A colonoscopy technique involving repeat intubation of the sigmoid colon significantly improves detection of adenomas compared with conventional colonoscopy evaluations, new research showed.

“After eliminating the impact of time, the adenoma-detection rate [with a second intubation vs standard withdrawal] was still significantly increased, indicating that the second intubation technique could enhance the visualization of the sigmoid colon mucosa and reduce the rate of missed lesions,” reported the authors of the study, published in The American Journal of Gastroenterology.

When precancerous polyps are removed during standard colonoscopies, as many as 70%-90% of colorectal cancers can be prevented; however, rates of missed polyps during colonoscopy are notoriously high.

Recent studies have shown improved adenoma-detection rates with the use of Endocuff, water-assisted colonoscopy, full-spectrum endoscopy, and repeat withdrawal examinations, which include retroflexion and forward-viewing methods.

The repeat colonoscopy examinations may represent “the easiest and most practical option for endoscopists as they do not require additional tools, staff, or funding,” the authors explained.

However, most studies on the issue have focused mainly on the right colon and forward-viewing examinations, whereas the sigmoid colon, which has the most turns and is the most easily compressed, can be easily missed during withdrawal observation.

To investigate if use of a second colon intubation of the sigmoid colon could improve detection rates, senior author Jianning Yao, MD, of the Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China, conducted a randomized trial, enrolling 650 patients between December 2023 and April 2024 who were aged 45 or older and had overweight or obesity (BMI ≥ 24).

At the time of the first withdrawal during the colonoscopy, the patients were randomized 1:1 to groups of 325 each to either receive standard withdrawal, with withdrawal to the anus, or to receive a second intubation, with reinsertion into the sigmoid colon.

In the second intubation, the colonoscope was pushed forward without straightening, “allowing for slight looping that could be used to flatten the colonic folds as the tip of the instrument was advanced,” they explained.

The patients had a mean age of 55; about 25% had a smoking habit, and the mean BMI was about 28. There were no significant differences in other baseline characteristics.

The results showed that patients in the second-intubation group vs standard-withdrawal group had a substantially higher adenoma-detection rate (24.3% vs 14.5%) and polyp-detection rate (29.2% vs 17.8%, P = .001 for both) in the sigmoid colon.

In the second-intubation group, 85% of the adenomas discovered throughout the second inspection in the sigmoid colon were 5 mm or smaller in size. In addition, 90% of the 40 adenomas were somewhat raised or pedunculated, and all were tubular adenomas.

No high-grade dysplasia adenomas were discovered.

Of note, the colonoscopy in the second-intubation group’s colonoscopic examinations took just 1.47 minute longer overall than the standard-withdrawal group’s examinations.

Factors that were determined in a multivariate analysis to be independent predictors of higher adenoma detection in the second-intubation group included older age, smoking habit, longer duration of the second inspection, and the identification of lesions during the initial withdrawal from the sigmoid colon.

Patients’ vital signs were monitored at intervals of 3 minutes throughout the colonoscopy procedure, and patients were followed up to monitor for any adverse events occurring within 2 weeks after the examination, with no notable disparities observed between the two groups.

 

Alternative to AKS Approach in Second Intubation

The authors explained that, in their approach in the second intubation, the common axis-keeping shortening (AKS) was not utilized, and instead they pushed the colonoscope forward without straightening it, which offers important advantages.

“In this way, slight looping of the colonoscope can be used to flatten the colonic folds as the tip of the instrument is advanced, thereby achieving an observation effect that cannot be reached by any number of withdrawal examinations.”

In general, the stimulation of peristalsis during a second examination allows for the observation of the colonic mucosa from different angles, thereby reducing the rate of missed lesions, the authors added.

“Although the detection of these lesions may not significantly affect clinical outcomes, it serves as a reminder for patients regarding regular follow-ups and lifestyle adjustments,” they explained. “Additionally, it may reduce the likelihood of missing some smaller lesions that progress rapidly, such as de novo cancer.”

Based on the results, the authors concluded that older patients, patients who smoke, or those with lesions found on the first sigmoid inspection have a higher chance of having missed adenomas discovered in the sigmoid colon during the second intubation examination.

“If one of these risk factors is present, a second examination of the sigmoid colon may be considered to detect missed lesions,” they said.

The added time commitment of just 1.47 minutes can be a worthwhile tradeoff, they added.

“Considering the improvements in the adenoma-detection rate provided by the second intubation, this modest time increase may be acceptable.”

The authors had no disclosures to report.

A version of this article appeared on Medscape.com.

A colonoscopy technique involving repeat intubation of the sigmoid colon significantly improves detection of adenomas compared with conventional colonoscopy evaluations, new research showed.

“After eliminating the impact of time, the adenoma-detection rate [with a second intubation vs standard withdrawal] was still significantly increased, indicating that the second intubation technique could enhance the visualization of the sigmoid colon mucosa and reduce the rate of missed lesions,” reported the authors of the study, published in The American Journal of Gastroenterology.

When precancerous polyps are removed during standard colonoscopies, as many as 70%-90% of colorectal cancers can be prevented; however, rates of missed polyps during colonoscopy are notoriously high.

Recent studies have shown improved adenoma-detection rates with the use of Endocuff, water-assisted colonoscopy, full-spectrum endoscopy, and repeat withdrawal examinations, which include retroflexion and forward-viewing methods.

The repeat colonoscopy examinations may represent “the easiest and most practical option for endoscopists as they do not require additional tools, staff, or funding,” the authors explained.

However, most studies on the issue have focused mainly on the right colon and forward-viewing examinations, whereas the sigmoid colon, which has the most turns and is the most easily compressed, can be easily missed during withdrawal observation.

To investigate if use of a second colon intubation of the sigmoid colon could improve detection rates, senior author Jianning Yao, MD, of the Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China, conducted a randomized trial, enrolling 650 patients between December 2023 and April 2024 who were aged 45 or older and had overweight or obesity (BMI ≥ 24).

At the time of the first withdrawal during the colonoscopy, the patients were randomized 1:1 to groups of 325 each to either receive standard withdrawal, with withdrawal to the anus, or to receive a second intubation, with reinsertion into the sigmoid colon.

In the second intubation, the colonoscope was pushed forward without straightening, “allowing for slight looping that could be used to flatten the colonic folds as the tip of the instrument was advanced,” they explained.

The patients had a mean age of 55; about 25% had a smoking habit, and the mean BMI was about 28. There were no significant differences in other baseline characteristics.

The results showed that patients in the second-intubation group vs standard-withdrawal group had a substantially higher adenoma-detection rate (24.3% vs 14.5%) and polyp-detection rate (29.2% vs 17.8%, P = .001 for both) in the sigmoid colon.

In the second-intubation group, 85% of the adenomas discovered throughout the second inspection in the sigmoid colon were 5 mm or smaller in size. In addition, 90% of the 40 adenomas were somewhat raised or pedunculated, and all were tubular adenomas.

No high-grade dysplasia adenomas were discovered.

Of note, the colonoscopy in the second-intubation group’s colonoscopic examinations took just 1.47 minute longer overall than the standard-withdrawal group’s examinations.

Factors that were determined in a multivariate analysis to be independent predictors of higher adenoma detection in the second-intubation group included older age, smoking habit, longer duration of the second inspection, and the identification of lesions during the initial withdrawal from the sigmoid colon.

Patients’ vital signs were monitored at intervals of 3 minutes throughout the colonoscopy procedure, and patients were followed up to monitor for any adverse events occurring within 2 weeks after the examination, with no notable disparities observed between the two groups.

 

Alternative to AKS Approach in Second Intubation

The authors explained that, in their approach in the second intubation, the common axis-keeping shortening (AKS) was not utilized, and instead they pushed the colonoscope forward without straightening it, which offers important advantages.

“In this way, slight looping of the colonoscope can be used to flatten the colonic folds as the tip of the instrument is advanced, thereby achieving an observation effect that cannot be reached by any number of withdrawal examinations.”

In general, the stimulation of peristalsis during a second examination allows for the observation of the colonic mucosa from different angles, thereby reducing the rate of missed lesions, the authors added.

“Although the detection of these lesions may not significantly affect clinical outcomes, it serves as a reminder for patients regarding regular follow-ups and lifestyle adjustments,” they explained. “Additionally, it may reduce the likelihood of missing some smaller lesions that progress rapidly, such as de novo cancer.”

Based on the results, the authors concluded that older patients, patients who smoke, or those with lesions found on the first sigmoid inspection have a higher chance of having missed adenomas discovered in the sigmoid colon during the second intubation examination.

“If one of these risk factors is present, a second examination of the sigmoid colon may be considered to detect missed lesions,” they said.

The added time commitment of just 1.47 minutes can be a worthwhile tradeoff, they added.

“Considering the improvements in the adenoma-detection rate provided by the second intubation, this modest time increase may be acceptable.”

The authors had no disclosures to report.

A version of this article appeared on Medscape.com.

A colonoscopy technique involving repeat intubation of the sigmoid colon significantly improves detection of adenomas compared with conventional colonoscopy evaluations, new research showed.

“After eliminating the impact of time, the adenoma-detection rate [with a second intubation vs standard withdrawal] was still significantly increased, indicating that the second intubation technique could enhance the visualization of the sigmoid colon mucosa and reduce the rate of missed lesions,” reported the authors of the study, published in The American Journal of Gastroenterology.

When precancerous polyps are removed during standard colonoscopies, as many as 70%-90% of colorectal cancers can be prevented; however, rates of missed polyps during colonoscopy are notoriously high.

Recent studies have shown improved adenoma-detection rates with the use of Endocuff, water-assisted colonoscopy, full-spectrum endoscopy, and repeat withdrawal examinations, which include retroflexion and forward-viewing methods.

The repeat colonoscopy examinations may represent “the easiest and most practical option for endoscopists as they do not require additional tools, staff, or funding,” the authors explained.

However, most studies on the issue have focused mainly on the right colon and forward-viewing examinations, whereas the sigmoid colon, which has the most turns and is the most easily compressed, can be easily missed during withdrawal observation.

To investigate if use of a second colon intubation of the sigmoid colon could improve detection rates, senior author Jianning Yao, MD, of the Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China, conducted a randomized trial, enrolling 650 patients between December 2023 and April 2024 who were aged 45 or older and had overweight or obesity (BMI ≥ 24).

At the time of the first withdrawal during the colonoscopy, the patients were randomized 1:1 to groups of 325 each to either receive standard withdrawal, with withdrawal to the anus, or to receive a second intubation, with reinsertion into the sigmoid colon.

In the second intubation, the colonoscope was pushed forward without straightening, “allowing for slight looping that could be used to flatten the colonic folds as the tip of the instrument was advanced,” they explained.

The patients had a mean age of 55; about 25% had a smoking habit, and the mean BMI was about 28. There were no significant differences in other baseline characteristics.

The results showed that patients in the second-intubation group vs standard-withdrawal group had a substantially higher adenoma-detection rate (24.3% vs 14.5%) and polyp-detection rate (29.2% vs 17.8%, P = .001 for both) in the sigmoid colon.

In the second-intubation group, 85% of the adenomas discovered throughout the second inspection in the sigmoid colon were 5 mm or smaller in size. In addition, 90% of the 40 adenomas were somewhat raised or pedunculated, and all were tubular adenomas.

No high-grade dysplasia adenomas were discovered.

Of note, the colonoscopy in the second-intubation group’s colonoscopic examinations took just 1.47 minute longer overall than the standard-withdrawal group’s examinations.

Factors that were determined in a multivariate analysis to be independent predictors of higher adenoma detection in the second-intubation group included older age, smoking habit, longer duration of the second inspection, and the identification of lesions during the initial withdrawal from the sigmoid colon.

Patients’ vital signs were monitored at intervals of 3 minutes throughout the colonoscopy procedure, and patients were followed up to monitor for any adverse events occurring within 2 weeks after the examination, with no notable disparities observed between the two groups.

 

Alternative to AKS Approach in Second Intubation

The authors explained that, in their approach in the second intubation, the common axis-keeping shortening (AKS) was not utilized, and instead they pushed the colonoscope forward without straightening it, which offers important advantages.

“In this way, slight looping of the colonoscope can be used to flatten the colonic folds as the tip of the instrument is advanced, thereby achieving an observation effect that cannot be reached by any number of withdrawal examinations.”

In general, the stimulation of peristalsis during a second examination allows for the observation of the colonic mucosa from different angles, thereby reducing the rate of missed lesions, the authors added.

“Although the detection of these lesions may not significantly affect clinical outcomes, it serves as a reminder for patients regarding regular follow-ups and lifestyle adjustments,” they explained. “Additionally, it may reduce the likelihood of missing some smaller lesions that progress rapidly, such as de novo cancer.”

Based on the results, the authors concluded that older patients, patients who smoke, or those with lesions found on the first sigmoid inspection have a higher chance of having missed adenomas discovered in the sigmoid colon during the second intubation examination.

“If one of these risk factors is present, a second examination of the sigmoid colon may be considered to detect missed lesions,” they said.

The added time commitment of just 1.47 minutes can be a worthwhile tradeoff, they added.

“Considering the improvements in the adenoma-detection rate provided by the second intubation, this modest time increase may be acceptable.”

The authors had no disclosures to report.

A version of this article appeared on Medscape.com.

Intercept Pharmaceuticals has voluntarily withdrawn Ocaliva (obeticholic acid) for the treatment of primary biliary cholangitis (PBC) from the US market.

The decision follows a request from the FDA. The FDA has also placed a clinical hold on all of Intercept’s clinical trials involving obeticholic acid.

PBC is a rare, progressive, and chronic autoimmune disease that affects the bile ducts in the liver and is most prevalent in women older than 40 years of age. PBC causes a buildup of bile acid in the liver, resulting in inflammation and fibrosis, which — if not treated — can lead to cirrhosis, a liver transplant, or death.

Ocaliva, a farnesoid X receptor agonist, received accelerated FDA approval in 2016 for the treatment of PBC in adults with an inadequate response to or intolerance of ursodeoxycholic acid. 

Yet, in September 2024, staff reviewers at the FDA said a confirmatory trial did not show that the drug was effective for PBC.

Ocaliva has also been linked to an increased risk of serious liver injury in patients with PBC with and without cirrhosis. 

The company has advised patients currently taking Ocaliva for PBC to consult their healthcare provider before making any changes. 

Intercept will provide additional information to support healthcare professionals and patients as it works with the FDA on the transition process. 

Healthcare professionals who have questions about this development can contact Intercept Medical Information at medinfo@interceptpharma.com or call 1-844-782-4278.

 

A version of this article appeared on Medscape.com.

Intercept Pharmaceuticals has voluntarily withdrawn Ocaliva (obeticholic acid) for the treatment of primary biliary cholangitis (PBC) from the US market.

The decision follows a request from the FDA. The FDA has also placed a clinical hold on all of Intercept’s clinical trials involving obeticholic acid.

PBC is a rare, progressive, and chronic autoimmune disease that affects the bile ducts in the liver and is most prevalent in women older than 40 years of age. PBC causes a buildup of bile acid in the liver, resulting in inflammation and fibrosis, which — if not treated — can lead to cirrhosis, a liver transplant, or death.

Ocaliva, a farnesoid X receptor agonist, received accelerated FDA approval in 2016 for the treatment of PBC in adults with an inadequate response to or intolerance of ursodeoxycholic acid. 

Yet, in September 2024, staff reviewers at the FDA said a confirmatory trial did not show that the drug was effective for PBC.

Ocaliva has also been linked to an increased risk of serious liver injury in patients with PBC with and without cirrhosis. 

The company has advised patients currently taking Ocaliva for PBC to consult their healthcare provider before making any changes. 

Intercept will provide additional information to support healthcare professionals and patients as it works with the FDA on the transition process. 

Healthcare professionals who have questions about this development can contact Intercept Medical Information at medinfo@interceptpharma.com or call 1-844-782-4278.

 

A version of this article appeared on Medscape.com.

Intercept Pharmaceuticals has voluntarily withdrawn Ocaliva (obeticholic acid) for the treatment of primary biliary cholangitis (PBC) from the US market.

The decision follows a request from the FDA. The FDA has also placed a clinical hold on all of Intercept’s clinical trials involving obeticholic acid.

PBC is a rare, progressive, and chronic autoimmune disease that affects the bile ducts in the liver and is most prevalent in women older than 40 years of age. PBC causes a buildup of bile acid in the liver, resulting in inflammation and fibrosis, which — if not treated — can lead to cirrhosis, a liver transplant, or death.

