr. Sharma said. “After

further training and revising, an algorithm is developed for practice or clinical use.” The majority of the reviews of AI in gastroenterology have centered on AI-assisted endoscopy. A comparison of AI with endoscopic experts for diagnosing esophageal squamous cell carcinoma found the AI system significantly more sensitive than the 13 experts at detecting tumors and more accurate than the experts in distinguishing cancerous from noncancerous tissue (Gastrointest Endosc 2020;92[4]:848-855). “You can look at similar algorithms for the detection of Barrett’s esophagus associated neoplasia,” Dr. Sharma said. Using an initial set of 916 images and a test set of 458 patients with dysplasia or non-dysplasia, researchers were able to achieve an AI sensitivity of 99% in white light–only imaging, 92% with narrow band imaging only, and 96% using both in a recent pilot study (Gastrointest Endosc 2020;91[6]:1264-1271). “This suggests that areas in BE can be looked at and detected by these machine learning algorithms,” Dr. Sharma said. Data from randomized controlled trials have shown the benefits of AI in screening endoscopy. A published trial from Europe found that gastroenterologists who used a computer-aided diagnosis (CAD) and detection system had a significantly higher adenoma detection rate (ADR; 54.8%) than those who did not (40.4%) (Gastroenterology 2020;159[2]:512-520.e7). “Standard screening found 0.7 adenomas per patient, whereas CAD finds 1.07. Also, CAD finds more diminutive polyps, 34% compared with 27%, and more large polyps, 11% versus 6%,” Dr. Sharma said. see Catching Up, page 62

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For ‘Nonexpert’ Endoscopists, AI Boosts Competency In Colonoscopy

he use of artificial intelligence to aid colonoscopy improved the detection of adenomas by nonexpert endoscopists by 22% versus conventional colonoscopy, according to a study presented at the 2021 virtual Digestive Disease Week (abstract 338).

The AID-2 study evaluated the benefit of incorporating a computer-aided detection (CADe) system compared with unaided conventional colonoscopy during 660 colonoscopies performed by 10 endoscopists who had done less than 2,000 colonoscopies each. The primary outcome was adenoma detection rate (ADR). “Our conclusion was that nonexpert endoscopists gain benefit by the assistance of artificial intelligence, leading to an increased detection of colorectal neoplasia,” said Alessandro Repici, MD, of Humanitas University, in Milan. “This benefit appears equivalent to that achieved by CADe in expert endoscopists.” see Nonexpert, page 62

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Nonexpert continued from page 60

Dr. Repici and his colleagues previously showed that CADe improves ADR in the hands of more experienced endoscopists. In the AID-1 study of six expert endoscopists, the machine-learning technology improved ADR by 30%, from 40.4% to 54.8% (Gastroenterology 2020;159[2]:512-520). The current AID-2 study assessed CADe in a nonexpert setting and found it equally beneficial. The prospective randomized controlled, noninferiority trial enrolled 10 nonexpert endoscopists who performed screening, surveillance or diagnostic colonoscopies in consecutive subjects ages 40 to 80 years. The clinicians used high-definition colonoscopy with or without a real-time machine-learning CADe system (GI-Genius, Medtronic). Overall, the mean ADR was higher in the CADe group, at 53.3% versus 44.5% in the group that performed conventional colonoscopy (relative risk [RR], 1.22; P=0.017). After adjusting for age, sex and colonoscopy indication, the crude RR was 1.20 for ADR overall and 1.00 for advanced neoplasia. The ADR for advanced neoplasia was 2.7% in both groups. There was no difference between the groups in withdrawal time or resection of non-neoplastic lesions, suggesting the addition of CADe had no negative effect on the procedure. Benefit also was shown in the adenoma-percolonoscopy (APC) rate, which increased by 21% (1.26 vs. 1.04), mainly due to greater detection of subcentimeter flat and distal neoplasia, Dr. Repici added. When pooling these data with those from the previous AID-1 study, use of CADe, but not the level of

examiner experience, was associated with differences in ADR. The use of CADe increased the ADR by 29% (RR, 1.29), whereas no increase in ADR was observed according to increasing experience (RR, 1.02). Vanessa Shami, MD, a professor of medicine and the director of endosonography at the University of Virginia Health System, in Charlottesville, said, “The message, based on this randomized trial, is that the use of CADe increases ADRs, regardless of endoscopist’s experience. This translates to a better-quality exam.”

An ‘Extremely Important Topic’ Klaus Mergener, MD, PhD, the immediate pastpresident of the American Society for Gastrointestinal Endoscopy, said the study evaluates “an extremely important topic. “It’s fair to say we can all predict that AI and related technologies will be one of the next big revolutions in our field and will lead to paradigm shifts in terms of how we provide care,” Dr. Mergener said. “One of the million-dollar questions this study is starting to address is this: In what areas will AI be most useful? In what settings and for what providers? Similar to other areas, such as image enhancement technologies and caps on the tips of the endoscope, studies have clearly shown that certain subgroups of providers may or may not benefit from these add-on enhancement or therapies,” he added. “So, seeing results of this trial—showing that nonexpert providers might benefit the most from AI, or certainly be a subgroup that could be helped by AI—is very important. We can be certain that additional trials will follow up on this and also explore related topics.” —Caroline Helwick Drs. Mergener, Repici and Shami reported no relevant ﬁnancial disclosures.

Catching Up

The Near Horizon

continued from page 59

Harish Gagneja, MD, of Austin Gastroenterology in Texas, said he eagerly anticipates new AI-incorporating technology on the horizon, like an Olympus endoscope with a lidar scanner that gives the dimensions of a polyp, which may help gastroenterologists make more accurate recommendations for screening intervals. “Most people overestimate the size of a polyp,” he said. But Dr. Gagneja said he is more excited about a dictation system under development by Cerner that picks up the conversation between doctor and patient, using AI technology to incorporate appropriate verbiage and terminology. “We still have a 10% to 12% miss rate, and technology that helps endoscopists increase their ADR will be of great value,” he said. “But if someone can do my notes virtually? That would be awesome.”

IBD and Hepatology Although perhaps not as advanced as the research in polyp detection, AI is being investigated in other areas of gastroenterology. For instance, one study investigated the use of an ML model to predict remission in people with inflammatory bowel disease after their first dose of ustekinumab (Stelara, Janssen) (JAMA 2019;2[5]:e19372). “It’s almost like big data when you take so many granular data points and use ML to predict progression,” Sravanthi Parasa, MD, a gastroenterologist with the Swedish Medical Center, in Seattle, said. AI is also being used to improve diagnosis in hepatology using computer vision pattern recognition. “Regions identified by the pathology are put through the ML computer vision algorithm, and the algorithms basically identify these abnormal areas,” Dr. Parasa said, noting that the research so far has been mainly proof of concept.

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—Monica J. Smith Drs. Gagneja and Sharma are members of the editorial board of Gastroenterology & Endoscopy News.

Cirrhotic continued from page 58

To help determine if intravascular volume status can be accurately estimated by the waveform of a modified pulse oximeter, the researchers prospectively enrolled 42 men and women with cirrhosis into the trial between August 2018 and September 2019. All participants were undergoing first-time, nonemergent left or right heart catheterization for any indication. On the day of catheterization, the researchers recorded serum BNP and finger photoplethysmography waveforms before, during and after a 10-second breath-holding maneuver, as measured by an oral transducer. Volume overload was defined as a pulmonary capillary wedge or left ventricular pressure greater than 15 mm Hg. A total of 26 patients completed photoplethysmography measurement and underwent invasive cardiac pressure measurements. Of these, nine (35%) had intravascular volume overload. The machine learning algorithm determined the most significant features of the model using photoplethysmography waveform characteristics. After crossvalidation and regression analyses, it was found that the machine learning model correlated better with intravascular volume status than did serum BNP (R2=0.22). Furthermore, the presence of volume overload could be determined with an accuracy of 84% using the machine learning model, according to the researchers. The sensitivity of the method was found to be 80%, with a positive predictive value of 90%, they reported.

A Role in Telehealth Although the investigators acknowledged the need for more research to validate the findings, they foresaw a time when their model might play an important role in managing care for people with cirrhosis. “First of all, it can be a safety net,” Dr. Mazumder told Gastroenterology & Endoscopy News. “We often

send patients home with a dose of diuretics, but have little idea how they will react. But with a device like this, they might be able to determine their own volume status and whether or not they should be continuing with their current dose.” The model also may have a role in telehealth monitoring of patients with liver disease. “This is especially important during the COVID-19 pandemic, where office visits are much more limited,” Dr. Mazumder said. “Meeting with these patients virtually and seeing what the pulse oximeter says may help clinicians to decide the best course of action.” Finally, the investigators said the method may help identify possible cardiac complications in patients with cirrhosis. “It may help us determine which patients are at highest risk for these issues and catch them before they need hospitalization,” Dr. Mazumder said. Guadalupe Garcia-Tsao, MD, a professor of medicine at Yale University School of Medicine, in New Haven, Conn., said the methodology, if properly validated, could have important clinical implications, particularly for patients with decompensated cirrhosis in whom volume status is often difficult to determine. “The main setting where this would work is in the evaluation and management of patients with acute kidney injury and/or hyponatremia, where determining volume status would be key in their management at presentation,” Dr. Garcia-Tsao said. “Also, during admission, these patients often get an excess of intravenous albumin that could be counterproductive and lead not only to worsening of renal function but also to iatrogenic respiratory or heart failure. Having a noninvasive method to assess how much albumin is too much would be very important.” —Michael Vlessides Drs. Garcia-Tsao and Mazumder reported no relevant ﬁnancial disclosures.

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Experts Caution On False Positives in AI

ust as “alarm fatigue” can be a problem for clinicians in the hospital, experts fear that emerging systems of computer-aided polyp detection may be generating so

many false-positive findings that gastroenterologists who use the technology risk burnout.

In computer-assisted colonoscopy, suspected polyps are visualized as alarm boxes; false positives are anything besides a polyp, such as a bubble or a fold. Some false positives are inevitable, but too many can be a problem. What’s more, variation in how computer-aided polyp detection systems define false-positive results can dramatically affect the number of such findings, but researchers say they may have identified an ideal threshold, which could help in future comparisons of these systems. “Artificial intelligence in the evaluation of colorectal polyps is in its early stages, so we want to find ways to minimize certain effects, one of which is endoscopist burnout,” Erik Holzwanger, MD, a gastroenterology fellow at Tufts Medical Center, in Boston, told Gastroenterology & Endoscopy News. “If you keep seeing boxes light up and it’s not clear whether it’s a polyp or stool, which can happen if you don’t have a true definition of a false positive, your procedure can be much longer and more repetitive and add to burnout,” he said. To study the diagnostic performance of computer-aided polyp detection by false-positive threshold definitions, Dr. Holzwanger and his colleagues applied a previously validated system to videos of 62 colonoscopies performed between September 2016 and March 2017. They stratified the videos into three groups using different parameters for false-positive alerts. The alerts were defined as the time the computer continuously traced an alarm box around what it suspected to be a lesion. Group 1 equaled more than 0.5 seconds, group 2 was equal to or greater than one second, and group 3 was two or more seconds. The number of false positives fell precipitously as the length of time increased: There were 111 false positives in group 1, 23 in group 2, and three false positives in group 3. Specificity and accuracy improved

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with time duration, from 93% and 98%, respectively, in group 1 to 98.6% and 99.5% in group 2, and nearly 100% in group 3. Greater rates of false positives were associated with bowel preparation scores of fair and poor. Presenting the study at the 2020 virtual annual meeting of the American College of Gastroenterology (abstract P1182), Dr. Holzwanger said the analysis reveals the effects that different threshold definitions for false positives have on the reported diagnostic performance of computer-aided detection systems in colonoscopy. “We suggest that a greater than two-second falsepositive threshold is a clinically practical benchmark for standardizing the interpretation of data for computeraided colon polyp detection in colonoscopy,” he said. Ultimately, Dr. Holzwanger said he hoped the use of artificial intelligence in colonoscopy will help increase the adenoma detection rate (ADR) by picking up polyps that endoscopists miss. “That’s what piqued my interest in this; we’re always trying to increase polyp detection and ADR.” Prateek Sharma, MD, a professor of medicine at the University of Kansas School of Medicine, in Kansas City, who is a leading authority in the field of AI in endoscopy, said the clarification of the false positive definition for detection studies is an important topic. “Like this study evaluating patients undergoing AI colonoscopy, we’ll have to clarify false positive definitions for future studies in esophageal and gastric diseases,” Dr. Sharma said. “An evidence-based and consensus-based approach to this will be ideal.” —Monica J. Smith Dr. Sharma is a member of the editorial board of Gastroenterology & Endoscopy News.

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Improving Duodenoscope-Related Infection Control Requires A Multipronged Approach Vivek Kaul, MD, FASGE, FACG, AGAF

Seth A. Gross, MD, FACG, FASGE, AGAF

Segal-Watson Professor of Medicine Division of Gastroenterology and Hepatology University of Rochester Medical Center Rochester, New York

Professor of Medicine Clinical Chief Division of Gastroenterology and Hepatology NYU Langone Health New York, New York

rug-resistant infections associated with duodenoscopes can occur

during endoscopic retrograde cholangiopancreatography (ERCP), despite current reprocessing protocols. Advanced endoscopists perform more than 500,000 ERCP procedures annually in the United States, often for urgent, life-threatening conditions.1 Thus, minimizing or eliminating the risk for contracting infections from these procedures is critical.

