After making an insulting comment to a surgery scheduler, a surgeon become the subject of a peer review investigation.

The surgeon had been called in on a Saturday morning for surgery, but when he arrived at the hospital, staff informed him that the operating room had been incorrectly booked and asked him to come back that afternoon. When the surgeon returned, the room still wasn’t ready, recounted David Beran, DO, a peer reviewer and medical director for the emergency department at University Medical Center New Orleans, in Louisiana. After more waiting and staff uncertainty about which operating room was going to open, the surgeon became frustrated and said to the scheduler: “Any idiot could figure this out!”

During his peer review, the surgeon acknowledged that he shouldn’t have made the rude remark to the scheduler, Dr. Beran said. His exasperation stemmed from an ongoing problem – operating rooms at the hospital were being inefficiently managed.

“The surgeon acknowledged that even though there was a systems issue at the root, that’s not justification to speak to people unprofessionally,” Dr. Beran said. “So, there was education for the surgeon, but the surgeon was also able to explain the frustration that led to that point.”

System problems are commonly encountered by peer reviewers, said Dr. Beran.

“There’s a huge gap between administration and clinical professionals when it comes to peer review,” he said. “So many times, bad situations, whether they’re clinical or behavioral, often boil down to systems issues or some inadequacy, whether it’s an EMR [electronic medical record] problem, an inefficacy, or how complicated a process is for an end user. But having a peer review situation that then leads to a system-level change that prevents that problem from happening again is really unlikely. There’s a huge disconnect between those two.”

Peer review is generally a process that goes on behind closed doors. Although structures may differ, peer review is generally described as the process by which physicians assess the quality of their peers’ work to ensure that standards of care are being met. The process is often used to evaluate issues regarding clinical care as well as behavioral complaints against physicians.

Doctors who undergo peer review frequently share their experiences, but reviewers themselves rarely speak out. For this story, this news organization spoke with several current and former peer reviewers about what really goes on during peer reviews, what frustrates them, and what they’ve learned along the way.

“Peer review processes are in place to build stronger institutions and stronger practices, and they’re supposed to be helpful,” Dr. Beran said. “But because of how opaque they are, it immediately puts physicians on the defensive, and it doesn’t always succeed in what it’s trying to do. I think that’s one of the biggest challenges.”
 

Biased reviewers taint evaluations

A peer reviewer on and off throughout her career, Indiana family physician Lana Patch, MD, said she always strived to be fair when evaluating fellow physicians. But not every reviewer she encountered operated the same way, she said. Some were biased.

In one case, Dr. Patch peer reviewed a general surgeon who had performed a hysterectomy on a 16-year-old girl. The surgeon believed the teenager likely had an acute appendicitis, but it turned out she had a uterine pathology, Dr. Patch said. The surgeon saved the girl’s life, but the case came under review because of the patient’s age and the fact that her uterus was removed. A local obstetrician-gynecologist weighed in on the case.

“The local ob.gyn. saw it as a turf battle,” recalled Dr. Patch, who is now retired after 30 years of practice in eastern Indiana. “The doctor had nothing but bad to say about the surgeon. He was a competitor.”

Because it was a small hospital, the committee sometimes had trouble finding a specialist who was qualified to give an opinion and who wasn’t in competition with the physician in question, said Dr. Patch. Eventually they found an outside pediatric gynecologist who reviewed the case and concluded that the surgeon had followed the standard of care.

Personal agendas in can come from different directions, said Robert Marder, MD, the author of several books on peer review. Dr. Marder is a consultant who assists with peer review redesign. He has worked with hundreds of medical staff leaders and is a former vice president at the Greeley Company, a consulting firm in Danvers, Mass., that performs peer review redesign. Dr. Marder is president of Robert J. Marder Consulting.

“It goes both ways,” Dr. Marder said. “I’ve seen where somebody with a personal view decides to bring things to the peer review committee specifically because they want the peer review committee to have an adverse view of this person and get them off the medical staff. And I’ve seen hospitals that are uncomfortable with a certain person for whatever reason and want the peer review committee to address it, as opposed to addressing it from a human resource standpoint.”

Dr. Patch recalled a case in which reviewers and hospital leaders were at odds over the credentialing of a physician. Fifteen years earlier, while driving in California, the psychiatrist had been pulled over and was found with an ounce of marijuana, she said.

“We wanted to privilege him,” Dr. Patch said. “As staff physicians, we felt that was 15 years ago, people change over time. Doctors are human beings, too. He seemed to have good credentials and good training. The hospital said, ‘Oh no, we can’t have somebody like this.’ “

The psychiatrist was placed on probation and had to undergo a review every 90 days for about 3 years. Eventually, he was privileged, Dr. Patch said.

Bias among reviewers, including unintentional bias, is also a challenge, Dr. Marder noted. Some initial reviewers score a physician too harshly, he said, whereas others underscore.

“Underscoring is more insidious and more difficult to deal with,” Dr. Marder said. “Underscoring is where the reviewer is too nice. They tend to dismiss things from their colleagues rather than recognize them as an opportunity to help them improve. With underscoring, a lot of committees, if the initial reviewer says the care was appropriate, they don’t even look at the case. They just take that one person’s word for it.”
 

Reviewers: Looks can be deceiving

When first examining the documented details of a case, it can be easy for peer reviewers to make a quick judgment about what happened, Dr. Beran said.

“You get these complaints, and you read through it, and you think, ‘Oh man, this person really messed up,’ “ he said. “Then you hear the doctor’s side of it, and you realize, ‘No, there’s a much bigger picture at play.’ You realize both sides have valid perspectives on it.”

In one case, for example, Dr. Beran recalled a complaint against a physician who made a snarky remark to a nurse. The doctor had asked the nurse for a piece of equipment, and the nurse said she was busy preparing the room for a patient. The doctor made a comment along the lines of, “Well, would you like me to do that for you and also intubate the patient while you do some charting?!”

At first glance, it appeared that the physician lashed out inappropriately at the nurse. But when reviewers heard from the doctor, they learned that the nurses knew that a trauma patient was coming by ambulance and that he would likely require a ventilator, Dr. Beran said. As the minutes ticked by, however, the nurses were seen in the break room chatting. Nothing had been prepared in the room, including any airway supply.

“The patient had a prolonged course and a very difficult intubation and could have very easily wound up with a much worse outcome for something the nurses had been warned about prior to the patient’s arrival,” he said. “I can see anybody getting upset in that situation if I warned them 5 or 10 minutes beforehand, ‘Get this stuff ready,’ and then nothing was done.”

There was no direct penalty for the physician.

Just as some complaints can be misleading, the clinical record in some peer review cases can also lead reviewers astray.

Physicians frequently include too much irrelevant information in the record, which can cloud a peer review, said Hans Duvefelt, MD, a family physician at Pines Health Services, in Van Buren, Maine. Dr. Duvefelt is a former medical director at Bucksport Regional Health Center, in Ellsworth, Maine. Both facilities are federally qualified health centers where continuous, random peer reviews are required.

In one case, Dr. Duvefelt was peer reviewing a physician’s office note regarding an elderly patient with a low-grade fever. The final diagnosis was urinary tract infection. Dr. Duvefelt said he had trouble following the doctor’s line of thinking because of a plethora of unnecessary data in the 10-page document. The office note included past medical history, prior lab and imaging test results, and an extensive narrative section that included a mixture of active medical problems and ongoing relationships with specialists, he said.

After reading through the printout three times, Dr. Duvefelt said he finally found mention of increased urinary dribbling and details about an enlarged prostate. He also spotted a same-day urinalysis among nearly a dozen other previous lab tests that had no connection to body temperature. Dr. Duvefelt gave the physician a passing grade but also left a scathing note about all the irrelevant information.

“It’s very common,” Dr. Duvefelt said. “It’s a disaster. Other doctors can’t follow your thinking. A reviewer has a hard time determining whether the doctor acted reasonably.”
 

Slackers make bad reviewers

Although dedicated reviewers work hard to get to the bottom of cases, it’s not uncommon for some committee members to hardly work at all, according to experts.

Dr. Marder said he’s seen many instances in which reviewers were assigned a review but did not complete it for months. Most committees have set time frames in which reviewers must complete their review.

“That delays that review, and by that time, the review is older and it’s harder to remember things,” he said. “It’s not fair to the physician. If there was a problem the physician could fix and you don’t tell him for 3 or 4 months what it is, he may do the same thing again. The case might come before the committee again and it looks like he’s repeated something, but you never gave him the opportunity to improve.”

Other reviewers fail to attend meetings regularly. Peer review committee members are generally volunteers, and meetings are usually held in the early mornings or late evenings.

“There are reasons for not attending occasionally, but some people put on a committee just don’t take it seriously,” Dr. Marder said. “They don’t fulfill their responsibilities as well as they should. If you accept the job, do the job.”

For physicians considering becoming a peer reviewer, Dr. Beran offers these tips: Be transparent, help physicians understand next steps, and make yourself as available as allowed to answer questions.

Know your committee’s policies and procedures, and follow them, added Dr. Marder. It’s also a good idea to work with your hospital’s quality staff, he said.

Reviewers should keep in mind that they may not always be the one assessing someone else, Dr. Beran said.

“Realize very easily you could be on the other side of that table for things that are outside your control,” he said. “How would you want to be treated?”

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

After making an insulting comment to a surgery scheduler, a surgeon become the subject of a peer review investigation.

The surgeon had been called in on a Saturday morning for surgery, but when he arrived at the hospital, staff informed him that the operating room had been incorrectly booked and asked him to come back that afternoon. When the surgeon returned, the room still wasn’t ready, recounted David Beran, DO, a peer reviewer and medical director for the emergency department at University Medical Center New Orleans, in Louisiana. After more waiting and staff uncertainty about which operating room was going to open, the surgeon became frustrated and said to the scheduler: “Any idiot could figure this out!”

During his peer review, the surgeon acknowledged that he shouldn’t have made the rude remark to the scheduler, Dr. Beran said. His exasperation stemmed from an ongoing problem – operating rooms at the hospital were being inefficiently managed.

“The surgeon acknowledged that even though there was a systems issue at the root, that’s not justification to speak to people unprofessionally,” Dr. Beran said. “So, there was education for the surgeon, but the surgeon was also able to explain the frustration that led to that point.”

System problems are commonly encountered by peer reviewers, said Dr. Beran.

“There’s a huge gap between administration and clinical professionals when it comes to peer review,” he said. “So many times, bad situations, whether they’re clinical or behavioral, often boil down to systems issues or some inadequacy, whether it’s an EMR [electronic medical record] problem, an inefficacy, or how complicated a process is for an end user. But having a peer review situation that then leads to a system-level change that prevents that problem from happening again is really unlikely. There’s a huge disconnect between those two.”

Peer review is generally a process that goes on behind closed doors. Although structures may differ, peer review is generally described as the process by which physicians assess the quality of their peers’ work to ensure that standards of care are being met. The process is often used to evaluate issues regarding clinical care as well as behavioral complaints against physicians.

Doctors who undergo peer review frequently share their experiences, but reviewers themselves rarely speak out. For this story, this news organization spoke with several current and former peer reviewers about what really goes on during peer reviews, what frustrates them, and what they’ve learned along the way.

“Peer review processes are in place to build stronger institutions and stronger practices, and they’re supposed to be helpful,” Dr. Beran said. “But because of how opaque they are, it immediately puts physicians on the defensive, and it doesn’t always succeed in what it’s trying to do. I think that’s one of the biggest challenges.”
 

Biased reviewers taint evaluations

A peer reviewer on and off throughout her career, Indiana family physician Lana Patch, MD, said she always strived to be fair when evaluating fellow physicians. But not every reviewer she encountered operated the same way, she said. Some were biased.

In one case, Dr. Patch peer reviewed a general surgeon who had performed a hysterectomy on a 16-year-old girl. The surgeon believed the teenager likely had an acute appendicitis, but it turned out she had a uterine pathology, Dr. Patch said. The surgeon saved the girl’s life, but the case came under review because of the patient’s age and the fact that her uterus was removed. A local obstetrician-gynecologist weighed in on the case.

“The local ob.gyn. saw it as a turf battle,” recalled Dr. Patch, who is now retired after 30 years of practice in eastern Indiana. “The doctor had nothing but bad to say about the surgeon. He was a competitor.”

Because it was a small hospital, the committee sometimes had trouble finding a specialist who was qualified to give an opinion and who wasn’t in competition with the physician in question, said Dr. Patch. Eventually they found an outside pediatric gynecologist who reviewed the case and concluded that the surgeon had followed the standard of care.

Personal agendas in can come from different directions, said Robert Marder, MD, the author of several books on peer review. Dr. Marder is a consultant who assists with peer review redesign. He has worked with hundreds of medical staff leaders and is a former vice president at the Greeley Company, a consulting firm in Danvers, Mass., that performs peer review redesign. Dr. Marder is president of Robert J. Marder Consulting.

“It goes both ways,” Dr. Marder said. “I’ve seen where somebody with a personal view decides to bring things to the peer review committee specifically because they want the peer review committee to have an adverse view of this person and get them off the medical staff. And I’ve seen hospitals that are uncomfortable with a certain person for whatever reason and want the peer review committee to address it, as opposed to addressing it from a human resource standpoint.”

Dr. Patch recalled a case in which reviewers and hospital leaders were at odds over the credentialing of a physician. Fifteen years earlier, while driving in California, the psychiatrist had been pulled over and was found with an ounce of marijuana, she said.

“We wanted to privilege him,” Dr. Patch said. “As staff physicians, we felt that was 15 years ago, people change over time. Doctors are human beings, too. He seemed to have good credentials and good training. The hospital said, ‘Oh no, we can’t have somebody like this.’ “

The psychiatrist was placed on probation and had to undergo a review every 90 days for about 3 years. Eventually, he was privileged, Dr. Patch said.

Bias among reviewers, including unintentional bias, is also a challenge, Dr. Marder noted. Some initial reviewers score a physician too harshly, he said, whereas others underscore.

“Underscoring is more insidious and more difficult to deal with,” Dr. Marder said. “Underscoring is where the reviewer is too nice. They tend to dismiss things from their colleagues rather than recognize them as an opportunity to help them improve. With underscoring, a lot of committees, if the initial reviewer says the care was appropriate, they don’t even look at the case. They just take that one person’s word for it.”
 

Reviewers: Looks can be deceiving

When first examining the documented details of a case, it can be easy for peer reviewers to make a quick judgment about what happened, Dr. Beran said.

“You get these complaints, and you read through it, and you think, ‘Oh man, this person really messed up,’ “ he said. “Then you hear the doctor’s side of it, and you realize, ‘No, there’s a much bigger picture at play.’ You realize both sides have valid perspectives on it.”

In one case, for example, Dr. Beran recalled a complaint against a physician who made a snarky remark to a nurse. The doctor had asked the nurse for a piece of equipment, and the nurse said she was busy preparing the room for a patient. The doctor made a comment along the lines of, “Well, would you like me to do that for you and also intubate the patient while you do some charting?!”

At first glance, it appeared that the physician lashed out inappropriately at the nurse. But when reviewers heard from the doctor, they learned that the nurses knew that a trauma patient was coming by ambulance and that he would likely require a ventilator, Dr. Beran said. As the minutes ticked by, however, the nurses were seen in the break room chatting. Nothing had been prepared in the room, including any airway supply.

“The patient had a prolonged course and a very difficult intubation and could have very easily wound up with a much worse outcome for something the nurses had been warned about prior to the patient’s arrival,” he said. “I can see anybody getting upset in that situation if I warned them 5 or 10 minutes beforehand, ‘Get this stuff ready,’ and then nothing was done.”

There was no direct penalty for the physician.

Just as some complaints can be misleading, the clinical record in some peer review cases can also lead reviewers astray.

Physicians frequently include too much irrelevant information in the record, which can cloud a peer review, said Hans Duvefelt, MD, a family physician at Pines Health Services, in Van Buren, Maine. Dr. Duvefelt is a former medical director at Bucksport Regional Health Center, in Ellsworth, Maine. Both facilities are federally qualified health centers where continuous, random peer reviews are required.

In one case, Dr. Duvefelt was peer reviewing a physician’s office note regarding an elderly patient with a low-grade fever. The final diagnosis was urinary tract infection. Dr. Duvefelt said he had trouble following the doctor’s line of thinking because of a plethora of unnecessary data in the 10-page document. The office note included past medical history, prior lab and imaging test results, and an extensive narrative section that included a mixture of active medical problems and ongoing relationships with specialists, he said.

After reading through the printout three times, Dr. Duvefelt said he finally found mention of increased urinary dribbling and details about an enlarged prostate. He also spotted a same-day urinalysis among nearly a dozen other previous lab tests that had no connection to body temperature. Dr. Duvefelt gave the physician a passing grade but also left a scathing note about all the irrelevant information.

“It’s very common,” Dr. Duvefelt said. “It’s a disaster. Other doctors can’t follow your thinking. A reviewer has a hard time determining whether the doctor acted reasonably.”
 

Slackers make bad reviewers

Although dedicated reviewers work hard to get to the bottom of cases, it’s not uncommon for some committee members to hardly work at all, according to experts.

Dr. Marder said he’s seen many instances in which reviewers were assigned a review but did not complete it for months. Most committees have set time frames in which reviewers must complete their review.

“That delays that review, and by that time, the review is older and it’s harder to remember things,” he said. “It’s not fair to the physician. If there was a problem the physician could fix and you don’t tell him for 3 or 4 months what it is, he may do the same thing again. The case might come before the committee again and it looks like he’s repeated something, but you never gave him the opportunity to improve.”

Other reviewers fail to attend meetings regularly. Peer review committee members are generally volunteers, and meetings are usually held in the early mornings or late evenings.

“There are reasons for not attending occasionally, but some people put on a committee just don’t take it seriously,” Dr. Marder said. “They don’t fulfill their responsibilities as well as they should. If you accept the job, do the job.”

For physicians considering becoming a peer reviewer, Dr. Beran offers these tips: Be transparent, help physicians understand next steps, and make yourself as available as allowed to answer questions.