Ocaliva, a farnesoid X receptor agonist, received accelerated FDA approval in 2016 for the treatment of PBC in adults with an inadequate response to or intolerance of ursodeoxycholic acid. 

Yet, in September 2024, staff reviewers at the FDA said a confirmatory trial did not show that the drug was effective for PBC.

Ocaliva has also been linked to an increased risk of serious liver injury in patients with PBC with and without cirrhosis. 

The company has advised patients currently taking Ocaliva for PBC to consult their healthcare provider before making any changes. 

Intercept will provide additional information to support healthcare professionals and patients as it works with the FDA on the transition process. 

Healthcare professionals who have questions about this development can contact Intercept Medical Information at medinfo@interceptpharma.com or call 1-844-782-4278.

 

A version of this article appeared on Medscape.com.

Routine screening for Helicobacter pylori in patients hospitalized for myocardial infarction (MI) did not significantly reduce the risk for upper gastrointestinal bleeding overall — but benefits were seen in high-risk subgroups, according to the HELP-MI SWEDEHEART trial published in JAMA and presented at the European Society of Cardiology (ESC) Congress 2025.

Bleeding in the upper gastrointestinal tract is a common complication after MI. It increases morbidity and mortality itself but can also reduce the effectiveness of antithrombotic treatments and lead to new cardiovascular events. It is often related to infection with H. pylori, the bacterium that can cause stomach inflammation, ulcers, and cancer, said Robin Hofmann, MD, PhD, a cardiologist at the Karolinska Institute in Stockholm, Sweden, who presented the trial results.Hofmann and his colleagues wondered whether screening for the bacterium using a simple urea breath test would help reduce the risk for bleeds. Using Sweden’s national SWEDEHEART registry, researchers performed a cluster-randomized crossover trial of more than 18,000 patients with MI at 35 Swedish hospitals. They found that screening for H. pylori reduced the risk for upper gastrointestinal bleeding by 10%, but the results were not statistically significant.

Several factors may have contributed to the neutral result, noted Hofmann. Just 70% of the people in the screening population were actually screened — though he said that is a fairly good number for a diagnostic test. A relatively small number, around 23%, were positive for H. pylori, a much lower rate than in many other parts of the world, and about 25% of participants in both arms of the trial were already taking proton pump inhibitors to reduce the risk for bleeding.

 

Signals of Benefit in High-Risk Patients

But in some high-risk subgroups, there was a clearer signal of benefit. Patients with anemia or kidney failure, for example, who are at higher risk for bleeding, saw a relative risk reduction of around 50% in the screening group — though the numbers were too small for formal statistical analysis.

“In unselected patients with myocardial infarction we could not show a significant reduction in bleeding,” said Hofmann. “But it’s very likely that there is a clinical effect, at least in those individuals at increased risk of bleeding.”

Discussant Paul Ridker, MD, a cardiologist at Harvard Medical School, Boston, said he agreed that the trial was technically neutral but clinically positive. He noted that in every subgroup, the trend was in the direction of benefit, with only the top end of the cardiac indices crossing over into no benefit. And the benefit appeared larger among high-risk patients with anemia or kidney failure.

“These are the very patients I’m most concerned about and don’t want to bleed,” he said.Because the urea breath test and eradication therapy are simple, safe, and inexpensive, Hofmann said he thinks there is “good evidence to recommend H. pylori screening in patients at higher risk of bleeding.”

“I’m very sure from a clinical perspective that we will be able to identify the groups that are low-hanging fruit,” he said. “But the guideline committees will have to decide if this evidence is enough.”

Hofmann and Ridker reported having no financial conflicts of interest.

 

A version of this article appeared on Medscape.com.

Routine screening for Helicobacter pylori in patients hospitalized for myocardial infarction (MI) did not significantly reduce the risk for upper gastrointestinal bleeding overall — but benefits were seen in high-risk subgroups, according to the HELP-MI SWEDEHEART trial published in JAMA and presented at the European Society of Cardiology (ESC) Congress 2025.

Bleeding in the upper gastrointestinal tract is a common complication after MI. It increases morbidity and mortality itself but can also reduce the effectiveness of antithrombotic treatments and lead to new cardiovascular events. It is often related to infection with H. pylori, the bacterium that can cause stomach inflammation, ulcers, and cancer, said Robin Hofmann, MD, PhD, a cardiologist at the Karolinska Institute in Stockholm, Sweden, who presented the trial results.Hofmann and his colleagues wondered whether screening for the bacterium using a simple urea breath test would help reduce the risk for bleeds. Using Sweden’s national SWEDEHEART registry, researchers performed a cluster-randomized crossover trial of more than 18,000 patients with MI at 35 Swedish hospitals. They found that screening for H. pylori reduced the risk for upper gastrointestinal bleeding by 10%, but the results were not statistically significant.

Several factors may have contributed to the neutral result, noted Hofmann. Just 70% of the people in the screening population were actually screened — though he said that is a fairly good number for a diagnostic test. A relatively small number, around 23%, were positive for H. pylori, a much lower rate than in many other parts of the world, and about 25% of participants in both arms of the trial were already taking proton pump inhibitors to reduce the risk for bleeding.

 

Signals of Benefit in High-Risk Patients

But in some high-risk subgroups, there was a clearer signal of benefit. Patients with anemia or kidney failure, for example, who are at higher risk for bleeding, saw a relative risk reduction of around 50% in the screening group — though the numbers were too small for formal statistical analysis.

“In unselected patients with myocardial infarction we could not show a significant reduction in bleeding,” said Hofmann. “But it’s very likely that there is a clinical effect, at least in those individuals at increased risk of bleeding.”

Discussant Paul Ridker, MD, a cardiologist at Harvard Medical School, Boston, said he agreed that the trial was technically neutral but clinically positive. He noted that in every subgroup, the trend was in the direction of benefit, with only the top end of the cardiac indices crossing over into no benefit. And the benefit appeared larger among high-risk patients with anemia or kidney failure.

“These are the very patients I’m most concerned about and don’t want to bleed,” he said.Because the urea breath test and eradication therapy are simple, safe, and inexpensive, Hofmann said he thinks there is “good evidence to recommend H. pylori screening in patients at higher risk of bleeding.”

“I’m very sure from a clinical perspective that we will be able to identify the groups that are low-hanging fruit,” he said. “But the guideline committees will have to decide if this evidence is enough.”

Hofmann and Ridker reported having no financial conflicts of interest.

 

A version of this article appeared on Medscape.com.

Routine screening for Helicobacter pylori in patients hospitalized for myocardial infarction (MI) did not significantly reduce the risk for upper gastrointestinal bleeding overall — but benefits were seen in high-risk subgroups, according to the HELP-MI SWEDEHEART trial published in JAMA and presented at the European Society of Cardiology (ESC) Congress 2025.

Bleeding in the upper gastrointestinal tract is a common complication after MI. It increases morbidity and mortality itself but can also reduce the effectiveness of antithrombotic treatments and lead to new cardiovascular events. It is often related to infection with H. pylori, the bacterium that can cause stomach inflammation, ulcers, and cancer, said Robin Hofmann, MD, PhD, a cardiologist at the Karolinska Institute in Stockholm, Sweden, who presented the trial results.Hofmann and his colleagues wondered whether screening for the bacterium using a simple urea breath test would help reduce the risk for bleeds. Using Sweden’s national SWEDEHEART registry, researchers performed a cluster-randomized crossover trial of more than 18,000 patients with MI at 35 Swedish hospitals. They found that screening for H. pylori reduced the risk for upper gastrointestinal bleeding by 10%, but the results were not statistically significant.

Several factors may have contributed to the neutral result, noted Hofmann. Just 70% of the people in the screening population were actually screened — though he said that is a fairly good number for a diagnostic test. A relatively small number, around 23%, were positive for H. pylori, a much lower rate than in many other parts of the world, and about 25% of participants in both arms of the trial were already taking proton pump inhibitors to reduce the risk for bleeding.

 

Signals of Benefit in High-Risk Patients

But in some high-risk subgroups, there was a clearer signal of benefit. Patients with anemia or kidney failure, for example, who are at higher risk for bleeding, saw a relative risk reduction of around 50% in the screening group — though the numbers were too small for formal statistical analysis.

“In unselected patients with myocardial infarction we could not show a significant reduction in bleeding,” said Hofmann. “But it’s very likely that there is a clinical effect, at least in those individuals at increased risk of bleeding.”

Discussant Paul Ridker, MD, a cardiologist at Harvard Medical School, Boston, said he agreed that the trial was technically neutral but clinically positive. He noted that in every subgroup, the trend was in the direction of benefit, with only the top end of the cardiac indices crossing over into no benefit. And the benefit appeared larger among high-risk patients with anemia or kidney failure.

“These are the very patients I’m most concerned about and don’t want to bleed,” he said.Because the urea breath test and eradication therapy are simple, safe, and inexpensive, Hofmann said he thinks there is “good evidence to recommend H. pylori screening in patients at higher risk of bleeding.”

“I’m very sure from a clinical perspective that we will be able to identify the groups that are low-hanging fruit,” he said. “But the guideline committees will have to decide if this evidence is enough.”

Hofmann and Ridker reported having no financial conflicts of interest.

 

A version of this article appeared on Medscape.com.

PHOENIX – Three decades after he initiated the transformation of the Veterans Health Administration (VHA) into a model research and clinical health care system, former US Department of Veterans Affairs (VA) Under Secretary of Health Kenneth W. Kizer, MD, MPH, urged cancer specialists to embrace this challenging moment as an opportunity for bold innovation.

At the annual meeting of the Association of VA Hematology/Oncology (AVAHO), Kizer acknowledged that the VA faces an “uncertain and turbulent time” in areas such as funding, staffing, community care implementation, and the rollout of a new electronic health record system. 

He also noted the grim rise of global instability, economic turmoil, climate change, infectious diseases, political violence, and mass shootings.

“This can be stressful. It can create negative energy. But this uncertainty can also be liberating, and it can prompt positive energy and innovation, depending on choices that we make,” said Kizer, who also has served as California’s top health official prior to leading the VHA from 1994 to 1999.

From “Bloated Bureaucracy’ to High-Quality Health Care System

Kizer has been credited with revitalizing VHA care through a greater commitment to quality, and harkened to his work with the VA as an example of how bold goals can lead to bold innovation. 

“What were the perceptions of VA health care in 1994? Well, they weren’t very good, frankly,” Kizer recalled. He described the VA as having a reputation at that time as “highly dysfunctional” with “a very bloated and entrenched bureaucracy.” As for quality of care, it “wasn’t viewed as very good.”

The system’s problems were so severe that patients would park motorhomes in VA medical center parking lots as they waited for care. “While they might have an appointment for one day, they may not be seen for 3 or 4 or 5 days. So they would stay in their motorhome until they finally got into their clinic appointment,” Kizer said.

Overall, “the public viewed the VA as this bleak backwater of incompetence and difference and inefficiency, and there were very strong calls to privatize the VA,” Kizer said. 

Kizer asked colleagues about what he should do after he was asked to take the under secretary job. “With one exception, they all said, don’t go near it. Don’t touch it. Walk away. That it’s impossible to change the organization.

“I looked at the VA and I saw an opportunity. When I told [members of the President Bill] Clinton [Administration] yes, my bold aim was that I would like to pursue this was to make VHA a model of excellent health care, an exemplary health care system. Most everyone else thought that I was totally delusional, but sometimes it’s good to be delusional.”

Revolutionary Changes Despite Opposition

Kizer sought reforms in 5 major strategic objectives, all without explicit congressional approval: creating an accountable management structure, decentralizing decision-making, integrating care, implementing universal primary care, and pursuing eligibility reform to create the current 8-tier VA system.

One major innovation was the implementation of community-based outpatient clinics (CBOCs): “Those were strongly opposed initially,” Kizer said. “Everyone, the veteran community in particular, had been led to believe that the only good care was in the hospital.”

The resistance was substantial. “There was a lot of opposition when we said we’re going to move out into the community where you live to make [care] easier to access,” Kizer said.

To make things more difficult, Congress wouldn’t fund the project: “For the first 3 years, every CBOC had to be funded by redirected savings from other things that we could do within the system,” he said. “All of this was through redirected savings and finding ways to save and reinvest.”

Innovation From the Ground Up

Kizer emphasized that many breakthrough innovations came from frontline staff rather than executive mandates. He cited the example of Barcode Medication Administration, which originated from a nurse in Topeka, Kan.

The nurse saw a barcode scanner put to work at a rental car company where it was used to check cars in and out. She wondered, “Why can’t we do this with medications when they’re given on the floor? We followed up on it, pursued those things, tested it out, it worked.”

The results were dramatic. “I was told at a meeting that they had achieved close to 80% reduction in medication errors,” Kizer said. After verifying the results personally, he “authorized $20 million, and we moved forward with it systemwide.”

This experience reinforced his belief in harvesting ideas from staff at all levels. 

Innovation remains part of the VA’s culture “despite what some people would have you believe,” Kizer said. Recently, the VA has made major advances in areas such as patient transportation and the climate crisis, he said. 

Inside the Recipe for Innovation

Boldness, persistence, adaptability, and tolerance for risk are necessary ingredients for high-risk goals, Kizer said. Ambition is also part of the picture. 

He highlighted examples such as the Apollo moon landing, the first sub-4-minute mile, and the first swim across the English Channel by a woman.

In medicine, Kizer pointed to a national patient safety campaign that saved an estimated 122,000 lives. He also mentioned recent progress in organ transplantation such as recommendations from the National Academies of Sciences, Engineering, and Medicine to establish national performance goals and the Organ Procurement and Transplantation Network’s target of 60,000 deceased donor transplants by 2026.

Bold doesn’t mean being reckless or careless, Kizer said. “But it does require innovation. And it does require that you try some new things, some of which aren’t going to work out.”

The key mindset, he explained, is to “embrace the unknown” because “you often really don’t know how you will accomplish the aim when you start. But you’ll figure it out as you go.”

Kizer highlighted 2 opposing strategies to handling challenging times. 

According to him, the “negative energy” approach focuses on frustrations, limitations, and asking “Why is this happening to me?” 

In contrast, a “positive energy” approach expects problems, focuses on available resources and capabilities, and asks, “What are the opportunities that these changes are creating for me?”

Kizer made it crystal clear which option he prefers.

Dr. Kizer disclosed that his comments represent his opinions only, and he noted his ongoing connections to the VA.

PHOENIX – Three decades after he initiated the transformation of the Veterans Health Administration (VHA) into a model research and clinical health care system, former US Department of Veterans Affairs (VA) Under Secretary of Health Kenneth W. Kizer, MD, MPH, urged cancer specialists to embrace this challenging moment as an opportunity for bold innovation.

At the annual meeting of the Association of VA Hematology/Oncology (AVAHO), Kizer acknowledged that the VA faces an “uncertain and turbulent time” in areas such as funding, staffing, community care implementation, and the rollout of a new electronic health record system. 

He also noted the grim rise of global instability, economic turmoil, climate change, infectious diseases, political violence, and mass shootings.

“This can be stressful. It can create negative energy. But this uncertainty can also be liberating, and it can prompt positive energy and innovation, depending on choices that we make,” said Kizer, who also has served as California’s top health official prior to leading the VHA from 1994 to 1999.

From “Bloated Bureaucracy’ to High-Quality Health Care System

Kizer has been credited with revitalizing VHA care through a greater commitment to quality, and harkened to his work with the VA as an example of how bold goals can lead to bold innovation. 

“What were the perceptions of VA health care in 1994? Well, they weren’t very good, frankly,” Kizer recalled. He described the VA as having a reputation at that time as “highly dysfunctional” with “a very bloated and entrenched bureaucracy.” As for quality of care, it “wasn’t viewed as very good.”

The system’s problems were so severe that patients would park motorhomes in VA medical center parking lots as they waited for care. “While they might have an appointment for one day, they may not be seen for 3 or 4 or 5 days. So they would stay in their motorhome until they finally got into their clinic appointment,” Kizer said.

Overall, “the public viewed the VA as this bleak backwater of incompetence and difference and inefficiency, and there were very strong calls to privatize the VA,” Kizer said. 

Kizer asked colleagues about what he should do after he was asked to take the under secretary job. “With one exception, they all said, don’t go near it. Don’t touch it. Walk away. That it’s impossible to change the organization.

