In a new study, researchers stimulated immune cells to assemble into tertiary lymphoid structures that improved the efficacy of chemotherapy in a preclinical model of pancreatic cancer.

Overall, the evidence generated by the study supports the notion that induction of tertiary lymphoid structures may potentiate chemotherapy’s antitumor activity, at least in a murine model of pancreatic ductal adenocarcinoma (PDAC). A more detailed understanding of tertiary lymphoid structure “kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immuno-oncology,” Francesca Delvecchio of Queen Mary University of London and colleagues wrote in Cellular and Molecular Gastroenterology and Hepatology.

While the immune system can play a role in combating cancer, a dense stroma surrounds pancreatic cancer centers, often blocking the immune cells’ ability to access the tumor. As shown by Young and colleagues, this leads immunotherapies to have very little success in the management of pancreatic cancer, despite the efficacy of these therapies in other types of cancer.

In a proportion of patients with pancreatic cancer, clusters of immune cells known as tertiary lymphoid structures can assemble within the stroma. These structures are associated with improved survival in PDAC. In the study, Mr. Delvecchio and colleagues sought to further elucidate the role of tertiary lymphoid structures in PDAC, particularly the structures’ antitumor activity.

The investigators analyzed donated tissue samples from patients to identify the presence of the structures within chemotherapy-naive human pancreatic cancer. Tertiary lymphoid structures were defined by the presence of tissue zones that were rich in T cells, B cells, and dendritic cells. Staining techniques were used to visualize the various cell types in the samples, revealing tertiary lymphoid structures in approximately 30% of tissue microarrays and 42% of the full section.

Multicolor immunofluorescence and immunohistochemistry were also used to characterize tertiary lymphoid structures in murine models of pancreatic cancer. Additionally, the investigators developed the orthotopic murine model to assess the development of the structures and the effect of a combined chemotherapy and immunotherapy regimen on tumor growth. While tertiary lymphoid structures were not initially present in the preclinical murine model, B cells and T cells subsequently infiltrated into the tumor site following injection of lymphoid chemokines. These cells consequently assembled into the tertiary lymphoid structures.

In addition, the researchers combined chemotherapy gemcitabine with the intratumoral lymphoid chemokine and injected this combination treatment into orthotopic tumors. Following injection, the researchers observed “altered immune cell infiltration,” which facilitated the induction of tertiary lymphoid structures and potentiated antitumor activity of the chemotherapy. As a result, there was a significant reduction in the tumors, an effect the researchers did not find following the use of either treatment alone.

According to the investigators, the antitumor activity observed following induction of the tertiary lymphoid structures within the cancer is associated with B cell–mediated activation of dendritic cells, a requirement for the initiation of the immune response.

Based on the findings, the researchers concluded that the combination of chemotherapy and lymphoid chemokines could be a viable strategy for promoting an antitumor immune response in pancreatic cancer. In turn, the researchers suggest this strategy may result in better clinical outcomes for patients with the disease. Additionally, the researchers wrote that mature tertiary lymphoid structures in PDAC prior to an immune treatment could “be used as a biomarker to define inclusion criteria of patients in immunotherapy protocols, with the aim to boost the ongoing antitumor immune response.”

Given that the study relied on a mouse model, the findings may currently lack generalizability across humans. In the context of PDAC, the researchers wrote that further investigation and understanding of the formation of tertiary lymphoid structures may support the development of tailored treatments, including those that take advantage of the body’s immune system, to combat cancer and improve patient outcomes.

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

In a new study, researchers stimulated immune cells to assemble into tertiary lymphoid structures that improved the efficacy of chemotherapy in a preclinical model of pancreatic cancer.

Overall, the evidence generated by the study supports the notion that induction of tertiary lymphoid structures may potentiate chemotherapy’s antitumor activity, at least in a murine model of pancreatic ductal adenocarcinoma (PDAC). A more detailed understanding of tertiary lymphoid structure “kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immuno-oncology,” Francesca Delvecchio of Queen Mary University of London and colleagues wrote in Cellular and Molecular Gastroenterology and Hepatology.

While the immune system can play a role in combating cancer, a dense stroma surrounds pancreatic cancer centers, often blocking the immune cells’ ability to access the tumor. As shown by Young and colleagues, this leads immunotherapies to have very little success in the management of pancreatic cancer, despite the efficacy of these therapies in other types of cancer.

In a proportion of patients with pancreatic cancer, clusters of immune cells known as tertiary lymphoid structures can assemble within the stroma. These structures are associated with improved survival in PDAC. In the study, Mr. Delvecchio and colleagues sought to further elucidate the role of tertiary lymphoid structures in PDAC, particularly the structures’ antitumor activity.

The investigators analyzed donated tissue samples from patients to identify the presence of the structures within chemotherapy-naive human pancreatic cancer. Tertiary lymphoid structures were defined by the presence of tissue zones that were rich in T cells, B cells, and dendritic cells. Staining techniques were used to visualize the various cell types in the samples, revealing tertiary lymphoid structures in approximately 30% of tissue microarrays and 42% of the full section.

Multicolor immunofluorescence and immunohistochemistry were also used to characterize tertiary lymphoid structures in murine models of pancreatic cancer. Additionally, the investigators developed the orthotopic murine model to assess the development of the structures and the effect of a combined chemotherapy and immunotherapy regimen on tumor growth. While tertiary lymphoid structures were not initially present in the preclinical murine model, B cells and T cells subsequently infiltrated into the tumor site following injection of lymphoid chemokines. These cells consequently assembled into the tertiary lymphoid structures.

In addition, the researchers combined chemotherapy gemcitabine with the intratumoral lymphoid chemokine and injected this combination treatment into orthotopic tumors. Following injection, the researchers observed “altered immune cell infiltration,” which facilitated the induction of tertiary lymphoid structures and potentiated antitumor activity of the chemotherapy. As a result, there was a significant reduction in the tumors, an effect the researchers did not find following the use of either treatment alone.

According to the investigators, the antitumor activity observed following induction of the tertiary lymphoid structures within the cancer is associated with B cell–mediated activation of dendritic cells, a requirement for the initiation of the immune response.

Based on the findings, the researchers concluded that the combination of chemotherapy and lymphoid chemokines could be a viable strategy for promoting an antitumor immune response in pancreatic cancer. In turn, the researchers suggest this strategy may result in better clinical outcomes for patients with the disease. Additionally, the researchers wrote that mature tertiary lymphoid structures in PDAC prior to an immune treatment could “be used as a biomarker to define inclusion criteria of patients in immunotherapy protocols, with the aim to boost the ongoing antitumor immune response.”

Given that the study relied on a mouse model, the findings may currently lack generalizability across humans. In the context of PDAC, the researchers wrote that further investigation and understanding of the formation of tertiary lymphoid structures may support the development of tailored treatments, including those that take advantage of the body’s immune system, to combat cancer and improve patient outcomes.

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

In a new study, researchers stimulated immune cells to assemble into tertiary lymphoid structures that improved the efficacy of chemotherapy in a preclinical model of pancreatic cancer.

Overall, the evidence generated by the study supports the notion that induction of tertiary lymphoid structures may potentiate chemotherapy’s antitumor activity, at least in a murine model of pancreatic ductal adenocarcinoma (PDAC). A more detailed understanding of tertiary lymphoid structure “kinetics and their induction, owing to multiple host and tumor factors, may help design personalized therapies harnessing the potential of immuno-oncology,” Francesca Delvecchio of Queen Mary University of London and colleagues wrote in Cellular and Molecular Gastroenterology and Hepatology.

While the immune system can play a role in combating cancer, a dense stroma surrounds pancreatic cancer centers, often blocking the immune cells’ ability to access the tumor. As shown by Young and colleagues, this leads immunotherapies to have very little success in the management of pancreatic cancer, despite the efficacy of these therapies in other types of cancer.

In a proportion of patients with pancreatic cancer, clusters of immune cells known as tertiary lymphoid structures can assemble within the stroma. These structures are associated with improved survival in PDAC. In the study, Mr. Delvecchio and colleagues sought to further elucidate the role of tertiary lymphoid structures in PDAC, particularly the structures’ antitumor activity.

The investigators analyzed donated tissue samples from patients to identify the presence of the structures within chemotherapy-naive human pancreatic cancer. Tertiary lymphoid structures were defined by the presence of tissue zones that were rich in T cells, B cells, and dendritic cells. Staining techniques were used to visualize the various cell types in the samples, revealing tertiary lymphoid structures in approximately 30% of tissue microarrays and 42% of the full section.

Multicolor immunofluorescence and immunohistochemistry were also used to characterize tertiary lymphoid structures in murine models of pancreatic cancer. Additionally, the investigators developed the orthotopic murine model to assess the development of the structures and the effect of a combined chemotherapy and immunotherapy regimen on tumor growth. While tertiary lymphoid structures were not initially present in the preclinical murine model, B cells and T cells subsequently infiltrated into the tumor site following injection of lymphoid chemokines. These cells consequently assembled into the tertiary lymphoid structures.

In addition, the researchers combined chemotherapy gemcitabine with the intratumoral lymphoid chemokine and injected this combination treatment into orthotopic tumors. Following injection, the researchers observed “altered immune cell infiltration,” which facilitated the induction of tertiary lymphoid structures and potentiated antitumor activity of the chemotherapy. As a result, there was a significant reduction in the tumors, an effect the researchers did not find following the use of either treatment alone.

According to the investigators, the antitumor activity observed following induction of the tertiary lymphoid structures within the cancer is associated with B cell–mediated activation of dendritic cells, a requirement for the initiation of the immune response.

Based on the findings, the researchers concluded that the combination of chemotherapy and lymphoid chemokines could be a viable strategy for promoting an antitumor immune response in pancreatic cancer. In turn, the researchers suggest this strategy may result in better clinical outcomes for patients with the disease. Additionally, the researchers wrote that mature tertiary lymphoid structures in PDAC prior to an immune treatment could “be used as a biomarker to define inclusion criteria of patients in immunotherapy protocols, with the aim to boost the ongoing antitumor immune response.”

Given that the study relied on a mouse model, the findings may currently lack generalizability across humans. In the context of PDAC, the researchers wrote that further investigation and understanding of the formation of tertiary lymphoid structures may support the development of tailored treatments, including those that take advantage of the body’s immune system, to combat cancer and improve patient outcomes.

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

Years ago, when rheumatologist Leonard Sigal, MD, was undertaking research on Lyme disease and treating patients with the condition at the Robert Wood Johnson Medical School, New Brunswick, N.J., a regular stream of abuse and threats became the usual background noise of his work. He didn’t get used to it, but it never stopped.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

“I was accused of incredibly heinous crimes,” Dr. Sigal said in an interview. “I was accused of lying, cheating, of doing things to make money that were against the public interest and against the interest of patients in general.”

It’s an experience many doctors who treat Lyme disease have endured, so much so that some infectious disease doctors aren’t comfortable treating patients with Lyme disease, according to Timothy Flanigan, MD, a professor of infectious disease at Brown University, Providence, R.I.

But it wasn’t until Dr. Sigal left academia in 2003 that he realized the toll all that background abuse had been taking on him.

“It was a breath of fresh air,” he said. “I didn’t have to go into clinic and argue with people. I didn’t have to read articles in the newspaper that made no sense whatsoever. I didn’t have to hear through second and third parties how such and such was saying horrible things about me. I didn’t have to fight anymore. When I was in industry and working on stuff that had nothing to do with Lyme disease, I realized what a relief it was not to have that burden.”

So the last thing Dr. Sigal expected after all these years was to find himself named in a lawsuit alleging that he was part of a conspiracy to deny patients of what they claimed was appropriate treatment for Lyme disease. Yet, that’s exactly what happened in November 2017, when a group of 24 patients with Lyme disease, led by Texas resident Lisa Torrey, filed a lawsuit against the Infectious Diseases Society of America, eight insurance companies, and 7 of the doctors involved in producing the IDSA guidelines on Lyme disease diagnosis and management. Dr. Sigal himself had not even participated in writing the guidelines. He simply reviewed them, made a few grammatical suggestions, and said they looked good. Over the next 4 years, however, he and his fellow defendants rode an emotional roller coaster of seemingly endless motions, amendments, and other legal developments, waiting to find out whether they would owe millions of dollars for simply summarizing – or just reviewing – the available medical literature on Lyme disease.

“There were times I was on the verge of real anger. I was frustrated. There were times I was frightened, and, occasionally, I would just think of it as being silly. But when I thought of it as being silly, I had to remember I was being sued in Texas, because who knows what’s going to happen,” Dr. Sigal said. “It’s not as though I was being sued in a jurisdiction where anybody knew about Lyme disease. There are examples of physicians who are convicted of doing things they didn’t do because they were sued in the wrong jurisdiction.”

Several individuals who spoke with this news organization on condition of anonymity said that the district court where the suit was filed is notorious for being especially friendly to plaintiffs. But in legal rulings issued on Sept. 1 and Sept. 20, 2021, a federal judge in Texas dismissed all the patient group’s claims. The plaintiffs filed an appeal on Oct. 19. It’s unclear whether that has any reasonable chance of success.

“One of the things this court case does is validate the fact that our [guidelines] process is a legitimate process and there isn’t outside influence from insurance companies or pharma firms,” Daniel McQuillen, MD, president of IDSA, said in an interview. “We don’t really want anything other than to be vindicated, which we were, 100%.”

But that vindication came with a cost, both emotional and financial. Although IDSA’s insurance covered many of its legal costs, “it’s not a trivial expense,” Dr. McQuillen said. “We’re left with a baseless lawsuit with no facts that went on for 4 years, and our [medical] society basically bore all that expense, which isn’t really particularly fair.”
 

‘Preposterous’ accusations

The lawsuit alleged that the IDSA, the seven named physicians, and the insurance companies had “engaged in a decades-long conspiracy to deny the existence and prevent treatment of chronic Lyme disease.” The patient group claimed that the doctors knew that many patients with Lyme disease do not respond to short-term antibiotic treatment and instead need “long-term antibiotic treatment until the symptoms are resolved,” an assertion not supported by the scientific evidence.

What many patients call “chronic Lyme disease” is termed posttreatment Lyme disease syndrome (PTDLS), a constellation of symptoms that include pain, fatigue, and cognitive difficulties that some people experience after a 2- to 4-week course of antibiotics for Lyme disease. It took years of patient advocacy before the Centers for Disease Control and Prevention recognized PTLDS as a condition, but awareness of it has been increasing, said Dr. Flanigan, who was not involved in the lawsuit but treats patients with Lyme disease and PTLDS.

“Long haulers and sequelae of COVID have really opened the eyes of many practitioners that these long-term inflammatory conditions are real and very challenging to treat, and we need to work with patients to help them improve their health,” Dr. Flanigan said. “It’s a sad commentary on our society that the difficulty in treating patients with posttreatment Lyme disease syndrome, or what is commonly referred to by patients as chronic Lyme, ends up in a lawsuit in court.” He said he’s glad the lawsuit was dismissed but added that “there’s a crying need for additional high-quality, evidence-based research to help patients who are suffering from posttreatment Lyme disease syndrome.”

Patients fought for broader recognition of their condition, and some of them organized. They came up with their own ideas of what was causing their symptoms to persist. One that especially took hold was that infection from Borrelia burgdorferi, the bacteria that causes Lyme disease, persists after initial antibiotic treatment, causing so-called chronic Lyme disease. The cause of PTLDS is still under investigation, and the evidence does not support the idea of a persistent bacterial infection. Multiple studies from the National Institutes of Health have shown that long-term use of antibiotics does not benefit patients who continue to experience symptoms after initial treatment. Several studies have shown that severe adverse effects can result from extended intravenous antibiotic treatment, including death.

Nevertheless, the plaintiffs in the lawsuit argued that the insurance companies “enlisted the help of doctors who were researching Lyme disease – the IDSA panelists – and paid them large fees to develop arbitrary guidelines for testing Lyme disease,” thereby enabling the insurance companies to deny coverage for long-term antibiotic treatment to patients.

“The assertions were just preposterous,” Dr. McQuillen said.

In addition to the conspiracy charge, the plaintiffs brought additional accusations to the lawsuit over the years, including racketeering and claims that the guidelines contain false representations regarding Lyme disease testing and treatment. The plaintiffs claimed that the guidelines didn’t acknowledge that treatment can fail and included false information about how to test for Lyme disease. In reality, however, the guidelines do acknowledge that not all patients respond to the recommended 2- to 4-week course of antibiotics and that some diagnoses should be made clinically rather than on the basis of testing.

Regardless, guidelines are not stipulations. They’re a summation of the medical and scientific findings on Lyme disease based on careful review of hundreds of studies.

“They make really clear that adherence to the guidelines [is] voluntary. They aren’t a standard of care from which deviation of care is a problem,” Dr. McQuillen said. “You take those guidelines and apply it to the patient in front of you, and you see what fits best for that patient, because not every patient is going to fit into guidelines.”

Further, the authors said that IDSA vets their recommendations for any potential conflicts of interest in accordance with the organization’s guidelines practices.

“The point of the guidelines is to have people on the committee who don’t care what the guidelines are as long as we have good patient care,” Dr. McQuillen said.

Choosing to fight

Malpractice insurance does not cover this kind of lawsuit, because the doctors named in it did not personally treat any of the patients who filed it. Thus, the doctors were at risk of losing thousands, or millions, of dollars in legal fees, even if they ultimately prevail. Several of the physicians’ academic and health care institutions stepped in to cover some fees, and IDSA covered the rest in a joint defense.

“The IDSA provided me a lawyer at no cost to me, and I felt protected by them,” Dr. Sigal said. “They took care of me and made sure I was safe, and I am grateful to them for that.”

Dr. McQuillen said the expenses exceeded what the organization’s umbrella insurance covered. The physicians had invested their time and effort into the guidelines without any financial compensation.

“They’ve basically put a lot of sweat equity into producing guidelines” that follow the organization’s practices and ethics, Dr. McQuillen said. “To leave them out on an island by themselves is just not the right thing to do. We wouldn’t do that for any of our members who did something on behalf of our society.”

IDSA could have chosen to settle the lawsuit, as the insurance companies did.

“None of us on the board felt that was the right thing to do, because we believe in the process, and the science is right, and you shouldn’t be able to try to change that by having a lawsuit that’s baseless,” Dr. McQuillen said.

Several of the doctors named in the suit spoke with this news organization off the record about the exhaustion, frustration, and general suffering the suit has caused them over the past several years, including ongoing harassment that targeted their families and often became quite personal. But none expressed any wish that IDSA had chosen the faster, cheaper, easier route of settling.

“I love the organization for having done this rather than caving and paying,” Dr. Sigal said. “They showed real moral character, real integrity in fighting this suit, because they had done nothing wrong.”

Fighting the suit was about more than standing by the science, though. It’s essential to ensure physicians continue to conduct research and write clinical guidelines, even about ambiguous or controversial topics, said Raymond J. Dattwyler, MD, a professor of microbiology, immunology, and medicine at New York Medical College, Valhalla, who wrote the treatment part of the guidelines and was named in the suit.

“I was really surprised that someone would sue for scientific guidelines, because guidelines are common across medicine, and they’re just a roadmap to help practicing physicians understand how to handle evaluation or treatment of any number of particular problems,” Dr. Dattwyler said in an interview. But he wasn’t surprised that IDSA chose to fight the accusations, “because the principle involved is so compelling. It’s really standing up for all medical societies, and it’s very important to have guidelines. For the health and welfare of the American public, you need to have good information readily available to the practicing physicians.”

If the patient group had won in a settlement, it could potentially have led to less rigorous guidelines from other medical organizations, which would have had an adverse effect on public health, Dr. Dattwyler said. Such a chilling effect could reverberate far beyond the management of Lyme disease.

“One of the problems with our legal system is anybody can sue anybody, but it costs so much to defend yourself,” Dr. Dattwyler said. “This lawsuit costs millions, so that’s chilling. That’s going to inhibit guidelines, and it’s not only guidelines for infectious disease but it’s guidelines for cancer, guidelines for allergic diseases, guidelines for any number of things.”

To an extent, the threats and harassment that patient groups have directed toward different doctors have already had a chilling effect.

“For the people who gave of their time in good faith to generate these guidelines to get harassed everywhere, all the time, sometimes at home, sometimes at their place of work, it’s just unfair,” Dr. McQuillen said. “It also might discourage people from working in research to try to figure out better diagnostics or get a vaccine that actually works. Even if you really find it incredibly interesting, if laying over you is the threat that someone is going to sue you baselessly, and you’re going to have to put the time and effort into defending that, not to mention the money, I can’t see how that would be considered a positive that would encourage you to do it. In some ways, attacking people that are trying to help may drive them away from trying to help.

