MDedge Pediatrics

Experience with long COVID has shone a spotlight on persistent Lyme disease and other often debilitating chronic illnesses that follow known or suspected infections – and on the urgent need for a common and well-funded research agenda, education of physicians, growth of multidisciplinary clinics, and financially supported clinical care.

“We critically need to understand the epidemiology and pathogenesis of chronic symptoms, and identify more effective ways to manage, treat, and potentially cure these illnesses,” Lyle Petersen, MD, MPH, director of the division of vector-borne diseases at the Centers for Disease Control and Prevention, said at the start of a 2-day National Academies of Science, Engineering, and Medicine (NASEM) workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”

Thinking about infection-associated chronic illnesses as an entity – one predicated on commonalities in chronic symptoms and in leading hypotheses for causes – represents a paradigm shift that researchers and patient advocates said can avoid research redundancies and is essential to address what the NASEM calls an overlooked, growing public health problem.

An estimated 2 million people in the United States are living with what’s called posttreatment Lyme disease (PTLD) – a subset of patients with persistent or chronic Lyme disease – and an estimated 1.7-3.3 million people in the United States have diagnoses of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). More than 700,000 people are living with multiple sclerosis. And as of January 2023, 11% of people in the United States reported having long COVID symptoms; the incidence of long COVID is currently estimated at 10%-30% of nonhospitalized cases of COVID-19.

These illnesses “have come under one umbrella,” said Avindra Nath, MD, clinical director of the National Institute of Neurologic Disorders and Stroke (NINDS), Bethesda, Md.

Dr. Nath

Persistent infection, viral reactivation

RNA viral infections can lead to persistent inflammation and dysregulated immunity, with or without viral persistence over time, Timothy J. Henrich, MD, MMSc, associate professor of medicine at the University of California, San Francisco, said in a keynote address.

Research on Ebola survivors has documented long-lasting inflammation and severe immune dysfunction 2 years after infection, for instance. And it’s well known that HIV-1 leads to aberrant immune responses, inflammation, and organ damage despite antiretroviral therapy, said Dr. Henrich, who leads a laboratory/research group that studies approaches to HIV-1 cure and PET-based imaging approaches to characterize viral reservoirs and immune sequelae.

Viral persistence, which can be difficult to measure, has also been documented in Ebola survivors. And in patients living with HIV-1, HIV-1 RNA and protein expression have been shown to persist, again despite antiretroviral therapy. The UCSF Long-Term Immunological Impact of Novel Coronavirus (LIINC) study, for which Dr. Henrich is the principal investigator, found spike RNA in colorectal tissue more than 22 months post COVID, and other research documented viral protein in gut tissue for up to 6 months, he said.

“I think we’re appreciating now, in at least the scientific and treatment community, that there’s a potential for ‘acute’ infections to exhibit some degree of persistence leading to clinical morbidity,” said Dr. Henrich, one of several speakers to describe reports of pathogen persistence. Regarding long COVID, its “etiology is likely heterogeneous,” he said, but persistence of SARS-CoV-2 “may lay behind” other described mechanisms, from clotting/microvascular dysfunction to inflammation and tissue damage to immune dysregulation.

Reactivation of existing latent viral infections in the setting of new acute microbial illness may also play an etiologic role in chronic illnesses, Dr. Henrich said. Epstein-Barr virus (EBV) reactivation has been shown in some studies, including their UCSF COVID-19 cohort, to be associated with long COVID.

“Physicians have been trained to be skeptical about the role [of latent viral infections],” Michael Peluso, MD, an infectious disease physician and assistant professor at UCSF, said during a talk on viral reactivation. This skepticism needs to be “reexamined and overcome,” he said.

Herpesviruses have frequently been associated with ME/CFS, he noted. And evidence of a strong association between EBV and multiple sclerosis came recently from a prospective study of 10 million military recruits that found a 32-fold increased risk of MS after EBV infection but no increase after infection with other viruses, Dr. Peluso and Dr. Henrich both noted.
 