“I looked at the VA and I saw an opportunity. When I told [members of the President Bill] Clinton [Administration] yes, my bold aim was that I would like to pursue this was to make VHA a model of excellent health care, an exemplary health care system. Most everyone else thought that I was totally delusional, but sometimes it’s good to be delusional.”

Revolutionary Changes Despite Opposition

Kizer sought reforms in 5 major strategic objectives, all without explicit congressional approval: creating an accountable management structure, decentralizing decision-making, integrating care, implementing universal primary care, and pursuing eligibility reform to create the current 8-tier VA system.

One major innovation was the implementation of community-based outpatient clinics (CBOCs): “Those were strongly opposed initially,” Kizer said. “Everyone, the veteran community in particular, had been led to believe that the only good care was in the hospital.”

The resistance was substantial. “There was a lot of opposition when we said we’re going to move out into the community where you live to make [care] easier to access,” Kizer said.

To make things more difficult, Congress wouldn’t fund the project: “For the first 3 years, every CBOC had to be funded by redirected savings from other things that we could do within the system,” he said. “All of this was through redirected savings and finding ways to save and reinvest.”

Innovation From the Ground Up

Kizer emphasized that many breakthrough innovations came from frontline staff rather than executive mandates. He cited the example of Barcode Medication Administration, which originated from a nurse in Topeka, Kan.

The nurse saw a barcode scanner put to work at a rental car company where it was used to check cars in and out. She wondered, “Why can’t we do this with medications when they’re given on the floor? We followed up on it, pursued those things, tested it out, it worked.”

The results were dramatic. “I was told at a meeting that they had achieved close to 80% reduction in medication errors,” Kizer said. After verifying the results personally, he “authorized $20 million, and we moved forward with it systemwide.”

This experience reinforced his belief in harvesting ideas from staff at all levels. 

Innovation remains part of the VA’s culture “despite what some people would have you believe,” Kizer said. Recently, the VA has made major advances in areas such as patient transportation and the climate crisis, he said. 

Inside the Recipe for Innovation

Boldness, persistence, adaptability, and tolerance for risk are necessary ingredients for high-risk goals, Kizer said. Ambition is also part of the picture. 

He highlighted examples such as the Apollo moon landing, the first sub-4-minute mile, and the first swim across the English Channel by a woman.

In medicine, Kizer pointed to a national patient safety campaign that saved an estimated 122,000 lives. He also mentioned recent progress in organ transplantation such as recommendations from the National Academies of Sciences, Engineering, and Medicine to establish national performance goals and the Organ Procurement and Transplantation Network’s target of 60,000 deceased donor transplants by 2026.

Bold doesn’t mean being reckless or careless, Kizer said. “But it does require innovation. And it does require that you try some new things, some of which aren’t going to work out.”

The key mindset, he explained, is to “embrace the unknown” because “you often really don’t know how you will accomplish the aim when you start. But you’ll figure it out as you go.”

Kizer highlighted 2 opposing strategies to handling challenging times. 

According to him, the “negative energy” approach focuses on frustrations, limitations, and asking “Why is this happening to me?” 

In contrast, a “positive energy” approach expects problems, focuses on available resources and capabilities, and asks, “What are the opportunities that these changes are creating for me?”

Kizer made it crystal clear which option he prefers.

Dr. Kizer disclosed that his comments represent his opinions only, and he noted his ongoing connections to the VA.

PHOENIX – Three decades after he initiated the transformation of the Veterans Health Administration (VHA) into a model research and clinical health care system, former US Department of Veterans Affairs (VA) Under Secretary of Health Kenneth W. Kizer, MD, MPH, urged cancer specialists to embrace this challenging moment as an opportunity for bold innovation.

At the annual meeting of the Association of VA Hematology/Oncology (AVAHO), Kizer acknowledged that the VA faces an “uncertain and turbulent time” in areas such as funding, staffing, community care implementation, and the rollout of a new electronic health record system. 

He also noted the grim rise of global instability, economic turmoil, climate change, infectious diseases, political violence, and mass shootings.

“This can be stressful. It can create negative energy. But this uncertainty can also be liberating, and it can prompt positive energy and innovation, depending on choices that we make,” said Kizer, who also has served as California’s top health official prior to leading the VHA from 1994 to 1999.

From “Bloated Bureaucracy’ to High-Quality Health Care System

Kizer has been credited with revitalizing VHA care through a greater commitment to quality, and harkened to his work with the VA as an example of how bold goals can lead to bold innovation. 

“What were the perceptions of VA health care in 1994? Well, they weren’t very good, frankly,” Kizer recalled. He described the VA as having a reputation at that time as “highly dysfunctional” with “a very bloated and entrenched bureaucracy.” As for quality of care, it “wasn’t viewed as very good.”

The system’s problems were so severe that patients would park motorhomes in VA medical center parking lots as they waited for care. “While they might have an appointment for one day, they may not be seen for 3 or 4 or 5 days. So they would stay in their motorhome until they finally got into their clinic appointment,” Kizer said.

Overall, “the public viewed the VA as this bleak backwater of incompetence and difference and inefficiency, and there were very strong calls to privatize the VA,” Kizer said. 

Kizer asked colleagues about what he should do after he was asked to take the under secretary job. “With one exception, they all said, don’t go near it. Don’t touch it. Walk away. That it’s impossible to change the organization.

“I looked at the VA and I saw an opportunity. When I told [members of the President Bill] Clinton [Administration] yes, my bold aim was that I would like to pursue this was to make VHA a model of excellent health care, an exemplary health care system. Most everyone else thought that I was totally delusional, but sometimes it’s good to be delusional.”

Revolutionary Changes Despite Opposition

Kizer sought reforms in 5 major strategic objectives, all without explicit congressional approval: creating an accountable management structure, decentralizing decision-making, integrating care, implementing universal primary care, and pursuing eligibility reform to create the current 8-tier VA system.

One major innovation was the implementation of community-based outpatient clinics (CBOCs): “Those were strongly opposed initially,” Kizer said. “Everyone, the veteran community in particular, had been led to believe that the only good care was in the hospital.”

The resistance was substantial. “There was a lot of opposition when we said we’re going to move out into the community where you live to make [care] easier to access,” Kizer said.

To make things more difficult, Congress wouldn’t fund the project: “For the first 3 years, every CBOC had to be funded by redirected savings from other things that we could do within the system,” he said. “All of this was through redirected savings and finding ways to save and reinvest.”

Innovation From the Ground Up

Kizer emphasized that many breakthrough innovations came from frontline staff rather than executive mandates. He cited the example of Barcode Medication Administration, which originated from a nurse in Topeka, Kan.

The nurse saw a barcode scanner put to work at a rental car company where it was used to check cars in and out. She wondered, “Why can’t we do this with medications when they’re given on the floor? We followed up on it, pursued those things, tested it out, it worked.”

The results were dramatic. “I was told at a meeting that they had achieved close to 80% reduction in medication errors,” Kizer said. After verifying the results personally, he “authorized $20 million, and we moved forward with it systemwide.”

This experience reinforced his belief in harvesting ideas from staff at all levels. 

Innovation remains part of the VA’s culture “despite what some people would have you believe,” Kizer said. Recently, the VA has made major advances in areas such as patient transportation and the climate crisis, he said. 

Inside the Recipe for Innovation

Boldness, persistence, adaptability, and tolerance for risk are necessary ingredients for high-risk goals, Kizer said. Ambition is also part of the picture. 

He highlighted examples such as the Apollo moon landing, the first sub-4-minute mile, and the first swim across the English Channel by a woman.

In medicine, Kizer pointed to a national patient safety campaign that saved an estimated 122,000 lives. He also mentioned recent progress in organ transplantation such as recommendations from the National Academies of Sciences, Engineering, and Medicine to establish national performance goals and the Organ Procurement and Transplantation Network’s target of 60,000 deceased donor transplants by 2026.

Bold doesn’t mean being reckless or careless, Kizer said. “But it does require innovation. And it does require that you try some new things, some of which aren’t going to work out.”

The key mindset, he explained, is to “embrace the unknown” because “you often really don’t know how you will accomplish the aim when you start. But you’ll figure it out as you go.”

Kizer highlighted 2 opposing strategies to handling challenging times. 

According to him, the “negative energy” approach focuses on frustrations, limitations, and asking “Why is this happening to me?” 

In contrast, a “positive energy” approach expects problems, focuses on available resources and capabilities, and asks, “What are the opportunities that these changes are creating for me?”

Kizer made it crystal clear which option he prefers.

Dr. Kizer disclosed that his comments represent his opinions only, and he noted his ongoing connections to the VA.

Large language models (LLMs) may help streamline clinical guideline development by dramatically reducing the time and cost required for systematic reviews, according to a pilot study from the American Gastroenterological Association (AGA).

Faster, cheaper study screening could allow societies to update clinical recommendations more frequently, improving alignment with the latest evidence, lead author Sunny Chung, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.

“Each guideline typically requires 5 to 15 systematic reviews, making the process time-consuming (averaging more than 60 weeks) and costly (more than $140,000),” the investigators wrote in Gastroenterology . “One of the most critical yet time-consuming steps in systematic reviews is title and abstract screening. LLMs have the potential to make this step more efficient.”

To test this approach, the investigators developed, validated, and applied a dual-model LLM screening pipeline with human-in-the-loop oversight, focusing on randomized controlled trials in AGA guidelines. 

The system was built using the 2021 guideline on moderate-to-severe Crohn’s disease, targeting biologic therapies for induction and maintenance of remission. 

Using chain-of-thought prompting and structured inclusion criteria based on the PICO framework, the investigators deployed GPT-4o (OpenAI) and Gemini-1.5-Pro (Google DeepMind) as independent screeners, each assessing titles and abstracts according to standardized logic encoded in JavaScript Object Notation. This approach mimicked a traditional double-reviewer system.

After initial testing, the pipeline was validated in a 2025 update of the same guideline, this time spanning 6 focused clinical questions on advanced therapies and immunomodulators. Results were compared against manual screening by 2 experienced human reviewers, with total screening time documented. 

The system was then tested across 4 additional guideline topics: fecal microbiota transplantation (FMT) for irritable bowel syndrome and Clostridioides difficile, gastroparesis, and hepatocellular carcinoma. A final test applied the system to a forthcoming guideline on complications of acute pancreatitis.

Across all topics, the dual-LLM system achieved 100% sensitivity in identifying randomized controlled trials (RCTs). For the 2025 update of the AGA guideline on Crohn’s disease, the models flagged 418 of 4,377 abstracts for inclusion, captur-ing all 25 relevant RCTs in just 48 minutes. Manual screening of the same dataset previously took almost 13 hours.

Comparable accuracy and time savings were observed for the other topics. 

The pipeline correctly flagged all 13 RCTs in 4,820 studies on FMT for irritable bowel syndrome, and all 16 RCTs in 5,587 studies on FMT for Clostridioides difficile, requiring 27 and 66 minutes, respectively. Similarly, the system captured all 11 RCTs in 3,919 hepatocellular carcinoma abstracts and all 18 RCTs in 1,578 studies on gastroparesis, completing each task in under 65 minutes. Early testing on the upcoming guideline for pancreatitis yielded similar results.

Cost analysis underscored the efficiency of this approach. At an estimated $175–200 per hour for expert screeners, traditional abstract screening would cost around $2,500 per review, versus approximately $100 for the LLM approach—a 96% reduction.

The investigators cautioned that human oversight remains necessary to verify the relevance of studies flagged by the models. While the system’s sensitivity was consistent, it also selected articles that were ultimately excluded by expert reviewers. Broader validation will be required to assess performance across non-RCT study designs, such as observational or case-control studies, they added.

“As medical literature continues to expand, the integration of artificial intelligence into evidence synthesis processes will become increasingly vital,” Dr. Chung and colleagues wrote. “With further refinement and broader validation, this LLM-based pipeline has the potential to revolutionize evidence synthesis and set a new standard for guideline development.”

This study was funded by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. The investigators reported no conflicts of interest.
 

Large language models (LLMs) may help streamline clinical guideline development by dramatically reducing the time and cost required for systematic reviews, according to a pilot study from the American Gastroenterological Association (AGA).

Faster, cheaper study screening could allow societies to update clinical recommendations more frequently, improving alignment with the latest evidence, lead author Sunny Chung, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.

“Each guideline typically requires 5 to 15 systematic reviews, making the process time-consuming (averaging more than 60 weeks) and costly (more than $140,000),” the investigators wrote in Gastroenterology . “One of the most critical yet time-consuming steps in systematic reviews is title and abstract screening. LLMs have the potential to make this step more efficient.”

To test this approach, the investigators developed, validated, and applied a dual-model LLM screening pipeline with human-in-the-loop oversight, focusing on randomized controlled trials in AGA guidelines. 

The system was built using the 2021 guideline on moderate-to-severe Crohn’s disease, targeting biologic therapies for induction and maintenance of remission. 

Using chain-of-thought prompting and structured inclusion criteria based on the PICO framework, the investigators deployed GPT-4o (OpenAI) and Gemini-1.5-Pro (Google DeepMind) as independent screeners, each assessing titles and abstracts according to standardized logic encoded in JavaScript Object Notation. This approach mimicked a traditional double-reviewer system.

After initial testing, the pipeline was validated in a 2025 update of the same guideline, this time spanning 6 focused clinical questions on advanced therapies and immunomodulators. Results were compared against manual screening by 2 experienced human reviewers, with total screening time documented. 

The system was then tested across 4 additional guideline topics: fecal microbiota transplantation (FMT) for irritable bowel syndrome and Clostridioides difficile, gastroparesis, and hepatocellular carcinoma. A final test applied the system to a forthcoming guideline on complications of acute pancreatitis.

Across all topics, the dual-LLM system achieved 100% sensitivity in identifying randomized controlled trials (RCTs). For the 2025 update of the AGA guideline on Crohn’s disease, the models flagged 418 of 4,377 abstracts for inclusion, captur-ing all 25 relevant RCTs in just 48 minutes. Manual screening of the same dataset previously took almost 13 hours.

Comparable accuracy and time savings were observed for the other topics. 

The pipeline correctly flagged all 13 RCTs in 4,820 studies on FMT for irritable bowel syndrome, and all 16 RCTs in 5,587 studies on FMT for Clostridioides difficile, requiring 27 and 66 minutes, respectively. Similarly, the system captured all 11 RCTs in 3,919 hepatocellular carcinoma abstracts and all 18 RCTs in 1,578 studies on gastroparesis, completing each task in under 65 minutes. Early testing on the upcoming guideline for pancreatitis yielded similar results.

Cost analysis underscored the efficiency of this approach. At an estimated $175–200 per hour for expert screeners, traditional abstract screening would cost around $2,500 per review, versus approximately $100 for the LLM approach—a 96% reduction.

The investigators cautioned that human oversight remains necessary to verify the relevance of studies flagged by the models. While the system’s sensitivity was consistent, it also selected articles that were ultimately excluded by expert reviewers. Broader validation will be required to assess performance across non-RCT study designs, such as observational or case-control studies, they added.

“As medical literature continues to expand, the integration of artificial intelligence into evidence synthesis processes will become increasingly vital,” Dr. Chung and colleagues wrote. “With further refinement and broader validation, this LLM-based pipeline has the potential to revolutionize evidence synthesis and set a new standard for guideline development.”

This study was funded by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. The investigators reported no conflicts of interest.
 

Large language models (LLMs) may help streamline clinical guideline development by dramatically reducing the time and cost required for systematic reviews, according to a pilot study from the American Gastroenterological Association (AGA).

Faster, cheaper study screening could allow societies to update clinical recommendations more frequently, improving alignment with the latest evidence, lead author Sunny Chung, MD, of Yale School of Medicine, New Haven, Connecticut, and colleagues, reported.

“Each guideline typically requires 5 to 15 systematic reviews, making the process time-consuming (averaging more than 60 weeks) and costly (more than $140,000),” the investigators wrote in Gastroenterology . “One of the most critical yet time-consuming steps in systematic reviews is title and abstract screening. LLMs have the potential to make this step more efficient.”

To test this approach, the investigators developed, validated, and applied a dual-model LLM screening pipeline with human-in-the-loop oversight, focusing on randomized controlled trials in AGA guidelines. 

The system was built using the 2021 guideline on moderate-to-severe Crohn’s disease, targeting biologic therapies for induction and maintenance of remission. 