Know your committee’s policies and procedures, and follow them, added Dr. Marder. It’s also a good idea to work with your hospital’s quality staff, he said.

Reviewers should keep in mind that they may not always be the one assessing someone else, Dr. Beran said.

“Realize very easily you could be on the other side of that table for things that are outside your control,” he said. “How would you want to be treated?”

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

After making an insulting comment to a surgery scheduler, a surgeon become the subject of a peer review investigation.

The surgeon had been called in on a Saturday morning for surgery, but when he arrived at the hospital, staff informed him that the operating room had been incorrectly booked and asked him to come back that afternoon. When the surgeon returned, the room still wasn’t ready, recounted David Beran, DO, a peer reviewer and medical director for the emergency department at University Medical Center New Orleans, in Louisiana. After more waiting and staff uncertainty about which operating room was going to open, the surgeon became frustrated and said to the scheduler: “Any idiot could figure this out!”

During his peer review, the surgeon acknowledged that he shouldn’t have made the rude remark to the scheduler, Dr. Beran said. His exasperation stemmed from an ongoing problem – operating rooms at the hospital were being inefficiently managed.

“The surgeon acknowledged that even though there was a systems issue at the root, that’s not justification to speak to people unprofessionally,” Dr. Beran said. “So, there was education for the surgeon, but the surgeon was also able to explain the frustration that led to that point.”

System problems are commonly encountered by peer reviewers, said Dr. Beran.

“There’s a huge gap between administration and clinical professionals when it comes to peer review,” he said. “So many times, bad situations, whether they’re clinical or behavioral, often boil down to systems issues or some inadequacy, whether it’s an EMR [electronic medical record] problem, an inefficacy, or how complicated a process is for an end user. But having a peer review situation that then leads to a system-level change that prevents that problem from happening again is really unlikely. There’s a huge disconnect between those two.”

Peer review is generally a process that goes on behind closed doors. Although structures may differ, peer review is generally described as the process by which physicians assess the quality of their peers’ work to ensure that standards of care are being met. The process is often used to evaluate issues regarding clinical care as well as behavioral complaints against physicians.

Doctors who undergo peer review frequently share their experiences, but reviewers themselves rarely speak out. For this story, this news organization spoke with several current and former peer reviewers about what really goes on during peer reviews, what frustrates them, and what they’ve learned along the way.

“Peer review processes are in place to build stronger institutions and stronger practices, and they’re supposed to be helpful,” Dr. Beran said. “But because of how opaque they are, it immediately puts physicians on the defensive, and it doesn’t always succeed in what it’s trying to do. I think that’s one of the biggest challenges.”
 

Biased reviewers taint evaluations

A peer reviewer on and off throughout her career, Indiana family physician Lana Patch, MD, said she always strived to be fair when evaluating fellow physicians. But not every reviewer she encountered operated the same way, she said. Some were biased.

In one case, Dr. Patch peer reviewed a general surgeon who had performed a hysterectomy on a 16-year-old girl. The surgeon believed the teenager likely had an acute appendicitis, but it turned out she had a uterine pathology, Dr. Patch said. The surgeon saved the girl’s life, but the case came under review because of the patient’s age and the fact that her uterus was removed. A local obstetrician-gynecologist weighed in on the case.

“The local ob.gyn. saw it as a turf battle,” recalled Dr. Patch, who is now retired after 30 years of practice in eastern Indiana. “The doctor had nothing but bad to say about the surgeon. He was a competitor.”

Because it was a small hospital, the committee sometimes had trouble finding a specialist who was qualified to give an opinion and who wasn’t in competition with the physician in question, said Dr. Patch. Eventually they found an outside pediatric gynecologist who reviewed the case and concluded that the surgeon had followed the standard of care.

Personal agendas in can come from different directions, said Robert Marder, MD, the author of several books on peer review. Dr. Marder is a consultant who assists with peer review redesign. He has worked with hundreds of medical staff leaders and is a former vice president at the Greeley Company, a consulting firm in Danvers, Mass., that performs peer review redesign. Dr. Marder is president of Robert J. Marder Consulting.

“It goes both ways,” Dr. Marder said. “I’ve seen where somebody with a personal view decides to bring things to the peer review committee specifically because they want the peer review committee to have an adverse view of this person and get them off the medical staff. And I’ve seen hospitals that are uncomfortable with a certain person for whatever reason and want the peer review committee to address it, as opposed to addressing it from a human resource standpoint.”

Dr. Patch recalled a case in which reviewers and hospital leaders were at odds over the credentialing of a physician. Fifteen years earlier, while driving in California, the psychiatrist had been pulled over and was found with an ounce of marijuana, she said.

“We wanted to privilege him,” Dr. Patch said. “As staff physicians, we felt that was 15 years ago, people change over time. Doctors are human beings, too. He seemed to have good credentials and good training. The hospital said, ‘Oh no, we can’t have somebody like this.’ “

The psychiatrist was placed on probation and had to undergo a review every 90 days for about 3 years. Eventually, he was privileged, Dr. Patch said.

Bias among reviewers, including unintentional bias, is also a challenge, Dr. Marder noted. Some initial reviewers score a physician too harshly, he said, whereas others underscore.

“Underscoring is more insidious and more difficult to deal with,” Dr. Marder said. “Underscoring is where the reviewer is too nice. They tend to dismiss things from their colleagues rather than recognize them as an opportunity to help them improve. With underscoring, a lot of committees, if the initial reviewer says the care was appropriate, they don’t even look at the case. They just take that one person’s word for it.”
 

Reviewers: Looks can be deceiving

When first examining the documented details of a case, it can be easy for peer reviewers to make a quick judgment about what happened, Dr. Beran said.

“You get these complaints, and you read through it, and you think, ‘Oh man, this person really messed up,’ “ he said. “Then you hear the doctor’s side of it, and you realize, ‘No, there’s a much bigger picture at play.’ You realize both sides have valid perspectives on it.”

In one case, for example, Dr. Beran recalled a complaint against a physician who made a snarky remark to a nurse. The doctor had asked the nurse for a piece of equipment, and the nurse said she was busy preparing the room for a patient. The doctor made a comment along the lines of, “Well, would you like me to do that for you and also intubate the patient while you do some charting?!”

At first glance, it appeared that the physician lashed out inappropriately at the nurse. But when reviewers heard from the doctor, they learned that the nurses knew that a trauma patient was coming by ambulance and that he would likely require a ventilator, Dr. Beran said. As the minutes ticked by, however, the nurses were seen in the break room chatting. Nothing had been prepared in the room, including any airway supply.

“The patient had a prolonged course and a very difficult intubation and could have very easily wound up with a much worse outcome for something the nurses had been warned about prior to the patient’s arrival,” he said. “I can see anybody getting upset in that situation if I warned them 5 or 10 minutes beforehand, ‘Get this stuff ready,’ and then nothing was done.”

There was no direct penalty for the physician.

Just as some complaints can be misleading, the clinical record in some peer review cases can also lead reviewers astray.

Physicians frequently include too much irrelevant information in the record, which can cloud a peer review, said Hans Duvefelt, MD, a family physician at Pines Health Services, in Van Buren, Maine. Dr. Duvefelt is a former medical director at Bucksport Regional Health Center, in Ellsworth, Maine. Both facilities are federally qualified health centers where continuous, random peer reviews are required.

In one case, Dr. Duvefelt was peer reviewing a physician’s office note regarding an elderly patient with a low-grade fever. The final diagnosis was urinary tract infection. Dr. Duvefelt said he had trouble following the doctor’s line of thinking because of a plethora of unnecessary data in the 10-page document. The office note included past medical history, prior lab and imaging test results, and an extensive narrative section that included a mixture of active medical problems and ongoing relationships with specialists, he said.

After reading through the printout three times, Dr. Duvefelt said he finally found mention of increased urinary dribbling and details about an enlarged prostate. He also spotted a same-day urinalysis among nearly a dozen other previous lab tests that had no connection to body temperature. Dr. Duvefelt gave the physician a passing grade but also left a scathing note about all the irrelevant information.

“It’s very common,” Dr. Duvefelt said. “It’s a disaster. Other doctors can’t follow your thinking. A reviewer has a hard time determining whether the doctor acted reasonably.”
 

Slackers make bad reviewers

Although dedicated reviewers work hard to get to the bottom of cases, it’s not uncommon for some committee members to hardly work at all, according to experts.

Dr. Marder said he’s seen many instances in which reviewers were assigned a review but did not complete it for months. Most committees have set time frames in which reviewers must complete their review.

“That delays that review, and by that time, the review is older and it’s harder to remember things,” he said. “It’s not fair to the physician. If there was a problem the physician could fix and you don’t tell him for 3 or 4 months what it is, he may do the same thing again. The case might come before the committee again and it looks like he’s repeated something, but you never gave him the opportunity to improve.”

Other reviewers fail to attend meetings regularly. Peer review committee members are generally volunteers, and meetings are usually held in the early mornings or late evenings.

“There are reasons for not attending occasionally, but some people put on a committee just don’t take it seriously,” Dr. Marder said. “They don’t fulfill their responsibilities as well as they should. If you accept the job, do the job.”

For physicians considering becoming a peer reviewer, Dr. Beran offers these tips: Be transparent, help physicians understand next steps, and make yourself as available as allowed to answer questions.

Know your committee’s policies and procedures, and follow them, added Dr. Marder. It’s also a good idea to work with your hospital’s quality staff, he said.

Reviewers should keep in mind that they may not always be the one assessing someone else, Dr. Beran said.

“Realize very easily you could be on the other side of that table for things that are outside your control,” he said. “How would you want to be treated?”

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

Advances in Hematology and Oncology

• Integrated Care for Cancer-Related Distress
• Solid Tumor Checkpoint Inhibitor Dosing Models and Toxicity
• Evidence-Based Algorithm for Prostate Cancer Bone Health
• QOL and Toxicity After High-Dose Brachytherapy for Prostate Cancer
• An Interdisciplinary Approach to Comorbid Pancreatic Cancer and Substance Use Disorder
• Three Primary Cancers in a Veteran With Toxic Exposures

Advances in Hematology and Oncology

• Integrated Care for Cancer-Related Distress
• Solid Tumor Checkpoint Inhibitor Dosing Models and Toxicity
• Evidence-Based Algorithm for Prostate Cancer Bone Health
• QOL and Toxicity After High-Dose Brachytherapy for Prostate Cancer
• An Interdisciplinary Approach to Comorbid Pancreatic Cancer and Substance Use Disorder
• Three Primary Cancers in a Veteran With Toxic Exposures

Advances in Hematology and Oncology

• Integrated Care for Cancer-Related Distress
• Solid Tumor Checkpoint Inhibitor Dosing Models and Toxicity
• Evidence-Based Algorithm for Prostate Cancer Bone Health
• QOL and Toxicity After High-Dose Brachytherapy for Prostate Cancer
• An Interdisciplinary Approach to Comorbid Pancreatic Cancer and Substance Use Disorder
• Three Primary Cancers in a Veteran With Toxic Exposures

Contact lenses that detect glucose in tears. Capsules embedded in clothes that can be used to counteract the risk of sensitive skin conditions.

These are just two examples of technologies under development that are revolutionizing the future of medicine, and dermatology is one of the fields leading the way.

At the annual meeting of the Society for Pediatric Dermatology, Zayna Khayat, PhD, said that the future of medicine is driven by six shifts pulling society from a past oriented around the health care system – the buildings, clinicians, and payers – to a patient-oriented perspective. “That doesn’t just happen on its own,” said Dr. Khayat, a future strategist at Toronto-based SE Health. “There are big forces that are pulling us to the future whether we want it to or not. One is that patients have woken up. They have grown to have power in many other complex decisions in their life, and they’re expecting no less from our health care system.”

During her presentation, she discussed the six shifts:

1. The timing of service placement. The traditional model of medicine is “an intermittent and interventional science that waits for the symptoms and goes in and either fixes or manages them,” she said. “So, it’s not really health care; it’s sick care. That’s been fine in the industrial era when we needed to get medicine to stop catastrophic events. Not only is it shifting to be proactive and preventative but it’s shifting to a new science of medicine called predictive medicine.”

As for proactive and preventative care, she continued, each patient’s choice of behaviors related to diet, exercise, and stress “mingles with DNA to produce health, yet we spend about 90% of our resources on sick care. Now, health systems are moving their resources to things like education, housing, transportation, food security, equity, and racial divides. ... This is trickling down to how we train health care professionals. We know that patients live very little of their time in formal care settings, so all of their health is created – or destroyed – well outside of the clinical setting. We train our health professionals mostly in a clinical setting. Health systems are now starting to reimagine how training happens so we can train people to understand the fully loaded context of their patients’ lives.”

2. A shift in precision. For all its advances and science breakthroughs, medicine “is still quite crude,” said Dr. Khayat, who is also an adjunct professor in the Rotman School of Management at the University of Toronto. “It’s very analog, based on a one-size-fits-all approach. In the business world, we call this a segment of one: the idea that in some clinical trial, a result was produced that was based on the average of everybody, and therefore we just give everybody what worked for the average. ... We don’t need to have that trade-off anymore, because it won’t be a trade-off of higher cost to tailor down to an N of 1. It will be highly personalized, intelligent medicine, very precise.”

3. A shift from institution-centered to person-centered care. “The artifacts that health care was built on are very analog and are going to get decentralized out of buildings, dephysicalized, disintermediated,” she predicted. “We’ll have a seamless digital physical experience, expanded channels through which patients can access their services. Pick a channel that makes sense for the patient and don’t let care follow the place but rather let care follow the person.”

4. A shift in care duration, from episodic and intermittent care to more continuous care. “With very little input you should know what’s going on at any point in time instead of time-sharing access to diagnostics and to clinicians,” Dr. Khayat said. Wrist-worn devices that gather personal omics “are now really democratized, with every aspect of a diagnostic clinic available within or connected to a smartphone. This allows for data to be gathered and shared with clinicians, including tools under the skin that can get some of the biochemical data in real time instead of poking and prodding and waiting for a diagnostic lab.” These devices, she said, will become easier to use, cheaper, and will work faster, and provide much better data “at almost zero cost.”

Technologies being developed include tattoos that can read biomarkers, innovations in clothing that can detect biochemical reactions in the skin, underwear that can read vital signs, and contact lenses that can measure glucose levels. “The skin will become a major noninvasive way to obtain information,” she said.

5. A shift in power from providers to patients. “It’s estimated that about 80% of health care decisions could be self-managed by people in their communities,” Dr. Khayat said.

6. A shift from volume-based to value-based care. “Because we’ve been obsessed with the system, we’ve paid for stuff like visits, pills, MRI scans, et cetera,” she said. “We don’t need to do that anymore. Health systems don’t want to keep paying for stuff if they don’t see the results. Because of all the other shifts, we can pay for results. Some call this value-based care. I call it fee-for-health.”

She noted that the future of medicine is underpinned by innovations in AI/predictalytics, voice recognition, virtual reality, blockchain, IoT sensors, 3D printing, omics, robotics, autonomous transport, neurotechnology, nanobiology, and cellular therapy. “They’re moving at a very fast pace because they don’t need the kind of cost, capital, and expertise that the previous tools did,” she said. “This is the promise that technology can bring.”

Dr. Khayat disclosed that she has been a workshop participant for Roche Canada.

[email protected]

Contact lenses that detect glucose in tears. Capsules embedded in clothes that can be used to counteract the risk of sensitive skin conditions.

These are just two examples of technologies under development that are revolutionizing the future of medicine, and dermatology is one of the fields leading the way.

At the annual meeting of the Society for Pediatric Dermatology, Zayna Khayat, PhD, said that the future of medicine is driven by six shifts pulling society from a past oriented around the health care system – the buildings, clinicians, and payers – to a patient-oriented perspective. “That doesn’t just happen on its own,” said Dr. Khayat, a future strategist at Toronto-based SE Health. “There are big forces that are pulling us to the future whether we want it to or not. One is that patients have woken up. They have grown to have power in many other complex decisions in their life, and they’re expecting no less from our health care system.”

During her presentation, she discussed the six shifts:

1. The timing of service placement. The traditional model of medicine is “an intermittent and interventional science that waits for the symptoms and goes in and either fixes or manages them,” she said. “So, it’s not really health care; it’s sick care. That’s been fine in the industrial era when we needed to get medicine to stop catastrophic events. Not only is it shifting to be proactive and preventative but it’s shifting to a new science of medicine called predictive medicine.”

As for proactive and preventative care, she continued, each patient’s choice of behaviors related to diet, exercise, and stress “mingles with DNA to produce health, yet we spend about 90% of our resources on sick care. Now, health systems are moving their resources to things like education, housing, transportation, food security, equity, and racial divides. ... This is trickling down to how we train health care professionals. We know that patients live very little of their time in formal care settings, so all of their health is created – or destroyed – well outside of the clinical setting. We train our health professionals mostly in a clinical setting. Health systems are now starting to reimagine how training happens so we can train people to understand the fully loaded context of their patients’ lives.”

2. A shift in precision. For all its advances and science breakthroughs, medicine “is still quite crude,” said Dr. Khayat, who is also an adjunct professor in the Rotman School of Management at the University of Toronto. “It’s very analog, based on a one-size-fits-all approach. In the business world, we call this a segment of one: the idea that in some clinical trial, a result was produced that was based on the average of everybody, and therefore we just give everybody what worked for the average. ... We don’t need to have that trade-off anymore, because it won’t be a trade-off of higher cost to tailor down to an N of 1. It will be highly personalized, intelligent medicine, very precise.”

3. A shift from institution-centered to person-centered care. “The artifacts that health care was built on are very analog and are going to get decentralized out of buildings, dephysicalized, disintermediated,” she predicted. “We’ll have a seamless digital physical experience, expanded channels through which patients can access their services. Pick a channel that makes sense for the patient and don’t let care follow the place but rather let care follow the person.”