“At the same time, professional disagreements among practitioners – including a small minority who do treat patients with lengthy courses of antibiotics – can ultimately harm patient care, Dr. Flanigan said.

“There’s a lot of energy being expended fighting among different care providers, and often the individual needs of the patients seem to be not addressed,” Dr. Flanigan said. “The discord between different approaches often seems more important than spending time with the individual patient and trying to find a tailored approach to treatment which can benefit the patient best.”

At the same time, Dr. Sigal said he believes most of the clinicians who use non–evidence-based treatments for their patients do so because they genuinely believe it’s the right thing to do.

“I think they’re motivated by the same concerns that I have, and that is, I need to do what’s best for my patient,” Dr. Sigal said. Ultimately, the evidence should lead the way. “The only arbiter we possibly have in deciding these things is the medical scientific literature,” he added, “and if you can’t subscribe to that, then this way lies madness.”

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

Years ago, when rheumatologist Leonard Sigal, MD, was undertaking research on Lyme disease and treating patients with the condition at the Robert Wood Johnson Medical School, New Brunswick, N.J., a regular stream of abuse and threats became the usual background noise of his work. He didn’t get used to it, but it never stopped.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

“I was accused of incredibly heinous crimes,” Dr. Sigal said in an interview. “I was accused of lying, cheating, of doing things to make money that were against the public interest and against the interest of patients in general.”

It’s an experience many doctors who treat Lyme disease have endured, so much so that some infectious disease doctors aren’t comfortable treating patients with Lyme disease, according to Timothy Flanigan, MD, a professor of infectious disease at Brown University, Providence, R.I.

But it wasn’t until Dr. Sigal left academia in 2003 that he realized the toll all that background abuse had been taking on him.

“It was a breath of fresh air,” he said. “I didn’t have to go into clinic and argue with people. I didn’t have to read articles in the newspaper that made no sense whatsoever. I didn’t have to hear through second and third parties how such and such was saying horrible things about me. I didn’t have to fight anymore. When I was in industry and working on stuff that had nothing to do with Lyme disease, I realized what a relief it was not to have that burden.”

So the last thing Dr. Sigal expected after all these years was to find himself named in a lawsuit alleging that he was part of a conspiracy to deny patients of what they claimed was appropriate treatment for Lyme disease. Yet, that’s exactly what happened in November 2017, when a group of 24 patients with Lyme disease, led by Texas resident Lisa Torrey, filed a lawsuit against the Infectious Diseases Society of America, eight insurance companies, and 7 of the doctors involved in producing the IDSA guidelines on Lyme disease diagnosis and management. Dr. Sigal himself had not even participated in writing the guidelines. He simply reviewed them, made a few grammatical suggestions, and said they looked good. Over the next 4 years, however, he and his fellow defendants rode an emotional roller coaster of seemingly endless motions, amendments, and other legal developments, waiting to find out whether they would owe millions of dollars for simply summarizing – or just reviewing – the available medical literature on Lyme disease.

“There were times I was on the verge of real anger. I was frustrated. There were times I was frightened, and, occasionally, I would just think of it as being silly. But when I thought of it as being silly, I had to remember I was being sued in Texas, because who knows what’s going to happen,” Dr. Sigal said. “It’s not as though I was being sued in a jurisdiction where anybody knew about Lyme disease. There are examples of physicians who are convicted of doing things they didn’t do because they were sued in the wrong jurisdiction.”

Several individuals who spoke with this news organization on condition of anonymity said that the district court where the suit was filed is notorious for being especially friendly to plaintiffs. But in legal rulings issued on Sept. 1 and Sept. 20, 2021, a federal judge in Texas dismissed all the patient group’s claims. The plaintiffs filed an appeal on Oct. 19. It’s unclear whether that has any reasonable chance of success.

“One of the things this court case does is validate the fact that our [guidelines] process is a legitimate process and there isn’t outside influence from insurance companies or pharma firms,” Daniel McQuillen, MD, president of IDSA, said in an interview. “We don’t really want anything other than to be vindicated, which we were, 100%.”

But that vindication came with a cost, both emotional and financial. Although IDSA’s insurance covered many of its legal costs, “it’s not a trivial expense,” Dr. McQuillen said. “We’re left with a baseless lawsuit with no facts that went on for 4 years, and our [medical] society basically bore all that expense, which isn’t really particularly fair.”
 

‘Preposterous’ accusations

The lawsuit alleged that the IDSA, the seven named physicians, and the insurance companies had “engaged in a decades-long conspiracy to deny the existence and prevent treatment of chronic Lyme disease.” The patient group claimed that the doctors knew that many patients with Lyme disease do not respond to short-term antibiotic treatment and instead need “long-term antibiotic treatment until the symptoms are resolved,” an assertion not supported by the scientific evidence.

What many patients call “chronic Lyme disease” is termed posttreatment Lyme disease syndrome (PTDLS), a constellation of symptoms that include pain, fatigue, and cognitive difficulties that some people experience after a 2- to 4-week course of antibiotics for Lyme disease. It took years of patient advocacy before the Centers for Disease Control and Prevention recognized PTLDS as a condition, but awareness of it has been increasing, said Dr. Flanigan, who was not involved in the lawsuit but treats patients with Lyme disease and PTLDS.

“Long haulers and sequelae of COVID have really opened the eyes of many practitioners that these long-term inflammatory conditions are real and very challenging to treat, and we need to work with patients to help them improve their health,” Dr. Flanigan said. “It’s a sad commentary on our society that the difficulty in treating patients with posttreatment Lyme disease syndrome, or what is commonly referred to by patients as chronic Lyme, ends up in a lawsuit in court.” He said he’s glad the lawsuit was dismissed but added that “there’s a crying need for additional high-quality, evidence-based research to help patients who are suffering from posttreatment Lyme disease syndrome.”

Patients fought for broader recognition of their condition, and some of them organized. They came up with their own ideas of what was causing their symptoms to persist. One that especially took hold was that infection from Borrelia burgdorferi, the bacteria that causes Lyme disease, persists after initial antibiotic treatment, causing so-called chronic Lyme disease. The cause of PTLDS is still under investigation, and the evidence does not support the idea of a persistent bacterial infection. Multiple studies from the National Institutes of Health have shown that long-term use of antibiotics does not benefit patients who continue to experience symptoms after initial treatment. Several studies have shown that severe adverse effects can result from extended intravenous antibiotic treatment, including death.

Nevertheless, the plaintiffs in the lawsuit argued that the insurance companies “enlisted the help of doctors who were researching Lyme disease – the IDSA panelists – and paid them large fees to develop arbitrary guidelines for testing Lyme disease,” thereby enabling the insurance companies to deny coverage for long-term antibiotic treatment to patients.

“The assertions were just preposterous,” Dr. McQuillen said.

In addition to the conspiracy charge, the plaintiffs brought additional accusations to the lawsuit over the years, including racketeering and claims that the guidelines contain false representations regarding Lyme disease testing and treatment. The plaintiffs claimed that the guidelines didn’t acknowledge that treatment can fail and included false information about how to test for Lyme disease. In reality, however, the guidelines do acknowledge that not all patients respond to the recommended 2- to 4-week course of antibiotics and that some diagnoses should be made clinically rather than on the basis of testing.

Regardless, guidelines are not stipulations. They’re a summation of the medical and scientific findings on Lyme disease based on careful review of hundreds of studies.

“They make really clear that adherence to the guidelines [is] voluntary. They aren’t a standard of care from which deviation of care is a problem,” Dr. McQuillen said. “You take those guidelines and apply it to the patient in front of you, and you see what fits best for that patient, because not every patient is going to fit into guidelines.”

Further, the authors said that IDSA vets their recommendations for any potential conflicts of interest in accordance with the organization’s guidelines practices.

“The point of the guidelines is to have people on the committee who don’t care what the guidelines are as long as we have good patient care,” Dr. McQuillen said.

Choosing to fight

Malpractice insurance does not cover this kind of lawsuit, because the doctors named in it did not personally treat any of the patients who filed it. Thus, the doctors were at risk of losing thousands, or millions, of dollars in legal fees, even if they ultimately prevail. Several of the physicians’ academic and health care institutions stepped in to cover some fees, and IDSA covered the rest in a joint defense.

“The IDSA provided me a lawyer at no cost to me, and I felt protected by them,” Dr. Sigal said. “They took care of me and made sure I was safe, and I am grateful to them for that.”

Dr. McQuillen said the expenses exceeded what the organization’s umbrella insurance covered. The physicians had invested their time and effort into the guidelines without any financial compensation.

“They’ve basically put a lot of sweat equity into producing guidelines” that follow the organization’s practices and ethics, Dr. McQuillen said. “To leave them out on an island by themselves is just not the right thing to do. We wouldn’t do that for any of our members who did something on behalf of our society.”

IDSA could have chosen to settle the lawsuit, as the insurance companies did.

“None of us on the board felt that was the right thing to do, because we believe in the process, and the science is right, and you shouldn’t be able to try to change that by having a lawsuit that’s baseless,” Dr. McQuillen said.

Several of the doctors named in the suit spoke with this news organization off the record about the exhaustion, frustration, and general suffering the suit has caused them over the past several years, including ongoing harassment that targeted their families and often became quite personal. But none expressed any wish that IDSA had chosen the faster, cheaper, easier route of settling.

“I love the organization for having done this rather than caving and paying,” Dr. Sigal said. “They showed real moral character, real integrity in fighting this suit, because they had done nothing wrong.”

Fighting the suit was about more than standing by the science, though. It’s essential to ensure physicians continue to conduct research and write clinical guidelines, even about ambiguous or controversial topics, said Raymond J. Dattwyler, MD, a professor of microbiology, immunology, and medicine at New York Medical College, Valhalla, who wrote the treatment part of the guidelines and was named in the suit.

“I was really surprised that someone would sue for scientific guidelines, because guidelines are common across medicine, and they’re just a roadmap to help practicing physicians understand how to handle evaluation or treatment of any number of particular problems,” Dr. Dattwyler said in an interview. But he wasn’t surprised that IDSA chose to fight the accusations, “because the principle involved is so compelling. It’s really standing up for all medical societies, and it’s very important to have guidelines. For the health and welfare of the American public, you need to have good information readily available to the practicing physicians.”

If the patient group had won in a settlement, it could potentially have led to less rigorous guidelines from other medical organizations, which would have had an adverse effect on public health, Dr. Dattwyler said. Such a chilling effect could reverberate far beyond the management of Lyme disease.

“One of the problems with our legal system is anybody can sue anybody, but it costs so much to defend yourself,” Dr. Dattwyler said. “This lawsuit costs millions, so that’s chilling. That’s going to inhibit guidelines, and it’s not only guidelines for infectious disease but it’s guidelines for cancer, guidelines for allergic diseases, guidelines for any number of things.”

To an extent, the threats and harassment that patient groups have directed toward different doctors have already had a chilling effect.

“For the people who gave of their time in good faith to generate these guidelines to get harassed everywhere, all the time, sometimes at home, sometimes at their place of work, it’s just unfair,” Dr. McQuillen said. “It also might discourage people from working in research to try to figure out better diagnostics or get a vaccine that actually works. Even if you really find it incredibly interesting, if laying over you is the threat that someone is going to sue you baselessly, and you’re going to have to put the time and effort into defending that, not to mention the money, I can’t see how that would be considered a positive that would encourage you to do it. In some ways, attacking people that are trying to help may drive them away from trying to help.

“At the same time, professional disagreements among practitioners – including a small minority who do treat patients with lengthy courses of antibiotics – can ultimately harm patient care, Dr. Flanigan said.

“There’s a lot of energy being expended fighting among different care providers, and often the individual needs of the patients seem to be not addressed,” Dr. Flanigan said. “The discord between different approaches often seems more important than spending time with the individual patient and trying to find a tailored approach to treatment which can benefit the patient best.”

At the same time, Dr. Sigal said he believes most of the clinicians who use non–evidence-based treatments for their patients do so because they genuinely believe it’s the right thing to do.

“I think they’re motivated by the same concerns that I have, and that is, I need to do what’s best for my patient,” Dr. Sigal said. Ultimately, the evidence should lead the way. “The only arbiter we possibly have in deciding these things is the medical scientific literature,” he added, “and if you can’t subscribe to that, then this way lies madness.”

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

Years ago, when rheumatologist Leonard Sigal, MD, was undertaking research on Lyme disease and treating patients with the condition at the Robert Wood Johnson Medical School, New Brunswick, N.J., a regular stream of abuse and threats became the usual background noise of his work. He didn’t get used to it, but it never stopped.

CDC/ Dr. Amanda Loftis, Dr. William Nicholson, Dr. Will Reeves, Dr. Chris Paddock

“I was accused of incredibly heinous crimes,” Dr. Sigal said in an interview. “I was accused of lying, cheating, of doing things to make money that were against the public interest and against the interest of patients in general.”

It’s an experience many doctors who treat Lyme disease have endured, so much so that some infectious disease doctors aren’t comfortable treating patients with Lyme disease, according to Timothy Flanigan, MD, a professor of infectious disease at Brown University, Providence, R.I.

But it wasn’t until Dr. Sigal left academia in 2003 that he realized the toll all that background abuse had been taking on him.

“It was a breath of fresh air,” he said. “I didn’t have to go into clinic and argue with people. I didn’t have to read articles in the newspaper that made no sense whatsoever. I didn’t have to hear through second and third parties how such and such was saying horrible things about me. I didn’t have to fight anymore. When I was in industry and working on stuff that had nothing to do with Lyme disease, I realized what a relief it was not to have that burden.”

So the last thing Dr. Sigal expected after all these years was to find himself named in a lawsuit alleging that he was part of a conspiracy to deny patients of what they claimed was appropriate treatment for Lyme disease. Yet, that’s exactly what happened in November 2017, when a group of 24 patients with Lyme disease, led by Texas resident Lisa Torrey, filed a lawsuit against the Infectious Diseases Society of America, eight insurance companies, and 7 of the doctors involved in producing the IDSA guidelines on Lyme disease diagnosis and management. Dr. Sigal himself had not even participated in writing the guidelines. He simply reviewed them, made a few grammatical suggestions, and said they looked good. Over the next 4 years, however, he and his fellow defendants rode an emotional roller coaster of seemingly endless motions, amendments, and other legal developments, waiting to find out whether they would owe millions of dollars for simply summarizing – or just reviewing – the available medical literature on Lyme disease.

“There were times I was on the verge of real anger. I was frustrated. There were times I was frightened, and, occasionally, I would just think of it as being silly. But when I thought of it as being silly, I had to remember I was being sued in Texas, because who knows what’s going to happen,” Dr. Sigal said. “It’s not as though I was being sued in a jurisdiction where anybody knew about Lyme disease. There are examples of physicians who are convicted of doing things they didn’t do because they were sued in the wrong jurisdiction.”

Several individuals who spoke with this news organization on condition of anonymity said that the district court where the suit was filed is notorious for being especially friendly to plaintiffs. But in legal rulings issued on Sept. 1 and Sept. 20, 2021, a federal judge in Texas dismissed all the patient group’s claims. The plaintiffs filed an appeal on Oct. 19. It’s unclear whether that has any reasonable chance of success.

“One of the things this court case does is validate the fact that our [guidelines] process is a legitimate process and there isn’t outside influence from insurance companies or pharma firms,” Daniel McQuillen, MD, president of IDSA, said in an interview. “We don’t really want anything other than to be vindicated, which we were, 100%.”

But that vindication came with a cost, both emotional and financial. Although IDSA’s insurance covered many of its legal costs, “it’s not a trivial expense,” Dr. McQuillen said. “We’re left with a baseless lawsuit with no facts that went on for 4 years, and our [medical] society basically bore all that expense, which isn’t really particularly fair.”
 

‘Preposterous’ accusations

The lawsuit alleged that the IDSA, the seven named physicians, and the insurance companies had “engaged in a decades-long conspiracy to deny the existence and prevent treatment of chronic Lyme disease.” The patient group claimed that the doctors knew that many patients with Lyme disease do not respond to short-term antibiotic treatment and instead need “long-term antibiotic treatment until the symptoms are resolved,” an assertion not supported by the scientific evidence.

What many patients call “chronic Lyme disease” is termed posttreatment Lyme disease syndrome (PTDLS), a constellation of symptoms that include pain, fatigue, and cognitive difficulties that some people experience after a 2- to 4-week course of antibiotics for Lyme disease. It took years of patient advocacy before the Centers for Disease Control and Prevention recognized PTLDS as a condition, but awareness of it has been increasing, said Dr. Flanigan, who was not involved in the lawsuit but treats patients with Lyme disease and PTLDS.

“Long haulers and sequelae of COVID have really opened the eyes of many practitioners that these long-term inflammatory conditions are real and very challenging to treat, and we need to work with patients to help them improve their health,” Dr. Flanigan said. “It’s a sad commentary on our society that the difficulty in treating patients with posttreatment Lyme disease syndrome, or what is commonly referred to by patients as chronic Lyme, ends up in a lawsuit in court.” He said he’s glad the lawsuit was dismissed but added that “there’s a crying need for additional high-quality, evidence-based research to help patients who are suffering from posttreatment Lyme disease syndrome.”

Patients fought for broader recognition of their condition, and some of them organized. They came up with their own ideas of what was causing their symptoms to persist. One that especially took hold was that infection from Borrelia burgdorferi, the bacteria that causes Lyme disease, persists after initial antibiotic treatment, causing so-called chronic Lyme disease. The cause of PTLDS is still under investigation, and the evidence does not support the idea of a persistent bacterial infection. Multiple studies from the National Institutes of Health have shown that long-term use of antibiotics does not benefit patients who continue to experience symptoms after initial treatment. Several studies have shown that severe adverse effects can result from extended intravenous antibiotic treatment, including death.

Nevertheless, the plaintiffs in the lawsuit argued that the insurance companies “enlisted the help of doctors who were researching Lyme disease – the IDSA panelists – and paid them large fees to develop arbitrary guidelines for testing Lyme disease,” thereby enabling the insurance companies to deny coverage for long-term antibiotic treatment to patients.

“The assertions were just preposterous,” Dr. McQuillen said.

In addition to the conspiracy charge, the plaintiffs brought additional accusations to the lawsuit over the years, including racketeering and claims that the guidelines contain false representations regarding Lyme disease testing and treatment. The plaintiffs claimed that the guidelines didn’t acknowledge that treatment can fail and included false information about how to test for Lyme disease. In reality, however, the guidelines do acknowledge that not all patients respond to the recommended 2- to 4-week course of antibiotics and that some diagnoses should be made clinically rather than on the basis of testing.

Regardless, guidelines are not stipulations. They’re a summation of the medical and scientific findings on Lyme disease based on careful review of hundreds of studies.

“They make really clear that adherence to the guidelines [is] voluntary. They aren’t a standard of care from which deviation of care is a problem,” Dr. McQuillen said. “You take those guidelines and apply it to the patient in front of you, and you see what fits best for that patient, because not every patient is going to fit into guidelines.”

Further, the authors said that IDSA vets their recommendations for any potential conflicts of interest in accordance with the organization’s guidelines practices.

“The point of the guidelines is to have people on the committee who don’t care what the guidelines are as long as we have good patient care,” Dr. McQuillen said.

Choosing to fight

Malpractice insurance does not cover this kind of lawsuit, because the doctors named in it did not personally treat any of the patients who filed it. Thus, the doctors were at risk of losing thousands, or millions, of dollars in legal fees, even if they ultimately prevail. Several of the physicians’ academic and health care institutions stepped in to cover some fees, and IDSA covered the rest in a joint defense.

“The IDSA provided me a lawyer at no cost to me, and I felt protected by them,” Dr. Sigal said. “They took care of me and made sure I was safe, and I am grateful to them for that.”

Dr. McQuillen said the expenses exceeded what the organization’s umbrella insurance covered. The physicians had invested their time and effort into the guidelines without any financial compensation.

“They’ve basically put a lot of sweat equity into producing guidelines” that follow the organization’s practices and ethics, Dr. McQuillen said. “To leave them out on an island by themselves is just not the right thing to do. We wouldn’t do that for any of our members who did something on behalf of our society.”

IDSA could have chosen to settle the lawsuit, as the insurance companies did.