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Even when all guidelines are followed, reprocessing does not guarantee 100% removal of all organisms from duodenoscopes, and, thus, contamination from patient-ready duodenoscopes remains a concern. Preliminary findings from postmarket surveillance studies mandated by the FDA reveal that 9% of duodenoscopes remain contaminated after reprocessing.1 Subsequent studies demonstrate that even higher contamination rates are possible in this setting.2 The extent to which high-concern organisms on patient-ready duodenoscopes result in patient harm is not known, but outbreaks of multidrugresistant, carbapenem-resistant Enterobacteriaceae have been traced back to inadequately reprocessed duodenoscopes.3 After these outbreaks, in 2015, the FDA convened an expert panel from across the infection control, endoscopy, and medical device communities to devise effective strategies to reduce duodenoscope-related infections.4 Since then, the FDA has asked device manufacturers to collect and analyze postmarket data on reprocessing and develop potential alternatives to traditional duodenoscopes. There is no simple answer to eliminating the risk for duodenoscope-associated patient infections. An allencompassing solution is preferred but may not be realistic for gastroenterologists across various clinical settings with varying resources. To ensure patient safety remains a top priority, gastroenterologists will need to assess which reprocessing strategies or emerging technologies work best to minimize the risk for duodenoscope-related infection in their patients. Solutions will vary for gastroenterologists across clinical settings, but a multifaceted approach to patient safety is required for duodenoscope-associated infection to become a thing of the past. All physicians and clinical staff must adopt a strict, forward-thinking culture of safety that considers duodenoscope-associated infection to be possible but preventable.

Limitations of Reprocessing Flexible endoscope reprocessing includes 7 essential steps: manual precleaning, leak testing, manual cleaning, high-level disinfection (HLD), rinsing, drying, and storage. What is involved in these steps varies by the type of flexible endoscope, the manufacturer instructions for use, and society guidelines for infection control adopted by an institution. Reprocessing can take up to an hour or more to complete, whether it is a duodenoscope, a colonoscope, a bronchoscope, or other type of flexible endoscope. Reprocessing is driven by humans, who may not be able to comply with these complex processes for a variety of reasons, including inadequate training and lack of stringent protocols or supervision. Thus, there is an opportunity for human error, and quality assurance protocols should be in place to measure the success of reprocessing for each endoscope. How closely are reprocessing personnel following manufacturer

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recommendations for cleaning and disinfection? Are facilities culturing endoscopes after reprocessing to check for pathogenic bacteria? The CDC recommends that training for reprocessing personnel include explanations as to why each of the 7 essential steps—precleaning, leak testing, etc—are so important to reprocessing success.5 Staff also should be able to demonstrate the ability to adequately reprocess each specific type of endoscope they may be presented with in the reprocessing suite, according to CDC recommendations. It is well recognized that training for reprocessing personnel can be inadequate in some instances. In a 2018 survey conducted by Ofstead & Associates and the International Association of Healthcare Central Service Materiel Management, 70% of more than 2,300 surveyed sterile processing professionals reported they had received less than a week of training when starting their position.6 Despite these survey results, we believe most endoscope reprocessing units follow proper training protocols and provide supervision for this demanding work. For example, in large academic medical centers and hospital systems, rigorous protocols are in place in endoscope reprocessing rooms, which represent a significant investment on the part of these centers. Reprocessing personnel in these facilities undergo thorough training over many months and understand how important their job is in keeping endoscopes clean and patients safe. In addition to lengthy training by device manufacturers and senior staff members, surveillance by internal infection control teams and external surveying bodies, such as the Joint Commission, help root out cleaning- and disinfection-related deficiencies. That does not, however, remove the potential that other human factors will affect the adequacy of reprocessing. We know there are times when a high volume of cases will demand unrealistic speed from reprocessing technicians, leading to the potential for errors or substandard cleaning. Reprocessing technicians in busy hospitals may be charged with cleaning up to 30 flexible endoscopes of varying design and complexity in a single shift, according to a recent study.7 The physical challenges inherent to this work and time demands may lead technicians to inadvertently skip steps, especially if there isn’t a full understanding about why every reprocessing step is essential to the procedure’s success.8 In addition to juggling these multiple tasks, technicians must keep track of various guidelines and instructions for use for the various types of endoscopes being cleaned.9 Based on the literature, it appears that most of the missteps likely occur during the manual cleaning step. Manual cleaning shortcomings could lead to inadequate HLD, even in an automated endoscope reprocessor (AER). In the United States, manual cleaning more often is done outside of an AER, with the machines reserved for HLD. Recent studies suggest the use of an AER can be as efficient as manual cleaning.7 However, as long as manual cleaning is done by endoscope reprocessing

personnel, we believe regular retraining should include updated refresher courses on the proper procedures for manual cleaning to ensure continued compliance.

Problems Inherent to Design There also remains the issue of duodenoscope design. After all, it’s the unique and complex design of duodenoscopes that makes ERCP possible and effective as a therapeutic procedure. But the duodenoscope’s narrow channel, distal end cap, and elevator mechanism can potentially harbor pathogenic organisms. Debris or biofilm may be retained in these components, even when cleaning instructions are followed meticulously, potentially exposing patients to infectious agents. Studies have revealed contaminants in the working and suction channels of duodenoscopes, including Escherichia coli cultured from a biopsy channel after a lethal outbreak.10 One study shows higher bacterial culture rates from a biopsy channel brush than from the elevator,11 although positive cultures do not always translate into clinical infection or patient harm, and vice versa. Advances in duodenoscope design that simplify cleaning and eliminate the need to reprocess endoscope components that are prone to contamination are essential to reduce infection risk. The FDA recommends that hospitals and endoscopy facilities transition away from fixed-end cap duodenoscopes to those with newer design features that include disposable components or even fully disposable duodenoscopes.

Innovative Technologies Offer Multiple Solutions Several device manufacturers have updated duodenoscope designs, with the aim of limiting the risk for infection. The FDA cleared duodenoscopes with disposable end caps from Fujifilm, Olympus, and Pentax. In addition, Pentax also received clearance on a model with a fully disposable and replaceable elevator. Ambu and Boston Scientific released fully disposable duodenoscopes, designed for single use. Single-use end cap and elevator modules and singleuse duodenoscopes help reduce the risk that contaminants remain lodged in the end cap and elevator mechanism. The impact of these novel devices on patient safety will become clearer with further use, study, and analysis. Preliminary research into these new disposable options is promising. Abstracts from the 2020 Digestive Disease Week point to cases in which disposable duodenoscope components greatly reduce contamination rates12 after reprocessing and potentially lower costs for hospital systems.13 Single-use duodenoscopes offer financial benefits.

Although there is a need to purchase a new duodenoscope for every ERCP procedure, they eliminate all associated reprocessing and maintenance costs.14 Readily available and sterile endoscopes also can benefit smaller facilities that may lack reprocessing personnel and resources. In addition, disposable endoscopes potentially are useful in emergency department and ICU settings to facilitate urgent/emergent procedures without the need to transport traditional reusable endoscopes and towers to those units. Gastroenterologists also must weigh the performance capabilities of these new options when assessing which developing infection control measures will be best for their practice. Since ERCP can be a technically challenging procedure in the best of circumstances, any design innovations to prevent cross-contamination after reprocessing also need to account for the procedure’s complexity. The duodenoscope functionality, image quality, performance characteristics, and handling are going to be very important to get the job done safely and successfully. As any gastroenterologist who has performed ERCP can attest, the functionality of the duodenoscope is essential for procedural success. Navigation to the major papilla needs to be atraumatic, seamless, and efficient. Then, during and subsequent to cannulation of the desired duct, the duodenoscope must be able to respond adequately to the fine movements required to avoid papillary trauma and procedural complications. Most studies on the performance of fully disposable

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duodenoscopes have been conducted at high-volume ERCP centers, with highly trained and experienced expert endoscopists using this new technology. Initial results suggest that fully disposable duodenoscopes intended for one-time use can be effective for ERCP. However, it remains to be seen whether these disposable duodenoscopes perform as well with less experienced/low-volume endoscopists at smaller facilities and in more complex procedures. Hospital systems and outpatient clinics will need to undertake extensive due diligence on the technological capabilities of these endoscopes, including image quality and functionality, as well as their financial and environmental impacts, before making a switch. Disposable endoscopy can offer many infection control and financial benefits, but gastroenterologists must explore the applications that make the most sense for their practice and facility as the technology continues to evolve.

Creating a Culture of Safety Despite strict reprocessing protocols, thorough training programs, and hardworking staff, errors do occur in the endoscope reprocessing pathway. We have discussed

the various aspects relevant to this issue, including the importance of proper training, human factors related to compliance, and novel endoscope design/disposable endoscopes, each of which are important considerations in this realm. New technology should be evaluated in carefully conducted trials and adopted where it has transformational impact on patient care. Infection control related to ERCP should be a multifaceted approach, with hypervigilance and a culture of safety at its core. When using reprocessed duodenoscopes, facilities must adopt the strictest surveillance measures related to reprocessing, including optimal training of reprocessing personnel, while following FDA guidance. We believe institutions that have a culture of safety will be the most successful. In those institutions, it is less likely there will be clinically significant errors or negative outcomes that can be traced back to the reprocessing suite. All health care personnel working with duodenoscopes need to be hypervigilant and ensure maximum safety precautions are employed. Leadership is vital in making this message clear to staff, and all facilities should ensure that patient safety—not procedure volume—is the highest priority, always.

References 1.

FDA. The FDA is recommending transition to duodenoscopes with innovative designs to enhance safety: FDA Safety Communication. Accessed January 31, 2021. https:// www.fda.gov/medical-devices/safety-communications/ fda-recommending-transition-duodenoscopes-innovativedesigns-enhance-safety-fda-safety-communication

flexible endoscopes, December 27, 2018. Accessed January 31, 2021. https://www.cdc.gov/hicpac/recommendations/flexibleendoscope-reprocessing.html 6.

Ofstead CL, et al. PROCESS. 2019;July/August:61-71.

Alfa MJ, et al. Am J Infect Control. 2006;34(9):561-570.

Mark JA, et al. Gastrointest Endosc. 2020;91(6):1328-1333.

Ofstead CL, et al. Gastroenterol Nurs. 2010;33(4):304-311.

CDC. CDC Statement: Los Angeles County/UCLA Investigation of CRE transmission and duodenoscopes. July 10, 2015. Accessed January 31, 2021. https://www.cdc.gov/hai/outbreaks/ cdcstatement-la-cre.html

Hildebrand EA, et al. Proc Hum Factors Ergon Soc Annu Meet. 2011;55(1):748-752

FDA. Infections associated with reprocessed duodenoscopes. Accessed February 1, 2021. https://www.fda.gov/ medical-devices/reprocessing-reusable-medical-devices/ infections-associated-reprocessed-duodenoscopes

CDC. Healthcare Infection Control Practices Advisory Committee (HICPAC). Essential elements of a reprocessing program for

10. Snyder GM, et al. Gastroenterology. 2017;153(4):1018-1025. 11.

Rauwers AW, et al. Gut. 2018;67(9):1637-1645.

12. Rao HB, et al. Gastroenterology. 2020;158(6):abstract Su1509. 13. Barakat M, et al. Gastroenterology. 2020;158(6):abstract 775. 14. Das A, et al. Gastroenterology. 2020;158(6):abstract Tu1963.

Dr Gross reported ﬁnancial relationships with Ambu and Olympus. Dr Kaul reported a ﬁnancial relationship with Ambu.

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Latest Multi-Society Reprocessing Guidelines Aim to Follow the Evidence Valuable updates but some areas of potential confusion

ulti-society guidelines for reprocessing endoscopes date back to 2003, but the latest

iteration released in January provides more evidence-based recommendations than before. Increased research on reprocessing of endoscopes triggered by infectious outbreaks related to contaminated duodenoscopes since 2014 provided data for the guidelines authors to develop a comprehensive document.

“There’s probably been more research into the area of endoscope reprocessing in the last five years than in the entire history of GI endoscopes,” said V. Raman Muthusamy, MD, MAS, the medical director of endoscopy at the University of California, Los Angeles Health. “Traditionally, there’s been this perception that if you follow the manufacturer’s reprocessing instructions, everything will be fine, but the outbreaks happened at very experienced, high-volume centers where they were following protocol and doing all the steps. They weren’t fine,” said Dr. Muthusamy, a co-author of the recently published guidelines (Gastrointest Endosc 2021;93[1]:11-33e6). “What we wanted to do [with this update] is provide evidence, as much as possible, to answer four key questions and provide guidance in many other areas.”

Emphasis on Training Emmanuel S. Coronel, MD, an assistant professor of medicine at The University of Texas MD Anderson Cancer Center, in Houston, said the new guidelines have some major improvements over the 2016 guidelines. “While the basic recommendations have not changed,” he said, “the new guidelines do a better job at explaining their recommendations and providing the best available evidence.” Dr. Coronel said he also appreciates the emphasis on staff training and competency, as well as the overall transparency of the guidelines. Noting that Table 3 of the guidelines is devoted to acknowledging areas that need more research, he said this underscores the recognition “that a lot of these recommendations are not final.” Despite the need for more data, he called the

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guidelines document “very comprehensive,” saying “if you study this guideline with your team, you should have a pretty good direction in how to manage your infection control team and your reprocessing steps for your scopes.” Lawrence Muscarella, PhD, the president of LFM Healthcare Solutions, agreed that the new guidelines contain a vast amount of important updated information, but he pointed out some specific changes he thought could be perceived as a rollback or can be misinterpreted.