4. A shift in care duration, from episodic and intermittent care to more continuous care. “With very little input you should know what’s going on at any point in time instead of time-sharing access to diagnostics and to clinicians,” Dr. Khayat said. Wrist-worn devices that gather personal omics “are now really democratized, with every aspect of a diagnostic clinic available within or connected to a smartphone. This allows for data to be gathered and shared with clinicians, including tools under the skin that can get some of the biochemical data in real time instead of poking and prodding and waiting for a diagnostic lab.” These devices, she said, will become easier to use, cheaper, and will work faster, and provide much better data “at almost zero cost.”

Technologies being developed include tattoos that can read biomarkers, innovations in clothing that can detect biochemical reactions in the skin, underwear that can read vital signs, and contact lenses that can measure glucose levels. “The skin will become a major noninvasive way to obtain information,” she said.

5. A shift in power from providers to patients. “It’s estimated that about 80% of health care decisions could be self-managed by people in their communities,” Dr. Khayat said.

6. A shift from volume-based to value-based care. “Because we’ve been obsessed with the system, we’ve paid for stuff like visits, pills, MRI scans, et cetera,” she said. “We don’t need to do that anymore. Health systems don’t want to keep paying for stuff if they don’t see the results. Because of all the other shifts, we can pay for results. Some call this value-based care. I call it fee-for-health.”

She noted that the future of medicine is underpinned by innovations in AI/predictalytics, voice recognition, virtual reality, blockchain, IoT sensors, 3D printing, omics, robotics, autonomous transport, neurotechnology, nanobiology, and cellular therapy. “They’re moving at a very fast pace because they don’t need the kind of cost, capital, and expertise that the previous tools did,” she said. “This is the promise that technology can bring.”

Dr. Khayat disclosed that she has been a workshop participant for Roche Canada.

[email protected]

Contact lenses that detect glucose in tears. Capsules embedded in clothes that can be used to counteract the risk of sensitive skin conditions.

These are just two examples of technologies under development that are revolutionizing the future of medicine, and dermatology is one of the fields leading the way.

At the annual meeting of the Society for Pediatric Dermatology, Zayna Khayat, PhD, said that the future of medicine is driven by six shifts pulling society from a past oriented around the health care system – the buildings, clinicians, and payers – to a patient-oriented perspective. “That doesn’t just happen on its own,” said Dr. Khayat, a future strategist at Toronto-based SE Health. “There are big forces that are pulling us to the future whether we want it to or not. One is that patients have woken up. They have grown to have power in many other complex decisions in their life, and they’re expecting no less from our health care system.”

During her presentation, she discussed the six shifts:

1. The timing of service placement. The traditional model of medicine is “an intermittent and interventional science that waits for the symptoms and goes in and either fixes or manages them,” she said. “So, it’s not really health care; it’s sick care. That’s been fine in the industrial era when we needed to get medicine to stop catastrophic events. Not only is it shifting to be proactive and preventative but it’s shifting to a new science of medicine called predictive medicine.”

As for proactive and preventative care, she continued, each patient’s choice of behaviors related to diet, exercise, and stress “mingles with DNA to produce health, yet we spend about 90% of our resources on sick care. Now, health systems are moving their resources to things like education, housing, transportation, food security, equity, and racial divides. ... This is trickling down to how we train health care professionals. We know that patients live very little of their time in formal care settings, so all of their health is created – or destroyed – well outside of the clinical setting. We train our health professionals mostly in a clinical setting. Health systems are now starting to reimagine how training happens so we can train people to understand the fully loaded context of their patients’ lives.”

2. A shift in precision. For all its advances and science breakthroughs, medicine “is still quite crude,” said Dr. Khayat, who is also an adjunct professor in the Rotman School of Management at the University of Toronto. “It’s very analog, based on a one-size-fits-all approach. In the business world, we call this a segment of one: the idea that in some clinical trial, a result was produced that was based on the average of everybody, and therefore we just give everybody what worked for the average. ... We don’t need to have that trade-off anymore, because it won’t be a trade-off of higher cost to tailor down to an N of 1. It will be highly personalized, intelligent medicine, very precise.”

3. A shift from institution-centered to person-centered care. “The artifacts that health care was built on are very analog and are going to get decentralized out of buildings, dephysicalized, disintermediated,” she predicted. “We’ll have a seamless digital physical experience, expanded channels through which patients can access their services. Pick a channel that makes sense for the patient and don’t let care follow the place but rather let care follow the person.”

4. A shift in care duration, from episodic and intermittent care to more continuous care. “With very little input you should know what’s going on at any point in time instead of time-sharing access to diagnostics and to clinicians,” Dr. Khayat said. Wrist-worn devices that gather personal omics “are now really democratized, with every aspect of a diagnostic clinic available within or connected to a smartphone. This allows for data to be gathered and shared with clinicians, including tools under the skin that can get some of the biochemical data in real time instead of poking and prodding and waiting for a diagnostic lab.” These devices, she said, will become easier to use, cheaper, and will work faster, and provide much better data “at almost zero cost.”

Technologies being developed include tattoos that can read biomarkers, innovations in clothing that can detect biochemical reactions in the skin, underwear that can read vital signs, and contact lenses that can measure glucose levels. “The skin will become a major noninvasive way to obtain information,” she said.

5. A shift in power from providers to patients. “It’s estimated that about 80% of health care decisions could be self-managed by people in their communities,” Dr. Khayat said.

6. A shift from volume-based to value-based care. “Because we’ve been obsessed with the system, we’ve paid for stuff like visits, pills, MRI scans, et cetera,” she said. “We don’t need to do that anymore. Health systems don’t want to keep paying for stuff if they don’t see the results. Because of all the other shifts, we can pay for results. Some call this value-based care. I call it fee-for-health.”

She noted that the future of medicine is underpinned by innovations in AI/predictalytics, voice recognition, virtual reality, blockchain, IoT sensors, 3D printing, omics, robotics, autonomous transport, neurotechnology, nanobiology, and cellular therapy. “They’re moving at a very fast pace because they don’t need the kind of cost, capital, and expertise that the previous tools did,” she said. “This is the promise that technology can bring.”

Dr. Khayat disclosed that she has been a workshop participant for Roche Canada.

[email protected]

As an esophagologist that does not perform fundoplication, LINX, or TIF, I find it difficult to debate the merits of one procedure over another based on my experience. In fact, I have always stated that it is difficult to assess a procedure or test that one has not used. That being said, maybe the fact that I have not performed these procedures makes me more objective and I can only use my experience with patients and the data to make the case that we need options beyond Nissen fundoplication.

The recent VA Randomized trial in refractory GERD published by Spechler and colleagues once again highlighted the fact that there are some patients that require a mechanical solution to reflux disease.¹ In this study, the authors carefully defined a patient population with refractory GERD and showed that Nissen fundoplication was superior to medical management in patients who did not respond to proton pump inhibitors. However, of the 27 patients who underwent fundoplication, one patient had major complications which required a repeat operation and prolonged hospital stay. These findings highlight the main problem with Nissen fundoplication. Dr. Watson elegantly argued in his assertion during our debate that Nissen and fundoplication are not the same. In this position, he was noting the side effects associated with Nissen fundoplication,² and he focused his argument on the comparison between a partial wrap versus LINX and TIF to level the playing field. On that note, I agree with Dr. Watson that a well-done partial fundoplication is a great option for patients with a mechanical problem.

Nonetheless, I think we have the capacity to do better than Nissen fundoplication, and thus, a safer standardized reversible surgical option and a less invasive endoscopic approach have great appeal. Redo operations have an escalating risk of severe debilitating consequences and we should do everything possible to reduce that risk.³ The LINX and the TIF procedure have data to support their effectiveness, and the initial studies suggest a more favorable side effect profile.^4,5 The ability to perform these procedures in patients with hiatal hernia and the fact that these approaches do not exclude the possibility of fundoplication in the future make them an attractive alternative.

In the end, more rigorous comparative studies should be performed to truly determine which approach is better. Although we have good surgical and medical options, we all recognize that they are not perfect and we should not settle on the current state of GERD management.

John E. Pandolfino, MD, MSCI, is the Hans Popper Professor of Medicine and Division Chief, Gastroenterology and Hepatology at Northwestern University, Chicago. He disclosed relationships with Ethicon/Johnson & Johnson, Endogastric Solutions, and Medtronic. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2021.

References

1. Spechler SJ et al. N Engl J Med. 2019 Oct 17;381[16]:1513-23.

2. Yadlapati R et al. Am J Gastroenterol. 2018 Aug;113[8]:1137-47.

3. Singhal S et al. J Gastrointest Surg. 2018 Feb;22[2]:177-86.

4. Ganz RA et al. Clin Gastroenterol Hepatol. 2016 May;14(5):671-7.

5. Testoni PA et al. Endosc Int Open. 2019 May;7(5):E647-E654.

As an esophagologist that does not perform fundoplication, LINX, or TIF, I find it difficult to debate the merits of one procedure over another based on my experience. In fact, I have always stated that it is difficult to assess a procedure or test that one has not used. That being said, maybe the fact that I have not performed these procedures makes me more objective and I can only use my experience with patients and the data to make the case that we need options beyond Nissen fundoplication.

The recent VA Randomized trial in refractory GERD published by Spechler and colleagues once again highlighted the fact that there are some patients that require a mechanical solution to reflux disease.¹ In this study, the authors carefully defined a patient population with refractory GERD and showed that Nissen fundoplication was superior to medical management in patients who did not respond to proton pump inhibitors. However, of the 27 patients who underwent fundoplication, one patient had major complications which required a repeat operation and prolonged hospital stay. These findings highlight the main problem with Nissen fundoplication. Dr. Watson elegantly argued in his assertion during our debate that Nissen and fundoplication are not the same. In this position, he was noting the side effects associated with Nissen fundoplication,² and he focused his argument on the comparison between a partial wrap versus LINX and TIF to level the playing field. On that note, I agree with Dr. Watson that a well-done partial fundoplication is a great option for patients with a mechanical problem.

Nonetheless, I think we have the capacity to do better than Nissen fundoplication, and thus, a safer standardized reversible surgical option and a less invasive endoscopic approach have great appeal. Redo operations have an escalating risk of severe debilitating consequences and we should do everything possible to reduce that risk.³ The LINX and the TIF procedure have data to support their effectiveness, and the initial studies suggest a more favorable side effect profile.^4,5 The ability to perform these procedures in patients with hiatal hernia and the fact that these approaches do not exclude the possibility of fundoplication in the future make them an attractive alternative.

In the end, more rigorous comparative studies should be performed to truly determine which approach is better. Although we have good surgical and medical options, we all recognize that they are not perfect and we should not settle on the current state of GERD management.

John E. Pandolfino, MD, MSCI, is the Hans Popper Professor of Medicine and Division Chief, Gastroenterology and Hepatology at Northwestern University, Chicago. He disclosed relationships with Ethicon/Johnson & Johnson, Endogastric Solutions, and Medtronic. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2021.

References

1. Spechler SJ et al. N Engl J Med. 2019 Oct 17;381[16]:1513-23.

2. Yadlapati R et al. Am J Gastroenterol. 2018 Aug;113[8]:1137-47.

3. Singhal S et al. J Gastrointest Surg. 2018 Feb;22[2]:177-86.

4. Ganz RA et al. Clin Gastroenterol Hepatol. 2016 May;14(5):671-7.

5. Testoni PA et al. Endosc Int Open. 2019 May;7(5):E647-E654.

As an esophagologist that does not perform fundoplication, LINX, or TIF, I find it difficult to debate the merits of one procedure over another based on my experience. In fact, I have always stated that it is difficult to assess a procedure or test that one has not used. That being said, maybe the fact that I have not performed these procedures makes me more objective and I can only use my experience with patients and the data to make the case that we need options beyond Nissen fundoplication.

The recent VA Randomized trial in refractory GERD published by Spechler and colleagues once again highlighted the fact that there are some patients that require a mechanical solution to reflux disease.¹ In this study, the authors carefully defined a patient population with refractory GERD and showed that Nissen fundoplication was superior to medical management in patients who did not respond to proton pump inhibitors. However, of the 27 patients who underwent fundoplication, one patient had major complications which required a repeat operation and prolonged hospital stay. These findings highlight the main problem with Nissen fundoplication. Dr. Watson elegantly argued in his assertion during our debate that Nissen and fundoplication are not the same. In this position, he was noting the side effects associated with Nissen fundoplication,² and he focused his argument on the comparison between a partial wrap versus LINX and TIF to level the playing field. On that note, I agree with Dr. Watson that a well-done partial fundoplication is a great option for patients with a mechanical problem.

Nonetheless, I think we have the capacity to do better than Nissen fundoplication, and thus, a safer standardized reversible surgical option and a less invasive endoscopic approach have great appeal. Redo operations have an escalating risk of severe debilitating consequences and we should do everything possible to reduce that risk.³ The LINX and the TIF procedure have data to support their effectiveness, and the initial studies suggest a more favorable side effect profile.^4,5 The ability to perform these procedures in patients with hiatal hernia and the fact that these approaches do not exclude the possibility of fundoplication in the future make them an attractive alternative.

In the end, more rigorous comparative studies should be performed to truly determine which approach is better. Although we have good surgical and medical options, we all recognize that they are not perfect and we should not settle on the current state of GERD management.

John E. Pandolfino, MD, MSCI, is the Hans Popper Professor of Medicine and Division Chief, Gastroenterology and Hepatology at Northwestern University, Chicago. He disclosed relationships with Ethicon/Johnson & Johnson, Endogastric Solutions, and Medtronic. These remarks were made during one of the AGA Postgraduate Course sessions held at DDW 2021.

References

1. Spechler SJ et al. N Engl J Med. 2019 Oct 17;381[16]:1513-23.

2. Yadlapati R et al. Am J Gastroenterol. 2018 Aug;113[8]:1137-47.

3. Singhal S et al. J Gastrointest Surg. 2018 Feb;22[2]:177-86.

4. Ganz RA et al. Clin Gastroenterol Hepatol. 2016 May;14(5):671-7.

5. Testoni PA et al. Endosc Int Open. 2019 May;7(5):E647-E654.

When Denise M. Adams, MD, began her career as a pediatric oncologist 25 years ago, there were many interventions for vascular anomalies, but most were surgery based and medical options were limited.

“The medicines we had were believed to be antiangiogenic and they were used not only for tumors but for all sorts of malformations,” Dr. Adams, a pediatric hematologist-oncologist at Children’s Hospital of Philadelphia, recalled during the annual meeting of the Society for Pediatric Dermatology. “I didn’t understand how so many different phenotypes could respond to the same medicine. Not all of them did, but some did have some response.”

She also grew frustrated by the lack of clinical trials and collaborative research groups involving patients with vascular anomalies. “I called this the chicken soup of medical management,” she said. “As we got more involved in vascular anomalies, the power of one patient or that power of a few patients led us in a direction for improved medical management. Or knowledge was gained by one patient who failed all noted medical management and led us into a direction repurposing a drug that actually wound up working.”

Propranolol, for example, became a key medicine for the treatment of vascular anomalies when it was found to improve hemangiomas in children who were given the drug for other reasons. “From this observation a key prospective study was performed and this beta-blocker became FDA approved for the treatment of complicated hemangiomas,” said Dr. Adams, who directs the hospital’s Comprehensive Vascular Anomalies Program. “That was how a bedside observation let to bench intervention, and how presently we are investigating bench interventions related to the mechanism of propranolol therapy.”

Then there is the story of the mammalian target of rapamycin (mTOR) inhibitor sirolimus. In her previous role as medical director of the Hemangioma and Vascular Malformation Center at Cincinnati Children’s Hospital, Dr. Adams and colleagues cared for an infant who presented with a Kaposiform hemangioendothelioma (KHE). “At that time, she was given our standard of practice for the treatment, but our standard of practice was not good enough,” she said.

While other options were being discussed for this patient, “we had been doing some collaborative work with pathology and nephrology on the PIKC3A pathway, because we knew that germline mutations of TEK were involved in this pathway, and we knew that 50% of patients with PTEN mutations had vascular anomalies. So, we hypothesized that this pathway was involved in vascular anomalies.”

They also had earlier success using mTOR inhibition for tuberous sclerosis patients with angiomyolipomas and patients with neurofibromatosis. “We needed a medicine that could be given orally because we did not think this patient was going to do well, so we started her on sirolimus,” Dr. Adams said. “She had a great response. This was followed by a phase 2 study, which proved efficacy and led to discovery of biomarkers.” This is where the angiopoietin-2 story started, she said, noting that this biomarker is now used “to differentiate KLA [Kaposiform lymphangiomatosis] from KHE and KLAs and KHE from other disorders.”

This bedside work helped researchers to better understand the mechanism of action in other disorders, such as observing somatic mutations in PIK3CA in patients with CLOVES syndrome. “This meant that we could now correlate the phenotype to the genotype, and it opened up targeted therapy with developmental therapeutics that were already in use for oncology,” Dr. Adams said. “We know we had mTOR inhibition with sirolimus and everolimus. We now have an AKT inhibitor, a PIK3CA inhibitor, and we now have another side of the pathway which deals with RASopathies, and some other medicines that we can use.”

Miransertib, a potent PAN-AKT inhibitor initially used for breast cancer, is currently being evaluated in open-label, phase 1 and 2 trials in patients with PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome. The dose used in a pilot study is about one-sixth of the dose used for oncology patients, Dr. Adams said.

She and her colleagues used miransertib to treat a 3-year-old with CLOVES syndrome who had lipomatous infiltration of the abdomen and retroperitoneum with failure to thrive. “He was not eating and was G-tube dependent,” she recalled. “After a month of therapy, he started eating and had improvement in his quality of life,” although despite this improvement volumetric MRI remained unchanged.

Advances in bench to bedside approaches are also under way. Hakon Hakonarson, MD, PhD, the founding director of the Center for Applied Genomics at CHOP, has discovered several genes with in vitro testing and zebra fish modeling, which has been followed by testing medicines on patients.