“None of us on the board felt that was the right thing to do, because we believe in the process, and the science is right, and you shouldn’t be able to try to change that by having a lawsuit that’s baseless,” Dr. McQuillen said.

Several of the doctors named in the suit spoke with this news organization off the record about the exhaustion, frustration, and general suffering the suit has caused them over the past several years, including ongoing harassment that targeted their families and often became quite personal. But none expressed any wish that IDSA had chosen the faster, cheaper, easier route of settling.

“I love the organization for having done this rather than caving and paying,” Dr. Sigal said. “They showed real moral character, real integrity in fighting this suit, because they had done nothing wrong.”

Fighting the suit was about more than standing by the science, though. It’s essential to ensure physicians continue to conduct research and write clinical guidelines, even about ambiguous or controversial topics, said Raymond J. Dattwyler, MD, a professor of microbiology, immunology, and medicine at New York Medical College, Valhalla, who wrote the treatment part of the guidelines and was named in the suit.

“I was really surprised that someone would sue for scientific guidelines, because guidelines are common across medicine, and they’re just a roadmap to help practicing physicians understand how to handle evaluation or treatment of any number of particular problems,” Dr. Dattwyler said in an interview. But he wasn’t surprised that IDSA chose to fight the accusations, “because the principle involved is so compelling. It’s really standing up for all medical societies, and it’s very important to have guidelines. For the health and welfare of the American public, you need to have good information readily available to the practicing physicians.”

If the patient group had won in a settlement, it could potentially have led to less rigorous guidelines from other medical organizations, which would have had an adverse effect on public health, Dr. Dattwyler said. Such a chilling effect could reverberate far beyond the management of Lyme disease.

“One of the problems with our legal system is anybody can sue anybody, but it costs so much to defend yourself,” Dr. Dattwyler said. “This lawsuit costs millions, so that’s chilling. That’s going to inhibit guidelines, and it’s not only guidelines for infectious disease but it’s guidelines for cancer, guidelines for allergic diseases, guidelines for any number of things.”

To an extent, the threats and harassment that patient groups have directed toward different doctors have already had a chilling effect.

“For the people who gave of their time in good faith to generate these guidelines to get harassed everywhere, all the time, sometimes at home, sometimes at their place of work, it’s just unfair,” Dr. McQuillen said. “It also might discourage people from working in research to try to figure out better diagnostics or get a vaccine that actually works. Even if you really find it incredibly interesting, if laying over you is the threat that someone is going to sue you baselessly, and you’re going to have to put the time and effort into defending that, not to mention the money, I can’t see how that would be considered a positive that would encourage you to do it. In some ways, attacking people that are trying to help may drive them away from trying to help.

“At the same time, professional disagreements among practitioners – including a small minority who do treat patients with lengthy courses of antibiotics – can ultimately harm patient care, Dr. Flanigan said.

“There’s a lot of energy being expended fighting among different care providers, and often the individual needs of the patients seem to be not addressed,” Dr. Flanigan said. “The discord between different approaches often seems more important than spending time with the individual patient and trying to find a tailored approach to treatment which can benefit the patient best.”

At the same time, Dr. Sigal said he believes most of the clinicians who use non–evidence-based treatments for their patients do so because they genuinely believe it’s the right thing to do.

“I think they’re motivated by the same concerns that I have, and that is, I need to do what’s best for my patient,” Dr. Sigal said. Ultimately, the evidence should lead the way. “The only arbiter we possibly have in deciding these things is the medical scientific literature,” he added, “and if you can’t subscribe to that, then this way lies madness.”

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

A noninvasive enhanced liver fibrosis (ELF) blood test identifies patients with nonalcoholic fatty liver disease (NAFLD) who are at increased risk of advanced fibrosis, according to a new study.

According to the study researchers, when combined with the fibrosis-4 (FIB-4) score the ELF test may be a reliable method that can assess for advanced fibrosis in clinical practice.

Despite the utility of identifying advanced fibrosis in the NAFLD population, significant barriers exist to “risk stratifying patients in clinical practice owing to the need for liver biopsy,” wrote study authors Zobair M. Younossi, MD, of the Inova Health System in Falls Church, Va., and colleagues in JAMA Network Open.

“NASH [nonalcoholic steatohepatitis] can only be diagnosed by biopsy and liver pathology yet validated noninvasive tests that accurately diagnose NASH don’t exist,” said Dr. Younossi in an interview. “Developing noninvasive tests to accurately risk stratify patients with significant fibrosis in NASH is highly desirable in clinical practice. A blood test such as ELF can open the opportunity to order this test anywhere in the country.”

The ELF test reflects extracellular matrix metabolism as opposed to tests that assess alterations in hepatic function. The study authors explain that the noninvasive ELF test is a “blood-derived panel of biomarkers consisting of three components: type III procollagen peptide, hyaluronic acid, and tissue inhibitor of metalloproteinase-1.”

To gain a further understanding of the role of ELF in predicting the risk of nonalcoholic steatohepatitis (NASH) in NAFLD, Dr. Younossi and colleagues performed a retrospective, cross-sectional analysis of outpatients within a community-based liver clinic from 2001 in 2020. The study cohort included 829 patients (mean age, 53.1 years) with NAFLD, which was characterized by steatosis greater than 5% without any other liver disease or excessive alcohol use.

In the overall study population, the mean FIB-4 score was 1.34. In the 463 patients with liver biopsy, approximately 24.4% presented with bridging fibrosis or cirrhosis. A total of 79 (17.1%) of the 462 patients with transient elastography data presented with liver stiffness results of 9.6 kPa or greater, which according to the researchers was indicative of advanced fibrosis.

Biopsy determined that those with advanced fibrosis in the study had significantly increased ELF scores versus patients without advanced fibrosis (10.1 vs. 8.6, respectively; P <.001). Moreover, patients with advanced fibrosis had significantly greater liver stiffness as determined by transient elastography (10.0 vs. 9.0; P <.001).

In the NAFLD population, the ELF test demonstrated excellent performance in identifying patients with advanced fibrosis, as reflected by an area under the receiver operating characteristic curve of 0.81 (95% confidence interval, 0.77-0.85) for those whose fibrosis was diagnosed by biopsy as well as 0.79 (95% CI, 0.75-0.82) for fibrosis diagnosed by transient elastography. Similar performances of the ELF score were reported among those with NAFLD who were aged 65 years or older (AUROC, 0.74; 95% CI, 0.58-0.87) or patients who had type 2 diabetes (AUROC, 0.78; 95% CI, 0.71-0.84).

The researchers regarded the combination of an ELF score of 7.2 or greater with a FIB-4 score of 0.74 or greater, as indicative of a negative predictive value of 95.1% (95% CI, 91.8%-98.4%) and a sensitivity of 92.5% (95% CI, 87.4%-97.5%). According to the investigators, these values “can reliably rule out advanced fibrosis.”

Additionally, the combination of an ELF score of 9.8 or greater with a FIB-4 score of 2.9 or greater, was associated with a positive predictive value of 95.0% (95% CI, 85.5%-100%) and a specificity of 99.7% (95% CI, 99.1%-100%), suggesting this combination can conversely “be used to rule in advanced fibrosis,” the researchers wrote.

Serologic approaches for predicting the risk of NASH are more widely available and “easier” to use than radiologic approaches, but the former may not be as reliable or accurate as the latter, explained Tibor Krisko, MD, a gastroenterologist at Weill Cornell Medicine and New York-Presbyterian, in an interview. “The choice of which serologic test is utilized is often guided by what is available in a region/practice, what the provider is familiar with, and what a given patient’s insurance covers,” said Dr. Krisko, who wasn’t involved in the study.

“The study by Dr. Younossi et al. perhaps confirms that ELF alone is unlikely to be the future standard of care, and the authors weave this to a conclusion and strength, highlighting that the combination had excellent accuracy,” commented Dr. Krisko. “This is an exciting and important area of research and clinical practice advancement, but all of these serological tests have limitations, such as their lack in liver specificity, their risk of being affected by clearance rate, and the fact that they are not biomarkers but rather surrogate markers.”

Therefore, added Dr. Krisko, clinicians should continue to consider each patient’s clinical picture carefully and utilize radiographic methods liberally, particularly when serologic results are deemed ambiguous.

Dr. Younossi reported conflicts of interest with several pharmaceutical companies. No funding was reported for the study. Dr. Krisko had no relevant conflicts to disclose.

A noninvasive enhanced liver fibrosis (ELF) blood test identifies patients with nonalcoholic fatty liver disease (NAFLD) who are at increased risk of advanced fibrosis, according to a new study.

According to the study researchers, when combined with the fibrosis-4 (FIB-4) score the ELF test may be a reliable method that can assess for advanced fibrosis in clinical practice.

Despite the utility of identifying advanced fibrosis in the NAFLD population, significant barriers exist to “risk stratifying patients in clinical practice owing to the need for liver biopsy,” wrote study authors Zobair M. Younossi, MD, of the Inova Health System in Falls Church, Va., and colleagues in JAMA Network Open.

“NASH [nonalcoholic steatohepatitis] can only be diagnosed by biopsy and liver pathology yet validated noninvasive tests that accurately diagnose NASH don’t exist,” said Dr. Younossi in an interview. “Developing noninvasive tests to accurately risk stratify patients with significant fibrosis in NASH is highly desirable in clinical practice. A blood test such as ELF can open the opportunity to order this test anywhere in the country.”

The ELF test reflects extracellular matrix metabolism as opposed to tests that assess alterations in hepatic function. The study authors explain that the noninvasive ELF test is a “blood-derived panel of biomarkers consisting of three components: type III procollagen peptide, hyaluronic acid, and tissue inhibitor of metalloproteinase-1.”

To gain a further understanding of the role of ELF in predicting the risk of nonalcoholic steatohepatitis (NASH) in NAFLD, Dr. Younossi and colleagues performed a retrospective, cross-sectional analysis of outpatients within a community-based liver clinic from 2001 in 2020. The study cohort included 829 patients (mean age, 53.1 years) with NAFLD, which was characterized by steatosis greater than 5% without any other liver disease or excessive alcohol use.

In the overall study population, the mean FIB-4 score was 1.34. In the 463 patients with liver biopsy, approximately 24.4% presented with bridging fibrosis or cirrhosis. A total of 79 (17.1%) of the 462 patients with transient elastography data presented with liver stiffness results of 9.6 kPa or greater, which according to the researchers was indicative of advanced fibrosis.

Biopsy determined that those with advanced fibrosis in the study had significantly increased ELF scores versus patients without advanced fibrosis (10.1 vs. 8.6, respectively; P <.001). Moreover, patients with advanced fibrosis had significantly greater liver stiffness as determined by transient elastography (10.0 vs. 9.0; P <.001).

In the NAFLD population, the ELF test demonstrated excellent performance in identifying patients with advanced fibrosis, as reflected by an area under the receiver operating characteristic curve of 0.81 (95% confidence interval, 0.77-0.85) for those whose fibrosis was diagnosed by biopsy as well as 0.79 (95% CI, 0.75-0.82) for fibrosis diagnosed by transient elastography. Similar performances of the ELF score were reported among those with NAFLD who were aged 65 years or older (AUROC, 0.74; 95% CI, 0.58-0.87) or patients who had type 2 diabetes (AUROC, 0.78; 95% CI, 0.71-0.84).

The researchers regarded the combination of an ELF score of 7.2 or greater with a FIB-4 score of 0.74 or greater, as indicative of a negative predictive value of 95.1% (95% CI, 91.8%-98.4%) and a sensitivity of 92.5% (95% CI, 87.4%-97.5%). According to the investigators, these values “can reliably rule out advanced fibrosis.”

Additionally, the combination of an ELF score of 9.8 or greater with a FIB-4 score of 2.9 or greater, was associated with a positive predictive value of 95.0% (95% CI, 85.5%-100%) and a specificity of 99.7% (95% CI, 99.1%-100%), suggesting this combination can conversely “be used to rule in advanced fibrosis,” the researchers wrote.

Serologic approaches for predicting the risk of NASH are more widely available and “easier” to use than radiologic approaches, but the former may not be as reliable or accurate as the latter, explained Tibor Krisko, MD, a gastroenterologist at Weill Cornell Medicine and New York-Presbyterian, in an interview. “The choice of which serologic test is utilized is often guided by what is available in a region/practice, what the provider is familiar with, and what a given patient’s insurance covers,” said Dr. Krisko, who wasn’t involved in the study.

“The study by Dr. Younossi et al. perhaps confirms that ELF alone is unlikely to be the future standard of care, and the authors weave this to a conclusion and strength, highlighting that the combination had excellent accuracy,” commented Dr. Krisko. “This is an exciting and important area of research and clinical practice advancement, but all of these serological tests have limitations, such as their lack in liver specificity, their risk of being affected by clearance rate, and the fact that they are not biomarkers but rather surrogate markers.”

Therefore, added Dr. Krisko, clinicians should continue to consider each patient’s clinical picture carefully and utilize radiographic methods liberally, particularly when serologic results are deemed ambiguous.

Dr. Younossi reported conflicts of interest with several pharmaceutical companies. No funding was reported for the study. Dr. Krisko had no relevant conflicts to disclose.

A noninvasive enhanced liver fibrosis (ELF) blood test identifies patients with nonalcoholic fatty liver disease (NAFLD) who are at increased risk of advanced fibrosis, according to a new study.

According to the study researchers, when combined with the fibrosis-4 (FIB-4) score the ELF test may be a reliable method that can assess for advanced fibrosis in clinical practice.

Despite the utility of identifying advanced fibrosis in the NAFLD population, significant barriers exist to “risk stratifying patients in clinical practice owing to the need for liver biopsy,” wrote study authors Zobair M. Younossi, MD, of the Inova Health System in Falls Church, Va., and colleagues in JAMA Network Open.

“NASH [nonalcoholic steatohepatitis] can only be diagnosed by biopsy and liver pathology yet validated noninvasive tests that accurately diagnose NASH don’t exist,” said Dr. Younossi in an interview. “Developing noninvasive tests to accurately risk stratify patients with significant fibrosis in NASH is highly desirable in clinical practice. A blood test such as ELF can open the opportunity to order this test anywhere in the country.”

The ELF test reflects extracellular matrix metabolism as opposed to tests that assess alterations in hepatic function. The study authors explain that the noninvasive ELF test is a “blood-derived panel of biomarkers consisting of three components: type III procollagen peptide, hyaluronic acid, and tissue inhibitor of metalloproteinase-1.”

To gain a further understanding of the role of ELF in predicting the risk of nonalcoholic steatohepatitis (NASH) in NAFLD, Dr. Younossi and colleagues performed a retrospective, cross-sectional analysis of outpatients within a community-based liver clinic from 2001 in 2020. The study cohort included 829 patients (mean age, 53.1 years) with NAFLD, which was characterized by steatosis greater than 5% without any other liver disease or excessive alcohol use.

In the overall study population, the mean FIB-4 score was 1.34. In the 463 patients with liver biopsy, approximately 24.4% presented with bridging fibrosis or cirrhosis. A total of 79 (17.1%) of the 462 patients with transient elastography data presented with liver stiffness results of 9.6 kPa or greater, which according to the researchers was indicative of advanced fibrosis.

Biopsy determined that those with advanced fibrosis in the study had significantly increased ELF scores versus patients without advanced fibrosis (10.1 vs. 8.6, respectively; P <.001). Moreover, patients with advanced fibrosis had significantly greater liver stiffness as determined by transient elastography (10.0 vs. 9.0; P <.001).

In the NAFLD population, the ELF test demonstrated excellent performance in identifying patients with advanced fibrosis, as reflected by an area under the receiver operating characteristic curve of 0.81 (95% confidence interval, 0.77-0.85) for those whose fibrosis was diagnosed by biopsy as well as 0.79 (95% CI, 0.75-0.82) for fibrosis diagnosed by transient elastography. Similar performances of the ELF score were reported among those with NAFLD who were aged 65 years or older (AUROC, 0.74; 95% CI, 0.58-0.87) or patients who had type 2 diabetes (AUROC, 0.78; 95% CI, 0.71-0.84).

The researchers regarded the combination of an ELF score of 7.2 or greater with a FIB-4 score of 0.74 or greater, as indicative of a negative predictive value of 95.1% (95% CI, 91.8%-98.4%) and a sensitivity of 92.5% (95% CI, 87.4%-97.5%). According to the investigators, these values “can reliably rule out advanced fibrosis.”

Additionally, the combination of an ELF score of 9.8 or greater with a FIB-4 score of 2.9 or greater, was associated with a positive predictive value of 95.0% (95% CI, 85.5%-100%) and a specificity of 99.7% (95% CI, 99.1%-100%), suggesting this combination can conversely “be used to rule in advanced fibrosis,” the researchers wrote.

Serologic approaches for predicting the risk of NASH are more widely available and “easier” to use than radiologic approaches, but the former may not be as reliable or accurate as the latter, explained Tibor Krisko, MD, a gastroenterologist at Weill Cornell Medicine and New York-Presbyterian, in an interview. “The choice of which serologic test is utilized is often guided by what is available in a region/practice, what the provider is familiar with, and what a given patient’s insurance covers,” said Dr. Krisko, who wasn’t involved in the study.

“The study by Dr. Younossi et al. perhaps confirms that ELF alone is unlikely to be the future standard of care, and the authors weave this to a conclusion and strength, highlighting that the combination had excellent accuracy,” commented Dr. Krisko. “This is an exciting and important area of research and clinical practice advancement, but all of these serological tests have limitations, such as their lack in liver specificity, their risk of being affected by clearance rate, and the fact that they are not biomarkers but rather surrogate markers.”

Therefore, added Dr. Krisko, clinicians should continue to consider each patient’s clinical picture carefully and utilize radiographic methods liberally, particularly when serologic results are deemed ambiguous.

Dr. Younossi reported conflicts of interest with several pharmaceutical companies. No funding was reported for the study. Dr. Krisko had no relevant conflicts to disclose.

The pandemic exacerbated the financial struggles of many primary care practices, and some still have not recovered from COVID-19–related losses, according to experts and the results of recent surveys by the Primary Care Collaborative (PCC).

Fewer than 30% (26.4%) of primary care clinicians report that their practices are financially healthy, according to the latest results from a periodic survey by the PCC. An earlier survey by the PCC suggests clinicians’ confidence in the financial viability of their practices has significantly declined since last year, when compared with the new survey’s results. When the older survey was taken between Sept. 4 and Sept. 8 of 2020, only 35% of primary care clinicians said that revenue and pay were significantly lower than they were before the pandemic.

Submissions to the new PCC survey were collected between Aug. 13 and Aug. 17 of 2021 and included 1,263 respondents from 49 states, the District of Columbia, and two territories. The PCC and the Larry A. Green Center have been regularly surveying primary care clinicians to better understand the impact of COVID-19 throughout the pandemic.

PCC President and CEO Ann Greiner said in an interview that the drop over a year follows a trend.

Though primary care faced struggles before the pandemic, the COVID-19 effect has been striking and cumulative, she noted.

“[Primary care practices] were healthier prepandemic,” said Ms. Greiner. “The precipitous drop in revenue when stay-at-home orders went into effect had a very big effect though pay structure and lack of investment in primary care was a problem long before COVID-19.”

COVID-19 has exacerbated all that ails primary care, and has increased fears of viability of primary care offices, she said.

Ms. Greiner pointed to a report from Health Affairs, that projected in 2020 that primary care would lose $65,000 in revenue per full-time physician by the end of the year for a total shortfall of $15 billion, following steep drops in office visits and fees for services from March to May, 2020.

In July of this year, she said, PCC’s survey found that, “Four in 10 clinicians worry that primary care will be gone in 5 years and one-fifth of respondents expect to leave the profession within the next three.”

The July PCC survey also showed that 13% of primary care clinicians said they have discussed selling their practice and cite high-level burnout/exhaustion as a main challenge for the next 6 months.

Robert L. Phillips, MD, a Virginia-based physician who oversees research for the American Board of Family Medicine, said, “Practices in our national primary care practice registry (PRIME) saw visit volumes drop 40% in the 2-3 months around the start of the pandemic and had not seen them return to normal as of June of this year. This means most remain financially underwater.”


 

End to paycheck protection hurt practices

Conrad L. Flick, MD, managing partner of Family Medical Associates in Raleigh, N.C., said the end of the federal Paycheck Protection Program (PPP) at the end of 2020 caused further distress to primary care and could also help explain the drop in healthy practices that PCC’s survey from last year suggested.