Question About Intermediate-Level Disinfection Although the multi-society’s update defines what “semi-critical devices” are and recommends that they be sterilized or treated with a high-level disinfectant if sterilization is not feasible, it includes a clause stating that “some semi-critical and non-critical devices may undergo intermediate-level disinfection,” Dr. Muscarella said. “But this clause appears to be new—it’s not in any of the prior multi-society guidelines—and there’s no reference given for it and no description of the specific semicritical devices the guidelines are referring to,” he added. “Guidelines are updated all the time, but if the rationale for the change is not provided, it can lead to some confusion in the context of reprocessing GI endoscopes.” The FDA advises thorough cleaning followed by intermediate- or low-level disinfection for non-critical items, not for semi-critical devices such as GI endoscopes, he added. Explaining the rationale for this guidance on semicritical devices, lead author of the guideline Luke Day, MD, the chief medical officer of Zuckerberg San Francisco General Hospital, said several members of the group felt it was necessary to include some semi-critical devices. Dr. Day noted that the information “was taken from the CDC guidance document on disinfection and the Spaulding classification that states, ‘Some items that may come in contact with non-intact skin for a brief period of time … should be treated with intermediate-level disinfection.’ While the CDC states that this ‘brief period of time’ makes it a non-critical device, some debated that this meets the definition of critical,” Dr. Day said. “Hence, we said some semi-critical devices.” Dr. Muscarella observed that this confusion could have been eliminated if the new guideline had explicitly identified GI endoscopes as semi-critical devices. “All three of the earlier versions—2003, 2011 and 2016—clearly stated this, but not the 2021 guideline, paving the way for the confusion that ‘some’ semi-critical devices can be intermediate-level disinfected.”

Sterilization Versus High-Level Disinfection In a discussion of the use of ethylene oxide (EtO) sterilization instead of high-level disinfection, the guidelines state that the former should be considered in selected settings (e.g., outbreaks) and patient populations.

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But this could appear to stray from the long-standing concept that all patients should receive the same standard of care, Dr. Muscarella said. “Ideally, we want one standard of care; we want it to be consistently high for all patients. We don’t really want to start choosing between disinfection or sterilization depending on what we think may be the status of a patient’s immune system, at least not without sound supporting evidence,” he said. “Otherwise, we can start getting into variations in care.” Dr. Muthusamy said there are no trials of patients in a non-outbreak setting in which the use of EtO has been shown to be better than high-level disinfection done properly. “But there are data showing that several institutions that had an outbreak were able to contain and stop the outbreak when they switched to EtO.” He also noted that it is hard to recommend EtO because of issues of availability, toxicity, flammability and cost that make it unfeasible for some institutions.

Role of Alcohol in Drying Another area of potential confusion Dr. Muscarella discussed relates to drying of endoscopes. The new guidelines point out two benefits of using an alcohol flush in the drying process but ultimately conclude that the data to “strongly support or refute the use of alcohol flushes for the drying of endoscopes” are scarce. However, the 2016 guidelines endorsed the use of a 70% to 90% ethyl or isopropyl alcohol rinse followed by forced-air drying and cited several references to support that advice, Dr. Muscarella said. “Some other countries’ guidelines do not recommend using alcohol because of concern that it could present potential protein fixation risks,” he added. “I think it’s possible the 2021 guideline may be deferring to another country’s guidelines and practices. The protein fixative properties are valid, but I am unaware of any published reports linking those properties directly to a specific case of infection involving a GI endoscope, while many reports support the use of an alcohol flush and forced air to reduce the risk of an endoscope transmitting waterborne microorganisms.” Dr. Muthusamy agreed with Dr. Muscarella’s point that the potential problem of protein fixation is largely theoretical but said the evidence to support using alcohol in the drying process is not overwhelming. “We’re not arguing that you should or shouldn’t use alcohol, but [we] don’t see irrefutable benefit one way or the other,” he said. “Ultimately, given this uncertainty, we recommend individualizing your response based on what the manufacturer of your device advises. We would be happy to see further research in this area to make a more definitive recommendation in future guidelines.” —Monica J. Smith Dr. Coronel reported a financial relationship with Boston Scientific (BS). Dr. Muscarella reported current and/or recent financial relationships with companies that market single-use flexible endoscopes and/or products for low-temperature sterilization of reusable endoscopes. Dr. Muthusamy reported financial relationships with BS and Medivators.

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Predict progression to esophageal cancer: What’s your patient’s risk?

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Systems Analysis for Predicting Barrett’s Risk Beats Expert Pathologists

n objective risk prediction system based on biomarkers and imaging has the

potential to fundamentally alter surveillance of Barrett’s esophagus, according to a roundup of clinical studies. The promise is individualized surveillance that is more reliable and less costly, experts said.

In one blinded cohort investigation, the predictive accuracy of the system was found to be “as good as the best-performing expert pathologists we could find for our study,” said Nicola F. Frei, MD, a gastroenterologist affiliated with Academic Medical Center, in Amsterdam. In a separate pooled analysis of four multinational studies, “utility was established not only in those with low-grade dysplasia but also in those with nondysplastic Barrett’s,” reported Prasad G. Iyer, MD, a professor of gastroenterology and hepatology at Mayo Clinic in Rochester, Minn. The studies of this emerging tool, called Tissue-Cypher (Cernostics), were presented at the 2021 virtual Digestive Disease Week. Each of the investigators said the fully automated system, unlike histologic analysis by pathologists, is standardized, objective and highly reproducible. TissueCypher uses fluorescent biomarkers to interrogate Barrett’s tissue embedded in paraffin. When the software integrates information from nine biomarkers in the context of morphologic features and clinical data, it produces risk scores ranging from 0 to 10, which, for clinical use, are categorized as low, medium or high. In her study comparing the predictive accuracy of TissueCypher and expert and community pathologists (abstract 43), Dr. Frei’s group evaluated tissue samples from 155 patients who had participated in a previous trial comparing radiofrequency ablation and endoscopic surveillance in people with low-grade dysplasia (JAMA 2014;311[12]:1209-1217). For distinguishing the 22% of patients who progressed from the remainder who did not, the sensitivity of the automated system and the pathologists was about the same (68% vs. 67%, respectively), according to the researchers. TissueCypher outperformed on

specificity (78% vs. 65%), but a receiver operating curve analysis showed substantial variability among pathologists not seen with TissueCypher. As a result, “only the best-performing pathologists came close” to the consistency of the automated system, Dr. Frei said. TissueCypher detected a subgroup of patients who progressed yet had been downstaged to nondysplastic Barrett’s by the pathologists, according to Dr. Frei, who noted a substantial proportion of histologic specimens that pathologists label as indeterminate. TissueCypher has the advantage of using parameters other than dysplasia to draw a conclusion about progression risk. With histologic analysis, “dysplasia is the sole determinant of management recommendations in Barrett’s,” Dr. Iyer said. But this approach ignores the fact that many other clinical factors, including patient age, sex and smoking have been identified as risk factors, he said. In addition to the variability in the skills of pathologists for histologic assessments, Dr. Iyer said gastroenterologists also vary in their compliance with surveillance recommendations. Objective systems analysis like TissueCypher, and others in development, have the potential to standardize risk assessment that includes factors other than histology, he said. In his pooled analysis of relatively large multicenter studies with TissueCypher, Dr. Iyer and his colleagues found that 152 of the 475 patients with Barrett’s who were evaluated progressed, and 323 did not. Using conditional logistical regression, multivariable models were constructed to identify factors that predict the incidence of progression with and without the TissueCypher risk score. A separate analysis of predictors was performed on nondysplastic Barrett’s. see Barrett’s Risk, page 76

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Trial Data May Signal Paradigm Shift In GERD, Esophageal Illnesses

any esophageal diseases, including gastroesophageal reflux disease, appear

to be driven by a dysregulated esophageal microbiome, new research indicates. The findings, presented at the 2021 virtual Digestive Disease Week, could represent the sort of paradigm shift that occurred in the wake of revelations in the early 1980s that Helicobacter pylori was the primary cause of peptic ulcers—a discovery that was initially met with disbelief. “This is a whole new concept. Who would have thought that GERD was an infectious disease? It is reminiscent of the H. pylori story,” said David A. Johnson, MD, the chief of gastroenterology at Eastern Virginia School of Medicine, in Norfolk. The theory and evidence to link dysbiosis to common esophageal diseases were outlined in a recently published paper by Steve D’Souza, MD, and his colleagues (World J Gastroenterol 2021 May 14). Clinical evidence that esophageal disorders caused by dysbiosis might be treatable was presented a week later at DDW (abstract Su537). Dr. Johnson was the senior author of both reports. The journal article argued that the immune response to an inappropriate balance of microorganisms produces an inflammatory cascade that in turn leads to esophageal illness. The study at DDW provided preliminary evidence that the inflammatory response and the

Barrett’s Risk continued from page 75

In the model with TissueCypher, age and sex were not independent predictors of progression. Although expert diagnosis of low-grade dysplasia versus nondysplastic Barrett’s was associated with an almost threefold increased likelihood of progression (odds ratio [OR], 2.90; P=0.011), a high- versus low-risk score on TissueCypher was associated with a more than sevenfold increase in the likelihood of progression (OR, 7.09; P<0.001). In patients with nondysplastic Barrett’s, the relative performance of TissueCypher for predicting progression

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symptoms of GERD can be reduced when the dysbiosis is treated with a prebiotic. In the case of GERD, the dysbiosis is characterized by an overabundance of gram-negative bacteria. The clinical study presented at DDW was primarily to show the safety of a specific prebiotic in controlling this dysbiosis, providing the first step in evaluating the cause-and-effect relationship of the dysbiosis and the development of GERD. Data were presented on 44 of more than 100 patients with symptomatic GERD enrolled in the study. Treatment consisted of four weeks of a 1-g dose daily of maltosylisomalto-oligosaccharides, a nondigestible, nonabsorbable prebiotic (ISOT-101, ISOThrive). The treatment was associated with a reduction in the frequency and severity of GERD symptoms and improvement in quality of life on the ReQuest GERD questionnaire, according to the researchers (Figure). The treatment was well tolerated.

New Understanding of the Gut Microbiome Emerging A placebo-controlled trial is now needed to validate these findings, but the results are consistent with the hypothesis that dysbiosis underlies GERD

found an even higher likelihood (OR, 18.07; P<0.00001). “The data establish the clinical utility of Tissue-Cypher not only for those with low-grade dysplasia but also for those with nondysplastic Barrett’s, where oftentimes the risk prediction is much more challenging,” Dr. Iyer said. The implication of these data, Dr. Iyer added, is that TissueCypher has the potential to individualize a surveillance schedule—an urgent need given the low rates of progression among patients with low-grade dysplasia and even lower rates among those with nondysplastic Barrett’s. “The surveillance yield with the current approach is low, and this is making current practice inefficient,” Dr. Iyer said.

pathophysiology, Dr. Johnson said. More specifically, the investigators believe that controlling dysbiosis stops cytokine release and the inflammatory cycle. Previous studies, including work cited by Dr. D’Souza and his colleagues, linked esophageal diseases to alterations in the microbiome. However, the investigators now think that an altered microbiome is not a marker for these diseases, but a cause. The analogy between this hypothesis and the H. pylori story is apt. Similar to peptic ulcers, GERD responds to acid control, but reducing acid does not address the pathophysiology. Peptic ulcers are now cured with eradication of H. pylori. If the hypothesis that an imbalance of microorganisms in the esophageal microbiome is the cause of at least some esophageal diseases, resolving the dysbiosis might also lead to cure by preventing the inflammatory response driving the factors that lead to disease. In other words, the theory leads in a completely new therapeutic direction. In the paper, the authors discuss the possibility that the causes of dysbiosis, such as diet and smoking, might be alternative targets for restoring a healthy esophageal microbiome. Regardless of the best treatment strategy, they contend that the esophageal microbiome “plays a major role in the pathogenesis of esophageal diseases.” This direction of research and the study evaluating a prebiotic for the treatment of GERD is “interesting,” and builds on previous studies demonstrating bacterial dysbiosis in patients with GERD, said David A. Katzka, MD, a professor in the Department of Gastroenterology and Hepatology at Mayo Clinic in Rochester, Minn. “The response curves and tolerability appear impressive, though the significance was not calculated,” Dr. Katzka said. “Further study will be needed using a placebo-controlled group and correlating the effects of the prebiotic on the esophageal microbiome with outcome.” He added that the basic premise “is a fascinating hypothesis and avenue of GERD treatments to further explore.” “This is an intriguing and provocative hypothesis,” said Ronnie Fass, MD, the chairman of the Division of Gastroenterology and Hepatology at MetroHealth Medical Center, in Cleveland. However, Dr. Fass said, the idea that bacteria play a

role in the pathogenesis of GERD has been raised before. Although he did not dismiss the possibility that dysbiosis within the esophageal microbiome plays a role in GERD, he said considers the potential for it to emerge as the sole, or even major, explanation for the condition “unlikely.” “There are other well described pathophysiological features, such as anatomical changes, that would not support dysbiosis as the only cause of GERD,” he said. Dr. Fass said he is not ready to discount dysbiosis as a target of treatment in at least some patients, but this will have to be proven first. “The clinical study at DDW that reported favorable response to prebiotics has several limitations,” he said. “It was not randomized and the presence of GERD at baseline was not documented. While the study results are positive, it does not provide clear support for the authors’ hypothesis.” Julian Abrams, MD, an associate professor of medicine and epidemiology in the Division of Digestive and Liver Diseases at Columbia University Medical Center, in New York City, agreed that this field is “very interesting.” Although Dr. Abrams has studied and published in the area, he remains cautious about the data so far. “There is very limited data associating bacteria with GERD or other esophageal diseases, whether Barrett’s esophagus, esophageal cancer or eosinophilic esophagitis, and essentially no good data showing that bacteria can cause any of these conditions,” Dr. Abrams said. Currently, he is intrigued by the concept that GERD might be caused by disturbance in the lower gut rather than the esophageal microbiome. One possibility is that dysbiosis in the lower gut contributes to factors that have a role in GERD, such as obesity, but at this point “this is all speculation,” he said. Dr. Abrams emphasized that the pathogenic role of an altered microbiome in GERD is, for now, “just a theory. Personally, I would not refer to this as paradigmshifting” data at the current time, he added.