One such patient, according to Dr. Adams, had a severe central conducting lymphatic anomaly, with a pericardial effusion and significant dysfunction of the central conducting system. The patient was found to have an ARAF mutation, which induces ERK activation. “ERK is downstream of MEK, so the question was whether a MEK inhibitor, trametinib, could be used to treat this patient,” she said. “Trametinib was first used in tissue culture, then used in a zebra fish model and it showed some positive results. Then it was taken to the patient, who had improvement of pulmonary function, remodeling of the lymphatic system, and decrease in the size of his legs.”

Other antiangiogenic agents being used for the treatment of vascular anomalies include bevacizumab, which is being used in hereditary hemorrhagic telangiectasia, and thalidomide for HHT and arteriovenous malformations. For more information, Dr. Adams recommended a comprehensive review of vascular anomalies, related genes, and treatments that was published in Circulation Research.

The goal of future drug therapies is to support normal growth, “so we don’t need a maximum tolerated dose,” Dr. Adams said. “We need to be very careful of short-term and long-term side effects.”

Going forward, she said that she would like to see more natural history studies of vascular anomalies, improved outcome measures for clinical trials, adaptive study design, preclinical testing, animal model studies, universal availability of genomic testing, improvement of NIH funding, research collaboration nationally and internationally, and industry support.

Dr. Adams disclosed that she is a consultant to Venthera and Novartis.

[email protected]

When Denise M. Adams, MD, began her career as a pediatric oncologist 25 years ago, there were many interventions for vascular anomalies, but most were surgery based and medical options were limited.

“The medicines we had were believed to be antiangiogenic and they were used not only for tumors but for all sorts of malformations,” Dr. Adams, a pediatric hematologist-oncologist at Children’s Hospital of Philadelphia, recalled during the annual meeting of the Society for Pediatric Dermatology. “I didn’t understand how so many different phenotypes could respond to the same medicine. Not all of them did, but some did have some response.”

She also grew frustrated by the lack of clinical trials and collaborative research groups involving patients with vascular anomalies. “I called this the chicken soup of medical management,” she said. “As we got more involved in vascular anomalies, the power of one patient or that power of a few patients led us in a direction for improved medical management. Or knowledge was gained by one patient who failed all noted medical management and led us into a direction repurposing a drug that actually wound up working.”

Propranolol, for example, became a key medicine for the treatment of vascular anomalies when it was found to improve hemangiomas in children who were given the drug for other reasons. “From this observation a key prospective study was performed and this beta-blocker became FDA approved for the treatment of complicated hemangiomas,” said Dr. Adams, who directs the hospital’s Comprehensive Vascular Anomalies Program. “That was how a bedside observation let to bench intervention, and how presently we are investigating bench interventions related to the mechanism of propranolol therapy.”

Then there is the story of the mammalian target of rapamycin (mTOR) inhibitor sirolimus. In her previous role as medical director of the Hemangioma and Vascular Malformation Center at Cincinnati Children’s Hospital, Dr. Adams and colleagues cared for an infant who presented with a Kaposiform hemangioendothelioma (KHE). “At that time, she was given our standard of practice for the treatment, but our standard of practice was not good enough,” she said.

While other options were being discussed for this patient, “we had been doing some collaborative work with pathology and nephrology on the PIKC3A pathway, because we knew that germline mutations of TEK were involved in this pathway, and we knew that 50% of patients with PTEN mutations had vascular anomalies. So, we hypothesized that this pathway was involved in vascular anomalies.”

They also had earlier success using mTOR inhibition for tuberous sclerosis patients with angiomyolipomas and patients with neurofibromatosis. “We needed a medicine that could be given orally because we did not think this patient was going to do well, so we started her on sirolimus,” Dr. Adams said. “She had a great response. This was followed by a phase 2 study, which proved efficacy and led to discovery of biomarkers.” This is where the angiopoietin-2 story started, she said, noting that this biomarker is now used “to differentiate KLA [Kaposiform lymphangiomatosis] from KHE and KLAs and KHE from other disorders.”

This bedside work helped researchers to better understand the mechanism of action in other disorders, such as observing somatic mutations in PIK3CA in patients with CLOVES syndrome. “This meant that we could now correlate the phenotype to the genotype, and it opened up targeted therapy with developmental therapeutics that were already in use for oncology,” Dr. Adams said. “We know we had mTOR inhibition with sirolimus and everolimus. We now have an AKT inhibitor, a PIK3CA inhibitor, and we now have another side of the pathway which deals with RASopathies, and some other medicines that we can use.”

Miransertib, a potent PAN-AKT inhibitor initially used for breast cancer, is currently being evaluated in open-label, phase 1 and 2 trials in patients with PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome. The dose used in a pilot study is about one-sixth of the dose used for oncology patients, Dr. Adams said.

She and her colleagues used miransertib to treat a 3-year-old with CLOVES syndrome who had lipomatous infiltration of the abdomen and retroperitoneum with failure to thrive. “He was not eating and was G-tube dependent,” she recalled. “After a month of therapy, he started eating and had improvement in his quality of life,” although despite this improvement volumetric MRI remained unchanged.

Advances in bench to bedside approaches are also under way. Hakon Hakonarson, MD, PhD, the founding director of the Center for Applied Genomics at CHOP, has discovered several genes with in vitro testing and zebra fish modeling, which has been followed by testing medicines on patients.

One such patient, according to Dr. Adams, had a severe central conducting lymphatic anomaly, with a pericardial effusion and significant dysfunction of the central conducting system. The patient was found to have an ARAF mutation, which induces ERK activation. “ERK is downstream of MEK, so the question was whether a MEK inhibitor, trametinib, could be used to treat this patient,” she said. “Trametinib was first used in tissue culture, then used in a zebra fish model and it showed some positive results. Then it was taken to the patient, who had improvement of pulmonary function, remodeling of the lymphatic system, and decrease in the size of his legs.”

Other antiangiogenic agents being used for the treatment of vascular anomalies include bevacizumab, which is being used in hereditary hemorrhagic telangiectasia, and thalidomide for HHT and arteriovenous malformations. For more information, Dr. Adams recommended a comprehensive review of vascular anomalies, related genes, and treatments that was published in Circulation Research.

The goal of future drug therapies is to support normal growth, “so we don’t need a maximum tolerated dose,” Dr. Adams said. “We need to be very careful of short-term and long-term side effects.”

Going forward, she said that she would like to see more natural history studies of vascular anomalies, improved outcome measures for clinical trials, adaptive study design, preclinical testing, animal model studies, universal availability of genomic testing, improvement of NIH funding, research collaboration nationally and internationally, and industry support.

Dr. Adams disclosed that she is a consultant to Venthera and Novartis.

[email protected]

When Denise M. Adams, MD, began her career as a pediatric oncologist 25 years ago, there were many interventions for vascular anomalies, but most were surgery based and medical options were limited.

“The medicines we had were believed to be antiangiogenic and they were used not only for tumors but for all sorts of malformations,” Dr. Adams, a pediatric hematologist-oncologist at Children’s Hospital of Philadelphia, recalled during the annual meeting of the Society for Pediatric Dermatology. “I didn’t understand how so many different phenotypes could respond to the same medicine. Not all of them did, but some did have some response.”

She also grew frustrated by the lack of clinical trials and collaborative research groups involving patients with vascular anomalies. “I called this the chicken soup of medical management,” she said. “As we got more involved in vascular anomalies, the power of one patient or that power of a few patients led us in a direction for improved medical management. Or knowledge was gained by one patient who failed all noted medical management and led us into a direction repurposing a drug that actually wound up working.”

Propranolol, for example, became a key medicine for the treatment of vascular anomalies when it was found to improve hemangiomas in children who were given the drug for other reasons. “From this observation a key prospective study was performed and this beta-blocker became FDA approved for the treatment of complicated hemangiomas,” said Dr. Adams, who directs the hospital’s Comprehensive Vascular Anomalies Program. “That was how a bedside observation let to bench intervention, and how presently we are investigating bench interventions related to the mechanism of propranolol therapy.”

Then there is the story of the mammalian target of rapamycin (mTOR) inhibitor sirolimus. In her previous role as medical director of the Hemangioma and Vascular Malformation Center at Cincinnati Children’s Hospital, Dr. Adams and colleagues cared for an infant who presented with a Kaposiform hemangioendothelioma (KHE). “At that time, she was given our standard of practice for the treatment, but our standard of practice was not good enough,” she said.

While other options were being discussed for this patient, “we had been doing some collaborative work with pathology and nephrology on the PIKC3A pathway, because we knew that germline mutations of TEK were involved in this pathway, and we knew that 50% of patients with PTEN mutations had vascular anomalies. So, we hypothesized that this pathway was involved in vascular anomalies.”

They also had earlier success using mTOR inhibition for tuberous sclerosis patients with angiomyolipomas and patients with neurofibromatosis. “We needed a medicine that could be given orally because we did not think this patient was going to do well, so we started her on sirolimus,” Dr. Adams said. “She had a great response. This was followed by a phase 2 study, which proved efficacy and led to discovery of biomarkers.” This is where the angiopoietin-2 story started, she said, noting that this biomarker is now used “to differentiate KLA [Kaposiform lymphangiomatosis] from KHE and KLAs and KHE from other disorders.”

This bedside work helped researchers to better understand the mechanism of action in other disorders, such as observing somatic mutations in PIK3CA in patients with CLOVES syndrome. “This meant that we could now correlate the phenotype to the genotype, and it opened up targeted therapy with developmental therapeutics that were already in use for oncology,” Dr. Adams said. “We know we had mTOR inhibition with sirolimus and everolimus. We now have an AKT inhibitor, a PIK3CA inhibitor, and we now have another side of the pathway which deals with RASopathies, and some other medicines that we can use.”

Miransertib, a potent PAN-AKT inhibitor initially used for breast cancer, is currently being evaluated in open-label, phase 1 and 2 trials in patients with PIK3CA-related overgrowth spectrum (PROS) and Proteus syndrome. The dose used in a pilot study is about one-sixth of the dose used for oncology patients, Dr. Adams said.

She and her colleagues used miransertib to treat a 3-year-old with CLOVES syndrome who had lipomatous infiltration of the abdomen and retroperitoneum with failure to thrive. “He was not eating and was G-tube dependent,” she recalled. “After a month of therapy, he started eating and had improvement in his quality of life,” although despite this improvement volumetric MRI remained unchanged.

Advances in bench to bedside approaches are also under way. Hakon Hakonarson, MD, PhD, the founding director of the Center for Applied Genomics at CHOP, has discovered several genes with in vitro testing and zebra fish modeling, which has been followed by testing medicines on patients.

One such patient, according to Dr. Adams, had a severe central conducting lymphatic anomaly, with a pericardial effusion and significant dysfunction of the central conducting system. The patient was found to have an ARAF mutation, which induces ERK activation. “ERK is downstream of MEK, so the question was whether a MEK inhibitor, trametinib, could be used to treat this patient,” she said. “Trametinib was first used in tissue culture, then used in a zebra fish model and it showed some positive results. Then it was taken to the patient, who had improvement of pulmonary function, remodeling of the lymphatic system, and decrease in the size of his legs.”

Other antiangiogenic agents being used for the treatment of vascular anomalies include bevacizumab, which is being used in hereditary hemorrhagic telangiectasia, and thalidomide for HHT and arteriovenous malformations. For more information, Dr. Adams recommended a comprehensive review of vascular anomalies, related genes, and treatments that was published in Circulation Research.

The goal of future drug therapies is to support normal growth, “so we don’t need a maximum tolerated dose,” Dr. Adams said. “We need to be very careful of short-term and long-term side effects.”

Going forward, she said that she would like to see more natural history studies of vascular anomalies, improved outcome measures for clinical trials, adaptive study design, preclinical testing, animal model studies, universal availability of genomic testing, improvement of NIH funding, research collaboration nationally and internationally, and industry support.

Dr. Adams disclosed that she is a consultant to Venthera and Novartis.

[email protected]

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

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

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

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

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

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3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

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8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

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11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

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25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

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

Orthopedic researchers from New York University have proposed standardizing prescribing patterns for patients after fracture surgery so as to include low-dose opioids.

In a paper presented at the annual meeting of the American Academy of Orthopaedic Surgeons, researchers from NYU reported on the implementation of their multimodal strategy, dubbed the “lopioid protocol.”

According to the 2019 National Survey on Drug Use and Health, orthopedic surgeons are the third-highest opioid prescribers in the United States.

Kennneth A. Egol, MD, vice chair of the department of orthopedic surgery at NYU, who is the first author of the study, was motivated to help create the protocol following misconceptions that orthopedic surgeons were helping to fuel the opioid epidemic.

Dr. Egol pointed to the year 1995, when pain became the fifth vital sign after body temperature, pulse rate, respiratory rate, and blood pressure.

Since then, in light of the opioid epidemic, the focus of physicians has shifted away from prescribing strong pain medication and reducing pain scores to zero to instead reducing pain to a manageable level.

Reducing opioid prescriptions can be challenging when patients are prescribed an anti-inflammatory and they subsequently ask their physician for a “pain pill.” Patients sometimes don’t understand that inflammation is what causes pain.

It can also be difficult to convince patients that medications that they can buy over the counter can adequately control their pain, as confirmed in numerous studies.

Multimodal pain therapy aims to reduce the need for opioids by supplementing their use with other oral medications and, at times, long-lasting regional nerve blocks.

Anti-inflammatories act at the site of injury or surgery where inflammation is occurring. Nerves then carry the pain signal to the brain. These signals can be dampened by medications such as gabapentin that act on the nerves themselves. The pain signal is received in the brain, where opioids act by binding to receptors in the brain.

The so-called lopioid protocol does not eliminate opioids completely but rather uses “safer” opioids, such as tramadol, in lieu of stronger narcotics.

The protocol began at NYU on Jan. 1, 2019. It consists in the prescribing of tramadol, meloxicam, gabapentin, and acetaminophen.

The study presented at the AAOS meeting demonstrated statistically significant reductions in visual analogue pain scores at discharge and subsequent medication refills for the 931 patients in the lopioid group, compared with a group of 848 patients who received narcotic prescriptions containing oxycodone from the year prior to the protocol initiation.

Educating patients on the rationale for the prescription combination can help to allay their fears. Dr. Egol thinks it’s important for physicians to explain the dangers of opioids to patients. He said in an interview that he also believes surgeons need to “give [patients] an understanding of why we are pursuing these protocols. They also need to know we will not ignore their pain and concerns.”

Brannon Orton, MD, is an orthopedic surgeon at Confluence Health, in Moses Lake, Wash. He sees a large number of trauma patients and thinks NYU is doing a good job of addressing a difficult problem in orthopedics – especially in the field of trauma.

He said in an interview: “Managing narcotics postoperatively can be challenging due to the fact that many people come into these fractures with a history of narcotic use.” Not only are they used to turning to opioids for pain relief, but they also may have built up a tolerance to them.

Although he hasn’t been using the lopioid protocol specifically, he has been following a multimodal approach regarding the postoperative use of narcotics. Of the study by Dr. Egol and colleagues, he said, “I think their paper presents an effective way of decreasing use of oral narcotics and still adequately managing patients’ pain postoperatively.” Dr. Orton’s own practice utilizes tramadol, acetaminophen, and ibuprofen after fracture surgery.

From Dr. Orton’s perspective, a significant challenge in implementing the lopioid protocol in practice is simply sticking to the plan. “It can become difficult when patients are pressuring staff or physicians for more narcotics. However, I feel that if everybody is on the same page with the plan, then it can be very doable.”

Dr. Egol and NYU try to limit narcotic prescriptions beginning with the patient’s initial visit to the ED. The ED physicians at his institution only “prescribe small amounts of narcotics. Our ED people really limit the amount of opioids prescribed.”

Dr. Egol recommends that all practitioners begin with nonnarcotic medication, even if treating a fracture nonoperatively. “Start low and go higher. I always try to start with NSAIDs and Tylenol,” he said.

Dr. Egol and Dr. Orton reported no relevant financial disclosures.

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

Orthopedic researchers from New York University have proposed standardizing prescribing patterns for patients after fracture surgery so as to include low-dose opioids.

In a paper presented at the annual meeting of the American Academy of Orthopaedic Surgeons, researchers from NYU reported on the implementation of their multimodal strategy, dubbed the “lopioid protocol.”

According to the 2019 National Survey on Drug Use and Health, orthopedic surgeons are the third-highest opioid prescribers in the United States.

Kennneth A. Egol, MD, vice chair of the department of orthopedic surgery at NYU, who is the first author of the study, was motivated to help create the protocol following misconceptions that orthopedic surgeons were helping to fuel the opioid epidemic.

Dr. Egol pointed to the year 1995, when pain became the fifth vital sign after body temperature, pulse rate, respiratory rate, and blood pressure.

Since then, in light of the opioid epidemic, the focus of physicians has shifted away from prescribing strong pain medication and reducing pain scores to zero to instead reducing pain to a manageable level.

Reducing opioid prescriptions can be challenging when patients are prescribed an anti-inflammatory and they subsequently ask their physician for a “pain pill.” Patients sometimes don’t understand that inflammation is what causes pain.

It can also be difficult to convince patients that medications that they can buy over the counter can adequately control their pain, as confirmed in numerous studies.

Multimodal pain therapy aims to reduce the need for opioids by supplementing their use with other oral medications and, at times, long-lasting regional nerve blocks.

Anti-inflammatories act at the site of injury or surgery where inflammation is occurring. Nerves then carry the pain signal to the brain. These signals can be dampened by medications such as gabapentin that act on the nerves themselves. The pain signal is received in the brain, where opioids act by binding to receptors in the brain.

The so-called lopioid protocol does not eliminate opioids completely but rather uses “safer” opioids, such as tramadol, in lieu of stronger narcotics.

The protocol began at NYU on Jan. 1, 2019. It consists in the prescribing of tramadol, meloxicam, gabapentin, and acetaminophen.

The study presented at the AAOS meeting demonstrated statistically significant reductions in visual analogue pain scores at discharge and subsequent medication refills for the 931 patients in the lopioid group, compared with a group of 848 patients who received narcotic prescriptions containing oxycodone from the year prior to the protocol initiation.