Research needs, treatment trials

Research needs are vast: The need to learn more about the mechanisms of pathogen persistence and immune evasion, for instance, and the need for more biomarker studies, more imaging studies and tissue analyses, more study of microbiome composition and activity, and continued development and application of metagenomic next-generation sequencing.

Workshop participants also spoke of the need to better understand the molecular mimicry that can occur between pathogen-produced proteins and self-antigens, for instance, and the effects of inflammation and infection-related immune changes on neuronal and microglial function in the brain.

“We should perform similar forms of analysis [across] patients with different infection-associated chronic conditions,” said Amy Proal, PhD, president of the PolyBio Research Foundation, which funds research on infection-associated chronic infections. And within individual conditions and well-characterized study groups “we should perform many different forms of analysis … so we can define endotypes and get more solid biomarkers so that industry [will have more confidence] to run clinical trials.”

In the meantime, patients need fast-moving treatment trials for long COVID, long Lyme, and other infection-associated chronic illnesses, speakers emphasized. “We all agree that treatment trials are overdue,” said the NINDS’ Dr. Nath. “We can’t afford to wait for another decade until we understand all the mechanisms, but rather we can do clinical trials based on what we understand now and study the pathophysiology in the context of the clinical trials.”

Just as was done with HIV, said Steven G. Deeks, MD, professor of medicine at UCSF, researchers must “practice experimental medicine” and select pathways and mechanisms of interest, interrupt those pathways in a controlled manner, and assess impact. “Much of this can be done by repurposing existing drugs,” he said, like antivirals for persistent viral infection, EBV-directed therapies for EBV reactivation, anti-inflammatory drugs for inflammation, B–cell-directed therapies for autoantibodies, and antiplatelet drugs for microvascular disease.

When done correctly, he said, such “probe” studies can deepen mechanistic understandings, lead to biomarkers, and provide proof-of-concept that “will encourage massive investment in developing new therapies” for long COVID and other infection-associated chronic illnesses.

Trials of treatments for long COVID “are starting, so I’m optimistic,” said Dr. Deeks, an expert on HIV pathogenesis and treatment and a principal investigator of the Researching COVID to Enhance Recovery (RECOVER) study. Among the trials: A study of intravenous immunoglobulin (IVIG) for neurologic long COVID; a study of an anti-SARS-CoV-2 monoclonal antibody that can deplete tissue/cellular reservoirs of viral particles (replicating or not); and a study evaluating baricitinib (Olumiant), a Janus kinase inhibitor, for neurocognitive impairment and cardiopulmonary symptoms of long COVID.

Alessio Fasano, MD, professor of pediatrics at Harvard Medical School and professor of nutrition at the Harvard T.H. Chan School of Public Health, Boston, described at the workshop how he began investigating the use of larazotide acetate – an inhibitor of the protein zonulin, which increases intestinal permeability – in children with COVID-19 Multisystem Inflammatory Syndrome (MIS-C) after learning that SARS-CoV-2 viral particles persist in the gastrointestinal tract, causing dysbiosis and zonulin upregulation.

In an ongoing phase 2, double-blind, placebo-controlled trial, the agent thus far has expedited the resolution of gastrointestinal symptoms and clearance of spike protein from the circulation, he said. A phase 2 trial of the agent for pediatric patients with long COVID and SARS-CoV-2 antigenemia is underway. “What if we were to stop [chains of events] by stopping the passage of elements from the virus into circulation?’ he said.

In the realm of Lyme disease, a recently launched Clinical Trials Network for Lyme and Other Tick-Borne Diseases has awarded pilot study grants to evaluate treatments aimed at a variety of possible disease mechanisms that, notably, are similar to those of other chronic illnesses: persistence of infection or remnants of infection, immune dysregulation and autoimmune reactions, neural dysfunction, and gut microbiome changes. (Microclots and mitochondrial dysfunction have not been as well studied in Lyme.)