Nicholas J. Shaheen, MD, the chief of the Division of Gastroenterology and Hepatology at the University of North Carolina at Chapel Hill, said the studies are part of “a growing literature suggesting that Tissue-Cypher is effective” for risk stratification. TissueCypher “appears to perform somewhat better than a panel of expert pathologists,” said Dr. Shaheen in a state-of-the-art address on Barrett’s surveillance when he cited Dr. Frei’s data specifically. In particular, he was impressed with the evidence that TissueCypher appears to be accurate for downgrading a substantial proportion of patients with indeterminate risk to low risk.

Although Dr. Shaheen noted that this method and several others for improving risk assessment have yet to achieve widespread adoption in Barrett’s management, he agreed that there is a need for objective and reproducible methods for assessing risk for Barrett’s progression.

—Ted Bosworth Drs. Abrams and Johnson reported a ﬁnancial relationship with ISOThrive, the company that is developing ISOT-101. Dr. Fass is a member of the editorial board of Gastroenterology & Endoscopy News. Dr. Katzka reported ﬁnancial relationships with Mallinckrodt, Medtronic, Merck and Tetraphase.

—Ted Bosworth Dr. Frei reported no relevant financial disclosures. Dr. Iyer reported financial relationships with Exact Sciences, Medtronic and Pentax Medical. Dr. Shaheen reported financial relationships with CDx Medical, Cernostics, Cook Medical, Interpace Biosciences, Medtronic, Pentax and Steris.

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‘Undiagnosing’ Barrett’s Is a Frequent Task For Esophageal Experts

vidence-based guidelines discourage biopsies for Barrett’s esophagus unless patients meet specific criteria on endoscopic evaluation. Despite this guidance, many people who don’t qualify are being biopsied and diagnosed

with the condition anyway, only to find out later they don’t have it.

Whether this practice is driven by a zeal to provide the best patient care or reflects excessive caution and fear of liability, it has given rise to a new kind of diagnosis—in reverse. “One of the most common diagnoses in my clinic is un-Barrett’s esophagus,” said Nicholas Shaheen, MD, MPH, the Bozymski-Heizer Distinguished Professor of Medicine at the University of North Carolina at Chapel Hill School of Medicine.

What Barrett’s Is Not A diagnosis of Barrett’s requires evidence on endoscopy with biopsy confirmation of intestinal metaplasia extending at least 1 cm into the esophagus proximal

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to the gastroesophageal junction, or Z line. Although effective treatments exist for Barrett’s, the condition is not known to spontaneously heal itself. So, where are all these un-Barrett’s patients coming from? “In any suspected Barrett’s segment less than 1 cm, studies show considerable interobserver variability in delineating the segment; this is much less of an issue for segment lengths greater than 1 cm,” said Gary W. Falk, MD, MS, a professor of medicine at the University of Pennsylvania Perelman School of Medicine, in Philadelphia. “These biopsies may be coming from the cardia. People might be misinterpreting part of a hiatal hernia as Barrett’s.” Intestinal metaplasia from the cardia is fairly

common, seen in about 20% of people undergoing routine endoscopy. Compared with Barrett’s, its risk for progression to cancer is much lower. When it is misdiagnosed as Barrett’s, it can trigger a cascade of potentially harmful events that are hard to undo. “The patient learns of their diagnosis, often goes to Dr. Google and makes a series of associations: Barrett’s esophagus, cancer risk, esophageal cancer—I’m going to get esophageal cancer,” Dr. Falk said. The consequences are not limited to patient anxiety. Flagged as having a precancerous condition, they may have trouble obtaining life insurance. Their health insurance premiums may increase. Furthermore, they may set themselves up for a series of endoscopic evaluations they don’t need, and face all the pitfalls associated with oversurveillance. “The foremost drawback of that is cost—each endoscopy with biopsy is $800 or $900 and lost time from work,” according to Joel Rubenstein, MD, MSc, a research scientist at the Veterans Affairs Center for Clinical Management Research and a professor of internal medicine at the University of Michigan, in Ann Arbor. “That’s a lot of money, considering the risk of cancer is exceedingly small.” Patients also face potential harm from the procedure and the sedation it requires. “Those risks are very small, but they’re not zero,” Dr. Rubenstein said. All these variables lead to the recommendation in the guidelines against biopsy of a normal-appearing Z line or a Z line with less than 1 cm of irregularity. “If there are mucosal abnormalities, no matter how subtle, or nodularity, that’s an entirely different story. Those need to be biopsied or removed endoscopically. But if the mucosal appearance of the Z line is totally normal, there’s really no reason to obtain tissue,” Dr. Falk said. “Guideline adaptation has always been problematic, but this issue has been going on for many years and shows no signs of abating. It’s unfortunately too common in the United States today.”

Undiagnosing Barrett’s When dealing with an undiagnosing situation, Dr. Falk puts patients through a process he calls “delabeling.” Delabeling involves one repeat endoscopy with careful documentation of the landmarks: the diaphragm, top of the gastric folds and squamocolumnar junction. “If the squamocolumnar junction and the top of the gastric folds are at the same location, they don’t have Barrett’s. I no longer perform biopsies on these patients,” Dr. Falk said. “I photo-document the landmarks, give the endoscopic report to the patient, and say, ‘There’s no endoscopic evidence of Barrett’s, and surveillance is no longer warranted.’”

Patient reactions to an undiagnosis often are mixed. “Sometimes relieved, sometimes frightened, almost always confused; sometimes they are very ready to believe it,” Dr. Shaheen said. “Fortunately, because we’re a Barrett’s center and people are referred specifically for that condition, the ground is set for them to believe us, but it’s not unusual for them to question that, to ask about one more look, just to be sure.” Gastroenterologists who do not have the reputation of a major Barrett’s center or an academic institution behind them may have a harder time convincing patients that routine surveillance is unnecessary, Dr. Shaheen said. “That puts them in a potentially difficult situation,” he said. “If someone switches caregivers and you’re the second gastroenterologist in, that may be the reason for some of the referrals we see.”

Putting an End To Un-Barrett’s The first step toward reducing un-Barrett’s diagnoses is to prevent Barrett’s overdiagnoses. “If you are slow to give the diagnosis in the first place, that will avert a lot of this,” Dr. Shaheen said. When the Z line appears regular, leave it alone. On the fence about an irregularity that may or may not be Barrett’s? “Call it ’not,’” Dr. Shaheen said, “because— worst-case scenario—if it actually is ultra–shortsegment Barrett’s, you’re still only exposing them to nominally increased risk of esophageal cancer over the general population.” In addition, it’s important that patients are educated on the risks of both cancer and surveillance, Dr. Rubenstein said. “The risk for a patient with intestinal metaplasia of the gastric cardia getting cancer in the next decade is less than 1%. The risk for complication from each procedure is also less than 1%, but that adds up with each procedure until it exceeds the risk of cancer.” For healthy patients who are still worried about the Barrett’s they probably do not have, Dr. Rubenstein will offer to perform one final endoscopy, but recommend stopping surveillance if all he finds is gastric cardia intestinal metaplasia. “I would say 95% of the time, patients are agreeable with that,” he said. —Monica J. Smith

Selected Reading Shaheen NJ, et al. ACG clinical guidelines: diagnosis and management of Barrett’s esophagus. Am J Gastroenterol. 2016;111(1):30-50. Wani S, et al. An analysis of the GIQuIC Nationwide Quality Registry reveals unnecessary surveillance endoscopies in patients with normal and irregular Z lines. Am J Gastroenterol. 2020;111(11):1869-1878.

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Dr. Sharma’s Endoscopy Insights: GERD

or this column, I’ve chosen three recent excellent

publications that address clinically important issues regarding gastroesophageal reflux disease.

PRATEEK SHARMA, MD Professor of medicine at the University of Kansas School of Medicine, in Kansas City

In the first study, patients with typical GERD symptoms not responsive to treatment with proton pump inhibitors underwent 96 hours of pH monitoring. They had no endoscopic evidence of esophagitis. Acid exposure time on reflux monitoring predicted the ability to discontinue PPIs without affecting symptoms. The findings suggest that monitoring reflux after a few weeks of acid suppression can limit prolonged use of PPI therapy in patients who may not be responding to the drugs. The second paper is a systematic review and meta-analysis that evaluated the prevalence of Barrett’s esophagus and esophageal cancer in patients with GERD, which is a major risk factor for these two complications. Global estimates, such as those provided by this study, can help

individual countries devise their own individual screening programs and understand whether screening for Barrett’s esophagus and esophageal cancer is cost-effective in their GERD population. Finally, patients with achalasia are increasingly being treated with peroral endoscopic myotomy (POEM), but one of the major adverse events of this approach is postprocedural GERD, which has been reported in up to 50% of patients. The third study I chose highlights the success of performing endoscopic fundoplication at the same time as POEM, as a preventive measure for GERD. Having a strategy to counter post-POEM GERD is critical, whether that means medical therapy, endoscopic fundoplication or even partial laparoscopic fundoplication.

Ambulatory reflux monitoring guides proton pump inhibitor discontinuation in patients with gastroesophageal reflux symptoms: a clinical trial (Yadlapati R, et al. Gastroenterology 2021;160[1]:174-182.e1) Researchers enrolled 100 participants with symptomatic GERD despite use of a PPI to undergo 96-hour wireless reflux monitoring. Patients were a mean age of 48.6 years, and 59 were women. Participants completed the Reflux Symptom Questionnaire electronic Diary (RESQ-eD) and the gastroesophageal reflux disease questionnaire (GerdQ) throughout the study. Following a one-week period of discontinued PPI use, patients underwent reflux monitoring and continued for an additional two weeks without PPIs. Both physicians and patients were blinded to the results of monitoring when they subsequently decided whether to resume or discontinue PPI treatment. Findings showed that 34% of patients discontinued PPIs after the three-week cessation period. Objective findings of GERD—or its absence—during reflux monitoring predicted successful discontinuation or resumption of PPIs in 71% of cases.

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Patients who resumed PPI therapy had higher baseline RESQ-eD scores than those who discontinued PPIs (17.8 vs. 12; P=0.02) and had higher baseline GerdQ scores (9.3 vs. 7.2; P=0.01). Each additional day with an acid exposure time (AET) over 4% was associated with a nearly twofold increase in the odds of resuming PPI treatment (odds ratio [OR], 1.82; 95% CI, 1.34-2.56; P<0.001). In contrast, patients with no days of AET over 4% were 10 times more likely to successfully discontinue PPIs than those with four days of AET above that level (OR, 10; 95% CI, 2.19-13.44; P<0.01).

Global prevalence of Barrett’s oesophagus and oesophageal cancer in individuals with gastro-oesophageal reflux: a systematic review and meta-analysis (Eusebi LH, et al. Gut 2021;70[3]:456-463) This meta-analysis of 44 studies found a pooled histologically confirmed prevalence of 7% for Barrett’s esophagus in GERD patients (95% CI, 5.4%-9.3%), and a pooled endo-scopically suspected prevalence of 12% (95% CI, 5.5%-20.3%).

Single-session endoscopic fundoplication after peroral endoscopic myotomy (POEM+F) for prevention of post gastroesophageal reflux 1-year follow-up study (Bapaye A, et al. Endoscopy Published online Dec 8, 2020. doi:10.1055/a-1332-5911) Researchers examined 25 patients with achalasia who had undergone single-stage POEM and endoscopic fundoplication. The combined procedure was technically successful in 92% of patients and averaged two hours. Twelve percent of patients had minor delayed adverse events that did not require intervention.

Less than 40% of cases of endoscopically suspected Barrett’s esophagus were confirmed histologically. Of those that were confirmed histologically, 14% involved low-grade dysplasia. Men were twice as likely as women to have Barrett’s esophagus and short-segment disease was significantly more common than longsegment disease. The prevalence of Barrett’s esophagus varied by geography, with rates of histologically confirmed disease ranging from 3% in the Middle East to 14% in North America. Endoscopically suspected Barrett’s esophagus was most prevalent in South America (38%) and least common in Asia (2%).