Educating patients on the rationale for the prescription combination can help to allay their fears. Dr. Egol thinks it’s important for physicians to explain the dangers of opioids to patients. He said in an interview that he also believes surgeons need to “give [patients] an understanding of why we are pursuing these protocols. They also need to know we will not ignore their pain and concerns.”

Brannon Orton, MD, is an orthopedic surgeon at Confluence Health, in Moses Lake, Wash. He sees a large number of trauma patients and thinks NYU is doing a good job of addressing a difficult problem in orthopedics – especially in the field of trauma.

He said in an interview: “Managing narcotics postoperatively can be challenging due to the fact that many people come into these fractures with a history of narcotic use.” Not only are they used to turning to opioids for pain relief, but they also may have built up a tolerance to them.

Although he hasn’t been using the lopioid protocol specifically, he has been following a multimodal approach regarding the postoperative use of narcotics. Of the study by Dr. Egol and colleagues, he said, “I think their paper presents an effective way of decreasing use of oral narcotics and still adequately managing patients’ pain postoperatively.” Dr. Orton’s own practice utilizes tramadol, acetaminophen, and ibuprofen after fracture surgery.

From Dr. Orton’s perspective, a significant challenge in implementing the lopioid protocol in practice is simply sticking to the plan. “It can become difficult when patients are pressuring staff or physicians for more narcotics. However, I feel that if everybody is on the same page with the plan, then it can be very doable.”

Dr. Egol and NYU try to limit narcotic prescriptions beginning with the patient’s initial visit to the ED. The ED physicians at his institution only “prescribe small amounts of narcotics. Our ED people really limit the amount of opioids prescribed.”

Dr. Egol recommends that all practitioners begin with nonnarcotic medication, even if treating a fracture nonoperatively. “Start low and go higher. I always try to start with NSAIDs and Tylenol,” he said.

Dr. Egol and Dr. Orton reported no relevant financial disclosures.

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

Orthopedic researchers from New York University have proposed standardizing prescribing patterns for patients after fracture surgery so as to include low-dose opioids.

In a paper presented at the annual meeting of the American Academy of Orthopaedic Surgeons, researchers from NYU reported on the implementation of their multimodal strategy, dubbed the “lopioid protocol.”

According to the 2019 National Survey on Drug Use and Health, orthopedic surgeons are the third-highest opioid prescribers in the United States.

Kennneth A. Egol, MD, vice chair of the department of orthopedic surgery at NYU, who is the first author of the study, was motivated to help create the protocol following misconceptions that orthopedic surgeons were helping to fuel the opioid epidemic.

Dr. Egol pointed to the year 1995, when pain became the fifth vital sign after body temperature, pulse rate, respiratory rate, and blood pressure.

Since then, in light of the opioid epidemic, the focus of physicians has shifted away from prescribing strong pain medication and reducing pain scores to zero to instead reducing pain to a manageable level.

Reducing opioid prescriptions can be challenging when patients are prescribed an anti-inflammatory and they subsequently ask their physician for a “pain pill.” Patients sometimes don’t understand that inflammation is what causes pain.

It can also be difficult to convince patients that medications that they can buy over the counter can adequately control their pain, as confirmed in numerous studies.

Multimodal pain therapy aims to reduce the need for opioids by supplementing their use with other oral medications and, at times, long-lasting regional nerve blocks.

Anti-inflammatories act at the site of injury or surgery where inflammation is occurring. Nerves then carry the pain signal to the brain. These signals can be dampened by medications such as gabapentin that act on the nerves themselves. The pain signal is received in the brain, where opioids act by binding to receptors in the brain.

The so-called lopioid protocol does not eliminate opioids completely but rather uses “safer” opioids, such as tramadol, in lieu of stronger narcotics.

The protocol began at NYU on Jan. 1, 2019. It consists in the prescribing of tramadol, meloxicam, gabapentin, and acetaminophen.

The study presented at the AAOS meeting demonstrated statistically significant reductions in visual analogue pain scores at discharge and subsequent medication refills for the 931 patients in the lopioid group, compared with a group of 848 patients who received narcotic prescriptions containing oxycodone from the year prior to the protocol initiation.

Educating patients on the rationale for the prescription combination can help to allay their fears. Dr. Egol thinks it’s important for physicians to explain the dangers of opioids to patients. He said in an interview that he also believes surgeons need to “give [patients] an understanding of why we are pursuing these protocols. They also need to know we will not ignore their pain and concerns.”

Brannon Orton, MD, is an orthopedic surgeon at Confluence Health, in Moses Lake, Wash. He sees a large number of trauma patients and thinks NYU is doing a good job of addressing a difficult problem in orthopedics – especially in the field of trauma.

He said in an interview: “Managing narcotics postoperatively can be challenging due to the fact that many people come into these fractures with a history of narcotic use.” Not only are they used to turning to opioids for pain relief, but they also may have built up a tolerance to them.

Although he hasn’t been using the lopioid protocol specifically, he has been following a multimodal approach regarding the postoperative use of narcotics. Of the study by Dr. Egol and colleagues, he said, “I think their paper presents an effective way of decreasing use of oral narcotics and still adequately managing patients’ pain postoperatively.” Dr. Orton’s own practice utilizes tramadol, acetaminophen, and ibuprofen after fracture surgery.

From Dr. Orton’s perspective, a significant challenge in implementing the lopioid protocol in practice is simply sticking to the plan. “It can become difficult when patients are pressuring staff or physicians for more narcotics. However, I feel that if everybody is on the same page with the plan, then it can be very doable.”

Dr. Egol and NYU try to limit narcotic prescriptions beginning with the patient’s initial visit to the ED. The ED physicians at his institution only “prescribe small amounts of narcotics. Our ED people really limit the amount of opioids prescribed.”

Dr. Egol recommends that all practitioners begin with nonnarcotic medication, even if treating a fracture nonoperatively. “Start low and go higher. I always try to start with NSAIDs and Tylenol,” he said.

Dr. Egol and Dr. Orton reported no relevant financial disclosures.

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

Not so long ago, Heather Simpson of Dallas was known as the anti-vaccine mom who dressed as “the measles” for Halloween. She painted red spots on her face and posted her photo on Facebook, joking: “Was trying to think of the least scary thing I could be for Halloween … so I became the measles.” It went viral with the anti-vaccine crowd.

But between that Halloween and today, a series of “aha” moments transformed Ms. Simpson’s attitudes toward vaccines.

In January 2021, one of those moments involved her daughter, now 4, who was scratched by a feral cat, raising concerns about tetanus. Her daughter had been bitten by a dog when she was just 1, and Ms. Simpson turned down advice then to get a tetanus shot. “I was convinced the tetanus shot would kill her faster than the tetanus.”

After the cat incident, the anxiety was so exhausting, she listened to the nurse practitioner at the clinic, whom she trusted. The nurse gently reassured Ms. Simpson that the shot was less risky than the possibility of tetanus – but did not bombard her with statistics – and that won over Ms. Simpson and triggered an overall rethinking of her vaccine stance.

Fast-forward to February, and that “aha” turned into action when Ms. Simpson launched a “Back to the Vax” effort with a fellow former vaccine opponent. Through their website, Facebook page, and podcasts, they now encourage people to get the COVID-19 vaccine, as well as other immunizations.
 

Challenge: Reaching the rest

With just over 52% of those eligible in the United States fully vaccinated as of Sept. 1, health care providers and others have a continuing challenge ahead: Trying to convince those who are eligible but still holding out to get vaccinated.

Recent data and a poll show some movement in the right direction, as immunizations are increasing and hesitancy is declining among certain groups. According to federal officials, about 14 million people in the United States got their first dose in August, an increase of 4 million, compared to the numbers who got it in July.

And a new poll from the Axios-IPSOS Coronavirus Index found only one in five Americans, or 20%, say they are not likely to get the vaccine, while “hard opposition,” those not at all likely, has dropped to 14% of those adults.

But there is still a lot of work to do. So, how do medical professionals or concerned citizens reach those who haven’t gotten vaccinated yet, whatever their reason?

Many experts in communication and persuasion that this news organization talked to agree that throwing statistics at people hesitant to get the COVID-19 vaccine is generally useless and often backfires.

So what does work, according to these experts?

• Emphasizing the trends of more people getting vaccinated.
• Focusing on everyone’s freedom of choice.
• Listening to concerns without judgment.
• Offering credible information.
• Correcting myths when necessary.
• Helping them fit vaccination into their “world view.”

Stories over statistics

Talking about the trends of vaccinations can definitely change minds about getting vaccinated, said Robert Cialdini, PhD, regents professor emeritus of psychology and marketing at Arizona State University, Tempe, and author of the recently updated book, “Influence: The Psychology of Persuasion,” which has sold over 5 million copies since it was first published in 1984.

Face-to-face with a hesitant patient, a doctor can say: “More and more people are being vaccinated every day,” Dr. Cialdini says. “The reason you say more and more is [that] it conveys a trend. When people see a trend, they project it into the future that it is going to get even larger.”

A focus on choice can also help people change their minds and accept the vaccine, he says. “A lot of conspiracy theorists claim they don’t want to do it because they are being pushed or forced by the government, and they are resisting that.”

If that’s the case, presenting people with new information, such as the increased infectiousness of the Delta variant, and suggesting that a decision be made based on the new information, can work, Dr. Cialdini says, but be sure to end with: “It’s completely up to you.”

“This removes all their sense of being pushed. It says, ‘Here is all the evidence.’ ” At this point, a doctor’s personal recommendation with a patient who trusts him or her may sway them, Dr. Cialdini said. “I think you have to personalize the communication in both directions. That is, to say, ‘For someone in your situation, I would personally recommend that you get the vaccine.’ ” A health care professional’s authority and expertise can carry the day, he says, although “not always.”

This approach worked, Dr. Cialdini says, with a friend of the family hesitant about the COVID-19 vaccine. “I told him: ‘We have gotten it. You trust us, right?’ ” He waited for the person to say yes.

Then: “For someone in your position, my personal recommendation is to get vaccinated. There is new information about the vaccine, and more and more people are getting vaccinated. And of course, it is completely up to you.”

The person decided to get the vaccine.
 

‘Live in that space’

“People develop negative attitudes [about vaccines] by accessing alternative sources of information, anecdotes, and personal stories,” said Matthew Seeger, PhD, dean of the College of Fine, Performing, and Communication Arts and codirector of the Center for Emerging Infectious Diseases at Wayne State University in Detroit.

“If we are going to change their opinion, we need to live in that space.” That means listening first, he says. Ask: “Where did you get that information? How credible do you think the sources are? What do you mean about the vaccine changing DNA?”

Then, you might respond, he said, by addressing that specific information, such as, “We have no cases of DNA being changed.”

Dr. Seeger recalls that his mother would simply talk louder when she couldn’t understand someone who wasn’t a native English speaker. “That’s what we are trying to do with the vaccine-hesitant,” he says. “In some cases, we are yelling at them.” Instead, he says, probe their sources of information.

For some who are vaccine-hesitant, Dr. Seeger said, it is not just about the vaccine. The attitude about vaccines is tied in, often, with a distrust of government and feelings about personal freedom. “That’s one reason it’s so hard to change the attitude.” For some, getting the vaccine in a family against the vaccine might also disrupt their social structure or even get them ostracized.

For these people, a health care provider might give opportunities to get the vaccine without affecting either what they see as their political stance or upsetting family harmony. “There are places you can go, make an appointment, get a vaccine, and nobody knows,” Dr. Seeger said.

One Missouri doctor told CNN that some people calling for a vaccine appointment do request privacy, such as going through a drive-thru or having the shot as they sit in their cars. She said the hospital tries to accommodate them, reasoning that every additional vaccine shot is a win.

Dr. Seeger agrees. “Of course there are still public records,” he says, “but you can still claim you are a vaccine denier. It’s very difficult to persuade people to give up their whole world. Vaccine denial is part of that world. At this point, we need to do whatever we can to get people vaccinated.”
 

From peer to peer

A theme that runs through many of these persuasion techniques is peer pressure.

One example, while a bit more profane and confrontational than some groups, is COVIDAteMyFace, a subgroup, or “subreddit,” of the popular online site Reddit, which hosts numerous forums inviting users to share news and comments on a variety of topics. The subreddit has over 20,000 members. Its purpose, says the sub’s creator, “was to document the folks who denied COVID, then got bitten in the ass by it.” Reports are of actual cases.

“It’s interesting and powerful that Reddit users are taking this on,” Dr. Seeger said. And this kind of peer pressure, or peer-to-peer information, can be persuasive, he says. “We often seek consensual validation from peers about risk messages and risk behaviors.”

For instance, hurricane evacuation notices are more effective, he said, when people learn their neighbors are leaving.

Peer information – “the number of others who are doing or believing or responding to something – definitely persuades people,” agreed Dr. Cialdini. “When a lot of others are responding in a particular way – for example, getting vaccinated – people follow for three reasons: The action seems more appropriate or correct, it appears more feasible to perform, and it avoids social disapproval from those others.”
 

Let them talk, give them time

Gladys Jimenez is a contact tracer and “vaccine ambassador” for Tracing Health, a partnership between the Oregon Public Health Institute and the Public Health Institute that has nearly 300 bilingual contract tracers who serve the ethnic communities they’re from. During a typical week, she talks to 50 people or more, and promoting the vaccine is top of mind.

The conversations, Ms. Jimenez said, are like a dance. She presents information, then steps back and lets them talk. “I want to hear the person talk, where they are coming from, where they are at.” Depending on what they say, she gives them more information or corrects their misinformation. “They often will say, ‘Oh, I didn’t know that.’ ”

It’s rarely one conversation that convinces hesitant people, she said. “I’m planting this seed in their brain. ... people want someone to listen to them ... they want to vent.”

Once you let them do that, Ms. Jimenez said, “I can tell the person is in a different state of mind.” She also knows that people “will make the decision in their own time.”

With time, people can change their minds, as a Southern California woman who resisted at first (and asked to remain anonymous) can attest. “When the vaccine first came out, I remember thinking [that] it was a quick fix to a very big problem,” she said. The lack of full FDA approval, which has since been granted, was also an issue. She doesn’t oppose vaccines, she said, but was leery just of the COVID-19 vaccine.

When her longtime partner got his vaccine, he urged her to go right away for hers. She stalled. He got his second dose and grew impatient with her hesitancy. It began to wear on the relationship. Finally, the woman talked to two health care professionals she knew socially. They both follow the science, and “they both could explain vaccination to me in a way that resonated. The information was coming from sources I already trusted.”

Those conversations are what convinced her to get vaccinated this summer.
 

Simpson’s transformation

Ms. Simpson of Back to the Vax got her first COVID-19 immunization April 16. She had an allergic reaction, including severe itchiness and a bad headache, and needed emergency care, she said. Even so, she scheduled her second shot appointment.

Like many who turned against vaccines as adults, Ms. Simpson had all her childhood vaccines, but she developed a distrust after watching a lengthy documentary series that warned of vaccine dangers as an adult.

Looking back at that documentary, she thought about how it seems to blame everything – childhood cancer, ADHD, autism, allergies – on vaccinations. That suddenly seemed like sketchy science to her.

So did the claim from a family friend who said she knew someone who got the flu shot and began walking backward. She researched on her own, and with time, she decided to be pro-vaccines.

These days, she continues to find that stories, not statistics, are changing the minds of many who decide to get vaccinated. If the nurse practitioner urging the tetanus shot for her daughter had told her that the tetanus shot is linked with problems in one of a specific number of people who get it, no matter how large that second number was, Ms. Simpson said she would have thought: “What if she is that one?”

So she relies on stories that point out how universally vulnerable people are to COVID-19 first, facts next.

“Facts help once you are already moved,” Ms. Simpson said.

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

Not so long ago, Heather Simpson of Dallas was known as the anti-vaccine mom who dressed as “the measles” for Halloween. She painted red spots on her face and posted her photo on Facebook, joking: “Was trying to think of the least scary thing I could be for Halloween … so I became the measles.” It went viral with the anti-vaccine crowd.

But between that Halloween and today, a series of “aha” moments transformed Ms. Simpson’s attitudes toward vaccines.

In January 2021, one of those moments involved her daughter, now 4, who was scratched by a feral cat, raising concerns about tetanus. Her daughter had been bitten by a dog when she was just 1, and Ms. Simpson turned down advice then to get a tetanus shot. “I was convinced the tetanus shot would kill her faster than the tetanus.”

After the cat incident, the anxiety was so exhausting, she listened to the nurse practitioner at the clinic, whom she trusted. The nurse gently reassured Ms. Simpson that the shot was less risky than the possibility of tetanus – but did not bombard her with statistics – and that won over Ms. Simpson and triggered an overall rethinking of her vaccine stance.

Fast-forward to February, and that “aha” turned into action when Ms. Simpson launched a “Back to the Vax” effort with a fellow former vaccine opponent. Through their website, Facebook page, and podcasts, they now encourage people to get the COVID-19 vaccine, as well as other immunizations.
 

Challenge: Reaching the rest

With just over 52% of those eligible in the United States fully vaccinated as of Sept. 1, health care providers and others have a continuing challenge ahead: Trying to convince those who are eligible but still holding out to get vaccinated.

Recent data and a poll show some movement in the right direction, as immunizations are increasing and hesitancy is declining among certain groups. According to federal officials, about 14 million people in the United States got their first dose in August, an increase of 4 million, compared to the numbers who got it in July.

And a new poll from the Axios-IPSOS Coronavirus Index found only one in five Americans, or 20%, say they are not likely to get the vaccine, while “hard opposition,” those not at all likely, has dropped to 14% of those adults.

But there is still a lot of work to do. So, how do medical professionals or concerned citizens reach those who haven’t gotten vaccinated yet, whatever their reason?

Many experts in communication and persuasion that this news organization talked to agree that throwing statistics at people hesitant to get the COVID-19 vaccine is generally useless and often backfires.

So what does work, according to these experts?