Current and upcoming studies include evaluations of transcutaneous auricular vagus nerve stimulation for those with persistent Lyme fatigue, transcranial direct current stimulation with cognitive retraining for Lyme brain fog, and tetracycline for PTLD, said Brian Fallon, MD, MPH, professor of clinical psychiatry at Columbia University, New York, who directs the Lyme & Tick-Borne Diseases Research Center and the coordinating center of the new network.

Columbia University Irving Medical Center

Calls for a new NIH center and patient involvement

Patients and patient advocacy organizations have played a vital role in research thus far: They’ve documented post-COVID symptoms that academic researchers said they would not otherwise have known of. Leaders of the Patient-Led Research Collaborative have coauthored published reviews with leading long COVID experts. And patients with tick-borne illnesses have enrolled in the MyLymeData patient registry run by LymeDisease.org, which has documented patient-experienced efficacy of alternative treatments and described antibiotic responders and nonresponders.

At the workshop, they shared findings alongside academic experts, and researchers called for their continued involvement. “Patient engagement at every step of the research process is critical,” Dr. Nath said.

“We need to ensure that research is reflective of lived experiences … and [that we’re] accelerating clinical trials of therapeutics that are of priority to the patient community,” said Lisa McCorkell, cofounder of the long COVID-focused Patient-Led Research Collaborative.

Ms. McCorkell also called for the creation of an office for infection-associated chronic illnesses in the NIH director’s office. Others voiced their support. “I think it’s a great idea to have an NIH center for infection-associated chronic illnesses,” said Dr. Fallon. “I think it would have a profound impact.”

The other great need, of course, is funding. “We have ideas, we have drugs that can be repurposed, we have a highly informed and engaged community that will enroll in and be retained in studies, and we have outcomes we can measure,” Dr. Deeks said. “What we’re missing is industry engagement and funding. We need massive engagement from the NIH.”
 

Real-world treatment needs

In the meantime, patients are seeking treatment, and “clinicians need to have uncertainty tolerance” and try multiple treatments simultaneously, said David Putrino, PT, PhD, director of rehabilitation innovation for the Mount Sinai Health System and professor of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai, New York. He oversees a multidisciplinary hybrid clinical care research center that has seen over 1,500 patients with long COVID and is beginning to see patients with other infection-associated chronic illnesses.

Claudia Paul

It’s a model that should be replicated to help fill the “enormous unmet clinical need” of patients with infection-associated chronic illness, said Peter Rowe, MD, professor of pediatrics at the Johns Hopkins School of Medicine and an expert on ME/CFS. And “as we request [more research funding], we will also need [financial] support for clinical care,” he emphasized, to provide equitable access for patients and to attract treating physicians.

Moreover, said Linda Geng, MD, PhD, the culture of stigma needs to change. Right now, patients with long COVID often feel dismissed not only by friends, families, and coworkers, but by clinicians who find it find it hard “to grasp that this is real and a biological condition.”

And it’s not just conditions such as long COVID that are stigmatized, but treatments as well, she said. For instance, some clinicians view low-dose naltrexone, a treatment increasingly being used for inflammation, with suspicion because it is used for opioid use disorder and alcohol use disorder – or because the “low-dose” label summons mistrust of homeopathy. “Even with therapies, there are preconceived notions and biases,” said Dr. Geng, cofounder and codirector of the Stanford (Calif.) Long COVID program.

“What almost killed me,” said Meghan O’Rourke, who has ongoing effects from long-undiagnosed tick-borne illness, “was the invisibility of the illness.” Ms. O’Rourke teaches at Yale University and is the author of “The Invisible Kingdom: Reimagining Chronic Illness.”

Teaching young physicians about these illnesses would help, she and others said. During a question and answer session, Dr. Putrino shared that the Icahn School of Medicine has recently committed to “create a complex chronic illness medical curriculum” that will impact medical education from the first year of medical school through residencies. Dr. Putrino said his team is also working on materials to help other clinics develop care models similar to those at his Mount Sinai clinic.