Follow-up assessments up to one year showed that 11% of patients had GERD at follow-up, including one patient with significant reflux symptoms. In addition, 18% of patients had asymptomatic grade A esophagitis with normal esophageal acid exposure time. All patients had significant improvements in dysphagia, as measured by the Eckardt score (8.21 vs. 0.1 before and after, respectively; P=0.001), and 83% of patients had an intact wrap at one year of follow-up.

—Compiled and written by David Wild

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Esophageal Resection Reasonable Alternative To Esophagectomy For T1b Cancer

or surgical treatment of T1b esophageal adenocarcinoma, endoscopic resection is associated

with similar rates of survival at five years as surgical esophagectomy, according to data from a large national database.

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The retrospective analysis might not establish endoscopic resection as first-line in T1b cancers, but it does appear to support resection as an effective alternative for patients who are not candidates for major surgery or who refuse esophagectomy, according to Daryl Ramai, MD, a resident at the Brooklyn Hospital Center, in New York City. Dr. Ramai led a multicenter collaborative effort he started with Douglas G. Adler, MD, a professor of medicine at the University of Utah School of Medicine, in Salt Lake City. The optimal treatment of T1b cancers remains incompletely defined, particularly in regard to higher risk subsets such as patients with lymph node involvement or poor differentiation. In a 2019 update, the American Gastroenterological Association (AGA) identified both endoscopic mucosal resection (EMR) and submucosal dissection as acceptable alternatives to esophagectomy in selected patients, but added qualifiers (Clin Gastroenterol Hepatol 2019;17[11]:2161-2166).

Unruly Lesions When compared with T1a lesions, T1b lesions are less likely to remain localized, making more aggressive therapy attractive. For this reason, esophagectomy in T1b lesions “remains the mainstay of treatment,” not least because “the prevalence of lymph node metastases is not negligible,” according to the AGA recommendations. Esophagectomy also has relative advantages for upstaging and downstaging lesions. A 2020 AGA Clinical Practice Update on treatment of dysplasia or early cancer called endoscopic therapy “a reasonable alternative to esophagectomy” for T1b adenocarcinoma with low-risk features defined as less than 500 mcm of submucosal invasion, good to moderate differentiation and no lymphatic invasion (Gastroenterology 2020;158[3]:760-769). Neither of the two sets of guidelines was based on a randomized study. This gap prompted the authors of the new research, presented at the 2020 virtual meeting of the American College of Gastroenterology (abstract 4), to conduct a large retrospective cohort analysis. Of the 603 patients with T1b esophageal carcinoma identified over a 16-year period, 451 were evaluable. Of these patients, 84 (18.6%) underwent EMR and the remaining underwent esophagectomy. Fewer than 30% had lymph node metastases. Most tumors were moderately (45%) or poorly differentiated (33%). For EMR relative to esophagectomy, no or moderate differences in survival were observed at one year (both

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groups, 91%), three years (78% vs. 84%) and five years (74% vs. 73%). The presence of lymph node metastases more than doubled the risk for mortality regardless of treatment (hazard ratio [HR], 2.16; P=0.006), but the researchers did not find a difference between the surgical approaches for long-term survival among patients with or without such spread. Few randomized trials have compared treatment approaches specific to T1b esophageal cancers with different risk profiles. According to the AGA guidelines, treatment choices should be based on other factors, such as depth of tumor and lymphovascular invasion, rather than tumor grade alone. One study cited in the guidelines found that chemotherapy after endoscopic treatment for T1b esophageal cancer produced three- and five-year survival rates comparable to esophagectomy, but metastatic recurrence was observed in 20% of the patients with lymph node metastases versus none of those without metastases (Clin Transl Gastroenterol 2017;8:e110). Other such data encourage treatment individualization based on risk factors. The relatively large patient sample in the study does not preclude advantages of esophagectomy in selected subgroups of patients with T1b grade esophageal cancers, but no advantage was seen in an unselected population, Dr. Ramai said. Based on the “similar cancer-specific outcomes” for those treated with EMR rather than esophagectomy, the data provide support for this approach when esophagectomy is not feasible or refused, he said. One potential limitation of relying on retrospective data to compare outcomes is that an “accurate diagnosis of T1b cancers requires an endoscopic resection,” Prateek Sharma, MD, a professor of medicine at the University of Kanas, in Kansas City, said. As a result, it is “sometimes not possible to differentiate between diagnostic versus therapeutic resections.” Despite this consideration, “this study does confirm the role of endoscopic therapy as an alternative to esophagectomy for patients with T1b cancers,” Dr. Sharma added. “With more data, endoscopic therapy may be the major treatment for these cancers.” —Ted Bosworth Dr. Ramai reported no relevant financial disclosures. Dr. Sharma reported financial relationships with several manufacturers of devices related to endoscopic treatment of cancer, such as Boston Scientific, Medtronic and Olympus. He is a member of the editorial board of Gastroenterology & Endoscopy News.

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For additional information, please call 1-800-874-6756 ^ÓäÓ£ À> ÌÀii >L À>Ì À iÃ] V° Ƃ À } ÌÃ ÀiÃiÀÛi`° Óä£ Ón ÛÓ Õ i ÓäÓ£

THE TABLET CHOICE FOR BOWEL PREPARATION

• NO SODIUM PHOSPHATE1 • SAFE AND EFFECTIVE1,2 • ACG-RECOMMENDED SPLIT-DOSE REGIMEN3 – Two SUTAB doses are required for a complete preparation1 Dose 1 consists of 12 tablets and 16 oz of water Dose 2 consists of 12 tablets and 16 oz of water Each dose is followed by two additional 16 oz of water

92% OF PATIENTS IN TWO PIVOTAL TRIALS ACHIEVED SUCCESSFUL BOWEL CLEANSING WITH SUTAB1,2* 91% OF PATIENTS IN ONE PIVOTAL TRIAL RATED SUTAB AS TOLERABLE TO VERY EASY TO CONSUME2† • 52% of all SUTAB and MoviPrep® patients reported at least one selected gastrointestinal adverse reaction1,2‡ r /QTG 576#$ RCVKGPVU TGRQTVGF GZRGTKGPEKPI PCWUGC CPF XQOKVKPI VJCP EQORGVKVQT YKVJ Ű QH VJGUG TGRQTVU considered severe2‡

78% OF PATIENTS IN ONE PIVOTAL TRIAL WOULD REQUEST SUTAB AGAIN FOR A FUTURE COLONOSCOPY2† I -ÕVViÃÃ Ü>Ã Ì i «À >ÀÞ i `« Ì > ` Ü>Ã ìw i` >Ã > ÛiÀ> V i> Ã } >ÃÃiÃÃ i Ì v Î } `® À { iÝVi i Ì® LÞ Ì i L ì` i ` ÃV « ÃÌÆ ÃV ÀiÃ ÜiÀi >ÃÃ } i` v Ü } V « iÌ v V ÃV «Þ° † *>Ì i ÌÃ V « iÌi` > «ÀiviÀi Vi µÕiÃÌ > Ài v Ü } V « iÌ v ÃÌÕ`Þ `ÀÕ} Ì V>«ÌÕÀi Ì i À «iÀVi«Ì Ã v Ì i «Ài«>À>Ì iÝ«iÀ i Vi° / Ã µÕiÃÌ > Ài >Ã Ì Õ ìÀ} i v À > Û> `>Ì ° ‡ *>Ì i ÌÃ ÜiÀi µÕiÀ i` v À Ãi iVÌi` }>ÃÌÀ ÌiÃÌ > >`ÛiÀÃi Ài>VÌ Ã v Õ««iÀ >L` > «> ] >L` > ` ÃÌi Ã ] >ÕÃi>] > ` Û Ì } v Ü } V « iÌ v ÃÌÕ`Þ `ÀÕ}] À>Ì } Ì i Ìi Ã ÌÞ >Ã `] ìÀ>Ìi] À ÃiÛiÀi°£]Ó Ƃ rƂ iÀ V> i}i v >ÃÌÀ i ÌiÀ }Þ Packaging and tablets Û *Ài«® Ã > Ài} ÃÌiÀi` ÌÀ>ì >À v 6i À Ƃ ° not shown actual size.

IMPORTANT SAFETY INFORMATION -1/Ƃ ® Ã ` Õ ÃÕ v>Ìi] >} iÃ Õ ÃÕ v>Ìi] « Ì>ÃÃ Õ V À ì® Ì>L iÌÃ v À À> ÕÃi Ã > Ã Ì V >Ý>Ì Ûi ` V>Ìi` v À V i> Ã } v Ì i V «Ài«>À>Ì v À V ÃV «Þ >`Õ ÌÃ° DOSAGE AND ADMINISTRATION: Ƃ Ü ÀiÃ `Õi LÀi> v>ÃÌ >Þ Li V ÃÕ i`° ƂvÌiÀ LÀi> v>ÃÌ] Þ V i>À µÕ `Ã >Þ Li V ÃÕ i` Õ Ì >vÌiÀ Ì i V ÃV «Þ° Ƃ` ÃÌÀ>Ì v ÌÜ ` ÃiÃ v -1/Ƃ Ó{ Ì>L iÌÃ® >Ài ÀiµÕ Ài` v À > V « iÌi «Ài«>À>Ì v À V ÃV «Þ° /Üi Ûi £Ó® Ì>L iÌÃ >Ài iµÕ Û> i Ì Ì i ` Ãi° 7>ÌiÀ ÕÃÌ Li V ÃÕ i` Ü Ì i>V ` Ãi v -1/Ƃ > ` >`` Ì > Ü>ÌiÀ ÕÃÌ Li V ÃÕ i` >vÌiÀ i>V ` Ãi° « iÌi > -1/Ƃ Ì>L iÌÃ > ` ÀiµÕ Ài` Ü>ÌiÀ >Ì i>ÃÌ Ó ÕÀÃ Liv Ài V ÃV «Þ° CONTRAINDICATIONS: 1Ãi Ã V ÌÀ> ` V>Ìi` Ì i v Ü } V ` Ì Ã\ }>ÃÌÀ ÌiÃÌ > LÃÌÀÕVÌ À iÕÃ] L Üi «iÀv À>Ì ] Ì Ý V V Ì Ã À Ì Ý V i}>V ] }>ÃÌÀ V ÀiÌi Ì ° WARNINGS AND PRECAUTIONS: , Ã v yÕ ` > ` i iVÌÀ ÞÌi >L À > Ì iÃ\ V ÕÀ>}i >ìµÕ>Ìi Þ`À>Ì ] >ÃÃiÃÃ V VÕÀÀi Ì i` V>Ì Ã > ` V Ã ìÀ >L À>Ì ÀÞ >ÃÃiÃÃ i ÌÃ «À À Ì > ` >vÌiÀ i>V ÕÃiÆ Cardiac arrhythmias\

Ã ìÀ «Ài ` Ãi > ` « ÃÌ V ÃV «Þ Ã «>Ì i ÌÃ >Ì VÀi>Ãi` À Ã Æ Seizures\ 1Ãi V>ÕÌ «>Ì i ÌÃ Ü Ì > ÃÌ ÀÞ v Ãi âÕÀiÃ > ` «>Ì i ÌÃ >Ì VÀi>Ãi` À Ã v Ãi âÕÀiÃ] V Õ` } i` V>Ì Ã Ì >Ì ÜiÀ Ì i Ãi âÕÀi Ì ÀiÃ `Æ *>Ì i ÌÃ Ü Ì Ài > «> À i Ì À Ì> } V V Ì> Ì i` V>Ì Ã Ì >Ì >vviVÌ Ài > vÕ VÌ \ 1Ãi V>ÕÌ ] i ÃÕÀi >ìµÕ>Ìi Þ`À>Ì > ` V Ã ìÀ >L À>Ì ÀÞ ÌiÃÌ }Æ Suspected GI LÃÌÀÕVÌ À «iÀv À>Ì \ ,Õ i ÕÌ Ì i ` >} Ã Ã Liv Ài >` ÃÌÀ>Ì ° ADVERSE REACTIONS: ÃÌ V }>ÃÌÀ ÌiÃÌ > >`ÛiÀÃi Ài>VÌ Ã >Ài\ >ÕÃi>] >L` > ` ÃÌi Ã ] Û Ì } > ` Õ««iÀ >L` > «> ° DRUG INTERACTIONS: ÀÕ}Ã Ì >Ì VÀi>Ãi À Ã v yÕ ` > ` i iVÌÀ ÞÌi L> > Vi° Please see Brief Summary of Prescribing Information on reverse side. See Full Prescribing Information and Medication Guide at SUTAB.com.

From the makers of SUPREP® Bowel Prep Kit (sodium sulfate, potassium sulfate and magnesium sulfate) Oral Solution for adults—

THE #1 MOST PRESCRIBED, BRANDED BOWEL PREP KIT4

PRINTER-FRIENDLY VERSION AVAILABLE AT GASTROENDONEWS.COM

Bowel Preparation Quality: How to Get Perfect Bowel Preparation for Every Patient

EKTA GUPTA, MD Division of Gastroenterology and Hepatology Johns Hopkins University School of Medicine Baltimore, Maryland

n ideal bowel preparation should have many attributes, including the ability to reliably empty the colon in a rapid fashion, without causing any gross or histologic alteration of colonic mucosa, shifts in fluids and electrolytes, or

patient discomfort, and it should be relatively inexpensive.

This article discusses quality measures for bowel preparation, as well as various tools to measure the quality of bowel preparation and ways to improve it. This review is meant to provide gastroenterologists and endoscopists with strategies and best practices to get their patients to optimize bowel preparation.