“Many of us who struggled financially as the pandemic hit last year were really worried. PPP certainly shored that up for a lot of us. But now it’s no longer here,” he said.

Dr. Flick said his 10-clinician independent practice is financially sound and he credits that to having the PPP loan, shared savings from an accountable care organization, and holding some profit over from last year to this year.

His practice had to cut two nurse practitioners this year when volume did not return to prepandemic levels.

“The PPP loan let us keep [those NPs] employed through spring, but we were hoping the volume would come back. Come spring this year the volume hasn’t come back, and we couldn’t afford to keep the office at full staff,” he said.

The way primary care physicians are paid is what makes them so vulnerable in a pandemic, he explained.

“Our revenue is purely based on how many people I can get through my office at a given period of time. We don’t have ways to generate revenue and build a cushion.”

Family physician L. Allen Dobson, MD, said the survey results may have become even more grim in the last year, because primary care practices, especially small practices, have not recovered from the 2020 losses and effects have snowballed.

Even though primary care offices have largely reopened and many patients have returned to in-person visits, he said, physicians are dealing with uncertainties of COVID-19 surges and variants and are having trouble recruiting and maintaining staff.

Revenue that should have come to primary care practices in testing and distributing vaccines instead went elsewhere to larger vaccination sites and retail clinics, noted Dr. Dobson, who is chair of the board of managers of Community Care Physicians Network in Mount Pleasant, N.C., which provides assistance with administrative tasks to small and solo primary care practices.
 

COVID-19 brought ‘accelerated change’

COVID-19 brought “an accelerated change,” in decreasing revenue, Dr. Dobson said.

Small primary care practices have followed the rules of changing to electronic health records, getting patient-centered medical home certification, and documenting quality improvement measures, but they have not reaped the financial benefits from these changes, he explained.

A report commissioned by the Physician Advocacy Institute found that the pandemic accelerated a long national trend of hospitals and corporate entities acquiring physician practices and employing physicians.

From January 2019 to January 2021, these entities acquired 20,900 additional physician practices and 48,000 additional physicians left independent practice for employment by hospital systems or other corporate entities.

Further straining practices is a thinning workforce, with 21% or respondents to the most recent PCC survey having said they were unable to hire clinicians for open positions and 54% saying they are unable to hire staff for open positions.

One respondent to the PCC survey from Utah said, “We need more support. It’s a moral injury to have our pay cut and be severely understaffed. Most of the burden of educating patients and getting them vaccinated has fallen to primary care and we are already overwhelmed with taking care of patients with worsening mental and physical health.”

According to Bruce Landon, MD, MBA, professor of health care policy at the Harvard Medical School’s Center for Primary Care, Boston, another source of financial strain for primary care practices is that they are having difficulty attracting doctors, nurses, and administrators.

These practices often need to increase pay for those positions to recruit people, and they are leaving many positions unfilled, Dr. Landon explained.

Plus, COVID-19 introduced costs for personal protective equipment (PPE) and cleaning products, and those expenses generally have not been reimbursed, Dr. Landon said.
 

Uncertainty around telemedicine

A new risk for primary care is a decline in telemedicine payments at a time when practices are still relying on telemedicine for revenue.

In the most recent PCC report, 40% of clinicians said they use telemedicine for at least a fifth of all office visits.

Even though most practices have reopened there’s still a fair amount of telemedicine and that will continue, Dr. Landon said in an interview.

In March of 2020, the Centers for Medicare & Medicaid Services lifted restrictions and that helped physicians with getting reimbursed for the services as they would office visits. But some commercial payers are starting to back off full payment for telemedicine, Dr. Landon noted.

“At some point the feds will probably start to do that with Medicare. I think that’s a mistake. [Telemedicine] has been one of the silver linings of this cloud of the pandemic,” he said.

If prepandemic payment regulations are restored, 41% of clinicians said, in the most recent PCC survey, that they worry their practices will no longer be able to support telemedicine.
 

Possible safety nets

Dr. Landon said that one thing that’s also clear is that some form of primary care capitation payment is necessary, at least for some of the work in primary care.

The practices that had capitation as part of payment were the ones who were most easily able to handle the pandemic because they didn’t see the immediate drop in revenue that fee-for-service practices saw, he noted.

“If we have a next pandemic, having a steady revenue stream to support primary care is really important and having a different way to pay for primary care is probably the best way to do that,” he said. “These longer-term strategies are going to be really crucial if we want to have a primary care system 10 years from now.”

Ms. Greiner, Dr. Flick, Dr. Phillips, Dr. Dobson, and Dr. Landon report no relevant financial relationships.

The pandemic exacerbated the financial struggles of many primary care practices, and some still have not recovered from COVID-19–related losses, according to experts and the results of recent surveys by the Primary Care Collaborative (PCC).

Fewer than 30% (26.4%) of primary care clinicians report that their practices are financially healthy, according to the latest results from a periodic survey by the PCC. An earlier survey by the PCC suggests clinicians’ confidence in the financial viability of their practices has significantly declined since last year, when compared with the new survey’s results. When the older survey was taken between Sept. 4 and Sept. 8 of 2020, only 35% of primary care clinicians said that revenue and pay were significantly lower than they were before the pandemic.

Submissions to the new PCC survey were collected between Aug. 13 and Aug. 17 of 2021 and included 1,263 respondents from 49 states, the District of Columbia, and two territories. The PCC and the Larry A. Green Center have been regularly surveying primary care clinicians to better understand the impact of COVID-19 throughout the pandemic.

PCC President and CEO Ann Greiner said in an interview that the drop over a year follows a trend.

Though primary care faced struggles before the pandemic, the COVID-19 effect has been striking and cumulative, she noted.

“[Primary care practices] were healthier prepandemic,” said Ms. Greiner. “The precipitous drop in revenue when stay-at-home orders went into effect had a very big effect though pay structure and lack of investment in primary care was a problem long before COVID-19.”

COVID-19 has exacerbated all that ails primary care, and has increased fears of viability of primary care offices, she said.

Ms. Greiner pointed to a report from Health Affairs, that projected in 2020 that primary care would lose $65,000 in revenue per full-time physician by the end of the year for a total shortfall of $15 billion, following steep drops in office visits and fees for services from March to May, 2020.

In July of this year, she said, PCC’s survey found that, “Four in 10 clinicians worry that primary care will be gone in 5 years and one-fifth of respondents expect to leave the profession within the next three.”

The July PCC survey also showed that 13% of primary care clinicians said they have discussed selling their practice and cite high-level burnout/exhaustion as a main challenge for the next 6 months.

Robert L. Phillips, MD, a Virginia-based physician who oversees research for the American Board of Family Medicine, said, “Practices in our national primary care practice registry (PRIME) saw visit volumes drop 40% in the 2-3 months around the start of the pandemic and had not seen them return to normal as of June of this year. This means most remain financially underwater.”


 

End to paycheck protection hurt practices

Conrad L. Flick, MD, managing partner of Family Medical Associates in Raleigh, N.C., said the end of the federal Paycheck Protection Program (PPP) at the end of 2020 caused further distress to primary care and could also help explain the drop in healthy practices that PCC’s survey from last year suggested.

“Many of us who struggled financially as the pandemic hit last year were really worried. PPP certainly shored that up for a lot of us. But now it’s no longer here,” he said.

Dr. Flick said his 10-clinician independent practice is financially sound and he credits that to having the PPP loan, shared savings from an accountable care organization, and holding some profit over from last year to this year.

His practice had to cut two nurse practitioners this year when volume did not return to prepandemic levels.

“The PPP loan let us keep [those NPs] employed through spring, but we were hoping the volume would come back. Come spring this year the volume hasn’t come back, and we couldn’t afford to keep the office at full staff,” he said.

The way primary care physicians are paid is what makes them so vulnerable in a pandemic, he explained.

“Our revenue is purely based on how many people I can get through my office at a given period of time. We don’t have ways to generate revenue and build a cushion.”

Family physician L. Allen Dobson, MD, said the survey results may have become even more grim in the last year, because primary care practices, especially small practices, have not recovered from the 2020 losses and effects have snowballed.

Even though primary care offices have largely reopened and many patients have returned to in-person visits, he said, physicians are dealing with uncertainties of COVID-19 surges and variants and are having trouble recruiting and maintaining staff.

Revenue that should have come to primary care practices in testing and distributing vaccines instead went elsewhere to larger vaccination sites and retail clinics, noted Dr. Dobson, who is chair of the board of managers of Community Care Physicians Network in Mount Pleasant, N.C., which provides assistance with administrative tasks to small and solo primary care practices.
 

COVID-19 brought ‘accelerated change’

COVID-19 brought “an accelerated change,” in decreasing revenue, Dr. Dobson said.

Small primary care practices have followed the rules of changing to electronic health records, getting patient-centered medical home certification, and documenting quality improvement measures, but they have not reaped the financial benefits from these changes, he explained.

A report commissioned by the Physician Advocacy Institute found that the pandemic accelerated a long national trend of hospitals and corporate entities acquiring physician practices and employing physicians.

From January 2019 to January 2021, these entities acquired 20,900 additional physician practices and 48,000 additional physicians left independent practice for employment by hospital systems or other corporate entities.

Further straining practices is a thinning workforce, with 21% or respondents to the most recent PCC survey having said they were unable to hire clinicians for open positions and 54% saying they are unable to hire staff for open positions.

One respondent to the PCC survey from Utah said, “We need more support. It’s a moral injury to have our pay cut and be severely understaffed. Most of the burden of educating patients and getting them vaccinated has fallen to primary care and we are already overwhelmed with taking care of patients with worsening mental and physical health.”

According to Bruce Landon, MD, MBA, professor of health care policy at the Harvard Medical School’s Center for Primary Care, Boston, another source of financial strain for primary care practices is that they are having difficulty attracting doctors, nurses, and administrators.

These practices often need to increase pay for those positions to recruit people, and they are leaving many positions unfilled, Dr. Landon explained.

Plus, COVID-19 introduced costs for personal protective equipment (PPE) and cleaning products, and those expenses generally have not been reimbursed, Dr. Landon said.
 

Uncertainty around telemedicine

A new risk for primary care is a decline in telemedicine payments at a time when practices are still relying on telemedicine for revenue.

In the most recent PCC report, 40% of clinicians said they use telemedicine for at least a fifth of all office visits.

Even though most practices have reopened there’s still a fair amount of telemedicine and that will continue, Dr. Landon said in an interview.

In March of 2020, the Centers for Medicare & Medicaid Services lifted restrictions and that helped physicians with getting reimbursed for the services as they would office visits. But some commercial payers are starting to back off full payment for telemedicine, Dr. Landon noted.

“At some point the feds will probably start to do that with Medicare. I think that’s a mistake. [Telemedicine] has been one of the silver linings of this cloud of the pandemic,” he said.

If prepandemic payment regulations are restored, 41% of clinicians said, in the most recent PCC survey, that they worry their practices will no longer be able to support telemedicine.
 

Possible safety nets

Dr. Landon said that one thing that’s also clear is that some form of primary care capitation payment is necessary, at least for some of the work in primary care.

The practices that had capitation as part of payment were the ones who were most easily able to handle the pandemic because they didn’t see the immediate drop in revenue that fee-for-service practices saw, he noted.

“If we have a next pandemic, having a steady revenue stream to support primary care is really important and having a different way to pay for primary care is probably the best way to do that,” he said. “These longer-term strategies are going to be really crucial if we want to have a primary care system 10 years from now.”

Ms. Greiner, Dr. Flick, Dr. Phillips, Dr. Dobson, and Dr. Landon report no relevant financial relationships.

The pandemic exacerbated the financial struggles of many primary care practices, and some still have not recovered from COVID-19–related losses, according to experts and the results of recent surveys by the Primary Care Collaborative (PCC).

Fewer than 30% (26.4%) of primary care clinicians report that their practices are financially healthy, according to the latest results from a periodic survey by the PCC. An earlier survey by the PCC suggests clinicians’ confidence in the financial viability of their practices has significantly declined since last year, when compared with the new survey’s results. When the older survey was taken between Sept. 4 and Sept. 8 of 2020, only 35% of primary care clinicians said that revenue and pay were significantly lower than they were before the pandemic.

Submissions to the new PCC survey were collected between Aug. 13 and Aug. 17 of 2021 and included 1,263 respondents from 49 states, the District of Columbia, and two territories. The PCC and the Larry A. Green Center have been regularly surveying primary care clinicians to better understand the impact of COVID-19 throughout the pandemic.

PCC President and CEO Ann Greiner said in an interview that the drop over a year follows a trend.

Though primary care faced struggles before the pandemic, the COVID-19 effect has been striking and cumulative, she noted.

“[Primary care practices] were healthier prepandemic,” said Ms. Greiner. “The precipitous drop in revenue when stay-at-home orders went into effect had a very big effect though pay structure and lack of investment in primary care was a problem long before COVID-19.”

COVID-19 has exacerbated all that ails primary care, and has increased fears of viability of primary care offices, she said.

Ms. Greiner pointed to a report from Health Affairs, that projected in 2020 that primary care would lose $65,000 in revenue per full-time physician by the end of the year for a total shortfall of $15 billion, following steep drops in office visits and fees for services from March to May, 2020.

In July of this year, she said, PCC’s survey found that, “Four in 10 clinicians worry that primary care will be gone in 5 years and one-fifth of respondents expect to leave the profession within the next three.”

The July PCC survey also showed that 13% of primary care clinicians said they have discussed selling their practice and cite high-level burnout/exhaustion as a main challenge for the next 6 months.

Robert L. Phillips, MD, a Virginia-based physician who oversees research for the American Board of Family Medicine, said, “Practices in our national primary care practice registry (PRIME) saw visit volumes drop 40% in the 2-3 months around the start of the pandemic and had not seen them return to normal as of June of this year. This means most remain financially underwater.”


 

End to paycheck protection hurt practices

Conrad L. Flick, MD, managing partner of Family Medical Associates in Raleigh, N.C., said the end of the federal Paycheck Protection Program (PPP) at the end of 2020 caused further distress to primary care and could also help explain the drop in healthy practices that PCC’s survey from last year suggested.

“Many of us who struggled financially as the pandemic hit last year were really worried. PPP certainly shored that up for a lot of us. But now it’s no longer here,” he said.

Dr. Flick said his 10-clinician independent practice is financially sound and he credits that to having the PPP loan, shared savings from an accountable care organization, and holding some profit over from last year to this year.

His practice had to cut two nurse practitioners this year when volume did not return to prepandemic levels.

“The PPP loan let us keep [those NPs] employed through spring, but we were hoping the volume would come back. Come spring this year the volume hasn’t come back, and we couldn’t afford to keep the office at full staff,” he said.

The way primary care physicians are paid is what makes them so vulnerable in a pandemic, he explained.

“Our revenue is purely based on how many people I can get through my office at a given period of time. We don’t have ways to generate revenue and build a cushion.”

Family physician L. Allen Dobson, MD, said the survey results may have become even more grim in the last year, because primary care practices, especially small practices, have not recovered from the 2020 losses and effects have snowballed.

Even though primary care offices have largely reopened and many patients have returned to in-person visits, he said, physicians are dealing with uncertainties of COVID-19 surges and variants and are having trouble recruiting and maintaining staff.

Revenue that should have come to primary care practices in testing and distributing vaccines instead went elsewhere to larger vaccination sites and retail clinics, noted Dr. Dobson, who is chair of the board of managers of Community Care Physicians Network in Mount Pleasant, N.C., which provides assistance with administrative tasks to small and solo primary care practices.
 

COVID-19 brought ‘accelerated change’

COVID-19 brought “an accelerated change,” in decreasing revenue, Dr. Dobson said.

Small primary care practices have followed the rules of changing to electronic health records, getting patient-centered medical home certification, and documenting quality improvement measures, but they have not reaped the financial benefits from these changes, he explained.

A report commissioned by the Physician Advocacy Institute found that the pandemic accelerated a long national trend of hospitals and corporate entities acquiring physician practices and employing physicians.

From January 2019 to January 2021, these entities acquired 20,900 additional physician practices and 48,000 additional physicians left independent practice for employment by hospital systems or other corporate entities.

Further straining practices is a thinning workforce, with 21% or respondents to the most recent PCC survey having said they were unable to hire clinicians for open positions and 54% saying they are unable to hire staff for open positions.

One respondent to the PCC survey from Utah said, “We need more support. It’s a moral injury to have our pay cut and be severely understaffed. Most of the burden of educating patients and getting them vaccinated has fallen to primary care and we are already overwhelmed with taking care of patients with worsening mental and physical health.”

According to Bruce Landon, MD, MBA, professor of health care policy at the Harvard Medical School’s Center for Primary Care, Boston, another source of financial strain for primary care practices is that they are having difficulty attracting doctors, nurses, and administrators.

These practices often need to increase pay for those positions to recruit people, and they are leaving many positions unfilled, Dr. Landon explained.

Plus, COVID-19 introduced costs for personal protective equipment (PPE) and cleaning products, and those expenses generally have not been reimbursed, Dr. Landon said.
 

Uncertainty around telemedicine

A new risk for primary care is a decline in telemedicine payments at a time when practices are still relying on telemedicine for revenue.

In the most recent PCC report, 40% of clinicians said they use telemedicine for at least a fifth of all office visits.

Even though most practices have reopened there’s still a fair amount of telemedicine and that will continue, Dr. Landon said in an interview.

In March of 2020, the Centers for Medicare & Medicaid Services lifted restrictions and that helped physicians with getting reimbursed for the services as they would office visits. But some commercial payers are starting to back off full payment for telemedicine, Dr. Landon noted.

“At some point the feds will probably start to do that with Medicare. I think that’s a mistake. [Telemedicine] has been one of the silver linings of this cloud of the pandemic,” he said.

If prepandemic payment regulations are restored, 41% of clinicians said, in the most recent PCC survey, that they worry their practices will no longer be able to support telemedicine.
 

Possible safety nets

Dr. Landon said that one thing that’s also clear is that some form of primary care capitation payment is necessary, at least for some of the work in primary care.

The practices that had capitation as part of payment were the ones who were most easily able to handle the pandemic because they didn’t see the immediate drop in revenue that fee-for-service practices saw, he noted.

“If we have a next pandemic, having a steady revenue stream to support primary care is really important and having a different way to pay for primary care is probably the best way to do that,” he said. “These longer-term strategies are going to be really crucial if we want to have a primary care system 10 years from now.”

Ms. Greiner, Dr. Flick, Dr. Phillips, Dr. Dobson, and Dr. Landon report no relevant financial relationships.

People who don’t get vaccinated against COVID-19 should expect to be reinfected with the coronavirus every 16 to 17 months on average, according to a recent study published in The Lancet Microbe.

Since COVID-19 hasn’t existed for long enough to perform a long-term study, researchers at Yale University and the University of North Carolina at Charlotte looked at reinfection data for six other human-infecting coronaviruses, including SARS and MERS.

“Reinfection can reasonably happen in three months or less,” Jeffrey Townsend, PhD, lead study author and a biostatistics professor at the Yale School of Public Health, said in a statement.

“Therefore, those who have been naturally infected should get vaccinated,” he said. “Previous infection alone can offer very little long-term protection against subsequent infections.”

The research team looked at post-infection data for six coronaviruses between 1984-2020 and found reinfection ranged from 128 days to 28 years. They calculated that reinfection with COVID-19 would likely occur between 3 months to 5 years after peak antibody response, with an average of 16 months. This is less than half the duration seen for other coronaviruses that circulate among humans.

The risk of COVID-19 reinfection is about 5% at three months, which jumps to 50% after 17 months, the research team found. Reinfection could become increasingly common as immunity wanes and new variants develop, they said.

“We tend to think about immunity as being immune or not immune. Our study cautions that we instead should be more focused on the risk of reinfection through time,” Alex Dornburg, PhD, senior study author and assistant professor of bioinformatics and genomics at UNC, said in the statement.

“As new variants arise, previous immune responses become less effective at combating the virus,” he said. “Those who were naturally infected early in the pandemic are increasingly likely to become reinfected in the near future.”

Study estimates are based on average times of declining immunity across different coronaviruses, the researchers told the Yale Daily News. At the individual level, people have different levels of immunity, which can provide shorter or longer duration of protection based on immune status, immunity within a community, age, underlying health conditions, environmental exposure, and other factors.