Using chain-of-thought prompting and structured inclusion criteria based on the PICO framework, the investigators deployed GPT-4o (OpenAI) and Gemini-1.5-Pro (Google DeepMind) as independent screeners, each assessing titles and abstracts according to standardized logic encoded in JavaScript Object Notation. This approach mimicked a traditional double-reviewer system.

After initial testing, the pipeline was validated in a 2025 update of the same guideline, this time spanning 6 focused clinical questions on advanced therapies and immunomodulators. Results were compared against manual screening by 2 experienced human reviewers, with total screening time documented. 

The system was then tested across 4 additional guideline topics: fecal microbiota transplantation (FMT) for irritable bowel syndrome and Clostridioides difficile, gastroparesis, and hepatocellular carcinoma. A final test applied the system to a forthcoming guideline on complications of acute pancreatitis.

Across all topics, the dual-LLM system achieved 100% sensitivity in identifying randomized controlled trials (RCTs). For the 2025 update of the AGA guideline on Crohn’s disease, the models flagged 418 of 4,377 abstracts for inclusion, captur-ing all 25 relevant RCTs in just 48 minutes. Manual screening of the same dataset previously took almost 13 hours.

Comparable accuracy and time savings were observed for the other topics. 

The pipeline correctly flagged all 13 RCTs in 4,820 studies on FMT for irritable bowel syndrome, and all 16 RCTs in 5,587 studies on FMT for Clostridioides difficile, requiring 27 and 66 minutes, respectively. Similarly, the system captured all 11 RCTs in 3,919 hepatocellular carcinoma abstracts and all 18 RCTs in 1,578 studies on gastroparesis, completing each task in under 65 minutes. Early testing on the upcoming guideline for pancreatitis yielded similar results.

Cost analysis underscored the efficiency of this approach. At an estimated $175–200 per hour for expert screeners, traditional abstract screening would cost around $2,500 per review, versus approximately $100 for the LLM approach—a 96% reduction.

The investigators cautioned that human oversight remains necessary to verify the relevance of studies flagged by the models. While the system’s sensitivity was consistent, it also selected articles that were ultimately excluded by expert reviewers. Broader validation will be required to assess performance across non-RCT study designs, such as observational or case-control studies, they added.

“As medical literature continues to expand, the integration of artificial intelligence into evidence synthesis processes will become increasingly vital,” Dr. Chung and colleagues wrote. “With further refinement and broader validation, this LLM-based pipeline has the potential to revolutionize evidence synthesis and set a new standard for guideline development.”

This study was funded by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. The investigators reported no conflicts of interest.
 

The first-ever global guidelines for pregnancy and inflammatory bowel disease (IBD) recommend continuing biologics and low-risk medications through pregnancy and lactation in women with IBD, suggesting this approach will not harm the fetus.

The guidelines also recommend that all women with IBD receive preconception counseling and be followed as high-risk pregnancies.

“Management of chronic illness in pregnant women has always been defined by fear of harming the fetus,” said Uma Mahadevan, MD, AGAF, director of the Colitis and Crohn’s Disease Center at the University of California San Francisco and chair of the Global Consensus Consortium that developed the guidelines. 

As a result, pregnant women are excluded from clinical trials of experimental therapies for IBD. And when a new therapy achieves regulatory approval, there are no human pregnancy safety data, only animal data. To fill this gap, the PIANO study, of which Mahadevan is principal investigator, looked at the safety of IBD medications in pregnancy and short- and long-term outcomes of the children.

“With our ongoing work in pregnancy in the patient with IBD, we realized that inflammation in the mother is the leading cause of poor outcome for the infant,” she told GI & Hepatology News. 

“We also have a better understanding of placental transfer of biologic agents” and the lack of exposure to the fetus during the first trimester, “a key period of organogenesis,” she added. 

Final recommendations were published simultaneously in six international journals, namely, Clinical Gastroenterology and Hepatology, American Journal of Gastroenterology, GUT, Inflammatory Bowel Diseases, Journal of Crohn’s and Colitis, and Alimentary Pharmacology and Therapeutics.

 

Surprising, Novel Findings

Limited provider knowledge led to varied practices in caring for women with IBD who become pregnant, according to the consensus authors. Practices are affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus. 

“The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike,” the authors of the guidelines wrote. 

Therefore, the Global Consensus Consortium — a group of 39 IBD experts, including teratologists and maternal fetal medicine specialists and seven patient advocates from six continents — convened to review and assess current data and come to an agreement on best practices. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used when sufficient published data were available, and the Research and Development process when expert opinion was needed to guide consistent practice.

“Some of the findings were expected, but others were novel,” said Mahadevan. 

Recommendations that might surprise clinicians include GRADE statement 9, which suggests that pregnant women with IBD take low-dose aspirin by 12 to 16 weeks’ gestation to prevent preterm preeclampsia. “This is based on the ASPRE study, showing that women at risk of preeclampsia can lower their risk by taking low-dose aspirin,” with no risk for flare, Mahadevan said.

In addition, GRADE statements 17-20 recommend/suggest that women continue their biologic throughout pregnancy without stopping. “North America has always recommended continuing during the third trimester, while Europe only recently has come to this,” Mahadevan said. “However, there was always some looseness about stopping at week X, Y, or Z. Now, we do recommend continuing the dose on schedule with no holding.”

Continuing medications considered low risk for use during pregnancy, such as 5-amino salicylic acids, sulfasalazine, thiopurines, and all monoclonal antibodies during preconception, pregnancy, and lactation, was also recommended. 

However, small-molecule drugs such as S1P receptor molecules and JAK inhibitors should be avoided for at least 1 month, and in some cases for 3 months prior to attempting conception, unless there is no alternative for the health of the mother. They should also be avoided during lactation.

Grade statement 33, which suggests that live rotavirus vaccine may be provided in children with in utero exposure to biologics, is also new, Mahadevan noted. “All prior recommendations were that no live vaccine should be given in the first 6 months or longer if infants were exposed to biologics in utero, but based on a prospective Canadian study, there is no harm when given to these infants.”

Another novel recommendation is that women with IBD on any monoclonal antibodies, including newer interleukin-23s, may breastfeed even though there are not clinical trial data at this point. The recommendation to continue them through pregnancy and lactation is based on placental physiology, as well as on the physiology of monoclonal antibody transfer in breast milk, according to the consortium.

Furthermore, the authors noted, there was no increase in infant infections at 4 months or 12 months if they were exposed to a biologic or thiopurine (or both) during pregnancy.

Overall, the consortium recommended that all pregnancies for women with IBD be considered as “high risk” for complications. This is due to the fact that many parts of the world, including the US, are “resource-limited,” Mahadevan explained. Since maternal fetal medicine specialists are not widely available, the consortium suggested all these patients be followed with increased monitoring and surveillance based on available resources.

In addition to the guidelines, patient videos in seven languages, a professional slide deck in English and Spanish, and a video on the global consensus are all available at https://pianostudy.org/.

This study was funded by The Leona B. and Harry H. Helmsley Charitable Trust.

Mahadevan reported being a consultant for AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Enveda, Gilead, Janssen, Lilly, Merck, Pfizer, Protagonist, Roivant, and Takeda.

A version of this article appeared on Medscape.com. 

The first-ever global guidelines for pregnancy and inflammatory bowel disease (IBD) recommend continuing biologics and low-risk medications through pregnancy and lactation in women with IBD, suggesting this approach will not harm the fetus.

The guidelines also recommend that all women with IBD receive preconception counseling and be followed as high-risk pregnancies.

“Management of chronic illness in pregnant women has always been defined by fear of harming the fetus,” said Uma Mahadevan, MD, AGAF, director of the Colitis and Crohn’s Disease Center at the University of California San Francisco and chair of the Global Consensus Consortium that developed the guidelines. 

As a result, pregnant women are excluded from clinical trials of experimental therapies for IBD. And when a new therapy achieves regulatory approval, there are no human pregnancy safety data, only animal data. To fill this gap, the PIANO study, of which Mahadevan is principal investigator, looked at the safety of IBD medications in pregnancy and short- and long-term outcomes of the children.

“With our ongoing work in pregnancy in the patient with IBD, we realized that inflammation in the mother is the leading cause of poor outcome for the infant,” she told GI & Hepatology News. 

“We also have a better understanding of placental transfer of biologic agents” and the lack of exposure to the fetus during the first trimester, “a key period of organogenesis,” she added. 

Final recommendations were published simultaneously in six international journals, namely, Clinical Gastroenterology and Hepatology, American Journal of Gastroenterology, GUT, Inflammatory Bowel Diseases, Journal of Crohn’s and Colitis, and Alimentary Pharmacology and Therapeutics.

 

Surprising, Novel Findings

Limited provider knowledge led to varied practices in caring for women with IBD who become pregnant, according to the consensus authors. Practices are affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus. 

“The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike,” the authors of the guidelines wrote. 

Therefore, the Global Consensus Consortium — a group of 39 IBD experts, including teratologists and maternal fetal medicine specialists and seven patient advocates from six continents — convened to review and assess current data and come to an agreement on best practices. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used when sufficient published data were available, and the Research and Development process when expert opinion was needed to guide consistent practice.

“Some of the findings were expected, but others were novel,” said Mahadevan. 

Recommendations that might surprise clinicians include GRADE statement 9, which suggests that pregnant women with IBD take low-dose aspirin by 12 to 16 weeks’ gestation to prevent preterm preeclampsia. “This is based on the ASPRE study, showing that women at risk of preeclampsia can lower their risk by taking low-dose aspirin,” with no risk for flare, Mahadevan said.

In addition, GRADE statements 17-20 recommend/suggest that women continue their biologic throughout pregnancy without stopping. “North America has always recommended continuing during the third trimester, while Europe only recently has come to this,” Mahadevan said. “However, there was always some looseness about stopping at week X, Y, or Z. Now, we do recommend continuing the dose on schedule with no holding.”

Continuing medications considered low risk for use during pregnancy, such as 5-amino salicylic acids, sulfasalazine, thiopurines, and all monoclonal antibodies during preconception, pregnancy, and lactation, was also recommended. 

However, small-molecule drugs such as S1P receptor molecules and JAK inhibitors should be avoided for at least 1 month, and in some cases for 3 months prior to attempting conception, unless there is no alternative for the health of the mother. They should also be avoided during lactation.

Grade statement 33, which suggests that live rotavirus vaccine may be provided in children with in utero exposure to biologics, is also new, Mahadevan noted. “All prior recommendations were that no live vaccine should be given in the first 6 months or longer if infants were exposed to biologics in utero, but based on a prospective Canadian study, there is no harm when given to these infants.”

Another novel recommendation is that women with IBD on any monoclonal antibodies, including newer interleukin-23s, may breastfeed even though there are not clinical trial data at this point. The recommendation to continue them through pregnancy and lactation is based on placental physiology, as well as on the physiology of monoclonal antibody transfer in breast milk, according to the consortium.

Furthermore, the authors noted, there was no increase in infant infections at 4 months or 12 months if they were exposed to a biologic or thiopurine (or both) during pregnancy.

Overall, the consortium recommended that all pregnancies for women with IBD be considered as “high risk” for complications. This is due to the fact that many parts of the world, including the US, are “resource-limited,” Mahadevan explained. Since maternal fetal medicine specialists are not widely available, the consortium suggested all these patients be followed with increased monitoring and surveillance based on available resources.

In addition to the guidelines, patient videos in seven languages, a professional slide deck in English and Spanish, and a video on the global consensus are all available at https://pianostudy.org/.

This study was funded by The Leona B. and Harry H. Helmsley Charitable Trust.

Mahadevan reported being a consultant for AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Enveda, Gilead, Janssen, Lilly, Merck, Pfizer, Protagonist, Roivant, and Takeda.

A version of this article appeared on Medscape.com. 

The first-ever global guidelines for pregnancy and inflammatory bowel disease (IBD) recommend continuing biologics and low-risk medications through pregnancy and lactation in women with IBD, suggesting this approach will not harm the fetus.

The guidelines also recommend that all women with IBD receive preconception counseling and be followed as high-risk pregnancies.

“Management of chronic illness in pregnant women has always been defined by fear of harming the fetus,” said Uma Mahadevan, MD, AGAF, director of the Colitis and Crohn’s Disease Center at the University of California San Francisco and chair of the Global Consensus Consortium that developed the guidelines. 

As a result, pregnant women are excluded from clinical trials of experimental therapies for IBD. And when a new therapy achieves regulatory approval, there are no human pregnancy safety data, only animal data. To fill this gap, the PIANO study, of which Mahadevan is principal investigator, looked at the safety of IBD medications in pregnancy and short- and long-term outcomes of the children.

“With our ongoing work in pregnancy in the patient with IBD, we realized that inflammation in the mother is the leading cause of poor outcome for the infant,” she told GI & Hepatology News. 

“We also have a better understanding of placental transfer of biologic agents” and the lack of exposure to the fetus during the first trimester, “a key period of organogenesis,” she added. 

Final recommendations were published simultaneously in six international journals, namely, Clinical Gastroenterology and Hepatology, American Journal of Gastroenterology, GUT, Inflammatory Bowel Diseases, Journal of Crohn’s and Colitis, and Alimentary Pharmacology and Therapeutics.

 

Surprising, Novel Findings

Limited provider knowledge led to varied practices in caring for women with IBD who become pregnant, according to the consensus authors. Practices are affected by local dogma, available resources, individual interpretation of the literature, and fear of harming the fetus. 

“The variations in guidelines by different societies and countries reflect this and lead to confusion for physicians and patients alike,” the authors of the guidelines wrote. 

Therefore, the Global Consensus Consortium — a group of 39 IBD experts, including teratologists and maternal fetal medicine specialists and seven patient advocates from six continents — convened to review and assess current data and come to an agreement on best practices. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used when sufficient published data were available, and the Research and Development process when expert opinion was needed to guide consistent practice.

“Some of the findings were expected, but others were novel,” said Mahadevan. 

Recommendations that might surprise clinicians include GRADE statement 9, which suggests that pregnant women with IBD take low-dose aspirin by 12 to 16 weeks’ gestation to prevent preterm preeclampsia. “This is based on the ASPRE study, showing that women at risk of preeclampsia can lower their risk by taking low-dose aspirin,” with no risk for flare, Mahadevan said.

In addition, GRADE statements 17-20 recommend/suggest that women continue their biologic throughout pregnancy without stopping. “North America has always recommended continuing during the third trimester, while Europe only recently has come to this,” Mahadevan said. “However, there was always some looseness about stopping at week X, Y, or Z. Now, we do recommend continuing the dose on schedule with no holding.”

Continuing medications considered low risk for use during pregnancy, such as 5-amino salicylic acids, sulfasalazine, thiopurines, and all monoclonal antibodies during preconception, pregnancy, and lactation, was also recommended. 

However, small-molecule drugs such as S1P receptor molecules and JAK inhibitors should be avoided for at least 1 month, and in some cases for 3 months prior to attempting conception, unless there is no alternative for the health of the mother. They should also be avoided during lactation.

Grade statement 33, which suggests that live rotavirus vaccine may be provided in children with in utero exposure to biologics, is also new, Mahadevan noted. “All prior recommendations were that no live vaccine should be given in the first 6 months or longer if infants were exposed to biologics in utero, but based on a prospective Canadian study, there is no harm when given to these infants.”

Another novel recommendation is that women with IBD on any monoclonal antibodies, including newer interleukin-23s, may breastfeed even though there are not clinical trial data at this point. The recommendation to continue them through pregnancy and lactation is based on placental physiology, as well as on the physiology of monoclonal antibody transfer in breast milk, according to the consortium.

Furthermore, the authors noted, there was no increase in infant infections at 4 months or 12 months if they were exposed to a biologic or thiopurine (or both) during pregnancy.

Overall, the consortium recommended that all pregnancies for women with IBD be considered as “high risk” for complications. This is due to the fact that many parts of the world, including the US, are “resource-limited,” Mahadevan explained. Since maternal fetal medicine specialists are not widely available, the consortium suggested all these patients be followed with increased monitoring and surveillance based on available resources.

In addition to the guidelines, patient videos in seven languages, a professional slide deck in English and Spanish, and a video on the global consensus are all available at https://pianostudy.org/.

This study was funded by The Leona B. and Harry H. Helmsley Charitable Trust.

Mahadevan reported being a consultant for AbbVie, Bristol Myers Squibb, Boehringer Ingelheim, Celltrion, Enveda, Gilead, Janssen, Lilly, Merck, Pfizer, Protagonist, Roivant, and Takeda.