Why Measure the Quality Of Bowel Preparation? Having reliable measures of the quality of bowel preparation is important, as that quality affects our ability to detect polyps during colonoscopy as well as the

cost of colonoscopy. Poor or incomplete visualization of the colon reduces the yield of screening colonoscopies and increases health care costs, due to longer procedure times and aborted procedures. Chokshi et al studied the prevalence of missed adenomas in patients with inadequate bowel preparation for screening colonoscopy and noted that among 133 patients with initially suboptimal bowel preparation, 33.8% had at least 1 adenoma detected on repeat colonoscopy and 18% had high-risk lesions detected.1 Tholey et al showed that excellent bowel preparation resulted in superior detection of sessile serrated polyps and advanced

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 02 1

adenomas compared with good preparation.2 Rex et al investigated the impact of bowel preparation on the efficiency and cost of colonoscopy; their cost analysis showed that imperfect bowel preparation results in a 12% increase in costs at university hospitals and a 22% increase in costs at public hospitals.3 They found that aborted examinations and earlier repeat surveillance examinations related to suboptimal bowel preparations increased the costs associated with colonoscopy.

Ways to Measure the Quality Of Bowel Preparation There are many ways to characterize bowel preparation. The quality can be labeled as excellent, good, fair, or poor; however, the lack of standardized definitions for these labels can cause significant interobserver variability. Bowel preparation quality also can be characterized as adequate versus inadequate based on its ability to allow for detection of polyps greater than 5 mm. Various scoring systems, such as the Boston Bowel Preparation Scale (BBPS) and Ottawa Bowel Preparation Scale (OBPS), have been well validated and have high interobserver and intra-observer reliability. The BBPS divides the colon into 3 broad regions: right side (cecum and ascending colon), transverse section (transverse colon including the hepatic and splenic flexures), and left side (descending colon, sigmoid colon, and rectum); each region of colon receives a segment score from 0 to 3 based on visual inspection of colon during colonoscopy. These segments are summed for a total BBPS score ranging from 0 (for an unprepared colon) to 9 (for a perfectly clean colon).

The BBPS is applied during the withdrawal phase of colonoscopy. If a procedure is aborted due to inadequate preparation, then any nonvisualized proximal segments are assigned a score of 0. The BBPS has been well validated and shown to have high inter- and intraobserver reliability. Also, higher BBPS scores (>5 vs <5) have been associated with higher polyp detection rates (40% vs 24%; P<0.02).4 The OBPS rating for each colon segment is different from the BBPS, such that a higher score is given to each segment for poor preparation and a score also is given for the amount of fluid in the whole colon. The scores of the right, transverse/descending, and sigmoid/rectum and the score for the fluid in the whole colon are added to generate an OBPS score ranging from 14 (very poor) to 0 (excellent).5 In the BBPS, analysis is done during withdrawal, after all the cleaning maneuvers, allowing better assessment of bowel preparation and reflecting an ability to detect polyps; in the OBPS, analysis is done before cleaning attempts by the endoscopist, comparing quality of cleanliness and reflecting efficacy of bowel preparation regimens (Table 1). The American Society for Gastrointestinal Endoscopy (ASGE)/American College of Gastroenterology (ACG) Task Force on Quality in Endoscopy published the quality indicators for colonoscopy.6 It sets performance targets of greater than 98% for documenting the quality of preparation in the procedure note and greater than 85% for adequate bowel preparations for outpatient colonoscopy examinations. An adequate bowel preparation allows detection of polyps greater

Table 1. Comparison of the Boston Bowel Preparation Scale And Ottawa Bowel Preparation Scale

Segments That Contribute to Scoring

Scale Range

Excellent Prep Score

Poor Prep Score

Timing of Scoring

Boston Bowel Preparation Scale

Scores from 0-3 (0 for unprepared colon to 3 for perfectly clean colon) for 3 segments (right side [cecum/ ascending colon], transverse colon, and left side [descending colon/sigmoid colon/rectum])

0-9

After washing and suctioning

Ottawa Bowel Preparation Scale

Scores from 0-4 (0-clean colon, 4-unprepared colon) for 3 segments (right side, transverse/ descending, and sigmoid/rectum) and 0-2 for the fluid in the whole colon

0-14

Before washing and suctioning

Scale

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than 5 mm in size; if bowel preparation is not adequate, then the procedure should be repeated within 1 year. If inadequate bowel preparation is noted in more than 15% of colonoscopy examinations at a facility, then it is imperative that the facilty reexamines its bowel preparation protocols, patient education, choice of purgative, and protocols for administering the purgative, with the goal of achieving the performance target.

Improve the Quality of Bowel Preparation To get perfect bowel preparation in each patient, it is important to identify factors associated with poor bowel preparation and target resources to patients who are at increased risk. Ness et al identified the predictors for inadequate bowel preparation for colonoscopy; these included procedure time, preparation instructions not followed, a history of cirrhosis, inpatient status, constipation as the indication for the procedure, tricyclic antidepressant use, male sex, and a history of stroke or dementia.7 Lebwohl et al studied socioeconomic and other predictors of colonoscopy preparation quality and identified Medicaid insurance and time of colonoscopy after 11 AM as factors associated with poor bowel preparation quality.8 Kunnackal et al identified factors affecting the quality of bowel preparation and found that poor health literacy, low functional status, and a high number of daily medications are significant factors predicting inadequate bowel preparation in the tertiary care setting.9 Future quality improvement efforts should target populations with these characteristics to successfully improve rates of adequate bowel preparation.

Another method shown to result in more satisfactory bowel preparation is the use of split-dose preparation. In a randomized controlled trial, Aoun et al compared the efficacy of 2 bowel preparation regimens: a whole dose (4 L) of polyethylene glycol electrolyte solution (PEG) with diet restriction on the night before the procedure versus a split dose (2 L of PEG on the evening before and 2 L on the morning of the procedure) with no diet restriction. Colonic preparation with splitdose PEG provides better colon cleansing than wholedose preparation (P=0.011), with no significant impact on patient tolerability or side effects.10 Enestvedt et al conducted a meta-analysis of split-dose PEG versus other bowel preparations and found that the pooled odds ratio (OR) for excellent or good bowel preparation quality for split-dose PEG was 3.46 compared with other methods (95% CI, 2.45-4.89; P<0.01); they concluded that split-dose PEG is better than other bowel preparation methods for colonoscopy and suggested that split-dose PEG should be considered the standard for bowel preparation methods.11 Siddiqui et al showed that bowel preparation quality varies inversely with the duration of the interval between the last dose of the bowel preparation agent and the start of colonoscopy, and the quality of bowel preparation decreased as the interval increased between the end of the preparation ingestion and start of the procedure, such that the optimal window was typically 8 hours or less.12 To improve the quality of bowel preparation, ideally one should aim for split dosing, such that half of the preparation is given on the day of the examination started 4 to 5 hours before the

Dark and murky

Brown and murky

Dark orange and semi-clear

Light orange and mostly clear

Yellow and clear (like urine)

NOT OK

Almost there!

YOU’RE READY!

Figure. The Colonoscopy Visual Preparation Card.

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Table 2. Characteristics of Commonly Used FDA-Approved Bowel Preparationsa Class

Product

Consideration

Limitation(s)

4-L PEG-ELS

GoLYTELY (Braintree), Colyte (Schwarz)

Preferred in patients with advanced liver disease, congestive heart failure, IBD

4-L sulfate-free PEG

NuLYTELY (Braintree), TriLyte (Schwarz)

Large volume and unpalatable taste lead to poor patient compliance; contraindicated in patients with allergies to PEG compounds, gastric outlet obstruction, bowel obstructionb,c

2-L PEG-ELS and bisacodyl delayed-release tablets

HalfLytely (Braintree)

2-L PEG with ascorbate

MoviPrep (Salix)

1-L PEG with ascorbate

Plenvu (Salix)

PEG

Others Sodium phosphate tablet

OsmoPrep (Salix)

More tolerable than PEG; effective in otherwise healthy patients with chronic constipation

Can cause renal failure due to hyperphosphatemia, especially in patients with chronic kidney disease and those taking NSAIDs or ACEIs; avoid in patients with suspicion of IBD or chronic diarrhea (aphthous ulcers)b,c

Sodium picosulfate, magnesium citrate, and anhydrous citric acid

Prepopik (Ferring)

Preferred in patients with bariatric surgery (low volume)

Can cause dehydrating effect and orthostatic hypotension; avoid in older patients b,c

Sodium sulfate

Suprep (Braintree)

Alternative to sodium phosphate

Avoid in patients with gout (can increase serum uric acid)b,c

Sodium sulfate, magnesium sulfate, and potassium chloride tablets

Sutab (Sebela)

Tablets; hence, avoid large volume of liquid preparation solutions; good alternative for patients with unpleasanttaste issues

Contains the active sulfate ingredients similar to Suprepb,c

a Additional bowel preparation regimens, such as PEG 3350 (MiraLax, Bayer) plus Gatorade, are used commonly but are not approved by the FDA. b

Osmotic agents may produce colonic mucosal aphthous ulcerations; use caution in patients with known or suspected IBD.

Risk for serious fluid and electrolyte abnormalities, especially if patients become dehydrated; correct fluid and electrolyte abnormalities before treatment; use with caution in patients who have conditions or are using medications that increase the risk for fluid and electrolyte disturbances or may increase the risk for adverse events including renal impairment.

ACEIs, angiotensin-converting enzyme inhibitors; ELS, electrolyte lavage solution; IBD, inflammatory bowel disease; NSAIDs, nonsteroidal anti-inflammatory drugs; PEG, polyethylene glycol

procedure and completed at least 2 hours before the procedure (to reduce aspiration risk). For patients who are scheduled for afternoon colonoscopies, the entire preparation can be ingested on the day of the exam. Another way to improve the quality of bowel preparation is by using a tool such as the “Colonoscopy Visual Preparation Card,” which is based on patients’ reported stool color from their last bowel movement, to evaluate the adequacy of their bowel preparation (Figure). This empowers patients to take necessary

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steps to improve the quality of their bowel preparation. The visual nature of this tool, along with definite written directions, may help allay anxiety and provide confidence to patients about the adequacy of their bowel preparation. This can translate into improvement in the quality of their bowel preparation scores. This tool has been validated in both direct access and outpatient colonoscopy settings.13 The color of the patient’s most recent stool before they arrive for the procedure was significantly associated with adequate

bowel preparation (P<0.001); compared with yellow and clear stools, the following stool colors were associated with higher odds of inadequate bowel preparation: light orange and mostly clear (OR, 4.1; P<0.01), dark orange and semi-clear (OR, 14.5; P<0.001), and brown and murky (OR, 18.1; P<0.001).14

Selecting a Bowel Preparation The common bowel preparations fall under 3 broad categories: 1) PEG solutions, which are high-volume gut lavage solutions; 2) osmotic agents, such as sodium phosphate, magnesium citrate, and the newly approved sodium sulfate, magnesium sulfate, and potassium chloride tablets (Sutab Sebela), which draw extracellular fluid across the bowel wall and into the lumen; and 3) stimulants, such as castor oil, senna, sodium picosulfate, and bisacodyl, which increase smooth muscle activity within the wall of the colon. The common commercially available bowel preparations are listed in Table 2. The PEG solutions are nonabsorbable, do not cause substantial shifts in fluids and electrolytes, and are relatively safer to use in patients with advanced liver disease, congestive heart failure, and renal failure. The major disadvantages of these PEG solutions are that ingestion of a large amount of solution that can have a poor salty taste is required, leading to poor patient compliance, and these products are contraindicated in patients with allergies to PEG compounds, gastric outlet obstruction, and bowel obstruction. In contrast, the sodium phosphate tablets are more tolerable to patients and do not require ingestion of

large volumes, but they can cause renal failure due to hyperphosphatemia (acute phosphate nephropathy), especially in patients who have chronic kidney disease, bowel obstruction, active colitis, or hypovolemia, and/or who take other medications including diuretics, angiotensin-converting enzyme inhibitors, or nonsteroidal anti-inflammatory agents. Sodium phosphate tablets should be avoided in patients with impaired renal function, advanced liver disease, congestive heart failure, and hypercalcemia. They also should be avoided in patients with suspicion of inflammatory bowel disease or chronic diarrhea because they may cause aphthous ulcers in these patients. The sodium picosulfate–based bowel preparations can be considered in patients with a history of bariatric surgery, given the low volume required, but these preparations can be dehydrating and can increase hemoglobin levels; they also should be avoided in older patients due to risks for hyponatremia and orthostatic hypotension.

Conclusion It is important to focus on the quality of bowel preparation to get a perfect bowel preparation in every patient because it significantly affects the ability to detect polyps and the costs associated with colonoscopy. Bowel preparation quality should be recorded for every colonoscopy, preferably using a validated scale. The choice of bowel preparation agent needs to be individualized to each patient and should be based on a patient’s age, comorbid conditions, and personal preference.

References 1.

Chokshi RV, Hovis CE, Hollander T, et al. Prevalence of missed adenomas in patients within adequate bowel preparation on screening colonoscopy. Gastrointest Endosc. 2012;75(6):1197-1203.

Tholey DM, Shelton CE, Francis G, et al. Adenoma detection in excellent versus good bowel preparation for colonoscopy. J Clin Gastroenterol. 2015;49(4):313-319.