The NASEM workshop did not collect or require disclosures of its participants.

Experience with long COVID has shone a spotlight on persistent Lyme disease and other often debilitating chronic illnesses that follow known or suspected infections – and on the urgent need for a common and well-funded research agenda, education of physicians, growth of multidisciplinary clinics, and financially supported clinical care.

“We critically need to understand the epidemiology and pathogenesis of chronic symptoms, and identify more effective ways to manage, treat, and potentially cure these illnesses,” Lyle Petersen, MD, MPH, director of the division of vector-borne diseases at the Centers for Disease Control and Prevention, said at the start of a 2-day National Academies of Science, Engineering, and Medicine (NASEM) workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”

Thinking about infection-associated chronic illnesses as an entity – one predicated on commonalities in chronic symptoms and in leading hypotheses for causes – represents a paradigm shift that researchers and patient advocates said can avoid research redundancies and is essential to address what the NASEM calls an overlooked, growing public health problem.

An estimated 2 million people in the United States are living with what’s called posttreatment Lyme disease (PTLD) – a subset of patients with persistent or chronic Lyme disease – and an estimated 1.7-3.3 million people in the United States have diagnoses of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). More than 700,000 people are living with multiple sclerosis. And as of January 2023, 11% of people in the United States reported having long COVID symptoms; the incidence of long COVID is currently estimated at 10%-30% of nonhospitalized cases of COVID-19.

These illnesses “have come under one umbrella,” said Avindra Nath, MD, clinical director of the National Institute of Neurologic Disorders and Stroke (NINDS), Bethesda, Md.

Dr. Nath

Persistent infection, viral reactivation

RNA viral infections can lead to persistent inflammation and dysregulated immunity, with or without viral persistence over time, Timothy J. Henrich, MD, MMSc, associate professor of medicine at the University of California, San Francisco, said in a keynote address.

Research on Ebola survivors has documented long-lasting inflammation and severe immune dysfunction 2 years after infection, for instance. And it’s well known that HIV-1 leads to aberrant immune responses, inflammation, and organ damage despite antiretroviral therapy, said Dr. Henrich, who leads a laboratory/research group that studies approaches to HIV-1 cure and PET-based imaging approaches to characterize viral reservoirs and immune sequelae.

Viral persistence, which can be difficult to measure, has also been documented in Ebola survivors. And in patients living with HIV-1, HIV-1 RNA and protein expression have been shown to persist, again despite antiretroviral therapy. The UCSF Long-Term Immunological Impact of Novel Coronavirus (LIINC) study, for which Dr. Henrich is the principal investigator, found spike RNA in colorectal tissue more than 22 months post COVID, and other research documented viral protein in gut tissue for up to 6 months, he said.

“I think we’re appreciating now, in at least the scientific and treatment community, that there’s a potential for ‘acute’ infections to exhibit some degree of persistence leading to clinical morbidity,” said Dr. Henrich, one of several speakers to describe reports of pathogen persistence. Regarding long COVID, its “etiology is likely heterogeneous,” he said, but persistence of SARS-CoV-2 “may lay behind” other described mechanisms, from clotting/microvascular dysfunction to inflammation and tissue damage to immune dysregulation.

Reactivation of existing latent viral infections in the setting of new acute microbial illness may also play an etiologic role in chronic illnesses, Dr. Henrich said. Epstein-Barr virus (EBV) reactivation has been shown in some studies, including their UCSF COVID-19 cohort, to be associated with long COVID.

“Physicians have been trained to be skeptical about the role [of latent viral infections],” Michael Peluso, MD, an infectious disease physician and assistant professor at UCSF, said during a talk on viral reactivation. This skepticism needs to be “reexamined and overcome,” he said.

Herpesviruses have frequently been associated with ME/CFS, he noted. And evidence of a strong association between EBV and multiple sclerosis came recently from a prospective study of 10 million military recruits that found a 32-fold increased risk of MS after EBV infection but no increase after infection with other viruses, Dr. Peluso and Dr. Henrich both noted.
 