The research team said that preventive health measures and global distribution of vaccines will be “critical” in minimizing reinfection and COVID-19 deaths. In areas with low vaccination rates, for instance, unvaccinated people should continue safety practices such as social distancing, wearing masks, and proper indoor ventilation to avoid reinfection.

“We need to be very aware of the fact that this disease is likely to be circulating over the long term and that we don’t have this long-term immunity that many people seem to be hoping to rely on in order to protect them from disease,” Dr. Townsend told the newspaper.

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

People who don’t get vaccinated against COVID-19 should expect to be reinfected with the coronavirus every 16 to 17 months on average, according to a recent study published in The Lancet Microbe.

Since COVID-19 hasn’t existed for long enough to perform a long-term study, researchers at Yale University and the University of North Carolina at Charlotte looked at reinfection data for six other human-infecting coronaviruses, including SARS and MERS.

“Reinfection can reasonably happen in three months or less,” Jeffrey Townsend, PhD, lead study author and a biostatistics professor at the Yale School of Public Health, said in a statement.

“Therefore, those who have been naturally infected should get vaccinated,” he said. “Previous infection alone can offer very little long-term protection against subsequent infections.”

The research team looked at post-infection data for six coronaviruses between 1984-2020 and found reinfection ranged from 128 days to 28 years. They calculated that reinfection with COVID-19 would likely occur between 3 months to 5 years after peak antibody response, with an average of 16 months. This is less than half the duration seen for other coronaviruses that circulate among humans.

The risk of COVID-19 reinfection is about 5% at three months, which jumps to 50% after 17 months, the research team found. Reinfection could become increasingly common as immunity wanes and new variants develop, they said.

“We tend to think about immunity as being immune or not immune. Our study cautions that we instead should be more focused on the risk of reinfection through time,” Alex Dornburg, PhD, senior study author and assistant professor of bioinformatics and genomics at UNC, said in the statement.

“As new variants arise, previous immune responses become less effective at combating the virus,” he said. “Those who were naturally infected early in the pandemic are increasingly likely to become reinfected in the near future.”

Study estimates are based on average times of declining immunity across different coronaviruses, the researchers told the Yale Daily News. At the individual level, people have different levels of immunity, which can provide shorter or longer duration of protection based on immune status, immunity within a community, age, underlying health conditions, environmental exposure, and other factors.

The research team said that preventive health measures and global distribution of vaccines will be “critical” in minimizing reinfection and COVID-19 deaths. In areas with low vaccination rates, for instance, unvaccinated people should continue safety practices such as social distancing, wearing masks, and proper indoor ventilation to avoid reinfection.

“We need to be very aware of the fact that this disease is likely to be circulating over the long term and that we don’t have this long-term immunity that many people seem to be hoping to rely on in order to protect them from disease,” Dr. Townsend told the newspaper.

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

People who don’t get vaccinated against COVID-19 should expect to be reinfected with the coronavirus every 16 to 17 months on average, according to a recent study published in The Lancet Microbe.

Since COVID-19 hasn’t existed for long enough to perform a long-term study, researchers at Yale University and the University of North Carolina at Charlotte looked at reinfection data for six other human-infecting coronaviruses, including SARS and MERS.

“Reinfection can reasonably happen in three months or less,” Jeffrey Townsend, PhD, lead study author and a biostatistics professor at the Yale School of Public Health, said in a statement.

“Therefore, those who have been naturally infected should get vaccinated,” he said. “Previous infection alone can offer very little long-term protection against subsequent infections.”

The research team looked at post-infection data for six coronaviruses between 1984-2020 and found reinfection ranged from 128 days to 28 years. They calculated that reinfection with COVID-19 would likely occur between 3 months to 5 years after peak antibody response, with an average of 16 months. This is less than half the duration seen for other coronaviruses that circulate among humans.

The risk of COVID-19 reinfection is about 5% at three months, which jumps to 50% after 17 months, the research team found. Reinfection could become increasingly common as immunity wanes and new variants develop, they said.

“We tend to think about immunity as being immune or not immune. Our study cautions that we instead should be more focused on the risk of reinfection through time,” Alex Dornburg, PhD, senior study author and assistant professor of bioinformatics and genomics at UNC, said in the statement.

“As new variants arise, previous immune responses become less effective at combating the virus,” he said. “Those who were naturally infected early in the pandemic are increasingly likely to become reinfected in the near future.”

Study estimates are based on average times of declining immunity across different coronaviruses, the researchers told the Yale Daily News. At the individual level, people have different levels of immunity, which can provide shorter or longer duration of protection based on immune status, immunity within a community, age, underlying health conditions, environmental exposure, and other factors.

The research team said that preventive health measures and global distribution of vaccines will be “critical” in minimizing reinfection and COVID-19 deaths. In areas with low vaccination rates, for instance, unvaccinated people should continue safety practices such as social distancing, wearing masks, and proper indoor ventilation to avoid reinfection.

“We need to be very aware of the fact that this disease is likely to be circulating over the long term and that we don’t have this long-term immunity that many people seem to be hoping to rely on in order to protect them from disease,” Dr. Townsend told the newspaper.

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

The popular antipsychotic quetiapine (Seroquel) seems to calm patients with multiple sclerosis (MS) who develop psychiatric distress after taking corticosteroids, a new case review says.

“Our case-report study observed that quetiapine was effective at decreasing irritability, reducing psychological distress, and improving sleep in patients with MS who experienced psychosis symptoms compared with patients who received no treatment. This has changed our practice as we now counsel all patients about the potential side effect of steroid-induced psychosis and discuss treatment options,” said Olinka Hrebicek, MD, medical director of Vancouver Island Multiple Sclerosis Clinic in Victoria, B.C., who was scheduled to present the study findings at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

According to Dr. Hrebicek, who spoke in an interview, nursing staff and neurologists at the Canadian clinic had typically attributed symptoms such as irritability, anger, insomnia, and psychological distress to the stress of experiencing a relapse. The treatment often was a prescription for a benzodiazepine or zopiclone.

In fact, she and colleagues wrote in their report, psychosis following treatment with high-dose corticosteroids for MS may be underreported.

“The purpose of the study was to determine whether quetiapine was effective for treating symptoms of steroid-induced psychosis in patients with MS,” study coauthor and clinic research assistant Niall Murphy said in an interview. “We also wanted to highlight the importance of looking for symptoms of steroid-induced psychosis as this is likely not the primary concern when treating patients for a relapse. In addition, nurses and neurologists may have less experience with the spectrum of clinical symptoms of psychosis than psychiatrists.”

For the case review, researchers examined 10 reports (8 female) of patients who had signs of psychiatric distress after treatment with steroids. Eight of the patients were treated with quetiapine (six female, two male).

All those who took quetiapine experienced benefits, while the two others didn’t improve.

Commenting on the study, E. Sherwood Brown, MD, PhD, MBA, professor of psychiatry at the University of Texas Southwestern Medical Center, Dallas, said in an interview that psychosis may not appear as expected in patients who develop it as a result of corticosteroid use. “Typically, psychosis refers to delusions, hallucinations, or disorganized thought processes. However, with corticosteroids severe mood and cognitive changes [for example, delirium] are also often included in the definition. Mild mood and memory changes appear to be fairly common with prescription corticosteroids. More severe symptoms are less common.”

Higher doses of corticosteroids – like those used in MS – boost the risk of psychosis, said Dr. Brown, who was not involved in the study.

As for quetiapine, Dr. Brown said it could be a good treatment option. “The use of quetiapine, a drug approved for schizophrenia and mania, is consistent with the idea suggested in the literature that the symptoms with corticosteroids tend to be similar to those of bipolar disorder and that they respond to medications for bipolar disorder,” he said. “A potential concern is that both corticosteroids and quetiapine can cause weight gain. However, this may not be a major problem with a brief course of the corticosteroids. It would be great to see a randomized, controlled trial.”

In British Columbia, the Victoria clinic has changed policy as a result of the analysis, Dr. Hrebicek said. “Nurses and physicians now ask more specific questions to decide if patients are experiencing symptoms of steroid-induced psychosis and whether they should be treated with an antipsychotic medication.”

And now, report coauthor Mr. Murphy said, “our clinic proactively offers patients a prescription for quetiapine that they can fill if they are experiencing symptoms of steroid psychosis.”

Dr. Brown supported the new policy of alerting patients to the psychosis risk. “Counseling patients about common side effects is a good idea,” he said. “I have seen data suggesting that patients may be hesitant to report psychiatric symptoms with corticosteroids to their physicians. Letting them know about the potential for these kinds of side effects might make them more forthcoming in reporting this side effect.”

No study funding is reported. The study authors reported no disclosures. Dr. Brown has a National Institutes of Health grant for studying the effect of corticosteroids on the brain.
 

The popular antipsychotic quetiapine (Seroquel) seems to calm patients with multiple sclerosis (MS) who develop psychiatric distress after taking corticosteroids, a new case review says.

“Our case-report study observed that quetiapine was effective at decreasing irritability, reducing psychological distress, and improving sleep in patients with MS who experienced psychosis symptoms compared with patients who received no treatment. This has changed our practice as we now counsel all patients about the potential side effect of steroid-induced psychosis and discuss treatment options,” said Olinka Hrebicek, MD, medical director of Vancouver Island Multiple Sclerosis Clinic in Victoria, B.C., who was scheduled to present the study findings at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

According to Dr. Hrebicek, who spoke in an interview, nursing staff and neurologists at the Canadian clinic had typically attributed symptoms such as irritability, anger, insomnia, and psychological distress to the stress of experiencing a relapse. The treatment often was a prescription for a benzodiazepine or zopiclone.

In fact, she and colleagues wrote in their report, psychosis following treatment with high-dose corticosteroids for MS may be underreported.

“The purpose of the study was to determine whether quetiapine was effective for treating symptoms of steroid-induced psychosis in patients with MS,” study coauthor and clinic research assistant Niall Murphy said in an interview. “We also wanted to highlight the importance of looking for symptoms of steroid-induced psychosis as this is likely not the primary concern when treating patients for a relapse. In addition, nurses and neurologists may have less experience with the spectrum of clinical symptoms of psychosis than psychiatrists.”

For the case review, researchers examined 10 reports (8 female) of patients who had signs of psychiatric distress after treatment with steroids. Eight of the patients were treated with quetiapine (six female, two male).

All those who took quetiapine experienced benefits, while the two others didn’t improve.

Commenting on the study, E. Sherwood Brown, MD, PhD, MBA, professor of psychiatry at the University of Texas Southwestern Medical Center, Dallas, said in an interview that psychosis may not appear as expected in patients who develop it as a result of corticosteroid use. “Typically, psychosis refers to delusions, hallucinations, or disorganized thought processes. However, with corticosteroids severe mood and cognitive changes [for example, delirium] are also often included in the definition. Mild mood and memory changes appear to be fairly common with prescription corticosteroids. More severe symptoms are less common.”

Higher doses of corticosteroids – like those used in MS – boost the risk of psychosis, said Dr. Brown, who was not involved in the study.

As for quetiapine, Dr. Brown said it could be a good treatment option. “The use of quetiapine, a drug approved for schizophrenia and mania, is consistent with the idea suggested in the literature that the symptoms with corticosteroids tend to be similar to those of bipolar disorder and that they respond to medications for bipolar disorder,” he said. “A potential concern is that both corticosteroids and quetiapine can cause weight gain. However, this may not be a major problem with a brief course of the corticosteroids. It would be great to see a randomized, controlled trial.”

In British Columbia, the Victoria clinic has changed policy as a result of the analysis, Dr. Hrebicek said. “Nurses and physicians now ask more specific questions to decide if patients are experiencing symptoms of steroid-induced psychosis and whether they should be treated with an antipsychotic medication.”

And now, report coauthor Mr. Murphy said, “our clinic proactively offers patients a prescription for quetiapine that they can fill if they are experiencing symptoms of steroid psychosis.”

Dr. Brown supported the new policy of alerting patients to the psychosis risk. “Counseling patients about common side effects is a good idea,” he said. “I have seen data suggesting that patients may be hesitant to report psychiatric symptoms with corticosteroids to their physicians. Letting them know about the potential for these kinds of side effects might make them more forthcoming in reporting this side effect.”

No study funding is reported. The study authors reported no disclosures. Dr. Brown has a National Institutes of Health grant for studying the effect of corticosteroids on the brain.
 

The popular antipsychotic quetiapine (Seroquel) seems to calm patients with multiple sclerosis (MS) who develop psychiatric distress after taking corticosteroids, a new case review says.

“Our case-report study observed that quetiapine was effective at decreasing irritability, reducing psychological distress, and improving sleep in patients with MS who experienced psychosis symptoms compared with patients who received no treatment. This has changed our practice as we now counsel all patients about the potential side effect of steroid-induced psychosis and discuss treatment options,” said Olinka Hrebicek, MD, medical director of Vancouver Island Multiple Sclerosis Clinic in Victoria, B.C., who was scheduled to present the study findings at the 2021 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC).

According to Dr. Hrebicek, who spoke in an interview, nursing staff and neurologists at the Canadian clinic had typically attributed symptoms such as irritability, anger, insomnia, and psychological distress to the stress of experiencing a relapse. The treatment often was a prescription for a benzodiazepine or zopiclone.

In fact, she and colleagues wrote in their report, psychosis following treatment with high-dose corticosteroids for MS may be underreported.

“The purpose of the study was to determine whether quetiapine was effective for treating symptoms of steroid-induced psychosis in patients with MS,” study coauthor and clinic research assistant Niall Murphy said in an interview. “We also wanted to highlight the importance of looking for symptoms of steroid-induced psychosis as this is likely not the primary concern when treating patients for a relapse. In addition, nurses and neurologists may have less experience with the spectrum of clinical symptoms of psychosis than psychiatrists.”

For the case review, researchers examined 10 reports (8 female) of patients who had signs of psychiatric distress after treatment with steroids. Eight of the patients were treated with quetiapine (six female, two male).

All those who took quetiapine experienced benefits, while the two others didn’t improve.

Commenting on the study, E. Sherwood Brown, MD, PhD, MBA, professor of psychiatry at the University of Texas Southwestern Medical Center, Dallas, said in an interview that psychosis may not appear as expected in patients who develop it as a result of corticosteroid use. “Typically, psychosis refers to delusions, hallucinations, or disorganized thought processes. However, with corticosteroids severe mood and cognitive changes [for example, delirium] are also often included in the definition. Mild mood and memory changes appear to be fairly common with prescription corticosteroids. More severe symptoms are less common.”

Higher doses of corticosteroids – like those used in MS – boost the risk of psychosis, said Dr. Brown, who was not involved in the study.

As for quetiapine, Dr. Brown said it could be a good treatment option. “The use of quetiapine, a drug approved for schizophrenia and mania, is consistent with the idea suggested in the literature that the symptoms with corticosteroids tend to be similar to those of bipolar disorder and that they respond to medications for bipolar disorder,” he said. “A potential concern is that both corticosteroids and quetiapine can cause weight gain. However, this may not be a major problem with a brief course of the corticosteroids. It would be great to see a randomized, controlled trial.”

In British Columbia, the Victoria clinic has changed policy as a result of the analysis, Dr. Hrebicek said. “Nurses and physicians now ask more specific questions to decide if patients are experiencing symptoms of steroid-induced psychosis and whether they should be treated with an antipsychotic medication.”

And now, report coauthor Mr. Murphy said, “our clinic proactively offers patients a prescription for quetiapine that they can fill if they are experiencing symptoms of steroid psychosis.”

Dr. Brown supported the new policy of alerting patients to the psychosis risk. “Counseling patients about common side effects is a good idea,” he said. “I have seen data suggesting that patients may be hesitant to report psychiatric symptoms with corticosteroids to their physicians. Letting them know about the potential for these kinds of side effects might make them more forthcoming in reporting this side effect.”

No study funding is reported. The study authors reported no disclosures. Dr. Brown has a National Institutes of Health grant for studying the effect of corticosteroids on the brain.
 

Several antiepileptic drugs (AEDs) are associated with an increased risk for priapism, new research suggests.

©Thinkstock

After analyzing U.S. adverse event reporting data, investigators found that among nearly 200 cases of priapism, a persistent, often painful erection unrelated to sexual interest or stimulation that lasts more than 4 hours, eight AEDs were associated with a positive “safety signal” for priapism.

These included valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine. Of these, valpromide had the largest association.

“Based on our results, we would recommend to clinicians to be cautious about the possibility of encountering priapism” in patients receiving the eight AEDs identified, lead researcher Ana Pejcic, PhD, department of pharmacology and toxicology, University of Kragujevac, Serbia, told meeting attendees.

If clinicians encounter such cases, they should be “reported to the regulatory authorities,” Dr. Pejcic added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

Noteworthy limitations

Dr. Pejcic told this news organization that the safety signal with AEDs “does not directly mean that a medicine has caused the reported adverse event” because an illness or other drug taken by the patient could be responsible instead.

She also noted that the U.S. Food and Drug Administration’s Adverse Event Reporting System relies on “spontaneous reports of adverse events,” which have multiple limitations.

These limitations include that the FDA “does not require that a causal relationship between a drug and event be proven, and reports do not always have enough information to properly evaluate an event.”

Nevertheless, Dr. Pejcic added that if a causal relationship was to be shown, the underlying mechanism could be linked to the pharmacological properties of the individual antiepileptic, such as altered alpha-1 adrenergic receptor expression or increased dopamine release.

Still, that would require “further evaluation in larger pharmacoepidemiological studies, with adjustment for potential confounding variables,” she said.
 

Replication needed

Priapism has recently been observed in case reports in association with the use of some AEDs. In addition, use of the drugs has been associated with hypo- and hypersexuality, as well as erectile and ejaculatory dysfunction.

Because the relationship between priapism and AED use “has not been well characterized,” the researchers mined data from the FDA’s Adverse Event Reporting System.

They examined entries from the first quarter of 2004 and the third quarter of 2020, focusing on 47 AEDs from the N03A subgroup of the Anatomical Therapeutic Chemical Classification System.

The researchers identified 8,122,037 cases for data analysis, of which 1,936 involved priapism as an adverse event. In total, 16 antiepileptic medications had at least one case of an adverse event involving priapism.

A positive safety signal was defined as a Proportional Reporting Ratio (PRR) of at least two, a chi-squared of at least four, or three or more cases. The signal was detected for valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine.

The largest association with priapism was with valpromide, at a PRR of 61.79. That was followed by PRR of 9.61 for brivaracetam, 7.28 for valproic acid, and 3.23 for topiramate.

“Considering that the proportionality analysis we applied in our study is used for hypothesis generation, our results will need to confirm in large cohorts and case-control studies,” said Dr. Pejcic.
 

New and important hypothesis?

Commenting on the study, Daniel Goldenholz, MD, PhD, instructor in the Division of Epilepsy, Beth Israel Deaconess Medical Center, Boston, said priapism is not something that practicing epileptologists are instructed “to look for.”

He noted that “the idea of looking for a hidden signal in a massive database like this is very appealing” because it could reveal patterns that were previously undetected.

However, the event rate in the study suggests priapism, which “in the right context would be considered a medical emergency, [is] relatively uncommon,” said Dr. Goldenholz, who was not involved with the research.

He noted that medications that could cause priapism, “such as antidepressants, blood pressure meds, and anticoagulants,” are commonly used by many people – including those with epilepsy.

It is consequently possible that “the finding from this study can be explained by comorbid medical problems,” Dr. Goldenholz said. This is particularly likely because many of the AEDs in question “have been on the market for decades,” he added.

“If a seemingly dangerous symptom would be happening as a result of one of these medications, it is quite surprising that it has not been noticed sooner,” he said.

Still, Dr. Goldenholz noted that it is “possible that these authors have a new and important hypothesis which must now be tested: Does priapism occur in patients with antiseizure medications when other causes are already ruled out?”

The investigators and Dr. Goldenholz have disclosed no relevant financial relationships.

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

Several antiepileptic drugs (AEDs) are associated with an increased risk for priapism, new research suggests.

©Thinkstock

After analyzing U.S. adverse event reporting data, investigators found that among nearly 200 cases of priapism, a persistent, often painful erection unrelated to sexual interest or stimulation that lasts more than 4 hours, eight AEDs were associated with a positive “safety signal” for priapism.

These included valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine. Of these, valpromide had the largest association.

“Based on our results, we would recommend to clinicians to be cautious about the possibility of encountering priapism” in patients receiving the eight AEDs identified, lead researcher Ana Pejcic, PhD, department of pharmacology and toxicology, University of Kragujevac, Serbia, told meeting attendees.