A version of this article appeared on Medscape.com. 

The addition of SGLT2 inhibitors was associated with a nearly one third lower incidence of serious liver events in individuals with cirrhosis who were receiving diuretic therapy, a large cohort study of more than 10,000 patients found.

Reporting in JAMA Network Open, Dian J. Chiang, MD, MPH, a section head of Hepatology at the Cleveland Clinic in Cleveland looked at the impact of these antihyperglycemic agents, also known as gliflozins, used in diabetes and kidney disease to block the reabsorption of glucose in the kidneys and causing more glucose to be excreted in the urine.

“Patients with cirrhosis were previously not included in SGLT2 inhibition clinical trials, and there is no large real-world evidence on the safety and effectiveness of this class of medication in patients with cirrhosis. Therefore, we decided to conduct the study to assess its safety and effectiveness,” Chiang told GI & Hepatology News.

The study’s primary endpoint was a composite of serious hepatic events, defined as ascites, varices, hyponatremia, and all-cause mortality. Secondary outcomes included variceal bleeding, paracentesis, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, liver carcinoma, hypoglycemia, and all-cause hospitalizations.

The cohort consisted of 10,660 propensity-matched adult patients with cirrhosis from more than 120 healthcare organizations in the TriNetX database who were receiving furosemide and spironolactone from January 2013 to July 2021. Those also receiving SGLT2 inhibitors (n = 5330) were compared with a matched control group receiving diuretics only (n = 5330). The mean age of participants was 63.8 years, 57.8% were men, 66.3% were White individuals, and all were followed for 3 years.

The SGLT2 inhibitor group had a 32% lower incidence of serious liver events than the control group, for a hazard ratio (HR) of 0.68 (95% CI, 0.66-0.71; P < .001).

Secondary risk reductions in the intervention group were as follows:

• Hepatorenal syndrome: HR, 0.47 (95% CI, 0.40-0.56)
• Spontaneous bacterial peritonitis: HR, 0.55 (95% CI, 0.46-0.65)
• Paracentesis: HR, 0.54 (95% CI, 0.50-0.60)
• Variceal bleeding: HR, 0.79 (95% CI, 0.73-0.84)
• Hypoglycemia: HR, 0.75 (95% CI, 0.62-0.91)
• All-cause hospitalizations: HR, 0.67 (95% CI, 0.63-0.71)

The authors conjectured that SGLT2 inhibition might also benefit patients with other stages of liver disease. They pointed to a 2020 study in patients with diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and high baseline fibrosis that revealed a significant reduction in fibrosis after 12 months’ SGLT2 inhibition.

The study findings also align with those of another large propensity-matched cohort in which patients with type 2 diabetes and cirrhosis receiving metformin plus SGLT2 inhibition showed significantly lower 5-year mortality, decreased incidence of decompensated cirrhosis, and reduced hepatocellular carcinoma incidence compared with those taking metformin alone.

Prospective trials are needed to further evaluate safety and efficacy, however, the authors stressed. Future studies should specifically examine changes in sodium levels following SGLT2 inhibitor initiation, as well as the incidence of recurrent urinary tract infections and euglycemic diabetic ketoacidosis, given that these are known adverse effects of this drug class. Additionally, research comparing different types and dosing regimens would provide valuable insights into optimizing treatment.

Commenting on the analysis but not participating in it, Karn Wijarnpreecha, MD, MPH, a hepatologist at College of Medicine, The University of Arizona, Phoenix, said the study was interesting but did not show the adjusted HR for all-cause mortality separately from other serious liver events, “so we do not know if SGLT2 inhibitor group was associated with lower mortality.”

It would be premature to conclude that using SGLT2 inhibitors in patients with cirrhosis and ascites and on diuretics will decrease the need for liver transplant or significantly improve liver-related outcomes based on this study, Wijarnpreecha told GI & Hepatology News. “Moreover, we do not know the dose of diuretics or specific drugs and doses for SGLT2 inhibitors that were used in the study. Indications for using SGLT2 inhibitors are mainly from diabetes and heart failure, so this may not apply to those with cirrhosis without these two conditions as well.”

In addition, the etiology of cirrhosis in this database study is unknown. “Is it mainly from MASLD or alcohol or other conditions such as viral hepatitis or autoimmmunity? We need more thorough study to answer this question.” He also pointed out that the authors urged caution in using SGLT2 inhibitors in the context of hepatic encephalopathy (HE), which could be worsened with these agents. “This should be taken into consideration before starting medication in decompensated cirrhosis with HE,” Wijarnpreecha said.

In an accompanying commentary, Mohamed I. Elsaid, PhD, MPH, a biomedical informatics researcher and assistant professor at The Ohio State University in Columbus, Ohio, said that if confirmed, the findings could substantially improve cirrhosis care. “The signal is exciting but needs strong confirmation from large observational studies and prospective trials,” he wrote. “To turn promise into practice, the next wave of observational studies must embrace the target-trial emulation framework for bolstering firm causal conclusions and doubly robust learners that tease apart who benefits, who does not, and why.”

He added that head-to-head comparisons with the type 2 diabetes drugs known as incretin mimetics will clarify the best antihyperglycemic agents for different patient phenotypes. “With these advanced causal-inference approaches, repurposed type 2 diabetes therapies could shift cirrhosis management from reactive to proactive, improving quality of life and bending the mortality curve,” Elsaid wrote.

For Wijarnpreecha, important pending questions include the benefits of SGLT2 inhibition in cirrhosis without diabetes or heart failure “Can it be used to prevent cirrhosis in MASLD if we start at the early fibrosis stage in F0-F3?”

Chiang conceded that the study had limitations as it relied on 10th revision of the International Classification of Diseases codes to define outcomes, which may not have captured the complexity of cirrhotic complications. “And the retrospective design may have introduced confounding, selection, and information bias, which could have impacted the results,” he said. “Future prospective studies may help confirm our findings.”

No specific funding was reported for this study. The study authors and Wijarnpreecha had no relevant conflicts of interest to declare. Elsaid reported receiving research funding from Genentech and AstraZeneca outside of the submitted work.

A version of this article first appeared on Medscape.com.

The addition of SGLT2 inhibitors was associated with a nearly one third lower incidence of serious liver events in individuals with cirrhosis who were receiving diuretic therapy, a large cohort study of more than 10,000 patients found.

Reporting in JAMA Network Open, Dian J. Chiang, MD, MPH, a section head of Hepatology at the Cleveland Clinic in Cleveland looked at the impact of these antihyperglycemic agents, also known as gliflozins, used in diabetes and kidney disease to block the reabsorption of glucose in the kidneys and causing more glucose to be excreted in the urine.

“Patients with cirrhosis were previously not included in SGLT2 inhibition clinical trials, and there is no large real-world evidence on the safety and effectiveness of this class of medication in patients with cirrhosis. Therefore, we decided to conduct the study to assess its safety and effectiveness,” Chiang told GI & Hepatology News.

The study’s primary endpoint was a composite of serious hepatic events, defined as ascites, varices, hyponatremia, and all-cause mortality. Secondary outcomes included variceal bleeding, paracentesis, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, liver carcinoma, hypoglycemia, and all-cause hospitalizations.

The cohort consisted of 10,660 propensity-matched adult patients with cirrhosis from more than 120 healthcare organizations in the TriNetX database who were receiving furosemide and spironolactone from January 2013 to July 2021. Those also receiving SGLT2 inhibitors (n = 5330) were compared with a matched control group receiving diuretics only (n = 5330). The mean age of participants was 63.8 years, 57.8% were men, 66.3% were White individuals, and all were followed for 3 years.

The SGLT2 inhibitor group had a 32% lower incidence of serious liver events than the control group, for a hazard ratio (HR) of 0.68 (95% CI, 0.66-0.71; P < .001).

Secondary risk reductions in the intervention group were as follows:

• Hepatorenal syndrome: HR, 0.47 (95% CI, 0.40-0.56)
• Spontaneous bacterial peritonitis: HR, 0.55 (95% CI, 0.46-0.65)
• Paracentesis: HR, 0.54 (95% CI, 0.50-0.60)
• Variceal bleeding: HR, 0.79 (95% CI, 0.73-0.84)
• Hypoglycemia: HR, 0.75 (95% CI, 0.62-0.91)
• All-cause hospitalizations: HR, 0.67 (95% CI, 0.63-0.71)

The authors conjectured that SGLT2 inhibition might also benefit patients with other stages of liver disease. They pointed to a 2020 study in patients with diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and high baseline fibrosis that revealed a significant reduction in fibrosis after 12 months’ SGLT2 inhibition.

The study findings also align with those of another large propensity-matched cohort in which patients with type 2 diabetes and cirrhosis receiving metformin plus SGLT2 inhibition showed significantly lower 5-year mortality, decreased incidence of decompensated cirrhosis, and reduced hepatocellular carcinoma incidence compared with those taking metformin alone.

Prospective trials are needed to further evaluate safety and efficacy, however, the authors stressed. Future studies should specifically examine changes in sodium levels following SGLT2 inhibitor initiation, as well as the incidence of recurrent urinary tract infections and euglycemic diabetic ketoacidosis, given that these are known adverse effects of this drug class. Additionally, research comparing different types and dosing regimens would provide valuable insights into optimizing treatment.

Commenting on the analysis but not participating in it, Karn Wijarnpreecha, MD, MPH, a hepatologist at College of Medicine, The University of Arizona, Phoenix, said the study was interesting but did not show the adjusted HR for all-cause mortality separately from other serious liver events, “so we do not know if SGLT2 inhibitor group was associated with lower mortality.”

It would be premature to conclude that using SGLT2 inhibitors in patients with cirrhosis and ascites and on diuretics will decrease the need for liver transplant or significantly improve liver-related outcomes based on this study, Wijarnpreecha told GI & Hepatology News. “Moreover, we do not know the dose of diuretics or specific drugs and doses for SGLT2 inhibitors that were used in the study. Indications for using SGLT2 inhibitors are mainly from diabetes and heart failure, so this may not apply to those with cirrhosis without these two conditions as well.”

In addition, the etiology of cirrhosis in this database study is unknown. “Is it mainly from MASLD or alcohol or other conditions such as viral hepatitis or autoimmmunity? We need more thorough study to answer this question.” He also pointed out that the authors urged caution in using SGLT2 inhibitors in the context of hepatic encephalopathy (HE), which could be worsened with these agents. “This should be taken into consideration before starting medication in decompensated cirrhosis with HE,” Wijarnpreecha said.

In an accompanying commentary, Mohamed I. Elsaid, PhD, MPH, a biomedical informatics researcher and assistant professor at The Ohio State University in Columbus, Ohio, said that if confirmed, the findings could substantially improve cirrhosis care. “The signal is exciting but needs strong confirmation from large observational studies and prospective trials,” he wrote. “To turn promise into practice, the next wave of observational studies must embrace the target-trial emulation framework for bolstering firm causal conclusions and doubly robust learners that tease apart who benefits, who does not, and why.”

He added that head-to-head comparisons with the type 2 diabetes drugs known as incretin mimetics will clarify the best antihyperglycemic agents for different patient phenotypes. “With these advanced causal-inference approaches, repurposed type 2 diabetes therapies could shift cirrhosis management from reactive to proactive, improving quality of life and bending the mortality curve,” Elsaid wrote.

For Wijarnpreecha, important pending questions include the benefits of SGLT2 inhibition in cirrhosis without diabetes or heart failure “Can it be used to prevent cirrhosis in MASLD if we start at the early fibrosis stage in F0-F3?”

Chiang conceded that the study had limitations as it relied on 10th revision of the International Classification of Diseases codes to define outcomes, which may not have captured the complexity of cirrhotic complications. “And the retrospective design may have introduced confounding, selection, and information bias, which could have impacted the results,” he said. “Future prospective studies may help confirm our findings.”

No specific funding was reported for this study. The study authors and Wijarnpreecha had no relevant conflicts of interest to declare. Elsaid reported receiving research funding from Genentech and AstraZeneca outside of the submitted work.

A version of this article first appeared on Medscape.com.

The addition of SGLT2 inhibitors was associated with a nearly one third lower incidence of serious liver events in individuals with cirrhosis who were receiving diuretic therapy, a large cohort study of more than 10,000 patients found.

Reporting in JAMA Network Open, Dian J. Chiang, MD, MPH, a section head of Hepatology at the Cleveland Clinic in Cleveland looked at the impact of these antihyperglycemic agents, also known as gliflozins, used in diabetes and kidney disease to block the reabsorption of glucose in the kidneys and causing more glucose to be excreted in the urine.

“Patients with cirrhosis were previously not included in SGLT2 inhibition clinical trials, and there is no large real-world evidence on the safety and effectiveness of this class of medication in patients with cirrhosis. Therefore, we decided to conduct the study to assess its safety and effectiveness,” Chiang told GI & Hepatology News.

The study’s primary endpoint was a composite of serious hepatic events, defined as ascites, varices, hyponatremia, and all-cause mortality. Secondary outcomes included variceal bleeding, paracentesis, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatorenal syndrome, liver carcinoma, hypoglycemia, and all-cause hospitalizations.

The cohort consisted of 10,660 propensity-matched adult patients with cirrhosis from more than 120 healthcare organizations in the TriNetX database who were receiving furosemide and spironolactone from January 2013 to July 2021. Those also receiving SGLT2 inhibitors (n = 5330) were compared with a matched control group receiving diuretics only (n = 5330). The mean age of participants was 63.8 years, 57.8% were men, 66.3% were White individuals, and all were followed for 3 years.

The SGLT2 inhibitor group had a 32% lower incidence of serious liver events than the control group, for a hazard ratio (HR) of 0.68 (95% CI, 0.66-0.71; P < .001).

Secondary risk reductions in the intervention group were as follows:

• Hepatorenal syndrome: HR, 0.47 (95% CI, 0.40-0.56)
• Spontaneous bacterial peritonitis: HR, 0.55 (95% CI, 0.46-0.65)
• Paracentesis: HR, 0.54 (95% CI, 0.50-0.60)
• Variceal bleeding: HR, 0.79 (95% CI, 0.73-0.84)
• Hypoglycemia: HR, 0.75 (95% CI, 0.62-0.91)
• All-cause hospitalizations: HR, 0.67 (95% CI, 0.63-0.71)

The authors conjectured that SGLT2 inhibition might also benefit patients with other stages of liver disease. They pointed to a 2020 study in patients with diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and high baseline fibrosis that revealed a significant reduction in fibrosis after 12 months’ SGLT2 inhibition.

The study findings also align with those of another large propensity-matched cohort in which patients with type 2 diabetes and cirrhosis receiving metformin plus SGLT2 inhibition showed significantly lower 5-year mortality, decreased incidence of decompensated cirrhosis, and reduced hepatocellular carcinoma incidence compared with those taking metformin alone.

Prospective trials are needed to further evaluate safety and efficacy, however, the authors stressed. Future studies should specifically examine changes in sodium levels following SGLT2 inhibitor initiation, as well as the incidence of recurrent urinary tract infections and euglycemic diabetic ketoacidosis, given that these are known adverse effects of this drug class. Additionally, research comparing different types and dosing regimens would provide valuable insights into optimizing treatment.

Commenting on the analysis but not participating in it, Karn Wijarnpreecha, MD, MPH, a hepatologist at College of Medicine, The University of Arizona, Phoenix, said the study was interesting but did not show the adjusted HR for all-cause mortality separately from other serious liver events, “so we do not know if SGLT2 inhibitor group was associated with lower mortality.”

It would be premature to conclude that using SGLT2 inhibitors in patients with cirrhosis and ascites and on diuretics will decrease the need for liver transplant or significantly improve liver-related outcomes based on this study, Wijarnpreecha told GI & Hepatology News. “Moreover, we do not know the dose of diuretics or specific drugs and doses for SGLT2 inhibitors that were used in the study. Indications for using SGLT2 inhibitors are mainly from diabetes and heart failure, so this may not apply to those with cirrhosis without these two conditions as well.”

In addition, the etiology of cirrhosis in this database study is unknown. “Is it mainly from MASLD or alcohol or other conditions such as viral hepatitis or autoimmmunity? We need more thorough study to answer this question.” He also pointed out that the authors urged caution in using SGLT2 inhibitors in the context of hepatic encephalopathy (HE), which could be worsened with these agents. “This should be taken into consideration before starting medication in decompensated cirrhosis with HE,” Wijarnpreecha said.