Rex DK, Imperial TF, Latinovich DR, et al. Impact of bowel preparation on efficiency and cost of colonoscopy. Am J Gastroenterol. 2002;97(7):1696-1700.

Calderwood AH, Jacobson BC. Comprehensive validation of the Boston Bowel Preparation Scale. Gastrointest Endosc. 2010;72(4):686-692.

Rostom A, Jolicoeur E. Validation of a new scale for the assessment of bowel preparation quality. Gastrointest Endosc. 2004;59(4):482-486.

Rex DK, Schoenfeld PS, Cohen J, et al. Quality indicators for colonoscopy. Gastrointest Endosc. 2015;81(1):31-53.

Ness RM, Manam R, Hoen H, et al. Predictors of inadequate bowel preparation for colonoscopy. Am J Gastroenterol. 2001;96(6):1797-1802.

Lebwohl B, Wang TC, Neugut AI. Socioeconomic and other predictors of colonoscopy preparation quality. Dig Dis Sci. 2010;55(7):2014-2020.

Kunnackal J, Thuluvath A, Carrier H, et al. Improving the quality of bowel preparation for colonoscopy: populations to target in an urban tertiary care setting. Gastroenterology. 2018;1549(6 suppl 1):S-142-S-143.

10. Aoun E, Abdul-Baki H, Azar C, et al. A randomized single-blind trial of split-dose PEG-electrolyte solution without dietary restriction compared with whole dose PEG-electrolyte solution with dietary restriction for colonoscopy preparation. Gastrointest Endosc. 2005;62(2):213-218. 11.

Enestvedt BK, Tofani C, Laine LA, et al. 4-Liter split-dose polyethylene glycol is superior to other bowel preparations, based on systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2012;10(11):1225-1231.

12. Siddiqui AA, Yang K, Spechler SJ, et al. Duration of the interval between the completion of bowel preparation and the start of colonoscopy predicts bowel-preparation quality. Gastrointest Endosc. 2009;69(3 pt 2):700-706. 13. Gupta E, Kunnackal J, Linda L. A novel tool “colonoscopy preparation card” using patient reported stool color to improve success of direct access endoscopy. Gastroenterology. 2018;154(6 suppl 1):S-891. 14. John GK, Thuluvath AJ, Gupta E, et al. Patient-reported stool color and perception of bowel preparation predicts success of outpatient bowel preparation in an urban tertiary care setting. Gastroenterology. 2018;155(1):e40-e41.

Dr Gupta reported no relevant financial disclosures.

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A #MondayNightIBD Conversation: Fatigue, a Frustrating, Multifactorial Manifestation of IBD ALINE CHARABATY, MD, AGAF, FACG Assistant Clinical Director Division of Gastroenterology Johns Hopkins School of Medicine Clinical Director, IBD Center Johns Hopkins–Sibley Memorial Hospital Washington, DC

@DCHARABATY WASEEM AHMED, MD Advanced Fellow in Inflammatory Bowel Disease Jill Roberts Center for Inflammatory Bowel Disease Division of Gastroenterology & Hepatology Weill Cornell Medicine New York, New York

@WASEEM_AHMEDMD SABINA ALI, MD Associate Clinical Professor Department of Pediatrics Inflammatory Disease Program UCSF Benioff Children’s Hospital Oakland, California

@SABPEDS

atigue is a common symptom experienced by patients with inflamma-

tory bowel disease. Although fatigue can be expected when a patient has a flare or nutrient deficiencies, it also is persistent in a significant proportion of patients despite adequate disease control and normal laboratory values.1

WHAT IS @MondayNIGHTIBD? @MondayNightIBD is an educational Twitter handle created by Aline Charabaty, MD, (@DCharabaty) to bring together health care professionals to discuss complex IBD clinical case scenarios. On Monday afternoons, an IBD clinician posts a clinical vignette, with a management question linked to a poll listing several reasonable options. A special focus is placed on “gray areas” of IBD management, in which guidelines or randomized controlled trials and solid data are lacking, and on “real-life situations,” in which comorbidities, life events, social history, and other details need to be taken into account in decision making. Clinicians— from gastroenterologists to colorectal surgeons, nutritionists, and psychologists— tweet to discuss their approach to the clinical case, citing peer-reviewed articles and sharing their medical expertise. This open forum allows for solid scientific discussions and medical education among peers from different areas of the country and the world, at different stages of their careers (trainees, seasoned clinicians, scientists, and academic and private practice clinicians) in a social media setting without the constraints of time and space. Free 1 AMA CME credit is offered with each #MondayNightIBD conversation. The opinions shared do not reflect medical advice. On Wednesday, a poll is offered to patients who wish to share their experience on the topic discussed by clinicians earlier in the week. The goal of these polls is to highlight patients’ experiences with IBD and help bring to light their unmet needs.

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in our conversation and the answers to the poll questions. We also propose an #IBDAlgorithm for the evaluation of fatigue in patients with IBD (Figure).

Table 1. HCP Poll: Which of the following diagnostic tests has the highest yield? Test

Vote, % (N=269) 58

Labs including vitamin B12, iron studies, C-reactive protein (CRP), fecal calprotectin Colonoscopy

Screen for depression and anxiety with appropriate referral

Sleep study

Table 2. Patient Poll 1: What is your experience with fatigue? When do you have fatigue, what exacerbates it? Factor

Response, % (N=143)

Fatigue mainly with active disease

Fatigue most of the time

Fatigue mainly with increased stress

I get tired “like others”

Table 3. Patient Poll 2: What measures improved your fatigue? Factor Correcting lab test deﬁciencies or treating other organic causes

Response, % (N=98) 23

Mental health therapy

Change in diet and/or physical activity

Nothing helped

In the absence of formal guidelines on the evaluation and management of fatigue in IBD, clinicians routinely need to address this frustrating symptom that affects patients’ quality of life (QOL). In this article, we review the case of a young patient with ileal Crohn’s disease (CD) presenting with fatigue and numerous associated symptoms. This case was discussed on @MondayNightIBD, with informed opinions from health care professionals (HCPs) who have a focus in IBD, including gastroenterologists, psychologists, and dieticians, as well as from patients with IBD. We review the literature on fatigue and IBD, referring to the opinions of participants

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Clinical Case Scenario Presented to HCPs A 19-year-old male patient with CD ileitis on infliximab, in clinical and endoscopic remission (colonoscopy 1 year ago), presents for follow-up. He complains of fatigue over the past 3 months and reports that he has poor sleep, wakes up feeling tired, and does not routinely exercise. In addition, he mentions breaking up with his girlfriend this past year. He has 1 to 2 loose, nonbloody bowel movements daily, with mild abdominal cramping, and has lost 3 lb coinciding with the fatigue. Our poll asked participants which of several tests have the highest diagnostic yield in this setting. The results are shown in Table 1.

Discussion Fatigue refers to a subjectively overwhelming sense of tiredness, lack of energy, and feeling of exhaustion that decreases one’s capacity for physical and mental activity. It affects physical, emotional, cognitive, and social functioning, negatively affecting one’s QOL.1 Fatigue is one of the most common symptoms reported by patients, affecting 80% of patients during an IBD flare. Despite the advent of therapies that effectively induce and maintain clinical and endoscopic remission, the prevalence of fatigue remains as high as 50% in patients during clinical remission.2 In our #MondayNightIBD patient polls, 66% of patients reported fatigue “most of the time,” including in times of disease control, and 47% expressed that “nothing helped,” including correcting labs and treating associated conditions, mental health therapy in any form (medications, psychotherapy, meditation, etc), and change in diet and physical activity (Tables 2 and 3). Many patients expressed frustration living with fatigue that is different from the “usual fatigue that others experience,” can be unpredictable in intensity from day to day, is exacerbated by stress and illness, and is not improved by rest or sleep. Gastroenterologists routinely face the challenge of assessing and managing ongoing fatigue in patients with IBD in remission. It is increasingly recognized that multiple factors contribute to this debilitating symptom, including anemia and nutrient deficiencies, sleep disorders, psychiatric disease and substance abuse, medication side effects, and associated conditions and comorbidities.3 However, it is also important to recognize that sometimes fatigue persists despite thorough evaluation and treatment, leading to the emerging concept that fatigue should be considered to be an extraintestinal manifestation of IBD that may or may not parallel luminal disease activity.

Active IBD Disease In our #MondayNightIBD case discussion, the majority of clinicians noted the high prevalence of fatigue during active disease and agreed that an objective assessment

of disease activity, by serum C-reactive protein, fecal calprotectin, and/or a colonoscopy with ileal intubation, was necessary to evaluate the patient’s fatigue. A Dutch study of 425 patients with IBD showed that the prevalence of fatigue was significantly higher in patients referred to a tertiary care center (with more severe and complicated disease) than in patients who present to a general hospital (65.7% vs 52.5%, respectively; P=0.01).4 A similar pattern of results was found in patients in remission in the referral center compared with those in the general hospital (53.3% vs 40.5%; P=0.061). In a single-center, cross-sectional study of 187 patients with IBD, 49% reported high levels of fatigue. On multivariable analysis, clinical remission (odds ratio [OR], 0.42; 95% CI, 0.23-0.76) and endoscopic remission (OR, 0.44; 95% CI, 0.22-0.88), but not histologic remission, were inversely associated with fatigue.5 Although a significant proportion of patients note persistence of fatigue despite clinical remission, it is important to remember that clinical remission is not a reliable marker of endoscopic healing in many IBD patients, particularly in patients with CD.6 Hence, a disease activity assessment and treatment of active subclinical inflammation remain paramount in the management of fatigue. Active disease causes fatigue likely through proinflammatory cytokine–mediated mechanisms. Inflammatory cytokines acting on the bidirectional brain–gut axis are thought to mediate fatigue via the hypothalamic–pituitary axis.7 A study of 84 patients with IBD in clinical remission stratified patients as having fatigue via the checklist individual strength-fatigue score. 8 The authors then conducted flow cytometry analysis and whole-blood stimulation to investigate differences in leukocyte subsets and expression of various cytokines. They noted significant differences in immune profiles between fatigued and nonfatigued patients, with higher levels of tumor necrosis factor–alpha (TNF-alpha), interferongamma, interleukin (IL)-12, and IL-10 in the fatigue group.

Anemia in IBD HCPs uniformly recommended further evaluation of the patient for anemia, with measurement of iron stores and screening for vitamin B12 and folate deficiency. Iron deficiency anemia (IDA) and anemia of chronic disease or inflammation (ACD) are the most common causes of anemia in patients with IBD, with IDA affecting 36% to 76% of patients. The Crohn’s & Colitis Foundation’s IBD anemia care pathway defines IDA as hemoglobin less than 12 g/dL in women and less than 13 g/dL in men, with a ferritin value less than 100 ng/mL or more than 100 ng/mL and a transferrin saturation less than 20%.9 It is important for clinicians to be able to distinguish between IDA and ACD, noting the different thresholds for serum ferritin, given its role as an acute-phase reactant (ferritin is normal to increased in ACD, generally >100 mcg/L), and for transferrin saturation (low in ACD, <20%).9 When routine testing of these parameters does not distinguish IDA from ACD, measurement of soluble transferrin receptor (sTfR) and sTfR-ferritin

#MondayNightIBD #GITwitter #MedTwitter Teaching Points • Fatigue is a common symptom in patients with active and inactive IBD. • A complaint of fatigue by a patient should prompt an objective assessment of disease activity by the clinician. • Comprehensive screening for anemia, associated conditions, medication side effects, malnutrition, and mood and sleep disorders is recommended.

index can help clarify the diagnosis. Prompt referral to a hematologist is necessary if the diagnosis remains unclear. In addition to treating the underlying active disease, clinicians should correct iron deficiency in the context of active inflammation—with IV iron rather than an oral iron supplement. Hepcidin is upregulated by inflammatory cytokines, reducing intestinal absorption of oral iron supplements. Particular attention should be paid to vitamin B12 and/or folic acid deficiencies in patients with ileal CD, a history of small bowel resection or short bowel syndrome, chronic dietary restrictions, risk factors for small intestinal bacterial overgrowth, or use of methotrexate or sulfasalazine.7,10 Clinicians contributing to the #MondayNightIBD discussion noted the wide range of what is considered a normal vitamin B12 level, advocating for a low threshold for reflex testing of methyl-malonic acid and homocysteine levels or empiric repletion for B12 values on the lower end of normal (<450 pg/mL). Finally, IBD patients are at increased risk for other macro- and micronutrient deficiencies related to malabsorption, dietary restrictions, and diarrhea.7 Patients with fatigue should be referred for a formal evaluation by a dietician when it is deemed appropriate.