Research needs, treatment trials

Research needs are vast: The need to learn more about the mechanisms of pathogen persistence and immune evasion, for instance, and the need for more biomarker studies, more imaging studies and tissue analyses, more study of microbiome composition and activity, and continued development and application of metagenomic next-generation sequencing.

Workshop participants also spoke of the need to better understand the molecular mimicry that can occur between pathogen-produced proteins and self-antigens, for instance, and the effects of inflammation and infection-related immune changes on neuronal and microglial function in the brain.

“We should perform similar forms of analysis [across] patients with different infection-associated chronic conditions,” said Amy Proal, PhD, president of the PolyBio Research Foundation, which funds research on infection-associated chronic infections. And within individual conditions and well-characterized study groups “we should perform many different forms of analysis … so we can define endotypes and get more solid biomarkers so that industry [will have more confidence] to run clinical trials.”

In the meantime, patients need fast-moving treatment trials for long COVID, long Lyme, and other infection-associated chronic illnesses, speakers emphasized. “We all agree that treatment trials are overdue,” said the NINDS’ Dr. Nath. “We can’t afford to wait for another decade until we understand all the mechanisms, but rather we can do clinical trials based on what we understand now and study the pathophysiology in the context of the clinical trials.”

Just as was done with HIV, said Steven G. Deeks, MD, professor of medicine at UCSF, researchers must “practice experimental medicine” and select pathways and mechanisms of interest, interrupt those pathways in a controlled manner, and assess impact. “Much of this can be done by repurposing existing drugs,” he said, like antivirals for persistent viral infection, EBV-directed therapies for EBV reactivation, anti-inflammatory drugs for inflammation, B–cell-directed therapies for autoantibodies, and antiplatelet drugs for microvascular disease.

When done correctly, he said, such “probe” studies can deepen mechanistic understandings, lead to biomarkers, and provide proof-of-concept that “will encourage massive investment in developing new therapies” for long COVID and other infection-associated chronic illnesses.

Trials of treatments for long COVID “are starting, so I’m optimistic,” said Dr. Deeks, an expert on HIV pathogenesis and treatment and a principal investigator of the Researching COVID to Enhance Recovery (RECOVER) study. Among the trials: A study of intravenous immunoglobulin (IVIG) for neurologic long COVID; a study of an anti-SARS-CoV-2 monoclonal antibody that can deplete tissue/cellular reservoirs of viral particles (replicating or not); and a study evaluating baricitinib (Olumiant), a Janus kinase inhibitor, for neurocognitive impairment and cardiopulmonary symptoms of long COVID.

Alessio Fasano, MD, professor of pediatrics at Harvard Medical School and professor of nutrition at the Harvard T.H. Chan School of Public Health, Boston, described at the workshop how he began investigating the use of larazotide acetate – an inhibitor of the protein zonulin, which increases intestinal permeability – in children with COVID-19 Multisystem Inflammatory Syndrome (MIS-C) after learning that SARS-CoV-2 viral particles persist in the gastrointestinal tract, causing dysbiosis and zonulin upregulation.

In an ongoing phase 2, double-blind, placebo-controlled trial, the agent thus far has expedited the resolution of gastrointestinal symptoms and clearance of spike protein from the circulation, he said. A phase 2 trial of the agent for pediatric patients with long COVID and SARS-CoV-2 antigenemia is underway. “What if we were to stop [chains of events] by stopping the passage of elements from the virus into circulation?’ he said.

In the realm of Lyme disease, a recently launched Clinical Trials Network for Lyme and Other Tick-Borne Diseases has awarded pilot study grants to evaluate treatments aimed at a variety of possible disease mechanisms that, notably, are similar to those of other chronic illnesses: persistence of infection or remnants of infection, immune dysregulation and autoimmune reactions, neural dysfunction, and gut microbiome changes. (Microclots and mitochondrial dysfunction have not been as well studied in Lyme.)