• Emphasizing the trends of more people getting vaccinated.
• Focusing on everyone’s freedom of choice.
• Listening to concerns without judgment.
• Offering credible information.
• Correcting myths when necessary.
• Helping them fit vaccination into their “world view.”

Stories over statistics

Talking about the trends of vaccinations can definitely change minds about getting vaccinated, said Robert Cialdini, PhD, regents professor emeritus of psychology and marketing at Arizona State University, Tempe, and author of the recently updated book, “Influence: The Psychology of Persuasion,” which has sold over 5 million copies since it was first published in 1984.

Face-to-face with a hesitant patient, a doctor can say: “More and more people are being vaccinated every day,” Dr. Cialdini says. “The reason you say more and more is [that] it conveys a trend. When people see a trend, they project it into the future that it is going to get even larger.”

A focus on choice can also help people change their minds and accept the vaccine, he says. “A lot of conspiracy theorists claim they don’t want to do it because they are being pushed or forced by the government, and they are resisting that.”

If that’s the case, presenting people with new information, such as the increased infectiousness of the Delta variant, and suggesting that a decision be made based on the new information, can work, Dr. Cialdini says, but be sure to end with: “It’s completely up to you.”

“This removes all their sense of being pushed. It says, ‘Here is all the evidence.’ ” At this point, a doctor’s personal recommendation with a patient who trusts him or her may sway them, Dr. Cialdini said. “I think you have to personalize the communication in both directions. That is, to say, ‘For someone in your situation, I would personally recommend that you get the vaccine.’ ” A health care professional’s authority and expertise can carry the day, he says, although “not always.”

This approach worked, Dr. Cialdini says, with a friend of the family hesitant about the COVID-19 vaccine. “I told him: ‘We have gotten it. You trust us, right?’ ” He waited for the person to say yes.

Then: “For someone in your position, my personal recommendation is to get vaccinated. There is new information about the vaccine, and more and more people are getting vaccinated. And of course, it is completely up to you.”

The person decided to get the vaccine.
 

‘Live in that space’

“People develop negative attitudes [about vaccines] by accessing alternative sources of information, anecdotes, and personal stories,” said Matthew Seeger, PhD, dean of the College of Fine, Performing, and Communication Arts and codirector of the Center for Emerging Infectious Diseases at Wayne State University in Detroit.

“If we are going to change their opinion, we need to live in that space.” That means listening first, he says. Ask: “Where did you get that information? How credible do you think the sources are? What do you mean about the vaccine changing DNA?”

Then, you might respond, he said, by addressing that specific information, such as, “We have no cases of DNA being changed.”

Dr. Seeger recalls that his mother would simply talk louder when she couldn’t understand someone who wasn’t a native English speaker. “That’s what we are trying to do with the vaccine-hesitant,” he says. “In some cases, we are yelling at them.” Instead, he says, probe their sources of information.

For some who are vaccine-hesitant, Dr. Seeger said, it is not just about the vaccine. The attitude about vaccines is tied in, often, with a distrust of government and feelings about personal freedom. “That’s one reason it’s so hard to change the attitude.” For some, getting the vaccine in a family against the vaccine might also disrupt their social structure or even get them ostracized.

For these people, a health care provider might give opportunities to get the vaccine without affecting either what they see as their political stance or upsetting family harmony. “There are places you can go, make an appointment, get a vaccine, and nobody knows,” Dr. Seeger said.

One Missouri doctor told CNN that some people calling for a vaccine appointment do request privacy, such as going through a drive-thru or having the shot as they sit in their cars. She said the hospital tries to accommodate them, reasoning that every additional vaccine shot is a win.

Dr. Seeger agrees. “Of course there are still public records,” he says, “but you can still claim you are a vaccine denier. It’s very difficult to persuade people to give up their whole world. Vaccine denial is part of that world. At this point, we need to do whatever we can to get people vaccinated.”
 

From peer to peer

A theme that runs through many of these persuasion techniques is peer pressure.

One example, while a bit more profane and confrontational than some groups, is COVIDAteMyFace, a subgroup, or “subreddit,” of the popular online site Reddit, which hosts numerous forums inviting users to share news and comments on a variety of topics. The subreddit has over 20,000 members. Its purpose, says the sub’s creator, “was to document the folks who denied COVID, then got bitten in the ass by it.” Reports are of actual cases.

“It’s interesting and powerful that Reddit users are taking this on,” Dr. Seeger said. And this kind of peer pressure, or peer-to-peer information, can be persuasive, he says. “We often seek consensual validation from peers about risk messages and risk behaviors.”

For instance, hurricane evacuation notices are more effective, he said, when people learn their neighbors are leaving.

Peer information – “the number of others who are doing or believing or responding to something – definitely persuades people,” agreed Dr. Cialdini. “When a lot of others are responding in a particular way – for example, getting vaccinated – people follow for three reasons: The action seems more appropriate or correct, it appears more feasible to perform, and it avoids social disapproval from those others.”
 

Let them talk, give them time

Gladys Jimenez is a contact tracer and “vaccine ambassador” for Tracing Health, a partnership between the Oregon Public Health Institute and the Public Health Institute that has nearly 300 bilingual contract tracers who serve the ethnic communities they’re from. During a typical week, she talks to 50 people or more, and promoting the vaccine is top of mind.

The conversations, Ms. Jimenez said, are like a dance. She presents information, then steps back and lets them talk. “I want to hear the person talk, where they are coming from, where they are at.” Depending on what they say, she gives them more information or corrects their misinformation. “They often will say, ‘Oh, I didn’t know that.’ ”

It’s rarely one conversation that convinces hesitant people, she said. “I’m planting this seed in their brain. ... people want someone to listen to them ... they want to vent.”

Once you let them do that, Ms. Jimenez said, “I can tell the person is in a different state of mind.” She also knows that people “will make the decision in their own time.”

With time, people can change their minds, as a Southern California woman who resisted at first (and asked to remain anonymous) can attest. “When the vaccine first came out, I remember thinking [that] it was a quick fix to a very big problem,” she said. The lack of full FDA approval, which has since been granted, was also an issue. She doesn’t oppose vaccines, she said, but was leery just of the COVID-19 vaccine.

When her longtime partner got his vaccine, he urged her to go right away for hers. She stalled. He got his second dose and grew impatient with her hesitancy. It began to wear on the relationship. Finally, the woman talked to two health care professionals she knew socially. They both follow the science, and “they both could explain vaccination to me in a way that resonated. The information was coming from sources I already trusted.”

Those conversations are what convinced her to get vaccinated this summer.
 

Simpson’s transformation

Ms. Simpson of Back to the Vax got her first COVID-19 immunization April 16. She had an allergic reaction, including severe itchiness and a bad headache, and needed emergency care, she said. Even so, she scheduled her second shot appointment.

Like many who turned against vaccines as adults, Ms. Simpson had all her childhood vaccines, but she developed a distrust after watching a lengthy documentary series that warned of vaccine dangers as an adult.

Looking back at that documentary, she thought about how it seems to blame everything – childhood cancer, ADHD, autism, allergies – on vaccinations. That suddenly seemed like sketchy science to her.

So did the claim from a family friend who said she knew someone who got the flu shot and began walking backward. She researched on her own, and with time, she decided to be pro-vaccines.

These days, she continues to find that stories, not statistics, are changing the minds of many who decide to get vaccinated. If the nurse practitioner urging the tetanus shot for her daughter had told her that the tetanus shot is linked with problems in one of a specific number of people who get it, no matter how large that second number was, Ms. Simpson said she would have thought: “What if she is that one?”

So she relies on stories that point out how universally vulnerable people are to COVID-19 first, facts next.

“Facts help once you are already moved,” Ms. Simpson said.

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

Not so long ago, Heather Simpson of Dallas was known as the anti-vaccine mom who dressed as “the measles” for Halloween. She painted red spots on her face and posted her photo on Facebook, joking: “Was trying to think of the least scary thing I could be for Halloween … so I became the measles.” It went viral with the anti-vaccine crowd.

But between that Halloween and today, a series of “aha” moments transformed Ms. Simpson’s attitudes toward vaccines.

In January 2021, one of those moments involved her daughter, now 4, who was scratched by a feral cat, raising concerns about tetanus. Her daughter had been bitten by a dog when she was just 1, and Ms. Simpson turned down advice then to get a tetanus shot. “I was convinced the tetanus shot would kill her faster than the tetanus.”

After the cat incident, the anxiety was so exhausting, she listened to the nurse practitioner at the clinic, whom she trusted. The nurse gently reassured Ms. Simpson that the shot was less risky than the possibility of tetanus – but did not bombard her with statistics – and that won over Ms. Simpson and triggered an overall rethinking of her vaccine stance.

Fast-forward to February, and that “aha” turned into action when Ms. Simpson launched a “Back to the Vax” effort with a fellow former vaccine opponent. Through their website, Facebook page, and podcasts, they now encourage people to get the COVID-19 vaccine, as well as other immunizations.
 

Challenge: Reaching the rest

With just over 52% of those eligible in the United States fully vaccinated as of Sept. 1, health care providers and others have a continuing challenge ahead: Trying to convince those who are eligible but still holding out to get vaccinated.

Recent data and a poll show some movement in the right direction, as immunizations are increasing and hesitancy is declining among certain groups. According to federal officials, about 14 million people in the United States got their first dose in August, an increase of 4 million, compared to the numbers who got it in July.

And a new poll from the Axios-IPSOS Coronavirus Index found only one in five Americans, or 20%, say they are not likely to get the vaccine, while “hard opposition,” those not at all likely, has dropped to 14% of those adults.

But there is still a lot of work to do. So, how do medical professionals or concerned citizens reach those who haven’t gotten vaccinated yet, whatever their reason?

Many experts in communication and persuasion that this news organization talked to agree that throwing statistics at people hesitant to get the COVID-19 vaccine is generally useless and often backfires.

So what does work, according to these experts?

• Emphasizing the trends of more people getting vaccinated.
• Focusing on everyone’s freedom of choice.
• Listening to concerns without judgment.
• Offering credible information.
• Correcting myths when necessary.
• Helping them fit vaccination into their “world view.”

Stories over statistics

Talking about the trends of vaccinations can definitely change minds about getting vaccinated, said Robert Cialdini, PhD, regents professor emeritus of psychology and marketing at Arizona State University, Tempe, and author of the recently updated book, “Influence: The Psychology of Persuasion,” which has sold over 5 million copies since it was first published in 1984.

Face-to-face with a hesitant patient, a doctor can say: “More and more people are being vaccinated every day,” Dr. Cialdini says. “The reason you say more and more is [that] it conveys a trend. When people see a trend, they project it into the future that it is going to get even larger.”

A focus on choice can also help people change their minds and accept the vaccine, he says. “A lot of conspiracy theorists claim they don’t want to do it because they are being pushed or forced by the government, and they are resisting that.”

If that’s the case, presenting people with new information, such as the increased infectiousness of the Delta variant, and suggesting that a decision be made based on the new information, can work, Dr. Cialdini says, but be sure to end with: “It’s completely up to you.”

“This removes all their sense of being pushed. It says, ‘Here is all the evidence.’ ” At this point, a doctor’s personal recommendation with a patient who trusts him or her may sway them, Dr. Cialdini said. “I think you have to personalize the communication in both directions. That is, to say, ‘For someone in your situation, I would personally recommend that you get the vaccine.’ ” A health care professional’s authority and expertise can carry the day, he says, although “not always.”

This approach worked, Dr. Cialdini says, with a friend of the family hesitant about the COVID-19 vaccine. “I told him: ‘We have gotten it. You trust us, right?’ ” He waited for the person to say yes.

Then: “For someone in your position, my personal recommendation is to get vaccinated. There is new information about the vaccine, and more and more people are getting vaccinated. And of course, it is completely up to you.”

The person decided to get the vaccine.
 

‘Live in that space’

“People develop negative attitudes [about vaccines] by accessing alternative sources of information, anecdotes, and personal stories,” said Matthew Seeger, PhD, dean of the College of Fine, Performing, and Communication Arts and codirector of the Center for Emerging Infectious Diseases at Wayne State University in Detroit.

“If we are going to change their opinion, we need to live in that space.” That means listening first, he says. Ask: “Where did you get that information? How credible do you think the sources are? What do you mean about the vaccine changing DNA?”

Then, you might respond, he said, by addressing that specific information, such as, “We have no cases of DNA being changed.”

Dr. Seeger recalls that his mother would simply talk louder when she couldn’t understand someone who wasn’t a native English speaker. “That’s what we are trying to do with the vaccine-hesitant,” he says. “In some cases, we are yelling at them.” Instead, he says, probe their sources of information.

For some who are vaccine-hesitant, Dr. Seeger said, it is not just about the vaccine. The attitude about vaccines is tied in, often, with a distrust of government and feelings about personal freedom. “That’s one reason it’s so hard to change the attitude.” For some, getting the vaccine in a family against the vaccine might also disrupt their social structure or even get them ostracized.

For these people, a health care provider might give opportunities to get the vaccine without affecting either what they see as their political stance or upsetting family harmony. “There are places you can go, make an appointment, get a vaccine, and nobody knows,” Dr. Seeger said.

One Missouri doctor told CNN that some people calling for a vaccine appointment do request privacy, such as going through a drive-thru or having the shot as they sit in their cars. She said the hospital tries to accommodate them, reasoning that every additional vaccine shot is a win.

Dr. Seeger agrees. “Of course there are still public records,” he says, “but you can still claim you are a vaccine denier. It’s very difficult to persuade people to give up their whole world. Vaccine denial is part of that world. At this point, we need to do whatever we can to get people vaccinated.”
 

From peer to peer

A theme that runs through many of these persuasion techniques is peer pressure.

One example, while a bit more profane and confrontational than some groups, is COVIDAteMyFace, a subgroup, or “subreddit,” of the popular online site Reddit, which hosts numerous forums inviting users to share news and comments on a variety of topics. The subreddit has over 20,000 members. Its purpose, says the sub’s creator, “was to document the folks who denied COVID, then got bitten in the ass by it.” Reports are of actual cases.

“It’s interesting and powerful that Reddit users are taking this on,” Dr. Seeger said. And this kind of peer pressure, or peer-to-peer information, can be persuasive, he says. “We often seek consensual validation from peers about risk messages and risk behaviors.”

For instance, hurricane evacuation notices are more effective, he said, when people learn their neighbors are leaving.

Peer information – “the number of others who are doing or believing or responding to something – definitely persuades people,” agreed Dr. Cialdini. “When a lot of others are responding in a particular way – for example, getting vaccinated – people follow for three reasons: The action seems more appropriate or correct, it appears more feasible to perform, and it avoids social disapproval from those others.”
 

Let them talk, give them time

Gladys Jimenez is a contact tracer and “vaccine ambassador” for Tracing Health, a partnership between the Oregon Public Health Institute and the Public Health Institute that has nearly 300 bilingual contract tracers who serve the ethnic communities they’re from. During a typical week, she talks to 50 people or more, and promoting the vaccine is top of mind.

The conversations, Ms. Jimenez said, are like a dance. She presents information, then steps back and lets them talk. “I want to hear the person talk, where they are coming from, where they are at.” Depending on what they say, she gives them more information or corrects their misinformation. “They often will say, ‘Oh, I didn’t know that.’ ”

It’s rarely one conversation that convinces hesitant people, she said. “I’m planting this seed in their brain. ... people want someone to listen to them ... they want to vent.”

Once you let them do that, Ms. Jimenez said, “I can tell the person is in a different state of mind.” She also knows that people “will make the decision in their own time.”

With time, people can change their minds, as a Southern California woman who resisted at first (and asked to remain anonymous) can attest. “When the vaccine first came out, I remember thinking [that] it was a quick fix to a very big problem,” she said. The lack of full FDA approval, which has since been granted, was also an issue. She doesn’t oppose vaccines, she said, but was leery just of the COVID-19 vaccine.

When her longtime partner got his vaccine, he urged her to go right away for hers. She stalled. He got his second dose and grew impatient with her hesitancy. It began to wear on the relationship. Finally, the woman talked to two health care professionals she knew socially. They both follow the science, and “they both could explain vaccination to me in a way that resonated. The information was coming from sources I already trusted.”

Those conversations are what convinced her to get vaccinated this summer.
 

Simpson’s transformation

Ms. Simpson of Back to the Vax got her first COVID-19 immunization April 16. She had an allergic reaction, including severe itchiness and a bad headache, and needed emergency care, she said. Even so, she scheduled her second shot appointment.

Like many who turned against vaccines as adults, Ms. Simpson had all her childhood vaccines, but she developed a distrust after watching a lengthy documentary series that warned of vaccine dangers as an adult.

Looking back at that documentary, she thought about how it seems to blame everything – childhood cancer, ADHD, autism, allergies – on vaccinations. That suddenly seemed like sketchy science to her.

So did the claim from a family friend who said she knew someone who got the flu shot and began walking backward. She researched on her own, and with time, she decided to be pro-vaccines.

These days, she continues to find that stories, not statistics, are changing the minds of many who decide to get vaccinated. If the nurse practitioner urging the tetanus shot for her daughter had told her that the tetanus shot is linked with problems in one of a specific number of people who get it, no matter how large that second number was, Ms. Simpson said she would have thought: “What if she is that one?”

So she relies on stories that point out how universally vulnerable people are to COVID-19 first, facts next.

“Facts help once you are already moved,” Ms. Simpson said.

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

Although well tolerated, metformin does not improve survival when given alongside chemoradiotherapy to patients with locally advanced non–small cell lung cancer (NSCLC), and may even make survival worse, suggest results from two recent phase 2 trials.

Epidemiologic studies have suggested that metformin is associated with a reduced incidence of cancer, while retrospective case studies have indicated that patients taking the drug have improved outcomes.

Moreover, preclinical data indicated that metformin has antineoplastic effects, with the drug showing both cytostatic and cytotoxic effects.

The current results cast doubt, however, over whether these benefits can be replicated in randomized controlled trials and thence brought to the clinic.