If clinicians encounter such cases, they should be “reported to the regulatory authorities,” Dr. Pejcic added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

Noteworthy limitations

Dr. Pejcic told this news organization that the safety signal with AEDs “does not directly mean that a medicine has caused the reported adverse event” because an illness or other drug taken by the patient could be responsible instead.

She also noted that the U.S. Food and Drug Administration’s Adverse Event Reporting System relies on “spontaneous reports of adverse events,” which have multiple limitations.

These limitations include that the FDA “does not require that a causal relationship between a drug and event be proven, and reports do not always have enough information to properly evaluate an event.”

Nevertheless, Dr. Pejcic added that if a causal relationship was to be shown, the underlying mechanism could be linked to the pharmacological properties of the individual antiepileptic, such as altered alpha-1 adrenergic receptor expression or increased dopamine release.

Still, that would require “further evaluation in larger pharmacoepidemiological studies, with adjustment for potential confounding variables,” she said.
 

Replication needed

Priapism has recently been observed in case reports in association with the use of some AEDs. In addition, use of the drugs has been associated with hypo- and hypersexuality, as well as erectile and ejaculatory dysfunction.

Because the relationship between priapism and AED use “has not been well characterized,” the researchers mined data from the FDA’s Adverse Event Reporting System.

They examined entries from the first quarter of 2004 and the third quarter of 2020, focusing on 47 AEDs from the N03A subgroup of the Anatomical Therapeutic Chemical Classification System.

The researchers identified 8,122,037 cases for data analysis, of which 1,936 involved priapism as an adverse event. In total, 16 antiepileptic medications had at least one case of an adverse event involving priapism.

A positive safety signal was defined as a Proportional Reporting Ratio (PRR) of at least two, a chi-squared of at least four, or three or more cases. The signal was detected for valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine.

The largest association with priapism was with valpromide, at a PRR of 61.79. That was followed by PRR of 9.61 for brivaracetam, 7.28 for valproic acid, and 3.23 for topiramate.

“Considering that the proportionality analysis we applied in our study is used for hypothesis generation, our results will need to confirm in large cohorts and case-control studies,” said Dr. Pejcic.
 

New and important hypothesis?

Commenting on the study, Daniel Goldenholz, MD, PhD, instructor in the Division of Epilepsy, Beth Israel Deaconess Medical Center, Boston, said priapism is not something that practicing epileptologists are instructed “to look for.”

He noted that “the idea of looking for a hidden signal in a massive database like this is very appealing” because it could reveal patterns that were previously undetected.

However, the event rate in the study suggests priapism, which “in the right context would be considered a medical emergency, [is] relatively uncommon,” said Dr. Goldenholz, who was not involved with the research.

He noted that medications that could cause priapism, “such as antidepressants, blood pressure meds, and anticoagulants,” are commonly used by many people – including those with epilepsy.

It is consequently possible that “the finding from this study can be explained by comorbid medical problems,” Dr. Goldenholz said. This is particularly likely because many of the AEDs in question “have been on the market for decades,” he added.

“If a seemingly dangerous symptom would be happening as a result of one of these medications, it is quite surprising that it has not been noticed sooner,” he said.

Still, Dr. Goldenholz noted that it is “possible that these authors have a new and important hypothesis which must now be tested: Does priapism occur in patients with antiseizure medications when other causes are already ruled out?”

The investigators and Dr. Goldenholz have disclosed no relevant financial relationships.

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

Several antiepileptic drugs (AEDs) are associated with an increased risk for priapism, new research suggests.

©Thinkstock

After analyzing U.S. adverse event reporting data, investigators found that among nearly 200 cases of priapism, a persistent, often painful erection unrelated to sexual interest or stimulation that lasts more than 4 hours, eight AEDs were associated with a positive “safety signal” for priapism.

These included valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine. Of these, valpromide had the largest association.

“Based on our results, we would recommend to clinicians to be cautious about the possibility of encountering priapism” in patients receiving the eight AEDs identified, lead researcher Ana Pejcic, PhD, department of pharmacology and toxicology, University of Kragujevac, Serbia, told meeting attendees.

If clinicians encounter such cases, they should be “reported to the regulatory authorities,” Dr. Pejcic added.

The findings were presented at the virtual congress of the European College of Neuropsychopharmacology.
 

Noteworthy limitations

Dr. Pejcic told this news organization that the safety signal with AEDs “does not directly mean that a medicine has caused the reported adverse event” because an illness or other drug taken by the patient could be responsible instead.

She also noted that the U.S. Food and Drug Administration’s Adverse Event Reporting System relies on “spontaneous reports of adverse events,” which have multiple limitations.

These limitations include that the FDA “does not require that a causal relationship between a drug and event be proven, and reports do not always have enough information to properly evaluate an event.”

Nevertheless, Dr. Pejcic added that if a causal relationship was to be shown, the underlying mechanism could be linked to the pharmacological properties of the individual antiepileptic, such as altered alpha-1 adrenergic receptor expression or increased dopamine release.

Still, that would require “further evaluation in larger pharmacoepidemiological studies, with adjustment for potential confounding variables,” she said.
 

Replication needed

Priapism has recently been observed in case reports in association with the use of some AEDs. In addition, use of the drugs has been associated with hypo- and hypersexuality, as well as erectile and ejaculatory dysfunction.

Because the relationship between priapism and AED use “has not been well characterized,” the researchers mined data from the FDA’s Adverse Event Reporting System.

They examined entries from the first quarter of 2004 and the third quarter of 2020, focusing on 47 AEDs from the N03A subgroup of the Anatomical Therapeutic Chemical Classification System.

The researchers identified 8,122,037 cases for data analysis, of which 1,936 involved priapism as an adverse event. In total, 16 antiepileptic medications had at least one case of an adverse event involving priapism.

A positive safety signal was defined as a Proportional Reporting Ratio (PRR) of at least two, a chi-squared of at least four, or three or more cases. The signal was detected for valpromide, brivaracetam, valproic acid, topiramate, oxcarbazepine, clonazepam, levetiracetam, and carbamazepine.

The largest association with priapism was with valpromide, at a PRR of 61.79. That was followed by PRR of 9.61 for brivaracetam, 7.28 for valproic acid, and 3.23 for topiramate.

“Considering that the proportionality analysis we applied in our study is used for hypothesis generation, our results will need to confirm in large cohorts and case-control studies,” said Dr. Pejcic.
 

New and important hypothesis?

Commenting on the study, Daniel Goldenholz, MD, PhD, instructor in the Division of Epilepsy, Beth Israel Deaconess Medical Center, Boston, said priapism is not something that practicing epileptologists are instructed “to look for.”

He noted that “the idea of looking for a hidden signal in a massive database like this is very appealing” because it could reveal patterns that were previously undetected.

However, the event rate in the study suggests priapism, which “in the right context would be considered a medical emergency, [is] relatively uncommon,” said Dr. Goldenholz, who was not involved with the research.

He noted that medications that could cause priapism, “such as antidepressants, blood pressure meds, and anticoagulants,” are commonly used by many people – including those with epilepsy.

It is consequently possible that “the finding from this study can be explained by comorbid medical problems,” Dr. Goldenholz said. This is particularly likely because many of the AEDs in question “have been on the market for decades,” he added.

“If a seemingly dangerous symptom would be happening as a result of one of these medications, it is quite surprising that it has not been noticed sooner,” he said.

Still, Dr. Goldenholz noted that it is “possible that these authors have a new and important hypothesis which must now be tested: Does priapism occur in patients with antiseizure medications when other causes are already ruled out?”

The investigators and Dr. Goldenholz have disclosed no relevant financial relationships.

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

“We each come to public service in our own unique way,” ADM Rachel Levine, MD, Assistant Secretary for Health at the US Department of Health and Human Services (HHS), told the Senate Health, Education, Labor and Pensions Committee at her confirmation hearing in February 2021.

In her case, unique and history-making. Levine was confirmed on Tuesday as the first-ever openly transgender—and firstwoman—four-star admiral in the history of the US Public Health Service Commissioned Corps. She is also the first openly transgender four-star officer and the first openly transgender person to be confirmed by the Senate. In fact, she is the nation’s highest-ranking openly transgender official—the first such across any of the eight uniformed services.

All those firsts aside, in her confirmation hearing remarks, ADM. Levine said, “At its core, my career has been about helping people live healthy lives.” She began her career at Mt. Sinai Medical Center in New York, in pediatric and adolescent medicine, focusing on mental and physical health. Moving to the Penn State College of Medicine, ADM Levine was a professor of pediatrics and psychiatry and vice-chair for clinical affairs for the Department of Pediatrics. At Penn State, she initiated the Division of Adolescent Medicine for the care of complex teens with medical and psychological problems. As chief of the Division of Adolescent Medicine and Eating Disorders at Penn State Hershey Medical Center, she also founded an eating disorders program, offering multidisciplinary treatment for children, adolescents, and adults.

In 2015, Pennsylvania Governor Tom Wolf nominated ADM Levine to be Physician General of the Commonwealth of Pennsylvania and she was confirmed unanimously by the state senate. In 2018, she was named Pennsylvania’s Secretary of Health. In these roles, she tackled the state’s massive opioid misuse and overdose crisis. She focused on opioid stewardship, developed continuing medical education programs, and established prescribing guidelines and a “robust” prescription drug monitoring program. She traveled extensively throughout small communities, doing public events with local officials and residents to talk about opioid abuse. The efforts began, slowly, to pay off. In 2015, 3,383 people died of drug overdose in Pennsylvania, a 23% increase from 2014. By 2018, 65% of drug overdose deaths involved opioids, but the total number of deaths fell to 2,866.

One of her most significant accomplishments as Physician General, Levine said, was to issue the first-ever statewide standing order for distribution of the anti-overdose drug naloxone, allowing law enforcement to carry the drug and Pennsylvania citizens to buy itover the counter. According to the Pennsylvania Opioid Data Dashboard, between January 1, 2018, and October 9, 2021, 62,954 doses of naloxone were administered by EMS.

In another of Levine’s projects, the Pennsylvania Rural Health Model, the goal was to move rural hospitals from fee-for-service models to global budget payments, which she said, “aligned incentives for providers to deliver value-based care and for rural hospitals to transform their care to better meet community health needs.”

Working in tandem with HHS, Levine’s teams also set up a maternal mortality review committee “to better understand and respond to the causes of maternal deaths,” and worked to improve childhood immunization rates.

“Of course, our focus changed dramatically last year,” Levine said, “and COVID-19 became my most urgent and primary focus.” She concentrated on three key priorities: containment with expansion of testing and contact tracing; mitigation with masks and distancing; and medical countermeasures, including monoclonal antibodies and vaccines. To carry out the strategies, she oversaw a health equity task force, which included community stakeholders such as the Black Coalition Against COVID-19, the Latino Connection, and a faith-based program that allowed people to get tested at their places of worship.

When lesbian, gay, bisexual, transgender, queer; lesbian, gay, bisexual, transgender, queer (LGBTQ+) advocates charged that states were not collecting data early in the pandemic on sexual orientation or gender identity, in another historic move, Levine announced in March 2020 that Pennsylvania would begin collecting demographic data on the coronavirus, making it the first state in the country to do so.

Levine has garnered praise from many sources. “This is a proud moment for us,” HHS Secretary Xavier Becerra said in a statement, calling her a “cherished and critical partner in our work to build a healthier America.” Alphonso David, then president of the Human Rights Campaign, said in a statement that Levine’s nomination to be the HHS Assistant Secretary for Health represented “real change” in the government’s approach to the coronavirus and LGBTQ+ health issues. Levine “led Pennsylvania’s public health response to the COVID-19 pandemic superbly,” he said.

She has also triggered a significant amount of outrage in conservative quarters. She was routinely castigated for her early actions in the pandemic. Writing for The American Spectator in May 2020, Paul Kengor, a former UPMC researcher, said UPMC’s overall handling of the virus was “impressive and inspired confidence.” However, tracking the data on fatalities, he said, he found the disproportionate number of deaths in nursing homes “alarming and strange.” Citing an investigative article in the Bucks County Courier Times, he blamed Pennsylvania officials—including Levine—for guidelines that directed licensed long-term care facilities to continue admitting new patients, including those discharged from hospitals back to nursing homes. However, Kengor claimed, the “partisan press” would protect Wolf and Levine: “Levine is a liberal darling as the nation’s first (and arguably highest-ranking) transgender public official.”

At the February 2021 federal confirmation hearing, Levine was pressed on data discrepancies in Pennsylvania’s public reports on nursing home coronavirus deaths and cases. Sen. Susan Collins (R-ME) cited Spotlight PA reporting that found weekly reports released by the state health department were consistently missing data for more than 100 of the 693 nursing homes. Levine, in response, pointed to lags in the state’s electronic death reporting system and to slow uploads. Pennsylvania health officials also referred to a state law that prohibits the release of disease records by state or local authorities.

In a June 2020 opinion article, Levine wrote that the Pennsylvania Health Department had followed Centers for Disease Control and Prevention (CDC) guidance, including limiting outside people from entering long-term care facilities. The Pennsylvania Health Department also sent thousands of shipments of personal protective equipment and conducted virtual inspections, including on-site inspections as warranted.

Despite those efforts, Levine said, “staff members who have dedicated their lives to caring for these vulnerable Pennsylvanians unknowingly contracted COVID-19 in their communities and carried it into these facilities.” She pointed out that residents who returned from hospitals had been isolated if they contracted COVID-19. Patients returning to nursing homes did not introduce COVID-19, Levine said, “because it was there that they first came into contact with the virus.” Moreover, those patients were isolated, just as they had been before they required hospital-level care, she added.

When a long-term care facility reports a case of COVID-19, Levine noted, the Pennsylvania Health Department considers it an outbreak and offers a variety of resources to the facility, including mitigation measures and the services of an infection control consultant, or even deploying the Pennsylvania National Guard to assist with staffing. Pennsylvania cannot force facilities to accept these services, she pointed out, but some refuse out of fear of receiving citations. “[O]ur top priority,” Levine said, “is halting COVID-19, not issuing citations.”

Her decisions on health restrictions and closures to combat the pandemic created controversy in the state, but much of the criticism also took aim at Levine identifying openly as transgender. Her selection as the first openly transgender official to be confirmed by the Senate has been targeted by conservative groups as a political gesture by President Biden. Tom Fitton, president of the conservative legal group Judicial Watch, posted on Facebook: “Biden gang playing quota politics with public health service.”

In her remarks to the Senate committee, however, Levine calmly noted that her appointment by Gov. Wolf was confirmed unanimously and that she was approved twice more on a bipartisan basis to be Secretary of Health. She met with nearly all of the senators personally. Her confirmation by the senate Republicans was particularly meaningful, she told NBC Out. “[They] judged me strictly on my professional qualifications.”

Social media has made much of Levine’s transgender identification, both pro and con. The Twitterverse, predictably, is packed with anti-Levine and anti-LGBTQ+ rants. But Levine’s rise has energized the LGBTQ+ community, who hail it as a breakthrough. Scout, the single-named executive director of the National LGBT Cancer Network, said, “The fact that she is trans is an inspiration for the many of us who have never had a role model this senior before.” Levine herself is determined to be a “beacon” in representing the LGBTQ+ community in her latest role at the corps: “Diversity makes us stronger,” she said.

“What people don’t understand, they fear,” Levine, who is a frequent public speaker, has said. “The more we can educate people and show that we’re productive members of the community—with families, lives, careers—that helps people understand us better.” That includes education of medical professionals. “We need to do a better job educating medical students about LGBT issues and transgender medicine,” she told NBC Out. She may need to start with the members of Congress. At Levine’s confirmation hearing to serve as Assistant Secretary for Health, Sen. Rand Paul, for instance, compared transgender surgery to “genital mutilation.”

HHS Secretary Becerra called Levine’s appointment as the first openly transgender four-star officer “a giant step forward toward equality as a nation.” US Surgeon General VADM Vivek Murthy, MD, MBA, said her appointment represents “an important step towards a more inclusive future and her service will undoubtedly advance the US Public Health Service Commissioned Corps’ mission to protect, promote, and advance the health and safety of our nation.”

Levine told the Senate committee, “There is still so much more to do.”

“We each come to public service in our own unique way,” ADM Rachel Levine, MD, Assistant Secretary for Health at the US Department of Health and Human Services (HHS), told the Senate Health, Education, Labor and Pensions Committee at her confirmation hearing in February 2021.

In her case, unique and history-making. Levine was confirmed on Tuesday as the first-ever openly transgender—and firstwoman—four-star admiral in the history of the US Public Health Service Commissioned Corps. She is also the first openly transgender four-star officer and the first openly transgender person to be confirmed by the Senate. In fact, she is the nation’s highest-ranking openly transgender official—the first such across any of the eight uniformed services.

All those firsts aside, in her confirmation hearing remarks, ADM. Levine said, “At its core, my career has been about helping people live healthy lives.” She began her career at Mt. Sinai Medical Center in New York, in pediatric and adolescent medicine, focusing on mental and physical health. Moving to the Penn State College of Medicine, ADM Levine was a professor of pediatrics and psychiatry and vice-chair for clinical affairs for the Department of Pediatrics. At Penn State, she initiated the Division of Adolescent Medicine for the care of complex teens with medical and psychological problems. As chief of the Division of Adolescent Medicine and Eating Disorders at Penn State Hershey Medical Center, she also founded an eating disorders program, offering multidisciplinary treatment for children, adolescents, and adults.

In 2015, Pennsylvania Governor Tom Wolf nominated ADM Levine to be Physician General of the Commonwealth of Pennsylvania and she was confirmed unanimously by the state senate. In 2018, she was named Pennsylvania’s Secretary of Health. In these roles, she tackled the state’s massive opioid misuse and overdose crisis. She focused on opioid stewardship, developed continuing medical education programs, and established prescribing guidelines and a “robust” prescription drug monitoring program. She traveled extensively throughout small communities, doing public events with local officials and residents to talk about opioid abuse. The efforts began, slowly, to pay off. In 2015, 3,383 people died of drug overdose in Pennsylvania, a 23% increase from 2014. By 2018, 65% of drug overdose deaths involved opioids, but the total number of deaths fell to 2,866.

One of her most significant accomplishments as Physician General, Levine said, was to issue the first-ever statewide standing order for distribution of the anti-overdose drug naloxone, allowing law enforcement to carry the drug and Pennsylvania citizens to buy itover the counter. According to the Pennsylvania Opioid Data Dashboard, between January 1, 2018, and October 9, 2021, 62,954 doses of naloxone were administered by EMS.

In another of Levine’s projects, the Pennsylvania Rural Health Model, the goal was to move rural hospitals from fee-for-service models to global budget payments, which she said, “aligned incentives for providers to deliver value-based care and for rural hospitals to transform their care to better meet community health needs.”

Working in tandem with HHS, Levine’s teams also set up a maternal mortality review committee “to better understand and respond to the causes of maternal deaths,” and worked to improve childhood immunization rates.

“Of course, our focus changed dramatically last year,” Levine said, “and COVID-19 became my most urgent and primary focus.” She concentrated on three key priorities: containment with expansion of testing and contact tracing; mitigation with masks and distancing; and medical countermeasures, including monoclonal antibodies and vaccines. To carry out the strategies, she oversaw a health equity task force, which included community stakeholders such as the Black Coalition Against COVID-19, the Latino Connection, and a faith-based program that allowed people to get tested at their places of worship.

When lesbian, gay, bisexual, transgender, queer; lesbian, gay, bisexual, transgender, queer (LGBTQ+) advocates charged that states were not collecting data early in the pandemic on sexual orientation or gender identity, in another historic move, Levine announced in March 2020 that Pennsylvania would begin collecting demographic data on the coronavirus, making it the first state in the country to do so.

Levine has garnered praise from many sources. “This is a proud moment for us,” HHS Secretary Xavier Becerra said in a statement, calling her a “cherished and critical partner in our work to build a healthier America.” Alphonso David, then president of the Human Rights Campaign, said in a statement that Levine’s nomination to be the HHS Assistant Secretary for Health represented “real change” in the government’s approach to the coronavirus and LGBTQ+ health issues. Levine “led Pennsylvania’s public health response to the COVID-19 pandemic superbly,” he said.