In an accompanying commentary, Mohamed I. Elsaid, PhD, MPH, a biomedical informatics researcher and assistant professor at The Ohio State University in Columbus, Ohio, said that if confirmed, the findings could substantially improve cirrhosis care. “The signal is exciting but needs strong confirmation from large observational studies and prospective trials,” he wrote. “To turn promise into practice, the next wave of observational studies must embrace the target-trial emulation framework for bolstering firm causal conclusions and doubly robust learners that tease apart who benefits, who does not, and why.”

He added that head-to-head comparisons with the type 2 diabetes drugs known as incretin mimetics will clarify the best antihyperglycemic agents for different patient phenotypes. “With these advanced causal-inference approaches, repurposed type 2 diabetes therapies could shift cirrhosis management from reactive to proactive, improving quality of life and bending the mortality curve,” Elsaid wrote.

For Wijarnpreecha, important pending questions include the benefits of SGLT2 inhibition in cirrhosis without diabetes or heart failure “Can it be used to prevent cirrhosis in MASLD if we start at the early fibrosis stage in F0-F3?”

Chiang conceded that the study had limitations as it relied on 10th revision of the International Classification of Diseases codes to define outcomes, which may not have captured the complexity of cirrhotic complications. “And the retrospective design may have introduced confounding, selection, and information bias, which could have impacted the results,” he said. “Future prospective studies may help confirm our findings.”

No specific funding was reported for this study. The study authors and Wijarnpreecha had no relevant conflicts of interest to declare. Elsaid reported receiving research funding from Genentech and AstraZeneca outside of the submitted work.

A version of this article first appeared on Medscape.com.

Background

Tall cell carcinoma with reversed polarity (TCCRP) is a rare and distinct subtype of invasive breast carcinoma, defined by tall columnar cells with eosinophilic cytoplasm and reversed nuclear polarity. TCCRP remains poorly characterized in the literature, with limited population-level evidence to guide management and prognostication. This study uses the National Cancer Database (NCDB) to examine the epidemiology, clinical features, and outcomes of this neoplasm.

Methods

A retrospective cohort analysis included 951 patients diagnosed with TCCRP (ICD-O-3 code 8509) from 2018–2020 using the NCDB. Demographic and treatment variables were analyzed using descriptive statistics. Incidence trends were assessed using linear regression, and overall survival was evaluated using Kaplan-Meier methods.

Results

Most patients were female (98.1%) with a mean age of 69.1 years. The majority were White (82.0%), followed by Black (9.0%) and Hispanic (8.7%). Primary tumor sites included overlapping breast lesions (28.5%) and the upper-inner quadrant (27.0%). Incidence remained stable (R² = 0.0). Most patients were diagnosed at Stage I (58.4%) and had a Charlson-Deyo score of 0 (76.2%). Socioeconomically, 41.8% lived in the highest income quartile (≥$74,063), and most had Medicare (64.7%). The most common treatment settings were comprehensive community cancer programs (40.3%). Surgery was performed in 95.6% of cases, with negative margins in 91.1%. Radiation therapy (46.6%) and hormone therapy (44.3%) were frequently used. Mortality was 1.1% at 30 days and 1.7% at 90 days. Survival was 98.9% at 2 years, 97.3% at 5 years, and 94.5% at 10 years, with a mean survival of 46.4 months.

Conclusions

This is the first NCDB-based study of TCCRP, highlighting favorable outcomes and distinct clinicodemographic features. Patients were predominantly older, White, and Medicare-insured, often receiving care at community cancer programs. These findings suggest that socioeconomic factors may influence access and treatment. Results may inform strategies to promote equitable care delivery across health systems and guide further research on clinical management and survivorship in TCCRP, particularly for rare cancers within community-based settings such as the VHA.

Background

Tall cell carcinoma with reversed polarity (TCCRP) is a rare and distinct subtype of invasive breast carcinoma, defined by tall columnar cells with eosinophilic cytoplasm and reversed nuclear polarity. TCCRP remains poorly characterized in the literature, with limited population-level evidence to guide management and prognostication. This study uses the National Cancer Database (NCDB) to examine the epidemiology, clinical features, and outcomes of this neoplasm.

Methods

A retrospective cohort analysis included 951 patients diagnosed with TCCRP (ICD-O-3 code 8509) from 2018–2020 using the NCDB. Demographic and treatment variables were analyzed using descriptive statistics. Incidence trends were assessed using linear regression, and overall survival was evaluated using Kaplan-Meier methods.

Results

Most patients were female (98.1%) with a mean age of 69.1 years. The majority were White (82.0%), followed by Black (9.0%) and Hispanic (8.7%). Primary tumor sites included overlapping breast lesions (28.5%) and the upper-inner quadrant (27.0%). Incidence remained stable (R² = 0.0). Most patients were diagnosed at Stage I (58.4%) and had a Charlson-Deyo score of 0 (76.2%). Socioeconomically, 41.8% lived in the highest income quartile (≥$74,063), and most had Medicare (64.7%). The most common treatment settings were comprehensive community cancer programs (40.3%). Surgery was performed in 95.6% of cases, with negative margins in 91.1%. Radiation therapy (46.6%) and hormone therapy (44.3%) were frequently used. Mortality was 1.1% at 30 days and 1.7% at 90 days. Survival was 98.9% at 2 years, 97.3% at 5 years, and 94.5% at 10 years, with a mean survival of 46.4 months.

Conclusions

This is the first NCDB-based study of TCCRP, highlighting favorable outcomes and distinct clinicodemographic features. Patients were predominantly older, White, and Medicare-insured, often receiving care at community cancer programs. These findings suggest that socioeconomic factors may influence access and treatment. Results may inform strategies to promote equitable care delivery across health systems and guide further research on clinical management and survivorship in TCCRP, particularly for rare cancers within community-based settings such as the VHA.

Background

Tall cell carcinoma with reversed polarity (TCCRP) is a rare and distinct subtype of invasive breast carcinoma, defined by tall columnar cells with eosinophilic cytoplasm and reversed nuclear polarity. TCCRP remains poorly characterized in the literature, with limited population-level evidence to guide management and prognostication. This study uses the National Cancer Database (NCDB) to examine the epidemiology, clinical features, and outcomes of this neoplasm.

Methods

A retrospective cohort analysis included 951 patients diagnosed with TCCRP (ICD-O-3 code 8509) from 2018–2020 using the NCDB. Demographic and treatment variables were analyzed using descriptive statistics. Incidence trends were assessed using linear regression, and overall survival was evaluated using Kaplan-Meier methods.

Results

Most patients were female (98.1%) with a mean age of 69.1 years. The majority were White (82.0%), followed by Black (9.0%) and Hispanic (8.7%). Primary tumor sites included overlapping breast lesions (28.5%) and the upper-inner quadrant (27.0%). Incidence remained stable (R² = 0.0). Most patients were diagnosed at Stage I (58.4%) and had a Charlson-Deyo score of 0 (76.2%). Socioeconomically, 41.8% lived in the highest income quartile (≥$74,063), and most had Medicare (64.7%). The most common treatment settings were comprehensive community cancer programs (40.3%). Surgery was performed in 95.6% of cases, with negative margins in 91.1%. Radiation therapy (46.6%) and hormone therapy (44.3%) were frequently used. Mortality was 1.1% at 30 days and 1.7% at 90 days. Survival was 98.9% at 2 years, 97.3% at 5 years, and 94.5% at 10 years, with a mean survival of 46.4 months.

Conclusions

This is the first NCDB-based study of TCCRP, highlighting favorable outcomes and distinct clinicodemographic features. Patients were predominantly older, White, and Medicare-insured, often receiving care at community cancer programs. These findings suggest that socioeconomic factors may influence access and treatment. Results may inform strategies to promote equitable care delivery across health systems and guide further research on clinical management and survivorship in TCCRP, particularly for rare cancers within community-based settings such as the VHA.

The first randomized controlled trial of forceps-assisted cannulation during endoscopic retrograde cholangiopancreatography (ERCP) has shown that this technique can significantly improve the success rate of the procedure.

The results emerged from the small, single-center SOCCER trial of 152 patients recruited from March 2022 to October 2024 and are published in The American Journal of Gastroenterology.

Both groups had a slightly higher number of female participants, and the mean ages of the participants were 61.9 years in the forceps group and 68.3 years in the no forceps group.

First author Steven M. Hadley Jr, an MD candidate at Northwestern Feinberg School of Medicine in Chicago, and colleagues reported that forceps assistance in difficult cannulations yielded significantly higher success rates than no forceps assistance (100% vs 83.9%; P < .001).

The investigators noted that difficult cannulations during ERCP have a frequency of 42%. Cannulation failure is associated with increased morbidity — including longer hospitalization, increased ICU admissions, readmissions, and increased financial cost — as well as mortality rates of up to 10%.

SOCCER defined difficult cannulation as a papilla in or on the rim of a diverticulum, five or more attempts, attempts lasting 5 or more minutes, or two or more unintended pancreatic duct wire passages. Other features were redundant tissue overlaying the papilla or a type 2, 3, or 4 papilla.

The study found forceps assistance also had a nonstatistically significant lower rate of difficult cannulations than no forceps (57.1% vs 69.1%; P = .132). The rate of post-ERCP pancreatitis (PEP) was similarly low in both groups: 5.7% with forceps vs 3.7% without forceps (P = .705). The no forceps group had significantly more cannulation attempts after randomization than the forceps group (14 vs 8.3; P = .026).

Patients who crossed over to forceps assistance all had successful cannulations.

The technique has long been used to overcome cannulation difficulties, said Timothy B. Gardner, MD, MS, a gastroenterologist at the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, and a coauthor of the study. “It was particularly effective for cannulations with redundant tissue limiting access to the papilla,” Gardner told GI & Hepatology News. “We decided to design a randomized trial to determine the extent to which this technique worked. We believed our study would answer an important question that would hopefully lead to an improvement in endoscopy practice.”

While a few case reports and video demos had described the technique, no trials had assessed its effectiveness, Hadley added. “We found the technique to be effective based on our experience, but it was exciting to see that a rigorously designed randomized trial proved that it is indeed a very effective technique to facilitate cannulation.”

Hadley noted the technique does not increase PEP incidence, unlike the commonly used precut sphincterotomy and the double-wire method for difficult cannulations. “As a result, the forceps-assisted technique may be an effective first-line option and may reduce the need for additional, more invasive procedures including surgery and repeat ERCP to obtain the therapeutic intent of the original ERCP.”

The paper outlines the technique’s methodology, he added, “so we believe endoscopists who read the manuscript will be able to start implementing the technique into their practice.”

Commenting on the paper but not involved in it, Christopher J. DiMaio, MD, regional director of Endoscopy for Northwell Health Physician Partners Gastroenterology and a gastroenterologist in Greenlawn, New York, called it potentially helpful but aimed at a niche group of expert practitioners. “The technique appears safe and very effective, which is the number one concern, and I would definitely keep it in my back pocket,” he said. “I expect it will be used more commonly now because of this study.”

He added that although expert endoscopists are familiar with the approach, they use more time-tested and sometimes more aggressive maneuvers to cope with difficult cannulations. “But this is a simple technique using a device that should be available to most high-volume endoscopists.”

DiMaio also noted that he would have liked to see an actual decrease in PEP incidence in the intervention group.

Looking ahead, Hadley said it would be interesting to compare the effectiveness of the double-wire technique against forceps-assisted cannulation in a randomized context. “A study we’re already looking into is seeing whether physician experience with the technique impacts outcomes.”

This study was supported by the American College of Gastroenterology. The authors and DiMaio reported having no relevant competing interests.

A version of this article first appeared on Medscape.com.

The first randomized controlled trial of forceps-assisted cannulation during endoscopic retrograde cholangiopancreatography (ERCP) has shown that this technique can significantly improve the success rate of the procedure.

The results emerged from the small, single-center SOCCER trial of 152 patients recruited from March 2022 to October 2024 and are published in The American Journal of Gastroenterology.

Both groups had a slightly higher number of female participants, and the mean ages of the participants were 61.9 years in the forceps group and 68.3 years in the no forceps group.

First author Steven M. Hadley Jr, an MD candidate at Northwestern Feinberg School of Medicine in Chicago, and colleagues reported that forceps assistance in difficult cannulations yielded significantly higher success rates than no forceps assistance (100% vs 83.9%; P < .001).

The investigators noted that difficult cannulations during ERCP have a frequency of 42%. Cannulation failure is associated with increased morbidity — including longer hospitalization, increased ICU admissions, readmissions, and increased financial cost — as well as mortality rates of up to 10%.

SOCCER defined difficult cannulation as a papilla in or on the rim of a diverticulum, five or more attempts, attempts lasting 5 or more minutes, or two or more unintended pancreatic duct wire passages. Other features were redundant tissue overlaying the papilla or a type 2, 3, or 4 papilla.

The study found forceps assistance also had a nonstatistically significant lower rate of difficult cannulations than no forceps (57.1% vs 69.1%; P = .132). The rate of post-ERCP pancreatitis (PEP) was similarly low in both groups: 5.7% with forceps vs 3.7% without forceps (P = .705). The no forceps group had significantly more cannulation attempts after randomization than the forceps group (14 vs 8.3; P = .026).

Patients who crossed over to forceps assistance all had successful cannulations.

The technique has long been used to overcome cannulation difficulties, said Timothy B. Gardner, MD, MS, a gastroenterologist at the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, and a coauthor of the study. “It was particularly effective for cannulations with redundant tissue limiting access to the papilla,” Gardner told GI & Hepatology News. “We decided to design a randomized trial to determine the extent to which this technique worked. We believed our study would answer an important question that would hopefully lead to an improvement in endoscopy practice.”

While a few case reports and video demos had described the technique, no trials had assessed its effectiveness, Hadley added. “We found the technique to be effective based on our experience, but it was exciting to see that a rigorously designed randomized trial proved that it is indeed a very effective technique to facilitate cannulation.”

Hadley noted the technique does not increase PEP incidence, unlike the commonly used precut sphincterotomy and the double-wire method for difficult cannulations. “As a result, the forceps-assisted technique may be an effective first-line option and may reduce the need for additional, more invasive procedures including surgery and repeat ERCP to obtain the therapeutic intent of the original ERCP.”

The paper outlines the technique’s methodology, he added, “so we believe endoscopists who read the manuscript will be able to start implementing the technique into their practice.”

Commenting on the paper but not involved in it, Christopher J. DiMaio, MD, regional director of Endoscopy for Northwell Health Physician Partners Gastroenterology and a gastroenterologist in Greenlawn, New York, called it potentially helpful but aimed at a niche group of expert practitioners. “The technique appears safe and very effective, which is the number one concern, and I would definitely keep it in my back pocket,” he said. “I expect it will be used more commonly now because of this study.”

He added that although expert endoscopists are familiar with the approach, they use more time-tested and sometimes more aggressive maneuvers to cope with difficult cannulations. “But this is a simple technique using a device that should be available to most high-volume endoscopists.”

DiMaio also noted that he would have liked to see an actual decrease in PEP incidence in the intervention group.

Looking ahead, Hadley said it would be interesting to compare the effectiveness of the double-wire technique against forceps-assisted cannulation in a randomized context. “A study we’re already looking into is seeing whether physician experience with the technique impacts outcomes.”

This study was supported by the American College of Gastroenterology. The authors and DiMaio reported having no relevant competing interests.

A version of this article first appeared on Medscape.com.

The first randomized controlled trial of forceps-assisted cannulation during endoscopic retrograde cholangiopancreatography (ERCP) has shown that this technique can significantly improve the success rate of the procedure.

The results emerged from the small, single-center SOCCER trial of 152 patients recruited from March 2022 to October 2024 and are published in The American Journal of Gastroenterology.

Both groups had a slightly higher number of female participants, and the mean ages of the participants were 61.9 years in the forceps group and 68.3 years in the no forceps group.

First author Steven M. Hadley Jr, an MD candidate at Northwestern Feinberg School of Medicine in Chicago, and colleagues reported that forceps assistance in difficult cannulations yielded significantly higher success rates than no forceps assistance (100% vs 83.9%; P < .001).

The investigators noted that difficult cannulations during ERCP have a frequency of 42%. Cannulation failure is associated with increased morbidity — including longer hospitalization, increased ICU admissions, readmissions, and increased financial cost — as well as mortality rates of up to 10%.