Medication Side Effects Because fatigue is a common potential side effect of several pharmacologic agents, it is especially important to review current medications and recent changes in medications in the assessment of IBD-related fatigue. Fatigue can be a direct drug-related adverse effect, from azathioprine, 6-mercaptopurine, or methotrexate, rather than a secondary mechanism of bone marrow suppression.3 Systemic corticosteroids can cause insomnia, mood changes, myopathy, and fatigue. In addition, rapid steroid tapering and steroid tapering

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after long-term use can lead to adrenal insufficiency and severe fatigue; early morning cortisol levels and adrenocorticotrophic hormone stimulation testing should be done in patients who have taken steroids, including budesonide, in the past.11,12 Antidepressants and narcotics, commonly prescribed for patients with IBD, can be associated with lethargy and somnolence.13 In contrast, patients randomly assigned to receive adalimumab in the CHARM trial and real-world experience of patients with IBD show that anti-TNF induction and maintenance therapy is associated with decreases in fatigue and depression symptoms, and improved QOL.4,14 Some studies investigating the use of cannabis in IBD showed that patients—especially young patients—can experience side effects such as sleepiness and dizziness,15,16 as well as depression symptoms.17

Noting the patient’s recent personal relationship difficulties, poor sleep, and decreased physical activity during our #MondayNightIBD discussion, HCPs also advocated for screening for mood and substance use disorders and lifestyle modifications. Per American College of Gastroenterology guidelines, screening for depression and anxiety is recommended for all patients with IBD, given that this population has an increased prevalence of anxiety and depression compared with the general population.18 Several studies show a bidirectional relationship between mood disorders and active symptoms,19 and psychological stress has been shown to increase mucosal TNF-alpha release and reactive oxygen metabolites and reduce rectal mucosal blood flow.20 Patients with a positive screening for

Fatigue and IBD

Fatigue and IBD 40%-50% of patients have fatigue despite clinical remission Prevalence: CD > UC Risk factors: • Anemia • Depression, sleep disturbance • Female sex • Thiopurine, MTX

Anemia and IBD Pearls • IDA and active IBD: IV iron more effective than oral iron • Ferric carboxymaltose, ferric dextran, and ferric sucrose: fewer infusion reactions than other IV ferrous formulations • Check sTfR to differentiate IDA from ACD • Supplement folate (1 mg per day) in patients taking MTX or SSZ • Monitor and correct vitamin B12 for ileal CD/resection/restricted diet/deﬁciency symptoms, even if B12 in low normal range • If macrocytosis persists after correction of B12 and discontinuation of IMM, consider hematology evaluation

Mental Health

Fatigue

Screen for Mood, Sleep, and Substance Use Disorders (ethyl alcohol, THC)

Assess for Anemia (Check B12, folate, iron, drug toxicity, etc)

Assess IBD Activity (CRP, FCP, CT/MRE, TDM, colonoscopy) If active disease

Optimize Therapy

Treat Anemia

Mucosal Healing

Anemia Resolved

Assess for Medical Comorbidities • • • • •

Hepatobiliary Endocrine Celiac disease Autoimmune Occult infection

Persistent Fatigue

Drug Adverse Effect

Figure 1. #IBDAlgorithm for the management of fatigue in inflammatory bowel disease. ACD, anemia of chronic disease or inflammation; CD, Crohn’s disease; IDA, iron deficiency anemia; IMM, immunomodulators (azathioprine, mercaptopurine, MTX); MMA, methylmalonic acid; MTX, methotrexate; SSZ, sulfasalazine; sTfR, soluble transferrin receptor; UC, ulcerative colitis

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mood disorders should be referred for formal evaluation, with consideration of psychotherapy and pharmacotherapy. Although HCPs recognize the importance of mental health care and emotional well-being in patients with IBD, they also recognize that patients have limited access to dedicated gastrointestinal psychologists.

Physical Inactivity Previous randomized controlled trials have demonstrated improved QOL in IBD patients undergoing a standardized low- to moderate-intensity physical activity regimen.21,22 However, IBD patients commonly are less physically active after their initial diagnosis, for many disease-related reasons (active symptoms, anemia, fatigue, poor body image, and others). A prospective multicenter, cross-sectional study assessed the level of

Positive Screen

(GI) Psych Referral (Polysomnography, evaluate sleep hygiene and medical treatment)

Nutritional Status (Screen for vitamin and micronutrient deﬁciencies)

IBD Dietician Evaluation

Optimize Nutrition

Lifestyle Modiﬁcations Consider high-dose thiamine

physical activity (with the Godin score) before and after a recent diagnosis of IBD in 158 patients who were in clinical remission or on a stable medication regimen.23 There was a significant decrease in the mean Godin score of 6.94 after IBD diagnosis (P=0.002), and one-third of the patients reduced their activity level after diagnosis. Patients with IBD should be encouraged to resume physical activity at a level that they can tolerate and enjoy.

Sleep Disorders Active disease and nocturnal symptoms are associated with sleep disturbances, and poor sleep has been postulated to be a marker of subclinical disease activ ity. In addition, it is increasingly recognized that even patients with inactive IBD are at higher risk for sleep disorders. In a recent prospective study, 36 patients with inactive IBD and 27 healthy controls underwent polysomnography.24 The inactive IBD cohort had significantly less rapid-eye-movement sleep than controls (23.7% vs 27.8%; P=0.047), and longer periods of oxygen desaturation below 90%. In light of these findings, clinicians should have a low threshold for a formal evaluation of patients by a sleep specialist and screening for a primary sleep disorder, in addition to screening IBD patients with poor sleep for active disease and mood disorders.25

The Thiamine Connection As mentioned previously and highlighted in our #MondayNightIBD patient experience poll (with 46% reporting no intervention was effective in helping with fatigue), fatigue can remain a frustrating symptom despite thorough evaluation and comprehensive interventions, pointing to other still obscure factors at play. The recent randomized, double-blind, placebo-controlled TARIF crossover trial has garnered attention by looking at high-dose oral thiamine supplementation in patients with quiescent IBD and severe, chronic fatigue.26 In the trial, 40 patients were randomly assigned to receive a weight-based high dose of oral thiamine for 4 weeks followed by 4 weeks of washout and 4 weeks of placebo, or oral placebo for 4 weeks with subsequent 4 weeks of washout and 4 weeks of high-dose oral thiamine. The supplementation dose in this study ranged from 600 to 1,800 mg per day, which is much higher than the recommended daily intake of 2 mg. Fatigue was measured using the IBD-Fatigue Questionnaire. Crossover analysis showed a mean reduction of 4.5 points in fatigue after thiamine supplementation compared with a mean increase of 0.75 points after placebo (P=0.0003). The number needed to treat to improve fatigue was 3. Despite the limitations of a small study, thiamine offers a potential effective option because it is an inexpensive and welltolerated intervention that improved fatigue independent of age, sex, IBD therapy, anxiety or depression, and thiamine levels at enrollment. Thiamine deficiency is uncommon in the Western world, and it is unlikely that fatigue in IBD is due to thiamine deficiency, but rather it could be due to a dysfunction in thiamine transport from blood to mitochondria and low intracellular thiamine levels.

G AST R O E N T E R O LO GY & E N D O S CO PY N E WS S P E C I A L E D I T I O N • O C TO B E R 2 02 1

Conclusion Fatigue in IBD is often a manifestation of active disease and/or its associated comorbidities. The mnemonic AAAMMENS can remind clinicians to assess for correctable factors: active IBD, anemia (iron, vitamin B12, folate), associated disorders (not covered here, but consider hepatobiliary disease, testing for thyroid and celiac disease, and testosterone level), medication side effects, mental health and exercise, nutrition, and sleep. Management of fatigue often requires a multidisciplinary approach that includes gastroenterologists, registered dietitians, and psychologists, as well as multidimensional interventions aimed at optimizing the basics of healthy living (physical activity, healthy eating, and restorative sleep).

However, fatigue often becomes a chronic and frustrating symptom refractory to interventions in many patients with IBD in remission, which lead some experts to consider fatigue as an extraintestinal manifestation of IBD. There is a clear immeasurable effect of IBD itself on the persistence of fatigue, and uncovered contributing factors likely exist, as suggested by the TARIF study.26 As a highly relevant patient-reported outcome, fatigue should be included in disease activity measurement scoring systems and assessment as well as in the end points of clinical trials in IBD. As a summary of the #MondayNightIBD conversation and review of the literature, we point to our #IBDAlgorithm for the evaluation of fatigue in IBD.

References 1.

Borren NZ, van der Woude CJ, Anantakrishnan AN. Fatigue in IBD: epidemiology, pathophysiology and management. Nat Rev Gastroenterol Hepatol. 2019;16(4):247-259. 2. Villoria A, Garcia V, Dosal A, et al. Fatigue in out-patients with inflammatory bowel -disease: prevalence and predictive factors. PLoS One. 2017;12(7):e0181435. 3. Kreijne JE, Lie MR, Vogelaar L, et al. Practical guideline for fatigue management in inflammatory bowel disease. J Crohns Colitis. 2016;10(1):105-111. 4. Vogelaar L, van’t Spijker A, van Tilburg AJ, et al. Determinants of fatigue in Crohn’s disease patients. Eur J Gastroenterol Hepatol. 2013;25(2):246-251. 5. Lakhani O, Durbin L, Agrawal M, et al. Fatigue is inversely associated with endoscopic but not histologic remission in IBD patients. Am J Gastroenterol. 2019;114(suppl):s413. 6. Pineton de Chambrun G, Blanc P, Peyrin-Biroulet L. Current evidence -supporting mucosal healing and deep remission as important treatment goals for inflammatory bowel disease. Expert Rev Gastroenterol Hepatol. 2016;10(8):915-927. 7. Nocerino A, Nguyen A, Agrawal M, et al. Fatigue in inflammatory bowel diseases: etiologies and management. Adv Ther. 2020;37(1):97-112. 8. Vogelaar L, de Haar C, Aerts BR, et al. Fatigue in patients with inflammatory bowel disease is associated with distinct differences in immune parameters. Clin Exp Gastroenterol. 2017;10:83-90. 9. Crohn’s & Colitis Foundation. Crohn’s & Colitis Foundation’s IBD anemia care pathway. Accessed June 25, 2021. https://www. crohnscolitisfoundation.org/sites/default/files/legacy/assets/ pdfs/anemiafactsheet.pdf 10. Murawska N, Fabisiak A, Fichna J. Anemia of chronic disease and iron deficiency anemia in inflammatory bowel diseases: pathophysiology, diagnosis, and treatment. Inflamm Bowel Dis. 2016;22(5):1198-1208. 11. Ibrahim A, Dahlqvist P, Olsson T, et al. The clinical course after glucocorticoid treatment in patients with inflammatory bowel disease is linked to suppression of the hypothalamic-pituitaryadrenal axis: a retrospective observational study. Therap Adv Gastroenterol. 2017;10(11):829-836. 12. Berkelhammer C, Trabolsi M, Andrejic J, et al. Severe adrenal insufficiency -complicating budesonide therapy for Crohn’s disease. Inflamm Bowel Dis. 2011;17(4):1053-1054. 13. Hashash JG, Ramos-Rivers C, Youk A, et al. Quality of sleep and coexistent psychopathology have significant Impact on fatigue burden in patients with inflammatory bowel disease. J Clin Gastroenterol. 2018;52(5):423-430.

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14. Loftus EV, Feagan BG, Colombel JF, et al. Effects of adalimumab maintenance therapy on health-related quality of life of patients with Crohn’s disease: patient-reported outcomes of the CHARM trial. Am J Gastroenterol. 2008;103(12):3132-3141. 15. Naftali T, Bar-Lev Schleider L, Dotan I, et al. Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. Clin Gastroenterol Hepatol. 2013;11(10):1276-1280.e1. 16. Naftali T, Lev LB, Yablecovitch D, et al. Treatment of Crohn’s disease with cannabis: an observational study. Isr Med Assoc J. 2011;13(8):455-458. 17. Leadbeater BJ, Ames ME, Linden-Carmichael AN. Age-varying effects of cannabis use frequency and disorder on symptoms of psychosis, depression and anxiety in adolescents and adults. Addiction. 2019;114(2):278-293. 18. Farraye FA, Melmed GY, Lichtenstein GR, et al. ACG Clinical Guideline: preventive care in inflammatory bowel disease. Am J Gastroenterol. 2017;112(2):241-258. 19. Gracie DJ, Guthrie EA, Hamlin PJ, et al. Bi-directionality of braingut interactions in patients with inflammatory bowel disease. Gastroenterology. 2018;154(6):1635-1646. 20. Mawdsley JE, Macey MG, Feakins RM, et al. The effect of acute psychologic stress on systemic and rectal mucosal measures of inflammation in ulcerative colitis. Gastroenterology. 2006;131(2):410-419. 21. Klare P, Nigg J, Nold J, et al. The impact of a ten-week physical exercise program on health-related quality of life in patients with inflammatory bowel disease: a prospective randomized controlled trial. Digestion. 2015;91(3):239-247. 22. Ng V, Millard W, Lebrun C, et al. Low-intensity exercise improves quality of life in patients with Crohn’s disease. Clin J Sport Med. 2007;17(5):384-388. 23. Gatt K, Schembri J, Katsanos KH, et al. Inflammatory bowel disease [IBD] and physical activity: a study on the impact of diagnosis on the level of exercise amongst patients with IBD. J Crohns Colitis. 2019;13(6):686-692. 24. Bar-Gil Shitrit A, Chen-Shuali C, Adar T, et al. Sleep disturbances can be prospectively observed in patients with an inactive inflammatory bowel disease. Dig Dis Sci. 2018;63(11):2992-2997. 25. Canakis A, Qazi T. Sleep and fatigue in IBD: an unrecognized but important extra-intestinal manifestation. Curr Gastroenterol Rep. 2020;22(2):8. 26. Bager P, Hvas CL, Rud CL, et al. Randomised clinical trial: highdose oral thiamine versus placebo for chronic fatigue in patients with quiescent inflammatory bowel disease. Aliment Pharmacol Ther. 2021;53(1):79-86.

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