She has also triggered a significant amount of outrage in conservative quarters. She was routinely castigated for her early actions in the pandemic. Writing for The American Spectator in May 2020, Paul Kengor, a former UPMC researcher, said UPMC’s overall handling of the virus was “impressive and inspired confidence.” However, tracking the data on fatalities, he said, he found the disproportionate number of deaths in nursing homes “alarming and strange.” Citing an investigative article in the Bucks County Courier Times, he blamed Pennsylvania officials—including Levine—for guidelines that directed licensed long-term care facilities to continue admitting new patients, including those discharged from hospitals back to nursing homes. However, Kengor claimed, the “partisan press” would protect Wolf and Levine: “Levine is a liberal darling as the nation’s first (and arguably highest-ranking) transgender public official.”

At the February 2021 federal confirmation hearing, Levine was pressed on data discrepancies in Pennsylvania’s public reports on nursing home coronavirus deaths and cases. Sen. Susan Collins (R-ME) cited Spotlight PA reporting that found weekly reports released by the state health department were consistently missing data for more than 100 of the 693 nursing homes. Levine, in response, pointed to lags in the state’s electronic death reporting system and to slow uploads. Pennsylvania health officials also referred to a state law that prohibits the release of disease records by state or local authorities.

In a June 2020 opinion article, Levine wrote that the Pennsylvania Health Department had followed Centers for Disease Control and Prevention (CDC) guidance, including limiting outside people from entering long-term care facilities. The Pennsylvania Health Department also sent thousands of shipments of personal protective equipment and conducted virtual inspections, including on-site inspections as warranted.

Despite those efforts, Levine said, “staff members who have dedicated their lives to caring for these vulnerable Pennsylvanians unknowingly contracted COVID-19 in their communities and carried it into these facilities.” She pointed out that residents who returned from hospitals had been isolated if they contracted COVID-19. Patients returning to nursing homes did not introduce COVID-19, Levine said, “because it was there that they first came into contact with the virus.” Moreover, those patients were isolated, just as they had been before they required hospital-level care, she added.

When a long-term care facility reports a case of COVID-19, Levine noted, the Pennsylvania Health Department considers it an outbreak and offers a variety of resources to the facility, including mitigation measures and the services of an infection control consultant, or even deploying the Pennsylvania National Guard to assist with staffing. Pennsylvania cannot force facilities to accept these services, she pointed out, but some refuse out of fear of receiving citations. “[O]ur top priority,” Levine said, “is halting COVID-19, not issuing citations.”

Her decisions on health restrictions and closures to combat the pandemic created controversy in the state, but much of the criticism also took aim at Levine identifying openly as transgender. Her selection as the first openly transgender official to be confirmed by the Senate has been targeted by conservative groups as a political gesture by President Biden. Tom Fitton, president of the conservative legal group Judicial Watch, posted on Facebook: “Biden gang playing quota politics with public health service.”

In her remarks to the Senate committee, however, Levine calmly noted that her appointment by Gov. Wolf was confirmed unanimously and that she was approved twice more on a bipartisan basis to be Secretary of Health. She met with nearly all of the senators personally. Her confirmation by the senate Republicans was particularly meaningful, she told NBC Out. “[They] judged me strictly on my professional qualifications.”

Social media has made much of Levine’s transgender identification, both pro and con. The Twitterverse, predictably, is packed with anti-Levine and anti-LGBTQ+ rants. But Levine’s rise has energized the LGBTQ+ community, who hail it as a breakthrough. Scout, the single-named executive director of the National LGBT Cancer Network, said, “The fact that she is trans is an inspiration for the many of us who have never had a role model this senior before.” Levine herself is determined to be a “beacon” in representing the LGBTQ+ community in her latest role at the corps: “Diversity makes us stronger,” she said.

“What people don’t understand, they fear,” Levine, who is a frequent public speaker, has said. “The more we can educate people and show that we’re productive members of the community—with families, lives, careers—that helps people understand us better.” That includes education of medical professionals. “We need to do a better job educating medical students about LGBT issues and transgender medicine,” she told NBC Out. She may need to start with the members of Congress. At Levine’s confirmation hearing to serve as Assistant Secretary for Health, Sen. Rand Paul, for instance, compared transgender surgery to “genital mutilation.”

HHS Secretary Becerra called Levine’s appointment as the first openly transgender four-star officer “a giant step forward toward equality as a nation.” US Surgeon General VADM Vivek Murthy, MD, MBA, said her appointment represents “an important step towards a more inclusive future and her service will undoubtedly advance the US Public Health Service Commissioned Corps’ mission to protect, promote, and advance the health and safety of our nation.”

Levine told the Senate committee, “There is still so much more to do.”

“We each come to public service in our own unique way,” ADM Rachel Levine, MD, Assistant Secretary for Health at the US Department of Health and Human Services (HHS), told the Senate Health, Education, Labor and Pensions Committee at her confirmation hearing in February 2021.

In her case, unique and history-making. Levine was confirmed on Tuesday as the first-ever openly transgender—and firstwoman—four-star admiral in the history of the US Public Health Service Commissioned Corps. She is also the first openly transgender four-star officer and the first openly transgender person to be confirmed by the Senate. In fact, she is the nation’s highest-ranking openly transgender official—the first such across any of the eight uniformed services.

All those firsts aside, in her confirmation hearing remarks, ADM. Levine said, “At its core, my career has been about helping people live healthy lives.” She began her career at Mt. Sinai Medical Center in New York, in pediatric and adolescent medicine, focusing on mental and physical health. Moving to the Penn State College of Medicine, ADM Levine was a professor of pediatrics and psychiatry and vice-chair for clinical affairs for the Department of Pediatrics. At Penn State, she initiated the Division of Adolescent Medicine for the care of complex teens with medical and psychological problems. As chief of the Division of Adolescent Medicine and Eating Disorders at Penn State Hershey Medical Center, she also founded an eating disorders program, offering multidisciplinary treatment for children, adolescents, and adults.

In 2015, Pennsylvania Governor Tom Wolf nominated ADM Levine to be Physician General of the Commonwealth of Pennsylvania and she was confirmed unanimously by the state senate. In 2018, she was named Pennsylvania’s Secretary of Health. In these roles, she tackled the state’s massive opioid misuse and overdose crisis. She focused on opioid stewardship, developed continuing medical education programs, and established prescribing guidelines and a “robust” prescription drug monitoring program. She traveled extensively throughout small communities, doing public events with local officials and residents to talk about opioid abuse. The efforts began, slowly, to pay off. In 2015, 3,383 people died of drug overdose in Pennsylvania, a 23% increase from 2014. By 2018, 65% of drug overdose deaths involved opioids, but the total number of deaths fell to 2,866.

One of her most significant accomplishments as Physician General, Levine said, was to issue the first-ever statewide standing order for distribution of the anti-overdose drug naloxone, allowing law enforcement to carry the drug and Pennsylvania citizens to buy itover the counter. According to the Pennsylvania Opioid Data Dashboard, between January 1, 2018, and October 9, 2021, 62,954 doses of naloxone were administered by EMS.

In another of Levine’s projects, the Pennsylvania Rural Health Model, the goal was to move rural hospitals from fee-for-service models to global budget payments, which she said, “aligned incentives for providers to deliver value-based care and for rural hospitals to transform their care to better meet community health needs.”

Working in tandem with HHS, Levine’s teams also set up a maternal mortality review committee “to better understand and respond to the causes of maternal deaths,” and worked to improve childhood immunization rates.

“Of course, our focus changed dramatically last year,” Levine said, “and COVID-19 became my most urgent and primary focus.” She concentrated on three key priorities: containment with expansion of testing and contact tracing; mitigation with masks and distancing; and medical countermeasures, including monoclonal antibodies and vaccines. To carry out the strategies, she oversaw a health equity task force, which included community stakeholders such as the Black Coalition Against COVID-19, the Latino Connection, and a faith-based program that allowed people to get tested at their places of worship.

When lesbian, gay, bisexual, transgender, queer; lesbian, gay, bisexual, transgender, queer (LGBTQ+) advocates charged that states were not collecting data early in the pandemic on sexual orientation or gender identity, in another historic move, Levine announced in March 2020 that Pennsylvania would begin collecting demographic data on the coronavirus, making it the first state in the country to do so.

Levine has garnered praise from many sources. “This is a proud moment for us,” HHS Secretary Xavier Becerra said in a statement, calling her a “cherished and critical partner in our work to build a healthier America.” Alphonso David, then president of the Human Rights Campaign, said in a statement that Levine’s nomination to be the HHS Assistant Secretary for Health represented “real change” in the government’s approach to the coronavirus and LGBTQ+ health issues. Levine “led Pennsylvania’s public health response to the COVID-19 pandemic superbly,” he said.

She has also triggered a significant amount of outrage in conservative quarters. She was routinely castigated for her early actions in the pandemic. Writing for The American Spectator in May 2020, Paul Kengor, a former UPMC researcher, said UPMC’s overall handling of the virus was “impressive and inspired confidence.” However, tracking the data on fatalities, he said, he found the disproportionate number of deaths in nursing homes “alarming and strange.” Citing an investigative article in the Bucks County Courier Times, he blamed Pennsylvania officials—including Levine—for guidelines that directed licensed long-term care facilities to continue admitting new patients, including those discharged from hospitals back to nursing homes. However, Kengor claimed, the “partisan press” would protect Wolf and Levine: “Levine is a liberal darling as the nation’s first (and arguably highest-ranking) transgender public official.”

At the February 2021 federal confirmation hearing, Levine was pressed on data discrepancies in Pennsylvania’s public reports on nursing home coronavirus deaths and cases. Sen. Susan Collins (R-ME) cited Spotlight PA reporting that found weekly reports released by the state health department were consistently missing data for more than 100 of the 693 nursing homes. Levine, in response, pointed to lags in the state’s electronic death reporting system and to slow uploads. Pennsylvania health officials also referred to a state law that prohibits the release of disease records by state or local authorities.

In a June 2020 opinion article, Levine wrote that the Pennsylvania Health Department had followed Centers for Disease Control and Prevention (CDC) guidance, including limiting outside people from entering long-term care facilities. The Pennsylvania Health Department also sent thousands of shipments of personal protective equipment and conducted virtual inspections, including on-site inspections as warranted.

Despite those efforts, Levine said, “staff members who have dedicated their lives to caring for these vulnerable Pennsylvanians unknowingly contracted COVID-19 in their communities and carried it into these facilities.” She pointed out that residents who returned from hospitals had been isolated if they contracted COVID-19. Patients returning to nursing homes did not introduce COVID-19, Levine said, “because it was there that they first came into contact with the virus.” Moreover, those patients were isolated, just as they had been before they required hospital-level care, she added.

When a long-term care facility reports a case of COVID-19, Levine noted, the Pennsylvania Health Department considers it an outbreak and offers a variety of resources to the facility, including mitigation measures and the services of an infection control consultant, or even deploying the Pennsylvania National Guard to assist with staffing. Pennsylvania cannot force facilities to accept these services, she pointed out, but some refuse out of fear of receiving citations. “[O]ur top priority,” Levine said, “is halting COVID-19, not issuing citations.”

Her decisions on health restrictions and closures to combat the pandemic created controversy in the state, but much of the criticism also took aim at Levine identifying openly as transgender. Her selection as the first openly transgender official to be confirmed by the Senate has been targeted by conservative groups as a political gesture by President Biden. Tom Fitton, president of the conservative legal group Judicial Watch, posted on Facebook: “Biden gang playing quota politics with public health service.”

In her remarks to the Senate committee, however, Levine calmly noted that her appointment by Gov. Wolf was confirmed unanimously and that she was approved twice more on a bipartisan basis to be Secretary of Health. She met with nearly all of the senators personally. Her confirmation by the senate Republicans was particularly meaningful, she told NBC Out. “[They] judged me strictly on my professional qualifications.”

Social media has made much of Levine’s transgender identification, both pro and con. The Twitterverse, predictably, is packed with anti-Levine and anti-LGBTQ+ rants. But Levine’s rise has energized the LGBTQ+ community, who hail it as a breakthrough. Scout, the single-named executive director of the National LGBT Cancer Network, said, “The fact that she is trans is an inspiration for the many of us who have never had a role model this senior before.” Levine herself is determined to be a “beacon” in representing the LGBTQ+ community in her latest role at the corps: “Diversity makes us stronger,” she said.

“What people don’t understand, they fear,” Levine, who is a frequent public speaker, has said. “The more we can educate people and show that we’re productive members of the community—with families, lives, careers—that helps people understand us better.” That includes education of medical professionals. “We need to do a better job educating medical students about LGBT issues and transgender medicine,” she told NBC Out. She may need to start with the members of Congress. At Levine’s confirmation hearing to serve as Assistant Secretary for Health, Sen. Rand Paul, for instance, compared transgender surgery to “genital mutilation.”

HHS Secretary Becerra called Levine’s appointment as the first openly transgender four-star officer “a giant step forward toward equality as a nation.” US Surgeon General VADM Vivek Murthy, MD, MBA, said her appointment represents “an important step towards a more inclusive future and her service will undoubtedly advance the US Public Health Service Commissioned Corps’ mission to protect, promote, and advance the health and safety of our nation.”

Levine told the Senate committee, “There is still so much more to do.”

Most patients with advanced chronic kidney disease (CKD) and non–ST-elevation myocardial infarction (NSTEMI) fare better with coronary angiography with and without revascularization than with medical therapy, a large nationwide study suggests.

Bruce Jancin/MDedge News

“Invasive management was associated with lower mortality, major adverse cardiovascular events (MACE), and need for revascularization, with a minimal increased risk of in-hospital, postprocedural acute kidney injury (AKI) requiring dialysis and major bleeding,” said lead researcher Ankur Kalra, MD, Cleveland Clinic.

Also, similar post-discharge safety outcomes were seen at 6 months, he said in an online presentation of “key abstracts” released in advance of next month’s Transcatheter Cardiovascular Therapeutics (TCT) 2021 hybrid meeting.

Advanced CKD is an independent predictor of mortality and morbidity in patients with NSTEMI. In CKD, however, current guidelines lack evidence on the efficacy and safety of invasive versus medical management, he noted.

A rare randomized clinical trial in this high-risk population, ISCHEMIA-CKD, recently found no benefit and an increase in stroke with initial invasive management compared with optimal medical therapy.

Session co-moderator Ziad A. Ali, MD, DPhil, St. Francis Hospital & Heart Center, New York, said the current study is “incredibly clinically impactful and answers a question that’s very difficult to answer because these patients aren’t randomized in randomized controlled trials, and there’s a general avoidance, which we’ve now coined ‘renalism,’ like racism, where people don’t really want to touch these patients.”

He questioned, however, how the authors reconcile the results of ISCHEMIA-CKD, a “small but meaningful randomized controlled trial,” with their findings from a large dataset. “Perhaps this is all selection bias, even though the numbers are very large.”

Dr. Kalra replied that ISCHEMIA-CKD examined stable ischemic heart disease, whereas they looked at NSTEMI. “Even though it may fall under the same rubric, I truly believe it is a different set of patients – they are at a heightened risk for future cardiovascular events and have had an acute coronary event.”

For the study, ICD-10 coding data from 2016-2018 in the Nationwide Readmission Database was used to identify NSTEMI patients with CKD stages 3, 4, 5, and end-stage renal disease (ESRD). A total of 141,052 patients were available for in-hospital outcomes and 133,642 patients for post-discharge outcomes.

In-hospital and 6-month mortality – the study’s primary outcome – favored invasive management across all CKD stages and ESRD but did not achieve statistical significance for CKD stage 5. The number needed to treat (NNT) for CKD stages 3, 4, 5, and ESRD were 26, 56, 48, and 18, respectively.

Six-month MACE, including mortality, MI, stroke, and heart failure readmission, was significantly better in all groups with invasive management.

Kaplan-Meier curves for mortality showed similar benefits with an invasive strategy across CKD stages, again barring stage 5 disease. 

With regard to in-hospital safety, stroke rates were not significantly different between the two treatment strategies across all groups.

Rates of AKI requiring dialysis, however, were lower with medical versus invasive management for CKD stage 3 (0.43% vs. 0.6%; hazard ratio, 1.39; P = .016), stage 4 (1.2% vs. 2.0%; HR 1.87; P < .001), and stage 5 (3.7% vs. 4.3%; HR 1.17; P = .527). The number needed to harm (NNH) was 588 for CKD 3 and 125 for CKD 4.

Major bleeding, defined as requiring transfusion, was lower with medical management for all CKD stages but not for ESRD. The rates are as follows:

• CKD stage 3: 2.5% vs. 2.8% (HR, 1.11; P = .078; NNH = 333)
• CKD stage 4: 2.9% vs. 4.0% (HR, 1.42; P < .001; NNH = 91)
• CKD stage 5: 2.2% vs. 4.7% (HR, 2.17; P = .008; NNH = 40)
• ESRD: 3.4% vs. 3.3% (HR, 0.97; P = .709)

“The risk of AKI requiring dialysis and bleeding, as has been shown previously in other studies, was high, but the number needed to harm was also high,” observed Dr. Kalra.

A separate analysis showed no difference in rates of AKI requiring dialysis among patients with CKD stages 3 and 4 who underwent angiography without revascularization and their peers who were medically managed.

Rates of the composite safety outcome of vascular complications, major bleeding, AKI, or stroke readmission at 6 months were not significantly different for invasive versus medical management for CKD stage 3 (both 3.3%), stage 4 (4.5% and 4.2%), stage 5 (3.9% vs. 4.3%), and ESRD (2.3% vs. 2.1%).

Besides the inherent limitations of observational studies and potential for selection bias, Dr. Kalra pointed out that the analysis relied on coding data for exact glomerular filtration rates and lacked information on contrast use, crystalloids before the procedure, and nephrotoxic medication use before or during admission. Out-of-hospital mortality was also not available in the database.

Co-moderator Allen Jeremias, MD, also with St. Francis Hospital & Heart Center, said one of the study’s strengths was that it included all comers, unlike randomized trials that typically exclude the highest risk patients.

“So, when we do these trials it’s very difficult to find the right balance, whereas this is a real-world analysis including everybody, and I think the benefits are clearly demonstrated,” he said. “So I think I’m bullish on doing complex [percutaneous coronary intervention] PCI in this patient population.”

Dr. Kalra reports having no relevant financial relationships.

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

Most patients with advanced chronic kidney disease (CKD) and non–ST-elevation myocardial infarction (NSTEMI) fare better with coronary angiography with and without revascularization than with medical therapy, a large nationwide study suggests.

Bruce Jancin/MDedge News

“Invasive management was associated with lower mortality, major adverse cardiovascular events (MACE), and need for revascularization, with a minimal increased risk of in-hospital, postprocedural acute kidney injury (AKI) requiring dialysis and major bleeding,” said lead researcher Ankur Kalra, MD, Cleveland Clinic.

Also, similar post-discharge safety outcomes were seen at 6 months, he said in an online presentation of “key abstracts” released in advance of next month’s Transcatheter Cardiovascular Therapeutics (TCT) 2021 hybrid meeting.

Advanced CKD is an independent predictor of mortality and morbidity in patients with NSTEMI. In CKD, however, current guidelines lack evidence on the efficacy and safety of invasive versus medical management, he noted.

A rare randomized clinical trial in this high-risk population, ISCHEMIA-CKD, recently found no benefit and an increase in stroke with initial invasive management compared with optimal medical therapy.

Session co-moderator Ziad A. Ali, MD, DPhil, St. Francis Hospital & Heart Center, New York, said the current study is “incredibly clinically impactful and answers a question that’s very difficult to answer because these patients aren’t randomized in randomized controlled trials, and there’s a general avoidance, which we’ve now coined ‘renalism,’ like racism, where people don’t really want to touch these patients.”

He questioned, however, how the authors reconcile the results of ISCHEMIA-CKD, a “small but meaningful randomized controlled trial,” with their findings from a large dataset. “Perhaps this is all selection bias, even though the numbers are very large.”

Dr. Kalra replied that ISCHEMIA-CKD examined stable ischemic heart disease, whereas they looked at NSTEMI. “Even though it may fall under the same rubric, I truly believe it is a different set of patients – they are at a heightened risk for future cardiovascular events and have had an acute coronary event.”

For the study, ICD-10 coding data from 2016-2018 in the Nationwide Readmission Database was used to identify NSTEMI patients with CKD stages 3, 4, 5, and end-stage renal disease (ESRD). A total of 141,052 patients were available for in-hospital outcomes and 133,642 patients for post-discharge outcomes.