Despite this, “I don’t think metformin is dead,” commented Heath D. Skinner, MD, PhD, first author on one of the trials, published in JAMA Oncology.

He said in an interview there are “a few key areas where I think metformin could be of benefit” in lung cancer, such as in combination with tyrosine kinase inhibitors, or with immunotherapy.

Dr. Skinner also highlighted the unexpectedly good performance of standard chemoradiation, showing the “progress” that has been made in recent years in treatment delivery and quality.
 

No survival benefit

In the first trial, which was an open-label phase 2 study, NRG-LU001, patients with unresectable stage 3 NSCLC who did not have diabetes were randomized to carboplatin and paclitaxel-based chemoradiation either alone or with metformin.

Among the 167 patients eligible for analysis, 1-year progression-free survival (PFS) was 60.4% in the control group and 51.3% in the metformin group (P = .24) after a median follow-up of 27.7 months.

The only clinical factor associated with progression-free survival on multivariate analysis was clinical stage, at a hazard ratio of 1.79 (P = .05), reports Dr. Skinner, from the University of Pittsburgh Hillman Cancer Center, and colleagues.

With 1-year overall survival at 80.2% in the control group and 80.8% in the metformin arm, and no significant differences in rates of locoregional recurrence or distant metastasis, the team concluded that adding metformin to chemoradiation may have been “well tolerated but did not improve survival.”
 

Not recommended

The second randomized controlled trial, OCOG-ALMERA, involved patients with locally advanced NSCLC stratified into stages 3A and 3B, again without diabetes.

They were treated with platinum-based chemoradiotherapy, with chest radiotherapy with or without consolidation chemotherapy. They were randomized to metformin or no additional treatment for up to 12 months.

The trial had to be stopped early because of slow accrual, with only 54 patients randomized between 2014 and 2019, wrote the authors who were led by Theodoros Tsakiridis, MD, PhD, Juravinski Cancer Center, McMaster University, Hamilton, Ont.

The results revealed that treatment failure at 1 year was seen in 69.2% of metformin patients and 42.9% of those in the control arm.

The 1-year progression survival was markedly worse with metformin, at 34.8% versus 63.0% in the control arm and an HR for progression of 2.42, while overall survival was 47.4% versus 85.2% and an HR for death of 3.80.

With more than twice as many metformin than control patients reporting at least one grade 3 or higher adverse event, the researchers conclude the drug is “not recommended in patients with locally advanced non–small cell lung cancer who are candidates for chemoradiotherapy.”
 

Future research directions

Do these results sound the death knell for metformin in the treatment of lung cancer, or could lessons be learned from both studies that leave the door open for future research?

Chukwuka Eze, MD, of the University Hospital LMU Munich (Germany), thinks there may well be.

In an editorial accompanying the two studies, he and colleagues wrote: “Despite the negative results of both studies, invaluable information for the subsequent design of future trials could be extracted.”

For example, “there might yet be a role for metformin in selected patients with non–small cell lung cancer patients,” they continued, such as those with KRAS/LKB1-mutated tumors, or with tumors that have elevated fluorodeoxyglucose metabolism.

They also suggested that future studies should include continuous assessment of metabolic parameters and “comprehensive” analysis of responses on imaging, as well as biomarker analysis.

Moreover, in the era of immuno-oncology, “special attention to the immunomodulatory effects of metformin in the host and tumor are pertinent.”
 

Better-than-expected outcomes

Beyond that, both studies were hampered by limitations that make drawing conclusions difficult.

In the OCOG-ALMERA trial, the lack of double-blinding or placebo control, and limited accrual are identified by the authors as “weaknesses.”

The “much slower than anticipated” accrual may have been caused not only by exclusion of patients with diabetes, but also bias against the trial among physicians, who may have looked instead to immunotherapy trials for their patients.

On the other hand, the issue for NRG-LU001 was the “better-than-expected” performance of control arm, the researchers noted.

They make the comparison with the PACIFIC trial, which showed that giving durvalumab (Imfinzi, AstraZeneca) after platinum-based doublet chemotherapy and concurrent radiotherapy was associated with a doubling of progression-free survival over chemoradiation alone.

However, Dr. Skinner and colleagues pointed out that the 1-year progression-free survival achieved in PACIFIC with durvalumab after chemoradiotherapy was, at 55.9%, lower than that seen in the control arm of NRG-LU001.

“The PFS in NRG-LU001 remains striking, particularly as PACIFIC trial patients were randomized only when progression was not detected after concurrent chemoradiation,” the researchers wrote.

Dr. Skinner said in an interview they expected the control arm in their study “to do far worse than it actually did.”

He continued that they did not follow up chemoradiation with adjuvant immunotherapy, as would be the case nowadays, because it was “not the standard when we started the trial,” and did not become so “until the very end of accrual.”

Dr. Skinner warned that there are “many caveats” to comparing two different trials, but looking at the current results alongside those from PACIFIC, he said that, “for me, it seems like we have been making progress in the delivery of concurrent chemoradiation. I think that good quality concurrent chemoradiation and improvement in delivery really is one of the take-homes from this trial.”

NRG-LU001 was supported by grants from NRG Oncology and the National Cancer Institute. OCOG-ALMERA was funded by a grant from the Canadian Institutes of Health Research to Dr Tsakiridis. The Ontario Clinical Oncology Group assumed the role of the sponsor of this trial. Dr. Skinner reported receiving research funding from the National Cancer Institute and National Institute of Dental and Craniofacial Research outside the submitted work and has previously received a grant from the National Cancer Institute for a separate metformin-related clinical trial. Dr. Tsakiridis reported receiving a grant from Sanofi Canada for prostate cancer research outside the submitted work. Dr. Eze declares no relevant relationships.

Although well tolerated, metformin does not improve survival when given alongside chemoradiotherapy to patients with locally advanced non–small cell lung cancer (NSCLC), and may even make survival worse, suggest results from two recent phase 2 trials.

Epidemiologic studies have suggested that metformin is associated with a reduced incidence of cancer, while retrospective case studies have indicated that patients taking the drug have improved outcomes.

Moreover, preclinical data indicated that metformin has antineoplastic effects, with the drug showing both cytostatic and cytotoxic effects.

The current results cast doubt, however, over whether these benefits can be replicated in randomized controlled trials and thence brought to the clinic.

Despite this, “I don’t think metformin is dead,” commented Heath D. Skinner, MD, PhD, first author on one of the trials, published in JAMA Oncology.

He said in an interview there are “a few key areas where I think metformin could be of benefit” in lung cancer, such as in combination with tyrosine kinase inhibitors, or with immunotherapy.

Dr. Skinner also highlighted the unexpectedly good performance of standard chemoradiation, showing the “progress” that has been made in recent years in treatment delivery and quality.
 

No survival benefit

In the first trial, which was an open-label phase 2 study, NRG-LU001, patients with unresectable stage 3 NSCLC who did not have diabetes were randomized to carboplatin and paclitaxel-based chemoradiation either alone or with metformin.

Among the 167 patients eligible for analysis, 1-year progression-free survival (PFS) was 60.4% in the control group and 51.3% in the metformin group (P = .24) after a median follow-up of 27.7 months.

The only clinical factor associated with progression-free survival on multivariate analysis was clinical stage, at a hazard ratio of 1.79 (P = .05), reports Dr. Skinner, from the University of Pittsburgh Hillman Cancer Center, and colleagues.

With 1-year overall survival at 80.2% in the control group and 80.8% in the metformin arm, and no significant differences in rates of locoregional recurrence or distant metastasis, the team concluded that adding metformin to chemoradiation may have been “well tolerated but did not improve survival.”
 

Not recommended

The second randomized controlled trial, OCOG-ALMERA, involved patients with locally advanced NSCLC stratified into stages 3A and 3B, again without diabetes.

They were treated with platinum-based chemoradiotherapy, with chest radiotherapy with or without consolidation chemotherapy. They were randomized to metformin or no additional treatment for up to 12 months.

The trial had to be stopped early because of slow accrual, with only 54 patients randomized between 2014 and 2019, wrote the authors who were led by Theodoros Tsakiridis, MD, PhD, Juravinski Cancer Center, McMaster University, Hamilton, Ont.

The results revealed that treatment failure at 1 year was seen in 69.2% of metformin patients and 42.9% of those in the control arm.

The 1-year progression survival was markedly worse with metformin, at 34.8% versus 63.0% in the control arm and an HR for progression of 2.42, while overall survival was 47.4% versus 85.2% and an HR for death of 3.80.

With more than twice as many metformin than control patients reporting at least one grade 3 or higher adverse event, the researchers conclude the drug is “not recommended in patients with locally advanced non–small cell lung cancer who are candidates for chemoradiotherapy.”
 

Future research directions

Do these results sound the death knell for metformin in the treatment of lung cancer, or could lessons be learned from both studies that leave the door open for future research?

Chukwuka Eze, MD, of the University Hospital LMU Munich (Germany), thinks there may well be.

In an editorial accompanying the two studies, he and colleagues wrote: “Despite the negative results of both studies, invaluable information for the subsequent design of future trials could be extracted.”

For example, “there might yet be a role for metformin in selected patients with non–small cell lung cancer patients,” they continued, such as those with KRAS/LKB1-mutated tumors, or with tumors that have elevated fluorodeoxyglucose metabolism.

They also suggested that future studies should include continuous assessment of metabolic parameters and “comprehensive” analysis of responses on imaging, as well as biomarker analysis.

Moreover, in the era of immuno-oncology, “special attention to the immunomodulatory effects of metformin in the host and tumor are pertinent.”
 

Better-than-expected outcomes

Beyond that, both studies were hampered by limitations that make drawing conclusions difficult.

In the OCOG-ALMERA trial, the lack of double-blinding or placebo control, and limited accrual are identified by the authors as “weaknesses.”

The “much slower than anticipated” accrual may have been caused not only by exclusion of patients with diabetes, but also bias against the trial among physicians, who may have looked instead to immunotherapy trials for their patients.

On the other hand, the issue for NRG-LU001 was the “better-than-expected” performance of control arm, the researchers noted.

They make the comparison with the PACIFIC trial, which showed that giving durvalumab (Imfinzi, AstraZeneca) after platinum-based doublet chemotherapy and concurrent radiotherapy was associated with a doubling of progression-free survival over chemoradiation alone.

However, Dr. Skinner and colleagues pointed out that the 1-year progression-free survival achieved in PACIFIC with durvalumab after chemoradiotherapy was, at 55.9%, lower than that seen in the control arm of NRG-LU001.

“The PFS in NRG-LU001 remains striking, particularly as PACIFIC trial patients were randomized only when progression was not detected after concurrent chemoradiation,” the researchers wrote.

Dr. Skinner said in an interview they expected the control arm in their study “to do far worse than it actually did.”

He continued that they did not follow up chemoradiation with adjuvant immunotherapy, as would be the case nowadays, because it was “not the standard when we started the trial,” and did not become so “until the very end of accrual.”

Dr. Skinner warned that there are “many caveats” to comparing two different trials, but looking at the current results alongside those from PACIFIC, he said that, “for me, it seems like we have been making progress in the delivery of concurrent chemoradiation. I think that good quality concurrent chemoradiation and improvement in delivery really is one of the take-homes from this trial.”

NRG-LU001 was supported by grants from NRG Oncology and the National Cancer Institute. OCOG-ALMERA was funded by a grant from the Canadian Institutes of Health Research to Dr Tsakiridis. The Ontario Clinical Oncology Group assumed the role of the sponsor of this trial. Dr. Skinner reported receiving research funding from the National Cancer Institute and National Institute of Dental and Craniofacial Research outside the submitted work and has previously received a grant from the National Cancer Institute for a separate metformin-related clinical trial. Dr. Tsakiridis reported receiving a grant from Sanofi Canada for prostate cancer research outside the submitted work. Dr. Eze declares no relevant relationships.

Although well tolerated, metformin does not improve survival when given alongside chemoradiotherapy to patients with locally advanced non–small cell lung cancer (NSCLC), and may even make survival worse, suggest results from two recent phase 2 trials.

Epidemiologic studies have suggested that metformin is associated with a reduced incidence of cancer, while retrospective case studies have indicated that patients taking the drug have improved outcomes.

Moreover, preclinical data indicated that metformin has antineoplastic effects, with the drug showing both cytostatic and cytotoxic effects.

The current results cast doubt, however, over whether these benefits can be replicated in randomized controlled trials and thence brought to the clinic.

Despite this, “I don’t think metformin is dead,” commented Heath D. Skinner, MD, PhD, first author on one of the trials, published in JAMA Oncology.

He said in an interview there are “a few key areas where I think metformin could be of benefit” in lung cancer, such as in combination with tyrosine kinase inhibitors, or with immunotherapy.

Dr. Skinner also highlighted the unexpectedly good performance of standard chemoradiation, showing the “progress” that has been made in recent years in treatment delivery and quality.
 

No survival benefit

In the first trial, which was an open-label phase 2 study, NRG-LU001, patients with unresectable stage 3 NSCLC who did not have diabetes were randomized to carboplatin and paclitaxel-based chemoradiation either alone or with metformin.

Among the 167 patients eligible for analysis, 1-year progression-free survival (PFS) was 60.4% in the control group and 51.3% in the metformin group (P = .24) after a median follow-up of 27.7 months.

The only clinical factor associated with progression-free survival on multivariate analysis was clinical stage, at a hazard ratio of 1.79 (P = .05), reports Dr. Skinner, from the University of Pittsburgh Hillman Cancer Center, and colleagues.

With 1-year overall survival at 80.2% in the control group and 80.8% in the metformin arm, and no significant differences in rates of locoregional recurrence or distant metastasis, the team concluded that adding metformin to chemoradiation may have been “well tolerated but did not improve survival.”
 

Not recommended

The second randomized controlled trial, OCOG-ALMERA, involved patients with locally advanced NSCLC stratified into stages 3A and 3B, again without diabetes.

They were treated with platinum-based chemoradiotherapy, with chest radiotherapy with or without consolidation chemotherapy. They were randomized to metformin or no additional treatment for up to 12 months.

The trial had to be stopped early because of slow accrual, with only 54 patients randomized between 2014 and 2019, wrote the authors who were led by Theodoros Tsakiridis, MD, PhD, Juravinski Cancer Center, McMaster University, Hamilton, Ont.

The results revealed that treatment failure at 1 year was seen in 69.2% of metformin patients and 42.9% of those in the control arm.

The 1-year progression survival was markedly worse with metformin, at 34.8% versus 63.0% in the control arm and an HR for progression of 2.42, while overall survival was 47.4% versus 85.2% and an HR for death of 3.80.

With more than twice as many metformin than control patients reporting at least one grade 3 or higher adverse event, the researchers conclude the drug is “not recommended in patients with locally advanced non–small cell lung cancer who are candidates for chemoradiotherapy.”
 

Future research directions

Do these results sound the death knell for metformin in the treatment of lung cancer, or could lessons be learned from both studies that leave the door open for future research?

Chukwuka Eze, MD, of the University Hospital LMU Munich (Germany), thinks there may well be.

In an editorial accompanying the two studies, he and colleagues wrote: “Despite the negative results of both studies, invaluable information for the subsequent design of future trials could be extracted.”

For example, “there might yet be a role for metformin in selected patients with non–small cell lung cancer patients,” they continued, such as those with KRAS/LKB1-mutated tumors, or with tumors that have elevated fluorodeoxyglucose metabolism.

They also suggested that future studies should include continuous assessment of metabolic parameters and “comprehensive” analysis of responses on imaging, as well as biomarker analysis.

Moreover, in the era of immuno-oncology, “special attention to the immunomodulatory effects of metformin in the host and tumor are pertinent.”
 

Better-than-expected outcomes

Beyond that, both studies were hampered by limitations that make drawing conclusions difficult.

In the OCOG-ALMERA trial, the lack of double-blinding or placebo control, and limited accrual are identified by the authors as “weaknesses.”

The “much slower than anticipated” accrual may have been caused not only by exclusion of patients with diabetes, but also bias against the trial among physicians, who may have looked instead to immunotherapy trials for their patients.

On the other hand, the issue for NRG-LU001 was the “better-than-expected” performance of control arm, the researchers noted.

They make the comparison with the PACIFIC trial, which showed that giving durvalumab (Imfinzi, AstraZeneca) after platinum-based doublet chemotherapy and concurrent radiotherapy was associated with a doubling of progression-free survival over chemoradiation alone.

However, Dr. Skinner and colleagues pointed out that the 1-year progression-free survival achieved in PACIFIC with durvalumab after chemoradiotherapy was, at 55.9%, lower than that seen in the control arm of NRG-LU001.

“The PFS in NRG-LU001 remains striking, particularly as PACIFIC trial patients were randomized only when progression was not detected after concurrent chemoradiation,” the researchers wrote.

Dr. Skinner said in an interview they expected the control arm in their study “to do far worse than it actually did.”

He continued that they did not follow up chemoradiation with adjuvant immunotherapy, as would be the case nowadays, because it was “not the standard when we started the trial,” and did not become so “until the very end of accrual.”

Dr. Skinner warned that there are “many caveats” to comparing two different trials, but looking at the current results alongside those from PACIFIC, he said that, “for me, it seems like we have been making progress in the delivery of concurrent chemoradiation. I think that good quality concurrent chemoradiation and improvement in delivery really is one of the take-homes from this trial.”

NRG-LU001 was supported by grants from NRG Oncology and the National Cancer Institute. OCOG-ALMERA was funded by a grant from the Canadian Institutes of Health Research to Dr Tsakiridis. The Ontario Clinical Oncology Group assumed the role of the sponsor of this trial. Dr. Skinner reported receiving research funding from the National Cancer Institute and National Institute of Dental and Craniofacial Research outside the submitted work and has previously received a grant from the National Cancer Institute for a separate metformin-related clinical trial. Dr. Tsakiridis reported receiving a grant from Sanofi Canada for prostate cancer research outside the submitted work. Dr. Eze declares no relevant relationships.

Equine therapy, which involves interactions with horses in a controlled environment, reduces fear and other symptoms of posttraumatic stress disorder, new research suggests.