SOCCER defined difficult cannulation as a papilla in or on the rim of a diverticulum, five or more attempts, attempts lasting 5 or more minutes, or two or more unintended pancreatic duct wire passages. Other features were redundant tissue overlaying the papilla or a type 2, 3, or 4 papilla.

The study found forceps assistance also had a nonstatistically significant lower rate of difficult cannulations than no forceps (57.1% vs 69.1%; P = .132). The rate of post-ERCP pancreatitis (PEP) was similarly low in both groups: 5.7% with forceps vs 3.7% without forceps (P = .705). The no forceps group had significantly more cannulation attempts after randomization than the forceps group (14 vs 8.3; P = .026).

Patients who crossed over to forceps assistance all had successful cannulations.

The technique has long been used to overcome cannulation difficulties, said Timothy B. Gardner, MD, MS, a gastroenterologist at the Dartmouth Hitchcock Medical Center in Lebanon, New Hampshire, and a coauthor of the study. “It was particularly effective for cannulations with redundant tissue limiting access to the papilla,” Gardner told GI & Hepatology News. “We decided to design a randomized trial to determine the extent to which this technique worked. We believed our study would answer an important question that would hopefully lead to an improvement in endoscopy practice.”

While a few case reports and video demos had described the technique, no trials had assessed its effectiveness, Hadley added. “We found the technique to be effective based on our experience, but it was exciting to see that a rigorously designed randomized trial proved that it is indeed a very effective technique to facilitate cannulation.”

Hadley noted the technique does not increase PEP incidence, unlike the commonly used precut sphincterotomy and the double-wire method for difficult cannulations. “As a result, the forceps-assisted technique may be an effective first-line option and may reduce the need for additional, more invasive procedures including surgery and repeat ERCP to obtain the therapeutic intent of the original ERCP.”

The paper outlines the technique’s methodology, he added, “so we believe endoscopists who read the manuscript will be able to start implementing the technique into their practice.”

Commenting on the paper but not involved in it, Christopher J. DiMaio, MD, regional director of Endoscopy for Northwell Health Physician Partners Gastroenterology and a gastroenterologist in Greenlawn, New York, called it potentially helpful but aimed at a niche group of expert practitioners. “The technique appears safe and very effective, which is the number one concern, and I would definitely keep it in my back pocket,” he said. “I expect it will be used more commonly now because of this study.”

He added that although expert endoscopists are familiar with the approach, they use more time-tested and sometimes more aggressive maneuvers to cope with difficult cannulations. “But this is a simple technique using a device that should be available to most high-volume endoscopists.”

DiMaio also noted that he would have liked to see an actual decrease in PEP incidence in the intervention group.

Looking ahead, Hadley said it would be interesting to compare the effectiveness of the double-wire technique against forceps-assisted cannulation in a randomized context. “A study we’re already looking into is seeing whether physician experience with the technique impacts outcomes.”

This study was supported by the American College of Gastroenterology. The authors and DiMaio reported having no relevant competing interests.

A version of this article first appeared on Medscape.com.

Hypereosinophilic syndrome (HES) is defined by marked, persistent absolute eosinophil count (AEC) > 1500 cells/μL on ≥ 2 peripheral smears separated by ≥ 1 month with evidence of accompanied end-organ damage, in the absence of other causes of eosinophilia such as malignancy, atopy, or parasitic infections.^1-5 Hypereosinophilic infiltration can impact almost every organ system; however, the most profound complications in patients with HES are related to leukemias and cardiac manifestations of the disease.^3,4 Although rare, the associated morbidity and mortality of HES are considerable, making prompt recognition and treatment essential. Management involves targeted therapy based on pathologic classification of HES and on decreasing associated inflammation, fibrosis, and end-organ damage.^3,5-7

The patient in this case report met the diagnostic criteria for HES. However, this patient had several clinical and laboratory features that made it difficult to characterize a specific HES variant. Moreover, she had additional immunomodulating factors in the setting of pregnancy. This is the first documented case of HES of undetermined etiology diagnosed postpartum and managed in the setting of a new pregnancy.^2,8

CASE PRESENTATION

A 32-year-old female active-duty military service member with allergic rhinitis and a history of childhood eczema was referred to allergy/immunology for evaluation of a new, progressive pruritic rash. Symptoms started 3 months after the birth of her first child, with a new diffuse erythematous skin rash sparing her palms, soles, and mucosal surfaces. Given her history of atopy, the rash was initially treated as severe atopic dermatitis with appropriate topical medications. The rash gradually worsened, with the development of intermittent facial swelling, night sweats, dyspnea, recurrent epigastric abdominal pain, and nausea with vomiting, resulting in decreased oral intake and weight loss.

The patient was hospitalized and received an expedited multidisciplinary evaluation by dermatology, hematology/oncology, and gastroenterology. Her AEC of 4787 cells/μL peaked on admission and was markedly elevated from the 1070 cells/μL reported in the third trimester of her pregnancy. She was found to have mature eosinophilia on skin biopsy (Figure 1), endoscopic duodenal biopsy (Figure 2), peripheral blood smear (Figure 3), and bone marrow biopsy (Figure 4). 

Radiographic imaging of the chest, abdomen, and pelvis revealed hepatomegaly without detectable neoplasm. There was no clinical evidence of cardiac involvement, and evaluation with electrocardiography and echocardiography did not indicate myocarditis. Extensive laboratory testing revealed no genetic mutations indicative of familial, myeloproliferative, or lymphocytic variants of HES. 

The patient received topical emollients, omeprazole 40 mg daily, and ondansetron 8 mg 3 times daily as needed for symptom management, and was started on oral prednisone 40 mg daily with improvement in dyspnea, night sweats, and gastrointestinal complaints. During the patient's 6-day hospitalization and treatment, her AECs gradually decreased to 2110 cells/μL, and decreased to 1600 cells/μL over the course of a month, remaining in the hypereosinophilic range. The patient was discovered to be pregnant while symptoms were improving, resulting in stepwise discontinuation of oral steroids, but she reported continued improvement in symptoms.

DISCUSSION

Peripheral eosinophilia has a broad differential diagnoses, including HES, parasitic infections, atopic hypersensitivity diseases, eosinophilic lung diseases, eosinophilic gastrointestinal diseases, vasculitides such as eosinophilic granulomatosis with polyangiitis, genetic syndromes predisposing to eosinophilia, episodic angioedema with eosinophilia, and chronic metabolic disease with adrenal insufficiency.^1-5 HES, although rare, is a disease process with potentially devastating associated morbidity and mortality if not promptly recognized and treated. HES is further delineated by hypereosinophilia with associated eosinophil-mediated organ damage or dysfunction.^3-5

Clinical manifestations of HES can differ greatly depending on the HES variant and degree of organ involvement at the time of diagnosis and throughout the disease course. Patients with HES, as well as those with asymptomatic eosinophilia or hypereosinophilia, should be closely monitored for disease progression. In addition to trending peripheral AECs, clinicians should screen for symptoms of organ involvement and perform targeted evaluation of the suspected organs to promptly identify early signs of organ involvement and initiate treatment.^1-4 Recommendations regarding screening intervals vary widely from monthly to annually, depending on a patient’s specific clinical picture. 

HES has been subdivided into clinically relevant variants, including myeloproliferative (M-HES), T lymphocytic (L-HES), organ-restricted (or overlap) HES, familial HES, idiopathic HES, and specific syndromes with associated hypereosinophilia.^3-5,9 Patients with M-HES have elevated circulating leukocyte precursors and clinical manifestations, including but not limited to hepatosplenomegaly, anemia, and thrombocytopenia. The most commonly associated genetic mutations include the FIP1L1-PDGFR-α fusion, BCR-ABL1, PDGFRA/B, JAK2, KIT, and FGFR1.^3-6 L-HES usually has predominant skin and soft tissue involvement secondary to immunoglobulin E-mediated actions with clonal expansion of T cells (most commonly CD3-4+ or CD3+CD4-CD8-).^3,5,6 Familial HES, a rare variant, follows an autosomal dominant inheritance pattern and is usually present at birth. It involves chromosome 5, which contains genes coding for cytokines that drive eosinophilic proliferation, including interleukin (IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor.^5,9 Hypereosinophilia in the setting of end-organ damage restricted to a single organ is considered organ-restricted HES. There can be significant hepatic and gastrointestinal dysfunction, with or without malabsorption. 

HES can also manifest with hematologic malignancy, restrictive obliterative cardiomyopathies, renal injury manifested by hematuria and electrolyte derangements, and neurologic complications including hemiparesis, dysarthria, and even coma.⁶ Endothelial damage due to eosinophil-driven inflammation can result in thrombus formation and increased risk of thromboembolic events in various organs.³ Idiopathic HES, otherwise known as HES of unknown etiology or significance, is a diagnosis of exclusion and constitutes a cohort of patients who do not fit into the other delineated categories.^3-5 These patients often have multisystem involvement, making classification and treatment a challenge.⁵

The patient described in this case met the diagnostic criteria for HES, but her complicated clinical and laboratory features were challenging to characterize into a specific variant of HES. Organ-restricted HES was ruled out due to skin, marrow, and duodenal infiltration. She also had the potential for lung involvement based on her clinical symptoms, however no biopsy was obtained. Laboratory testing revealed no deletions or mutations indicative of familial, myeloproliferative, or lymphocytic variants. Her multisystem involvement without an underlying associated syndrome suggests idiopathic HES or HES of undetermined significance.^1-5

Most patients with HES are diagnosed between the ages of 20 and 50 years.¹⁰ While HES has its peak incidence in the fourth decade of life, acute onset of new symptoms 3 months postpartum makes this an unusual presentation. In this unique case, it is important to highlight the role of the physiologic changes of pregnancy in inflammatory mediation. The physiologic changes that occur in pregnancy to ensure fetal tolerance can have profound implications for leukocyte count, AEC, and subsequent inflammatory responses. The phenomenon of inflammatory amelioration during pregnancy is well-documented, but there has only been 1 known published case report discussing decreasing HES symptoms during pregnancy with prepregnancy and postpartum hypereosinophilia.⁸ It is suggested that this amelioration is secondary to cortisol and progesterone shifts that occur in pregnancy. Physiologic increases in adrenocorticotropic hormone in pregnancy leads to subsequent secretion of endogenous steroids by the adrenal cortex. In turn, pregnancy can lead to leukocytosis and eosinopenia.⁸ Overall, pregnancy can have beneficial immunomodulating properties in the spectrum of hypereosinophilic syndromes. Even so, this patient with HES diagnosed postpartum remains at risk for the sequelae of hypereosinophilia, regardless of potential for AEC reduction during pregnancy. Therefore, treatment considerations need to be made with the safety of the maternal-fetal dyad as a priority.

Treatment

The treatment of symptomatic HES without acute life-threatening features or associated malignancy is generally determined by clinical variant.^2-4 There is insufficient data to support initiation of treatment solely based on persistently elevated AEC. Patients with peripheral eosinophilia and hypereosinophilia should be monitored periodically with appropriate subspecialist evaluation for occult end-organ involvement, and targeted therapies should be deferred until an HES diagnosis.^1-4 First-line therapy in most HES variants is systemic glucocorticoids.^2,3,7 Since the disease course for this patient did not precisely match an HES variant, it was challenging to ascertain the optimal personalized treatment regimen. The approach to therapy was further complicated by newly identified pregnancy necessitating cessation of systemic glucocorticoids. In addition to glucocorticoids, hydroxyurea and interferon-α are among treatments historically used for HES, with tyrosine kinase inhibitors and monoclonal antibodies targeting IL-5 becoming more common.^1-4 Although this patient may ultimately benefit from an IL-5 targeting biologic medication such as mepolizumab, safety in pregnancy is not well-studied and may require close clinical monitoring with treatment deferred until after delivery if possible.^3,7,8,11

Military service members with frequent geographic relocation have additional barriers to timely diagnosis with often-limited access to subspecialty care depending on the duty station. While the patient was able to receive care at a large military medical center with many subspecialists, prompt recognition and timely referral to specialists would be even more critical at a smaller treatment facility. Depending on the severity and variant of HES, patients may warrant evaluation and treatment by hematology/oncology, cardiology, pulmonology, and immunology. Although HES can present in young children and older adults, this condition is most often diagnosed during the third and fourth decades of life, putting clinicians on the front line of hypereosinophilia identification and evaluation.¹⁰ Military physicians have the additional duty to not only think ahead in their diverse clinical settings to ensure proper care for patients, but also maintain a broad differential inclusive of more rare disease processes such as HES.

CONCLUSIONS

This case emphasizes how uncontrolled or untreated HES can lead to significant end-organ damage involving multiple systems and high morbidity. Prompt recognition of hypereosinophilia with potential HES can help expedite coordination of multidisciplinary care across multiple specialties to minimize delays in diagnosis and treatment. Doing so may minimize associated morbidity and mortality, especially in individuals located at more remote duty stations or deployed to austere environments.

Hypereosinophilic syndrome (HES) is defined by marked, persistent absolute eosinophil count (AEC) > 1500 cells/μL on ≥ 2 peripheral smears separated by ≥ 1 month with evidence of accompanied end-organ damage, in the absence of other causes of eosinophilia such as malignancy, atopy, or parasitic infections.^1-5 Hypereosinophilic infiltration can impact almost every organ system; however, the most profound complications in patients with HES are related to leukemias and cardiac manifestations of the disease.^3,4 Although rare, the associated morbidity and mortality of HES are considerable, making prompt recognition and treatment essential. Management involves targeted therapy based on pathologic classification of HES and on decreasing associated inflammation, fibrosis, and end-organ damage.^3,5-7

The patient in this case report met the diagnostic criteria for HES. However, this patient had several clinical and laboratory features that made it difficult to characterize a specific HES variant. Moreover, she had additional immunomodulating factors in the setting of pregnancy. This is the first documented case of HES of undetermined etiology diagnosed postpartum and managed in the setting of a new pregnancy.^2,8

CASE PRESENTATION

A 32-year-old female active-duty military service member with allergic rhinitis and a history of childhood eczema was referred to allergy/immunology for evaluation of a new, progressive pruritic rash. Symptoms started 3 months after the birth of her first child, with a new diffuse erythematous skin rash sparing her palms, soles, and mucosal surfaces. Given her history of atopy, the rash was initially treated as severe atopic dermatitis with appropriate topical medications. The rash gradually worsened, with the development of intermittent facial swelling, night sweats, dyspnea, recurrent epigastric abdominal pain, and nausea with vomiting, resulting in decreased oral intake and weight loss.

The patient was hospitalized and received an expedited multidisciplinary evaluation by dermatology, hematology/oncology, and gastroenterology. Her AEC of 4787 cells/μL peaked on admission and was markedly elevated from the 1070 cells/μL reported in the third trimester of her pregnancy. She was found to have mature eosinophilia on skin biopsy (Figure 1), endoscopic duodenal biopsy (Figure 2), peripheral blood smear (Figure 3), and bone marrow biopsy (Figure 4). 

Radiographic imaging of the chest, abdomen, and pelvis revealed hepatomegaly without detectable neoplasm. There was no clinical evidence of cardiac involvement, and evaluation with electrocardiography and echocardiography did not indicate myocarditis. Extensive laboratory testing revealed no genetic mutations indicative of familial, myeloproliferative, or lymphocytic variants of HES. 

The patient received topical emollients, omeprazole 40 mg daily, and ondansetron 8 mg 3 times daily as needed for symptom management, and was started on oral prednisone 40 mg daily with improvement in dyspnea, night sweats, and gastrointestinal complaints. During the patient's 6-day hospitalization and treatment, her AECs gradually decreased to 2110 cells/μL, and decreased to 1600 cells/μL over the course of a month, remaining in the hypereosinophilic range. The patient was discovered to be pregnant while symptoms were improving, resulting in stepwise discontinuation of oral steroids, but she reported continued improvement in symptoms.