In-hospital and 6-month mortality – the study’s primary outcome – favored invasive management across all CKD stages and ESRD but did not achieve statistical significance for CKD stage 5. The number needed to treat (NNT) for CKD stages 3, 4, 5, and ESRD were 26, 56, 48, and 18, respectively.

Six-month MACE, including mortality, MI, stroke, and heart failure readmission, was significantly better in all groups with invasive management.

Kaplan-Meier curves for mortality showed similar benefits with an invasive strategy across CKD stages, again barring stage 5 disease. 

With regard to in-hospital safety, stroke rates were not significantly different between the two treatment strategies across all groups.

Rates of AKI requiring dialysis, however, were lower with medical versus invasive management for CKD stage 3 (0.43% vs. 0.6%; hazard ratio, 1.39; P = .016), stage 4 (1.2% vs. 2.0%; HR 1.87; P < .001), and stage 5 (3.7% vs. 4.3%; HR 1.17; P = .527). The number needed to harm (NNH) was 588 for CKD 3 and 125 for CKD 4.

Major bleeding, defined as requiring transfusion, was lower with medical management for all CKD stages but not for ESRD. The rates are as follows:

• CKD stage 3: 2.5% vs. 2.8% (HR, 1.11; P = .078; NNH = 333)
• CKD stage 4: 2.9% vs. 4.0% (HR, 1.42; P < .001; NNH = 91)
• CKD stage 5: 2.2% vs. 4.7% (HR, 2.17; P = .008; NNH = 40)
• ESRD: 3.4% vs. 3.3% (HR, 0.97; P = .709)

“The risk of AKI requiring dialysis and bleeding, as has been shown previously in other studies, was high, but the number needed to harm was also high,” observed Dr. Kalra.

A separate analysis showed no difference in rates of AKI requiring dialysis among patients with CKD stages 3 and 4 who underwent angiography without revascularization and their peers who were medically managed.

Rates of the composite safety outcome of vascular complications, major bleeding, AKI, or stroke readmission at 6 months were not significantly different for invasive versus medical management for CKD stage 3 (both 3.3%), stage 4 (4.5% and 4.2%), stage 5 (3.9% vs. 4.3%), and ESRD (2.3% vs. 2.1%).

Besides the inherent limitations of observational studies and potential for selection bias, Dr. Kalra pointed out that the analysis relied on coding data for exact glomerular filtration rates and lacked information on contrast use, crystalloids before the procedure, and nephrotoxic medication use before or during admission. Out-of-hospital mortality was also not available in the database.

Co-moderator Allen Jeremias, MD, also with St. Francis Hospital & Heart Center, said one of the study’s strengths was that it included all comers, unlike randomized trials that typically exclude the highest risk patients.

“So, when we do these trials it’s very difficult to find the right balance, whereas this is a real-world analysis including everybody, and I think the benefits are clearly demonstrated,” he said. “So I think I’m bullish on doing complex [percutaneous coronary intervention] PCI in this patient population.”

Dr. Kalra reports having no relevant financial relationships.

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

Most patients with advanced chronic kidney disease (CKD) and non–ST-elevation myocardial infarction (NSTEMI) fare better with coronary angiography with and without revascularization than with medical therapy, a large nationwide study suggests.

Bruce Jancin/MDedge News

“Invasive management was associated with lower mortality, major adverse cardiovascular events (MACE), and need for revascularization, with a minimal increased risk of in-hospital, postprocedural acute kidney injury (AKI) requiring dialysis and major bleeding,” said lead researcher Ankur Kalra, MD, Cleveland Clinic.

Also, similar post-discharge safety outcomes were seen at 6 months, he said in an online presentation of “key abstracts” released in advance of next month’s Transcatheter Cardiovascular Therapeutics (TCT) 2021 hybrid meeting.

Advanced CKD is an independent predictor of mortality and morbidity in patients with NSTEMI. In CKD, however, current guidelines lack evidence on the efficacy and safety of invasive versus medical management, he noted.

A rare randomized clinical trial in this high-risk population, ISCHEMIA-CKD, recently found no benefit and an increase in stroke with initial invasive management compared with optimal medical therapy.

Session co-moderator Ziad A. Ali, MD, DPhil, St. Francis Hospital & Heart Center, New York, said the current study is “incredibly clinically impactful and answers a question that’s very difficult to answer because these patients aren’t randomized in randomized controlled trials, and there’s a general avoidance, which we’ve now coined ‘renalism,’ like racism, where people don’t really want to touch these patients.”

He questioned, however, how the authors reconcile the results of ISCHEMIA-CKD, a “small but meaningful randomized controlled trial,” with their findings from a large dataset. “Perhaps this is all selection bias, even though the numbers are very large.”

Dr. Kalra replied that ISCHEMIA-CKD examined stable ischemic heart disease, whereas they looked at NSTEMI. “Even though it may fall under the same rubric, I truly believe it is a different set of patients – they are at a heightened risk for future cardiovascular events and have had an acute coronary event.”

For the study, ICD-10 coding data from 2016-2018 in the Nationwide Readmission Database was used to identify NSTEMI patients with CKD stages 3, 4, 5, and end-stage renal disease (ESRD). A total of 141,052 patients were available for in-hospital outcomes and 133,642 patients for post-discharge outcomes.

In-hospital and 6-month mortality – the study’s primary outcome – favored invasive management across all CKD stages and ESRD but did not achieve statistical significance for CKD stage 5. The number needed to treat (NNT) for CKD stages 3, 4, 5, and ESRD were 26, 56, 48, and 18, respectively.

Six-month MACE, including mortality, MI, stroke, and heart failure readmission, was significantly better in all groups with invasive management.

Kaplan-Meier curves for mortality showed similar benefits with an invasive strategy across CKD stages, again barring stage 5 disease. 

With regard to in-hospital safety, stroke rates were not significantly different between the two treatment strategies across all groups.

Rates of AKI requiring dialysis, however, were lower with medical versus invasive management for CKD stage 3 (0.43% vs. 0.6%; hazard ratio, 1.39; P = .016), stage 4 (1.2% vs. 2.0%; HR 1.87; P < .001), and stage 5 (3.7% vs. 4.3%; HR 1.17; P = .527). The number needed to harm (NNH) was 588 for CKD 3 and 125 for CKD 4.

Major bleeding, defined as requiring transfusion, was lower with medical management for all CKD stages but not for ESRD. The rates are as follows:

• CKD stage 3: 2.5% vs. 2.8% (HR, 1.11; P = .078; NNH = 333)
• CKD stage 4: 2.9% vs. 4.0% (HR, 1.42; P < .001; NNH = 91)
• CKD stage 5: 2.2% vs. 4.7% (HR, 2.17; P = .008; NNH = 40)
• ESRD: 3.4% vs. 3.3% (HR, 0.97; P = .709)

“The risk of AKI requiring dialysis and bleeding, as has been shown previously in other studies, was high, but the number needed to harm was also high,” observed Dr. Kalra.

A separate analysis showed no difference in rates of AKI requiring dialysis among patients with CKD stages 3 and 4 who underwent angiography without revascularization and their peers who were medically managed.

Rates of the composite safety outcome of vascular complications, major bleeding, AKI, or stroke readmission at 6 months were not significantly different for invasive versus medical management for CKD stage 3 (both 3.3%), stage 4 (4.5% and 4.2%), stage 5 (3.9% vs. 4.3%), and ESRD (2.3% vs. 2.1%).

Besides the inherent limitations of observational studies and potential for selection bias, Dr. Kalra pointed out that the analysis relied on coding data for exact glomerular filtration rates and lacked information on contrast use, crystalloids before the procedure, and nephrotoxic medication use before or during admission. Out-of-hospital mortality was also not available in the database.

Co-moderator Allen Jeremias, MD, also with St. Francis Hospital & Heart Center, said one of the study’s strengths was that it included all comers, unlike randomized trials that typically exclude the highest risk patients.

“So, when we do these trials it’s very difficult to find the right balance, whereas this is a real-world analysis including everybody, and I think the benefits are clearly demonstrated,” he said. “So I think I’m bullish on doing complex [percutaneous coronary intervention] PCI in this patient population.”

Dr. Kalra reports having no relevant financial relationships.

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

Autologous hematopoietic stem cell transplantation for the treatment of active secondary progressive multiple sclerosis (MS) is associated with better disability outcomes than other immunotherapies, a new Italian study suggests.

In the study, stem cell transplant was associated with a slowing of disability progression and a higher likelihood of disability improvement in patients with secondary progressive MS compared with other disease-modifying therapies.

“Our study shows that, although limited, sustained disability improvement is still possible during early active secondary progressive MS and seems to be more likely with stem cell transplant than other disease-modifying treatments,” said lead author Giacomo Boffa, MD, University of Genoa, Italy.

“Brain penetrating–intent immune suppression in long-term immunological reconstitution within the central nervous system could be responsible for this clinical efficacy,” he added.

Dr. Boffa presented the research at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He explained that compartmentalized inflation in the brain parenchyma, left meninges, and the cerebral spinal fluid (CSF) is a key driver of disability worsening in secondary progressive MS.

Although initial studies did not reveal an effect of disease-modifying therapies in secondary progressive MS, recent randomized trials have established some benefit of siponimod in reducing the risk of disability worsening, and consistent with this finding, observational studies have suggested that other available immunotherapies may also be beneficial for active secondary progressive MS, Dr. Boffa noted.

“Autologous hematopoietic stem cell transplantation has been widely investigated for the treatment of refractory MS, and although the ideal candidate for this procedure is a young patient with relapsing-remitting MS, there is some evidence to suggest that the procedure could also slow down neurological disability in patients with secondary progressive MS,” Dr. Boffa said.

“Indeed, all the drugs used in the transplant technology share the ability to cross the blood-brain barrier and exert a strong immunosuppressant effect within the brain parenchyma and CSF,” he added.  
 

Comparing treatment regimens

The aim of the current study was to compare the effect of autologous hematopoietic stem cell transplantation with other immunotherapies on disability worsening in patients with active secondary progressive MS.

Study endpoints included the Expanded Disability Status Scale (EDSS) score, 6-month worsening and improvement in disability, and sustained disability improvement over time.

The researchers studied patients with secondary progressive MS who had received autologous hematopoietic stem cell transplantation and were included in the Italian Bone Marrow Transplant Group. They were compared with a control group of patients in the Italian MS registry who had started a nontransplant disease-modifying therapy after the diagnosis of secondary progressive MS.

To control for many different variables, two separate analyses were preformed. One analyses was a propensity-score approach (patients were matched based on their propensity to receive bone marrow transplant or one of the other disease-modifying therapies). The other analysis used an overlap weighting approach (each patient was given a weight proportional to the probability of them belonging to the other treatment group).

The final cohort consisted of 79 bone marrow transplant recipients and 1,975 patients who had received other disease-modifying therapies.

Before matching, patients in the control group were older, had a longer disease duration, and had a lower annualized relapse rate than transplanted patients.

After propensity-score matching, there were 69 transplanted patients and 217 control patients who were well balanced in terms of clinical and demographic characteristics. After overlap weighting, the entire cohort was also well balanced for these variables.

In terms of the primary endpoint, stem cell transplant stabilized the EDSS score over time, while patients treated with other disease-modifying therapies had continuous progression of the EDSS score over time.

In the propensity-matched analysis, the EDSS score improved by 0.013 points per year in the stem cell transplant group compared with a worsening of 0.157 points per year in the control group. Similar results were seen in the overlap-weighting analysis.  

The effect of stem cell transplant on EDSS score translated into a significantly delayed time to confirmed disability progression in the stem cell transplant group compared with the control group (HR, 0.5; P = .005), Dr. Boffa reported.

Five years after the procedure, 62% of the transplant group were free of disability progression, compared with around 20% of the control group.  

Patients in the transplanted group were also more likely to show disability improvement over time. Five years after the procedure, almost 20% of the stem cell transplant group still maintained a disability improvement compared with only 4% of patients treated with other disease-modifying therapies.

“Our study population was composed of relatively young patients (average age 38 years) with clinical activity during secondary progressive MS, and the results of this study would not be applicable to patients with secondary progressive MS patients without signs of inflammatory activity,” Dr. Boffa commented.

“But on the other hand, our results reinforce the notion that ongoing inflammation during progressive MS requires adequate immunotherapy,” he added.   

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

Autologous hematopoietic stem cell transplantation for the treatment of active secondary progressive multiple sclerosis (MS) is associated with better disability outcomes than other immunotherapies, a new Italian study suggests.

In the study, stem cell transplant was associated with a slowing of disability progression and a higher likelihood of disability improvement in patients with secondary progressive MS compared with other disease-modifying therapies.

“Our study shows that, although limited, sustained disability improvement is still possible during early active secondary progressive MS and seems to be more likely with stem cell transplant than other disease-modifying treatments,” said lead author Giacomo Boffa, MD, University of Genoa, Italy.

“Brain penetrating–intent immune suppression in long-term immunological reconstitution within the central nervous system could be responsible for this clinical efficacy,” he added.

Dr. Boffa presented the research at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He explained that compartmentalized inflation in the brain parenchyma, left meninges, and the cerebral spinal fluid (CSF) is a key driver of disability worsening in secondary progressive MS.

Although initial studies did not reveal an effect of disease-modifying therapies in secondary progressive MS, recent randomized trials have established some benefit of siponimod in reducing the risk of disability worsening, and consistent with this finding, observational studies have suggested that other available immunotherapies may also be beneficial for active secondary progressive MS, Dr. Boffa noted.

“Autologous hematopoietic stem cell transplantation has been widely investigated for the treatment of refractory MS, and although the ideal candidate for this procedure is a young patient with relapsing-remitting MS, there is some evidence to suggest that the procedure could also slow down neurological disability in patients with secondary progressive MS,” Dr. Boffa said.

“Indeed, all the drugs used in the transplant technology share the ability to cross the blood-brain barrier and exert a strong immunosuppressant effect within the brain parenchyma and CSF,” he added.  
 

Comparing treatment regimens

The aim of the current study was to compare the effect of autologous hematopoietic stem cell transplantation with other immunotherapies on disability worsening in patients with active secondary progressive MS.

Study endpoints included the Expanded Disability Status Scale (EDSS) score, 6-month worsening and improvement in disability, and sustained disability improvement over time.

The researchers studied patients with secondary progressive MS who had received autologous hematopoietic stem cell transplantation and were included in the Italian Bone Marrow Transplant Group. They were compared with a control group of patients in the Italian MS registry who had started a nontransplant disease-modifying therapy after the diagnosis of secondary progressive MS.

To control for many different variables, two separate analyses were preformed. One analyses was a propensity-score approach (patients were matched based on their propensity to receive bone marrow transplant or one of the other disease-modifying therapies). The other analysis used an overlap weighting approach (each patient was given a weight proportional to the probability of them belonging to the other treatment group).

The final cohort consisted of 79 bone marrow transplant recipients and 1,975 patients who had received other disease-modifying therapies.

Before matching, patients in the control group were older, had a longer disease duration, and had a lower annualized relapse rate than transplanted patients.

After propensity-score matching, there were 69 transplanted patients and 217 control patients who were well balanced in terms of clinical and demographic characteristics. After overlap weighting, the entire cohort was also well balanced for these variables.

In terms of the primary endpoint, stem cell transplant stabilized the EDSS score over time, while patients treated with other disease-modifying therapies had continuous progression of the EDSS score over time.

In the propensity-matched analysis, the EDSS score improved by 0.013 points per year in the stem cell transplant group compared with a worsening of 0.157 points per year in the control group. Similar results were seen in the overlap-weighting analysis.  

The effect of stem cell transplant on EDSS score translated into a significantly delayed time to confirmed disability progression in the stem cell transplant group compared with the control group (HR, 0.5; P = .005), Dr. Boffa reported.

Five years after the procedure, 62% of the transplant group were free of disability progression, compared with around 20% of the control group.  

Patients in the transplanted group were also more likely to show disability improvement over time. Five years after the procedure, almost 20% of the stem cell transplant group still maintained a disability improvement compared with only 4% of patients treated with other disease-modifying therapies.

“Our study population was composed of relatively young patients (average age 38 years) with clinical activity during secondary progressive MS, and the results of this study would not be applicable to patients with secondary progressive MS patients without signs of inflammatory activity,” Dr. Boffa commented.

“But on the other hand, our results reinforce the notion that ongoing inflammation during progressive MS requires adequate immunotherapy,” he added.   

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

Autologous hematopoietic stem cell transplantation for the treatment of active secondary progressive multiple sclerosis (MS) is associated with better disability outcomes than other immunotherapies, a new Italian study suggests.

In the study, stem cell transplant was associated with a slowing of disability progression and a higher likelihood of disability improvement in patients with secondary progressive MS compared with other disease-modifying therapies.

“Our study shows that, although limited, sustained disability improvement is still possible during early active secondary progressive MS and seems to be more likely with stem cell transplant than other disease-modifying treatments,” said lead author Giacomo Boffa, MD, University of Genoa, Italy.

“Brain penetrating–intent immune suppression in long-term immunological reconstitution within the central nervous system could be responsible for this clinical efficacy,” he added.

Dr. Boffa presented the research at the annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

He explained that compartmentalized inflation in the brain parenchyma, left meninges, and the cerebral spinal fluid (CSF) is a key driver of disability worsening in secondary progressive MS.

Although initial studies did not reveal an effect of disease-modifying therapies in secondary progressive MS, recent randomized trials have established some benefit of siponimod in reducing the risk of disability worsening, and consistent with this finding, observational studies have suggested that other available immunotherapies may also be beneficial for active secondary progressive MS, Dr. Boffa noted.

“Autologous hematopoietic stem cell transplantation has been widely investigated for the treatment of refractory MS, and although the ideal candidate for this procedure is a young patient with relapsing-remitting MS, there is some evidence to suggest that the procedure could also slow down neurological disability in patients with secondary progressive MS,” Dr. Boffa said.

“Indeed, all the drugs used in the transplant technology share the ability to cross the blood-brain barrier and exert a strong immunosuppressant effect within the brain parenchyma and CSF,” he added.  
 

Comparing treatment regimens

The aim of the current study was to compare the effect of autologous hematopoietic stem cell transplantation with other immunotherapies on disability worsening in patients with active secondary progressive MS.

Study endpoints included the Expanded Disability Status Scale (EDSS) score, 6-month worsening and improvement in disability, and sustained disability improvement over time.

The researchers studied patients with secondary progressive MS who had received autologous hematopoietic stem cell transplantation and were included in the Italian Bone Marrow Transplant Group. They were compared with a control group of patients in the Italian MS registry who had started a nontransplant disease-modifying therapy after the diagnosis of secondary progressive MS.

To control for many different variables, two separate analyses were preformed. One analyses was a propensity-score approach (patients were matched based on their propensity to receive bone marrow transplant or one of the other disease-modifying therapies). The other analysis used an overlap weighting approach (each patient was given a weight proportional to the probability of them belonging to the other treatment group).

The final cohort consisted of 79 bone marrow transplant recipients and 1,975 patients who had received other disease-modifying therapies.

Before matching, patients in the control group were older, had a longer disease duration, and had a lower annualized relapse rate than transplanted patients.

After propensity-score matching, there were 69 transplanted patients and 217 control patients who were well balanced in terms of clinical and demographic characteristics. After overlap weighting, the entire cohort was also well balanced for these variables.

In terms of the primary endpoint, stem cell transplant stabilized the EDSS score over time, while patients treated with other disease-modifying therapies had continuous progression of the EDSS score over time.

In the propensity-matched analysis, the EDSS score improved by 0.013 points per year in the stem cell transplant group compared with a worsening of 0.157 points per year in the control group. Similar results were seen in the overlap-weighting analysis.  

The effect of stem cell transplant on EDSS score translated into a significantly delayed time to confirmed disability progression in the stem cell transplant group compared with the control group (HR, 0.5; P = .005), Dr. Boffa reported.

Five years after the procedure, 62% of the transplant group were free of disability progression, compared with around 20% of the control group.  

Patients in the transplanted group were also more likely to show disability improvement over time. Five years after the procedure, almost 20% of the stem cell transplant group still maintained a disability improvement compared with only 4% of patients treated with other disease-modifying therapies.

“Our study population was composed of relatively young patients (average age 38 years) with clinical activity during secondary progressive MS, and the results of this study would not be applicable to patients with secondary progressive MS patients without signs of inflammatory activity,” Dr. Boffa commented.

“But on the other hand, our results reinforce the notion that ongoing inflammation during progressive MS requires adequate immunotherapy,” he added.   

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