Current and upcoming studies include evaluations of transcutaneous auricular vagus nerve stimulation for those with persistent Lyme fatigue, transcranial direct current stimulation with cognitive retraining for Lyme brain fog, and tetracycline for PTLD, said Brian Fallon, MD, MPH, professor of clinical psychiatry at Columbia University, New York, who directs the Lyme & Tick-Borne Diseases Research Center and the coordinating center of the new network.

Columbia University Irving Medical Center

Calls for a new NIH center and patient involvement

Patients and patient advocacy organizations have played a vital role in research thus far: They’ve documented post-COVID symptoms that academic researchers said they would not otherwise have known of. Leaders of the Patient-Led Research Collaborative have coauthored published reviews with leading long COVID experts. And patients with tick-borne illnesses have enrolled in the MyLymeData patient registry run by LymeDisease.org, which has documented patient-experienced efficacy of alternative treatments and described antibiotic responders and nonresponders.

At the workshop, they shared findings alongside academic experts, and researchers called for their continued involvement. “Patient engagement at every step of the research process is critical,” Dr. Nath said.

“We need to ensure that research is reflective of lived experiences … and [that we’re] accelerating clinical trials of therapeutics that are of priority to the patient community,” said Lisa McCorkell, cofounder of the long COVID-focused Patient-Led Research Collaborative.

Ms. McCorkell also called for the creation of an office for infection-associated chronic illnesses in the NIH director’s office. Others voiced their support. “I think it’s a great idea to have an NIH center for infection-associated chronic illnesses,” said Dr. Fallon. “I think it would have a profound impact.”

The other great need, of course, is funding. “We have ideas, we have drugs that can be repurposed, we have a highly informed and engaged community that will enroll in and be retained in studies, and we have outcomes we can measure,” Dr. Deeks said. “What we’re missing is industry engagement and funding. We need massive engagement from the NIH.”
 

Real-world treatment needs

In the meantime, patients are seeking treatment, and “clinicians need to have uncertainty tolerance” and try multiple treatments simultaneously, said David Putrino, PT, PhD, director of rehabilitation innovation for the Mount Sinai Health System and professor of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai, New York. He oversees a multidisciplinary hybrid clinical care research center that has seen over 1,500 patients with long COVID and is beginning to see patients with other infection-associated chronic illnesses.

Claudia Paul

It’s a model that should be replicated to help fill the “enormous unmet clinical need” of patients with infection-associated chronic illness, said Peter Rowe, MD, professor of pediatrics at the Johns Hopkins School of Medicine and an expert on ME/CFS. And “as we request [more research funding], we will also need [financial] support for clinical care,” he emphasized, to provide equitable access for patients and to attract treating physicians.

Moreover, said Linda Geng, MD, PhD, the culture of stigma needs to change. Right now, patients with long COVID often feel dismissed not only by friends, families, and coworkers, but by clinicians who find it find it hard “to grasp that this is real and a biological condition.”

And it’s not just conditions such as long COVID that are stigmatized, but treatments as well, she said. For instance, some clinicians view low-dose naltrexone, a treatment increasingly being used for inflammation, with suspicion because it is used for opioid use disorder and alcohol use disorder – or because the “low-dose” label summons mistrust of homeopathy. “Even with therapies, there are preconceived notions and biases,” said Dr. Geng, cofounder and codirector of the Stanford (Calif.) Long COVID program.

“What almost killed me,” said Meghan O’Rourke, who has ongoing effects from long-undiagnosed tick-borne illness, “was the invisibility of the illness.” Ms. O’Rourke teaches at Yale University and is the author of “The Invisible Kingdom: Reimagining Chronic Illness.”

Teaching young physicians about these illnesses would help, she and others said. During a question and answer session, Dr. Putrino shared that the Icahn School of Medicine has recently committed to “create a complex chronic illness medical curriculum” that will impact medical education from the first year of medical school through residencies. Dr. Putrino said his team is also working on materials to help other clinics develop care models similar to those at his Mount Sinai clinic.