DISCUSSION

Peripheral eosinophilia has a broad differential diagnoses, including HES, parasitic infections, atopic hypersensitivity diseases, eosinophilic lung diseases, eosinophilic gastrointestinal diseases, vasculitides such as eosinophilic granulomatosis with polyangiitis, genetic syndromes predisposing to eosinophilia, episodic angioedema with eosinophilia, and chronic metabolic disease with adrenal insufficiency.^1-5 HES, although rare, is a disease process with potentially devastating associated morbidity and mortality if not promptly recognized and treated. HES is further delineated by hypereosinophilia with associated eosinophil-mediated organ damage or dysfunction.^3-5

Clinical manifestations of HES can differ greatly depending on the HES variant and degree of organ involvement at the time of diagnosis and throughout the disease course. Patients with HES, as well as those with asymptomatic eosinophilia or hypereosinophilia, should be closely monitored for disease progression. In addition to trending peripheral AECs, clinicians should screen for symptoms of organ involvement and perform targeted evaluation of the suspected organs to promptly identify early signs of organ involvement and initiate treatment.^1-4 Recommendations regarding screening intervals vary widely from monthly to annually, depending on a patient’s specific clinical picture. 

HES has been subdivided into clinically relevant variants, including myeloproliferative (M-HES), T lymphocytic (L-HES), organ-restricted (or overlap) HES, familial HES, idiopathic HES, and specific syndromes with associated hypereosinophilia.^3-5,9 Patients with M-HES have elevated circulating leukocyte precursors and clinical manifestations, including but not limited to hepatosplenomegaly, anemia, and thrombocytopenia. The most commonly associated genetic mutations include the FIP1L1-PDGFR-α fusion, BCR-ABL1, PDGFRA/B, JAK2, KIT, and FGFR1.^3-6 L-HES usually has predominant skin and soft tissue involvement secondary to immunoglobulin E-mediated actions with clonal expansion of T cells (most commonly CD3-4+ or CD3+CD4-CD8-).^3,5,6 Familial HES, a rare variant, follows an autosomal dominant inheritance pattern and is usually present at birth. It involves chromosome 5, which contains genes coding for cytokines that drive eosinophilic proliferation, including interleukin (IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor.^5,9 Hypereosinophilia in the setting of end-organ damage restricted to a single organ is considered organ-restricted HES. There can be significant hepatic and gastrointestinal dysfunction, with or without malabsorption. 

HES can also manifest with hematologic malignancy, restrictive obliterative cardiomyopathies, renal injury manifested by hematuria and electrolyte derangements, and neurologic complications including hemiparesis, dysarthria, and even coma.⁶ Endothelial damage due to eosinophil-driven inflammation can result in thrombus formation and increased risk of thromboembolic events in various organs.³ Idiopathic HES, otherwise known as HES of unknown etiology or significance, is a diagnosis of exclusion and constitutes a cohort of patients who do not fit into the other delineated categories.^3-5 These patients often have multisystem involvement, making classification and treatment a challenge.⁵

The patient described in this case met the diagnostic criteria for HES, but her complicated clinical and laboratory features were challenging to characterize into a specific variant of HES. Organ-restricted HES was ruled out due to skin, marrow, and duodenal infiltration. She also had the potential for lung involvement based on her clinical symptoms, however no biopsy was obtained. Laboratory testing revealed no deletions or mutations indicative of familial, myeloproliferative, or lymphocytic variants. Her multisystem involvement without an underlying associated syndrome suggests idiopathic HES or HES of undetermined significance.^1-5

Most patients with HES are diagnosed between the ages of 20 and 50 years.¹⁰ While HES has its peak incidence in the fourth decade of life, acute onset of new symptoms 3 months postpartum makes this an unusual presentation. In this unique case, it is important to highlight the role of the physiologic changes of pregnancy in inflammatory mediation. The physiologic changes that occur in pregnancy to ensure fetal tolerance can have profound implications for leukocyte count, AEC, and subsequent inflammatory responses. The phenomenon of inflammatory amelioration during pregnancy is well-documented, but there has only been 1 known published case report discussing decreasing HES symptoms during pregnancy with prepregnancy and postpartum hypereosinophilia.⁸ It is suggested that this amelioration is secondary to cortisol and progesterone shifts that occur in pregnancy. Physiologic increases in adrenocorticotropic hormone in pregnancy leads to subsequent secretion of endogenous steroids by the adrenal cortex. In turn, pregnancy can lead to leukocytosis and eosinopenia.⁸ Overall, pregnancy can have beneficial immunomodulating properties in the spectrum of hypereosinophilic syndromes. Even so, this patient with HES diagnosed postpartum remains at risk for the sequelae of hypereosinophilia, regardless of potential for AEC reduction during pregnancy. Therefore, treatment considerations need to be made with the safety of the maternal-fetal dyad as a priority.

Treatment

The treatment of symptomatic HES without acute life-threatening features or associated malignancy is generally determined by clinical variant.^2-4 There is insufficient data to support initiation of treatment solely based on persistently elevated AEC. Patients with peripheral eosinophilia and hypereosinophilia should be monitored periodically with appropriate subspecialist evaluation for occult end-organ involvement, and targeted therapies should be deferred until an HES diagnosis.^1-4 First-line therapy in most HES variants is systemic glucocorticoids.^2,3,7 Since the disease course for this patient did not precisely match an HES variant, it was challenging to ascertain the optimal personalized treatment regimen. The approach to therapy was further complicated by newly identified pregnancy necessitating cessation of systemic glucocorticoids. In addition to glucocorticoids, hydroxyurea and interferon-α are among treatments historically used for HES, with tyrosine kinase inhibitors and monoclonal antibodies targeting IL-5 becoming more common.^1-4 Although this patient may ultimately benefit from an IL-5 targeting biologic medication such as mepolizumab, safety in pregnancy is not well-studied and may require close clinical monitoring with treatment deferred until after delivery if possible.^3,7,8,11

Military service members with frequent geographic relocation have additional barriers to timely diagnosis with often-limited access to subspecialty care depending on the duty station. While the patient was able to receive care at a large military medical center with many subspecialists, prompt recognition and timely referral to specialists would be even more critical at a smaller treatment facility. Depending on the severity and variant of HES, patients may warrant evaluation and treatment by hematology/oncology, cardiology, pulmonology, and immunology. Although HES can present in young children and older adults, this condition is most often diagnosed during the third and fourth decades of life, putting clinicians on the front line of hypereosinophilia identification and evaluation.¹⁰ Military physicians have the additional duty to not only think ahead in their diverse clinical settings to ensure proper care for patients, but also maintain a broad differential inclusive of more rare disease processes such as HES.

CONCLUSIONS

This case emphasizes how uncontrolled or untreated HES can lead to significant end-organ damage involving multiple systems and high morbidity. Prompt recognition of hypereosinophilia with potential HES can help expedite coordination of multidisciplinary care across multiple specialties to minimize delays in diagnosis and treatment. Doing so may minimize associated morbidity and mortality, especially in individuals located at more remote duty stations or deployed to austere environments.

Hypereosinophilic syndrome (HES) is defined by marked, persistent absolute eosinophil count (AEC) > 1500 cells/μL on ≥ 2 peripheral smears separated by ≥ 1 month with evidence of accompanied end-organ damage, in the absence of other causes of eosinophilia such as malignancy, atopy, or parasitic infections.^1-5 Hypereosinophilic infiltration can impact almost every organ system; however, the most profound complications in patients with HES are related to leukemias and cardiac manifestations of the disease.^3,4 Although rare, the associated morbidity and mortality of HES are considerable, making prompt recognition and treatment essential. Management involves targeted therapy based on pathologic classification of HES and on decreasing associated inflammation, fibrosis, and end-organ damage.^3,5-7

The patient in this case report met the diagnostic criteria for HES. However, this patient had several clinical and laboratory features that made it difficult to characterize a specific HES variant. Moreover, she had additional immunomodulating factors in the setting of pregnancy. This is the first documented case of HES of undetermined etiology diagnosed postpartum and managed in the setting of a new pregnancy.^2,8

CASE PRESENTATION

A 32-year-old female active-duty military service member with allergic rhinitis and a history of childhood eczema was referred to allergy/immunology for evaluation of a new, progressive pruritic rash. Symptoms started 3 months after the birth of her first child, with a new diffuse erythematous skin rash sparing her palms, soles, and mucosal surfaces. Given her history of atopy, the rash was initially treated as severe atopic dermatitis with appropriate topical medications. The rash gradually worsened, with the development of intermittent facial swelling, night sweats, dyspnea, recurrent epigastric abdominal pain, and nausea with vomiting, resulting in decreased oral intake and weight loss.

The patient was hospitalized and received an expedited multidisciplinary evaluation by dermatology, hematology/oncology, and gastroenterology. Her AEC of 4787 cells/μL peaked on admission and was markedly elevated from the 1070 cells/μL reported in the third trimester of her pregnancy. She was found to have mature eosinophilia on skin biopsy (Figure 1), endoscopic duodenal biopsy (Figure 2), peripheral blood smear (Figure 3), and bone marrow biopsy (Figure 4). 

Radiographic imaging of the chest, abdomen, and pelvis revealed hepatomegaly without detectable neoplasm. There was no clinical evidence of cardiac involvement, and evaluation with electrocardiography and echocardiography did not indicate myocarditis. Extensive laboratory testing revealed no genetic mutations indicative of familial, myeloproliferative, or lymphocytic variants of HES. 

The patient received topical emollients, omeprazole 40 mg daily, and ondansetron 8 mg 3 times daily as needed for symptom management, and was started on oral prednisone 40 mg daily with improvement in dyspnea, night sweats, and gastrointestinal complaints. During the patient's 6-day hospitalization and treatment, her AECs gradually decreased to 2110 cells/μL, and decreased to 1600 cells/μL over the course of a month, remaining in the hypereosinophilic range. The patient was discovered to be pregnant while symptoms were improving, resulting in stepwise discontinuation of oral steroids, but she reported continued improvement in symptoms.

DISCUSSION

Peripheral eosinophilia has a broad differential diagnoses, including HES, parasitic infections, atopic hypersensitivity diseases, eosinophilic lung diseases, eosinophilic gastrointestinal diseases, vasculitides such as eosinophilic granulomatosis with polyangiitis, genetic syndromes predisposing to eosinophilia, episodic angioedema with eosinophilia, and chronic metabolic disease with adrenal insufficiency.^1-5 HES, although rare, is a disease process with potentially devastating associated morbidity and mortality if not promptly recognized and treated. HES is further delineated by hypereosinophilia with associated eosinophil-mediated organ damage or dysfunction.^3-5

Clinical manifestations of HES can differ greatly depending on the HES variant and degree of organ involvement at the time of diagnosis and throughout the disease course. Patients with HES, as well as those with asymptomatic eosinophilia or hypereosinophilia, should be closely monitored for disease progression. In addition to trending peripheral AECs, clinicians should screen for symptoms of organ involvement and perform targeted evaluation of the suspected organs to promptly identify early signs of organ involvement and initiate treatment.^1-4 Recommendations regarding screening intervals vary widely from monthly to annually, depending on a patient’s specific clinical picture. 

HES has been subdivided into clinically relevant variants, including myeloproliferative (M-HES), T lymphocytic (L-HES), organ-restricted (or overlap) HES, familial HES, idiopathic HES, and specific syndromes with associated hypereosinophilia.^3-5,9 Patients with M-HES have elevated circulating leukocyte precursors and clinical manifestations, including but not limited to hepatosplenomegaly, anemia, and thrombocytopenia. The most commonly associated genetic mutations include the FIP1L1-PDGFR-α fusion, BCR-ABL1, PDGFRA/B, JAK2, KIT, and FGFR1.^3-6 L-HES usually has predominant skin and soft tissue involvement secondary to immunoglobulin E-mediated actions with clonal expansion of T cells (most commonly CD3-4+ or CD3+CD4-CD8-).^3,5,6 Familial HES, a rare variant, follows an autosomal dominant inheritance pattern and is usually present at birth. It involves chromosome 5, which contains genes coding for cytokines that drive eosinophilic proliferation, including interleukin (IL)-3, IL-5, and granulocyte-macrophage colony-stimulating factor.^5,9 Hypereosinophilia in the setting of end-organ damage restricted to a single organ is considered organ-restricted HES. There can be significant hepatic and gastrointestinal dysfunction, with or without malabsorption. 

HES can also manifest with hematologic malignancy, restrictive obliterative cardiomyopathies, renal injury manifested by hematuria and electrolyte derangements, and neurologic complications including hemiparesis, dysarthria, and even coma.⁶ Endothelial damage due to eosinophil-driven inflammation can result in thrombus formation and increased risk of thromboembolic events in various organs.³ Idiopathic HES, otherwise known as HES of unknown etiology or significance, is a diagnosis of exclusion and constitutes a cohort of patients who do not fit into the other delineated categories.^3-5 These patients often have multisystem involvement, making classification and treatment a challenge.⁵

The patient described in this case met the diagnostic criteria for HES, but her complicated clinical and laboratory features were challenging to characterize into a specific variant of HES. Organ-restricted HES was ruled out due to skin, marrow, and duodenal infiltration. She also had the potential for lung involvement based on her clinical symptoms, however no biopsy was obtained. Laboratory testing revealed no deletions or mutations indicative of familial, myeloproliferative, or lymphocytic variants. Her multisystem involvement without an underlying associated syndrome suggests idiopathic HES or HES of undetermined significance.^1-5

Most patients with HES are diagnosed between the ages of 20 and 50 years.¹⁰ While HES has its peak incidence in the fourth decade of life, acute onset of new symptoms 3 months postpartum makes this an unusual presentation. In this unique case, it is important to highlight the role of the physiologic changes of pregnancy in inflammatory mediation. The physiologic changes that occur in pregnancy to ensure fetal tolerance can have profound implications for leukocyte count, AEC, and subsequent inflammatory responses. The phenomenon of inflammatory amelioration during pregnancy is well-documented, but there has only been 1 known published case report discussing decreasing HES symptoms during pregnancy with prepregnancy and postpartum hypereosinophilia.⁸ It is suggested that this amelioration is secondary to cortisol and progesterone shifts that occur in pregnancy. Physiologic increases in adrenocorticotropic hormone in pregnancy leads to subsequent secretion of endogenous steroids by the adrenal cortex. In turn, pregnancy can lead to leukocytosis and eosinopenia.⁸ Overall, pregnancy can have beneficial immunomodulating properties in the spectrum of hypereosinophilic syndromes. Even so, this patient with HES diagnosed postpartum remains at risk for the sequelae of hypereosinophilia, regardless of potential for AEC reduction during pregnancy. Therefore, treatment considerations need to be made with the safety of the maternal-fetal dyad as a priority.

Treatment

The treatment of symptomatic HES without acute life-threatening features or associated malignancy is generally determined by clinical variant.^2-4 There is insufficient data to support initiation of treatment solely based on persistently elevated AEC. Patients with peripheral eosinophilia and hypereosinophilia should be monitored periodically with appropriate subspecialist evaluation for occult end-organ involvement, and targeted therapies should be deferred until an HES diagnosis.^1-4 First-line therapy in most HES variants is systemic glucocorticoids.^2,3,7 Since the disease course for this patient did not precisely match an HES variant, it was challenging to ascertain the optimal personalized treatment regimen. The approach to therapy was further complicated by newly identified pregnancy necessitating cessation of systemic glucocorticoids. In addition to glucocorticoids, hydroxyurea and interferon-α are among treatments historically used for HES, with tyrosine kinase inhibitors and monoclonal antibodies targeting IL-5 becoming more common.^1-4 Although this patient may ultimately benefit from an IL-5 targeting biologic medication such as mepolizumab, safety in pregnancy is not well-studied and may require close clinical monitoring with treatment deferred until after delivery if possible.^3,7,8,11

Military service members with frequent geographic relocation have additional barriers to timely diagnosis with often-limited access to subspecialty care depending on the duty station. While the patient was able to receive care at a large military medical center with many subspecialists, prompt recognition and timely referral to specialists would be even more critical at a smaller treatment facility. Depending on the severity and variant of HES, patients may warrant evaluation and treatment by hematology/oncology, cardiology, pulmonology, and immunology. Although HES can present in young children and older adults, this condition is most often diagnosed during the third and fourth decades of life, putting clinicians on the front line of hypereosinophilia identification and evaluation.¹⁰ Military physicians have the additional duty to not only think ahead in their diverse clinical settings to ensure proper care for patients, but also maintain a broad differential inclusive of more rare disease processes such as HES.

CONCLUSIONS

This case emphasizes how uncontrolled or untreated HES can lead to significant end-organ damage involving multiple systems and high morbidity. Prompt recognition of hypereosinophilia with potential HES can help expedite coordination of multidisciplinary care across multiple specialties to minimize delays in diagnosis and treatment. Doing so may minimize associated morbidity and mortality, especially in individuals located at more remote duty stations or deployed to austere environments.