Man O'War Project

Results from a study of about 60 military veterans who underwent weekly sessions of horse-assisted therapy showed “marked reductions” in clinician-rated and self-reported symptoms of PTSD and depression up to 3 months post treatment.

“What we’re doing here with horses is helping people overcome something very specific to PTSD,” coinvestigator Yuval Neria, PhD, professor of clinical medical psychology and director of the PTSD treatment and research program, Columbia University Medical Center, New York, said in an interview.

“It offers the opportunity to overcome fear, to facilitate self-efficacy, to facilitate trust in yourself, to understand your feelings, and perhaps to change them over time, he said.

In addition, veterans loved the experience, Dr. Neria reported. He noted that many patients with PTSD have trouble with traditional treatments and are eager to try something “creative and new.”

The findings were published online Aug. 31, 2021, in the Journal of Clinical Psychiatry.
 

Building bonds

PTSD affects an estimated 10%-30% of U.S. military personnel. These rates are higher than in the general population because veterans may experience increased trauma through combat, injury, and sexual assault, the investigators noted.

Previous research has suggested that horse-human interactions can build bonds that foster behavioral changes. These powerful animals provide instantaneous feedback, allowing patients to develop emotional awareness.

“Horses are very sensitive to whatever we communicate with them, whether it’s fear or anger or stress,” said Dr. Neria.

Equine-assisted therapy is increasingly being used for various mental and physical conditions. Launching an open-label study to examine this type of treatment for PTSD “was an opportunity to look at something very, very different,” Dr. Neria said.

“This is not psychotherapy, it’s not medication, and it’s not neural stimulation,” he added.

The study included 63 veterans with PTSD (mean age, 50 years; 37% women). Of these, 47 were receiving psychotherapy alone, pharmacotherapy alone, or both. In addition, 48 had at least one comorbid disorder. All were divided into 16 groups of three to five participants each.

The program consisted of eight 90-minute weekly sessions conducted at a large equestrian center. Sessions were coled by a mental health professional and an equine specialist who guided participants in horse communication and behavior.

Early sessions focused on acquainting patients with the horses, grooming exercises, and learning “leading,” which involved directing a horse with a rope or wand. During subsequent sessions, patients became more comfortable with managing the horses in individual and teamwork exercises.

The horses were specifically chosen for their temperament and had no history of aggression. A horse wrangler attended sessions to further ensure safety.
 

Few dropouts

The study included four assessment points: pretreatment, midpoint, post treatment, and 3-month follow-up.

All 63 participants completed baseline assessments. Only five patients (7.9%) discontinued the program.

“We didn’t see dropouts at the rate we usually see in evidence-based therapies for PTSD, which is remarkable and suggests that people really loved it,” said Dr. Neria.

Man O'War Project

The primary outcome was the Clinician-Administered PTSD Scale–5 (CAPS-5), a structured interview that evaluates intrusive memories, social avoidance, and other symptoms based on DSM-5 criteria.

In the intent-to-treat analysis, mean CAPS-5 scores decreased from 38.6 at baseline to 26.9 post treatment. In addition, 29 (46.0%) and 23 (36.5%) participants scored below the PTSD diagnostic threshold of 25 at posttreatment and follow-up, respectively.

Notably, 50.8% of the study population had a clinically significant change, defined as 30% or greater decrease in CAPS-5 score, at post treatment; 54.0% had a significant change at follow-up.

Mean scores on the self-reported 20-item PTSD Checklist for DSM-5 questionnaire decreased from 50.7 at baseline to 34.6 at study termination.

Depression symptoms, measured by the clinician-rated Hamilton Depression Rating Scale and the self-reported Beck Depression Inventory–II, also improved.
 

Structural, functional change

The results did not differ by age, gender, or type of trauma. Dr. Neria noted that many women in the study had suffered sexual abuse or assault, suggesting that the intervention might be appropriate for PTSD outside the military.

“I’m very keen on moving this along into a civilian population,” he said.

The study did not examine potential mechanisms of action. The benefits may come from something inherent in the equine interactions, the human group process, or just being in the beautiful setting where the treatment took place, the investigators noted.

However, Dr. Neria thinks there is another potential explanation – real changes in the brain.

Neuroimaging of a subsample of 20 participants before and after the intervention showed a significant increase in caudate functional connectivity and a reduction in gray matter density of the thalamus and the caudate.

“We see a big change both structurally and functionally,” with the results pointing to an impact on the reward network of the brain, said Dr. Neria.

“This suggests that pleasure was perhaps the main mechanism of action,” which corresponds with patient reports of really enjoying the experience, he added.

Dr. Neria noted that equine therapy is different from bonding with a loyal dog. Interacting with a large and powerful animal may give veterans a sense of accomplishment and self-worth, which can be tremendously therapeutic.
 

Next step in therapy?

Commenting on the research, retired Col. Elspeth Cameron Ritchie, MD, chair of psychiatry, MedStar Washington Hospital Center, Washington, called equine therapy “innovative” in PTSD.

“I see this as the next step in finding acceptable therapies that people like to do,” she said.

Some patients have an aversion to talk therapy because it makes them relive their trauma; and many dislike the side effects of medications, which can include erectile dysfunction, said Dr. Ritchie, who was not involved with the research.

“So something like this that they can enjoy, have a sense of mastery, can bond with an animal, I think is wonderful,” she said.

Dr. Ritchie noted that working with animals offers “a kind of biofeedback” that may calm anxieties, help maintain control, and “is very nonjudgmental.”

However, she pointed out that equine therapy is not new. For example, horses have been used previously to treat patients with a variety of disabilities, including autism.

Dr. Ritchie thought it was “very wise” that study participants just learned to control the horses and didn’t actually ride them, because that could be a frightening experience.

Nonetheless, she noted equine therapy “is not going to be accessible for everybody.”

In addition, Dr. Ritchie was surprised that the investigators didn’t mention more of the quite extensive research that has been conducted on dog therapy in patients with PTSD.

Dr. Neria and Ritchie disclosed no relevant financial relationships.

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

Equine therapy, which involves interactions with horses in a controlled environment, reduces fear and other symptoms of posttraumatic stress disorder, new research suggests.

Man O'War Project

Results from a study of about 60 military veterans who underwent weekly sessions of horse-assisted therapy showed “marked reductions” in clinician-rated and self-reported symptoms of PTSD and depression up to 3 months post treatment.

“What we’re doing here with horses is helping people overcome something very specific to PTSD,” coinvestigator Yuval Neria, PhD, professor of clinical medical psychology and director of the PTSD treatment and research program, Columbia University Medical Center, New York, said in an interview.

“It offers the opportunity to overcome fear, to facilitate self-efficacy, to facilitate trust in yourself, to understand your feelings, and perhaps to change them over time, he said.

In addition, veterans loved the experience, Dr. Neria reported. He noted that many patients with PTSD have trouble with traditional treatments and are eager to try something “creative and new.”

The findings were published online Aug. 31, 2021, in the Journal of Clinical Psychiatry.
 

Building bonds

PTSD affects an estimated 10%-30% of U.S. military personnel. These rates are higher than in the general population because veterans may experience increased trauma through combat, injury, and sexual assault, the investigators noted.

Previous research has suggested that horse-human interactions can build bonds that foster behavioral changes. These powerful animals provide instantaneous feedback, allowing patients to develop emotional awareness.

“Horses are very sensitive to whatever we communicate with them, whether it’s fear or anger or stress,” said Dr. Neria.

Equine-assisted therapy is increasingly being used for various mental and physical conditions. Launching an open-label study to examine this type of treatment for PTSD “was an opportunity to look at something very, very different,” Dr. Neria said.

“This is not psychotherapy, it’s not medication, and it’s not neural stimulation,” he added.

The study included 63 veterans with PTSD (mean age, 50 years; 37% women). Of these, 47 were receiving psychotherapy alone, pharmacotherapy alone, or both. In addition, 48 had at least one comorbid disorder. All were divided into 16 groups of three to five participants each.

The program consisted of eight 90-minute weekly sessions conducted at a large equestrian center. Sessions were coled by a mental health professional and an equine specialist who guided participants in horse communication and behavior.

Early sessions focused on acquainting patients with the horses, grooming exercises, and learning “leading,” which involved directing a horse with a rope or wand. During subsequent sessions, patients became more comfortable with managing the horses in individual and teamwork exercises.

The horses were specifically chosen for their temperament and had no history of aggression. A horse wrangler attended sessions to further ensure safety.
 

Few dropouts

The study included four assessment points: pretreatment, midpoint, post treatment, and 3-month follow-up.

All 63 participants completed baseline assessments. Only five patients (7.9%) discontinued the program.

“We didn’t see dropouts at the rate we usually see in evidence-based therapies for PTSD, which is remarkable and suggests that people really loved it,” said Dr. Neria.

Man O'War Project

The primary outcome was the Clinician-Administered PTSD Scale–5 (CAPS-5), a structured interview that evaluates intrusive memories, social avoidance, and other symptoms based on DSM-5 criteria.

In the intent-to-treat analysis, mean CAPS-5 scores decreased from 38.6 at baseline to 26.9 post treatment. In addition, 29 (46.0%) and 23 (36.5%) participants scored below the PTSD diagnostic threshold of 25 at posttreatment and follow-up, respectively.

Notably, 50.8% of the study population had a clinically significant change, defined as 30% or greater decrease in CAPS-5 score, at post treatment; 54.0% had a significant change at follow-up.

Mean scores on the self-reported 20-item PTSD Checklist for DSM-5 questionnaire decreased from 50.7 at baseline to 34.6 at study termination.

Depression symptoms, measured by the clinician-rated Hamilton Depression Rating Scale and the self-reported Beck Depression Inventory–II, also improved.
 

Structural, functional change

The results did not differ by age, gender, or type of trauma. Dr. Neria noted that many women in the study had suffered sexual abuse or assault, suggesting that the intervention might be appropriate for PTSD outside the military.

“I’m very keen on moving this along into a civilian population,” he said.

The study did not examine potential mechanisms of action. The benefits may come from something inherent in the equine interactions, the human group process, or just being in the beautiful setting where the treatment took place, the investigators noted.

However, Dr. Neria thinks there is another potential explanation – real changes in the brain.

Neuroimaging of a subsample of 20 participants before and after the intervention showed a significant increase in caudate functional connectivity and a reduction in gray matter density of the thalamus and the caudate.

“We see a big change both structurally and functionally,” with the results pointing to an impact on the reward network of the brain, said Dr. Neria.

“This suggests that pleasure was perhaps the main mechanism of action,” which corresponds with patient reports of really enjoying the experience, he added.

Dr. Neria noted that equine therapy is different from bonding with a loyal dog. Interacting with a large and powerful animal may give veterans a sense of accomplishment and self-worth, which can be tremendously therapeutic.
 

Next step in therapy?

Commenting on the research, retired Col. Elspeth Cameron Ritchie, MD, chair of psychiatry, MedStar Washington Hospital Center, Washington, called equine therapy “innovative” in PTSD.

“I see this as the next step in finding acceptable therapies that people like to do,” she said.

Some patients have an aversion to talk therapy because it makes them relive their trauma; and many dislike the side effects of medications, which can include erectile dysfunction, said Dr. Ritchie, who was not involved with the research.

“So something like this that they can enjoy, have a sense of mastery, can bond with an animal, I think is wonderful,” she said.

Dr. Ritchie noted that working with animals offers “a kind of biofeedback” that may calm anxieties, help maintain control, and “is very nonjudgmental.”

However, she pointed out that equine therapy is not new. For example, horses have been used previously to treat patients with a variety of disabilities, including autism.

Dr. Ritchie thought it was “very wise” that study participants just learned to control the horses and didn’t actually ride them, because that could be a frightening experience.

Nonetheless, she noted equine therapy “is not going to be accessible for everybody.”

In addition, Dr. Ritchie was surprised that the investigators didn’t mention more of the quite extensive research that has been conducted on dog therapy in patients with PTSD.

Dr. Neria and Ritchie disclosed no relevant financial relationships.

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

Equine therapy, which involves interactions with horses in a controlled environment, reduces fear and other symptoms of posttraumatic stress disorder, new research suggests.

Man O'War Project

Results from a study of about 60 military veterans who underwent weekly sessions of horse-assisted therapy showed “marked reductions” in clinician-rated and self-reported symptoms of PTSD and depression up to 3 months post treatment.

“What we’re doing here with horses is helping people overcome something very specific to PTSD,” coinvestigator Yuval Neria, PhD, professor of clinical medical psychology and director of the PTSD treatment and research program, Columbia University Medical Center, New York, said in an interview.

“It offers the opportunity to overcome fear, to facilitate self-efficacy, to facilitate trust in yourself, to understand your feelings, and perhaps to change them over time, he said.

In addition, veterans loved the experience, Dr. Neria reported. He noted that many patients with PTSD have trouble with traditional treatments and are eager to try something “creative and new.”

The findings were published online Aug. 31, 2021, in the Journal of Clinical Psychiatry.
 

Building bonds

PTSD affects an estimated 10%-30% of U.S. military personnel. These rates are higher than in the general population because veterans may experience increased trauma through combat, injury, and sexual assault, the investigators noted.

Previous research has suggested that horse-human interactions can build bonds that foster behavioral changes. These powerful animals provide instantaneous feedback, allowing patients to develop emotional awareness.

“Horses are very sensitive to whatever we communicate with them, whether it’s fear or anger or stress,” said Dr. Neria.

Equine-assisted therapy is increasingly being used for various mental and physical conditions. Launching an open-label study to examine this type of treatment for PTSD “was an opportunity to look at something very, very different,” Dr. Neria said.

“This is not psychotherapy, it’s not medication, and it’s not neural stimulation,” he added.

The study included 63 veterans with PTSD (mean age, 50 years; 37% women). Of these, 47 were receiving psychotherapy alone, pharmacotherapy alone, or both. In addition, 48 had at least one comorbid disorder. All were divided into 16 groups of three to five participants each.

The program consisted of eight 90-minute weekly sessions conducted at a large equestrian center. Sessions were coled by a mental health professional and an equine specialist who guided participants in horse communication and behavior.

Early sessions focused on acquainting patients with the horses, grooming exercises, and learning “leading,” which involved directing a horse with a rope or wand. During subsequent sessions, patients became more comfortable with managing the horses in individual and teamwork exercises.

The horses were specifically chosen for their temperament and had no history of aggression. A horse wrangler attended sessions to further ensure safety.
 

Few dropouts

The study included four assessment points: pretreatment, midpoint, post treatment, and 3-month follow-up.

All 63 participants completed baseline assessments. Only five patients (7.9%) discontinued the program.

“We didn’t see dropouts at the rate we usually see in evidence-based therapies for PTSD, which is remarkable and suggests that people really loved it,” said Dr. Neria.

Man O'War Project

The primary outcome was the Clinician-Administered PTSD Scale–5 (CAPS-5), a structured interview that evaluates intrusive memories, social avoidance, and other symptoms based on DSM-5 criteria.

In the intent-to-treat analysis, mean CAPS-5 scores decreased from 38.6 at baseline to 26.9 post treatment. In addition, 29 (46.0%) and 23 (36.5%) participants scored below the PTSD diagnostic threshold of 25 at posttreatment and follow-up, respectively.

Notably, 50.8% of the study population had a clinically significant change, defined as 30% or greater decrease in CAPS-5 score, at post treatment; 54.0% had a significant change at follow-up.

Mean scores on the self-reported 20-item PTSD Checklist for DSM-5 questionnaire decreased from 50.7 at baseline to 34.6 at study termination.

Depression symptoms, measured by the clinician-rated Hamilton Depression Rating Scale and the self-reported Beck Depression Inventory–II, also improved.
 

Structural, functional change

The results did not differ by age, gender, or type of trauma. Dr. Neria noted that many women in the study had suffered sexual abuse or assault, suggesting that the intervention might be appropriate for PTSD outside the military.

“I’m very keen on moving this along into a civilian population,” he said.

The study did not examine potential mechanisms of action. The benefits may come from something inherent in the equine interactions, the human group process, or just being in the beautiful setting where the treatment took place, the investigators noted.

However, Dr. Neria thinks there is another potential explanation – real changes in the brain.

Neuroimaging of a subsample of 20 participants before and after the intervention showed a significant increase in caudate functional connectivity and a reduction in gray matter density of the thalamus and the caudate.

“We see a big change both structurally and functionally,” with the results pointing to an impact on the reward network of the brain, said Dr. Neria.

“This suggests that pleasure was perhaps the main mechanism of action,” which corresponds with patient reports of really enjoying the experience, he added.

Dr. Neria noted that equine therapy is different from bonding with a loyal dog. Interacting with a large and powerful animal may give veterans a sense of accomplishment and self-worth, which can be tremendously therapeutic.
 

Next step in therapy?

Commenting on the research, retired Col. Elspeth Cameron Ritchie, MD, chair of psychiatry, MedStar Washington Hospital Center, Washington, called equine therapy “innovative” in PTSD.

“I see this as the next step in finding acceptable therapies that people like to do,” she said.

Some patients have an aversion to talk therapy because it makes them relive their trauma; and many dislike the side effects of medications, which can include erectile dysfunction, said Dr. Ritchie, who was not involved with the research.

“So something like this that they can enjoy, have a sense of mastery, can bond with an animal, I think is wonderful,” she said.

Dr. Ritchie noted that working with animals offers “a kind of biofeedback” that may calm anxieties, help maintain control, and “is very nonjudgmental.”

However, she pointed out that equine therapy is not new. For example, horses have been used previously to treat patients with a variety of disabilities, including autism.

Dr. Ritchie thought it was “very wise” that study participants just learned to control the horses and didn’t actually ride them, because that could be a frightening experience.

Nonetheless, she noted equine therapy “is not going to be accessible for everybody.”

In addition, Dr. Ritchie was surprised that the investigators didn’t mention more of the quite extensive research that has been conducted on dog therapy in patients with PTSD.

Dr. Neria and Ritchie disclosed no relevant financial relationships.

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