The NASEM workshop did not collect or require disclosures of its participants.

Experience with long COVID has shone a spotlight on persistent Lyme disease and other often debilitating chronic illnesses that follow known or suspected infections – and on the urgent need for a common and well-funded research agenda, education of physicians, growth of multidisciplinary clinics, and financially supported clinical care.

“We critically need to understand the epidemiology and pathogenesis of chronic symptoms, and identify more effective ways to manage, treat, and potentially cure these illnesses,” Lyle Petersen, MD, MPH, director of the division of vector-borne diseases at the Centers for Disease Control and Prevention, said at the start of a 2-day National Academies of Science, Engineering, and Medicine (NASEM) workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”

Thinking about infection-associated chronic illnesses as an entity – one predicated on commonalities in chronic symptoms and in leading hypotheses for causes – represents a paradigm shift that researchers and patient advocates said can avoid research redundancies and is essential to address what the NASEM calls an overlooked, growing public health problem.

An estimated 2 million people in the United States are living with what’s called posttreatment Lyme disease (PTLD) – a subset of patients with persistent or chronic Lyme disease – and an estimated 1.7-3.3 million people in the United States have diagnoses of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). More than 700,000 people are living with multiple sclerosis. And as of January 2023, 11% of people in the United States reported having long COVID symptoms; the incidence of long COVID is currently estimated at 10%-30% of nonhospitalized cases of COVID-19.

These illnesses “have come under one umbrella,” said Avindra Nath, MD, clinical director of the National Institute of Neurologic Disorders and Stroke (NINDS), Bethesda, Md.

Dr. Nath

Persistent infection, viral reactivation

RNA viral infections can lead to persistent inflammation and dysregulated immunity, with or without viral persistence over time, Timothy J. Henrich, MD, MMSc, associate professor of medicine at the University of California, San Francisco, said in a keynote address.

Research on Ebola survivors has documented long-lasting inflammation and severe immune dysfunction 2 years after infection, for instance. And it’s well known that HIV-1 leads to aberrant immune responses, inflammation, and organ damage despite antiretroviral therapy, said Dr. Henrich, who leads a laboratory/research group that studies approaches to HIV-1 cure and PET-based imaging approaches to characterize viral reservoirs and immune sequelae.

Viral persistence, which can be difficult to measure, has also been documented in Ebola survivors. And in patients living with HIV-1, HIV-1 RNA and protein expression have been shown to persist, again despite antiretroviral therapy. The UCSF Long-Term Immunological Impact of Novel Coronavirus (LIINC) study, for which Dr. Henrich is the principal investigator, found spike RNA in colorectal tissue more than 22 months post COVID, and other research documented viral protein in gut tissue for up to 6 months, he said.

“I think we’re appreciating now, in at least the scientific and treatment community, that there’s a potential for ‘acute’ infections to exhibit some degree of persistence leading to clinical morbidity,” said Dr. Henrich, one of several speakers to describe reports of pathogen persistence. Regarding long COVID, its “etiology is likely heterogeneous,” he said, but persistence of SARS-CoV-2 “may lay behind” other described mechanisms, from clotting/microvascular dysfunction to inflammation and tissue damage to immune dysregulation.

Reactivation of existing latent viral infections in the setting of new acute microbial illness may also play an etiologic role in chronic illnesses, Dr. Henrich said. Epstein-Barr virus (EBV) reactivation has been shown in some studies, including their UCSF COVID-19 cohort, to be associated with long COVID.

“Physicians have been trained to be skeptical about the role [of latent viral infections],” Michael Peluso, MD, an infectious disease physician and assistant professor at UCSF, said during a talk on viral reactivation. This skepticism needs to be “reexamined and overcome,” he said.

Herpesviruses have frequently been associated with ME/CFS, he noted. And evidence of a strong association between EBV and multiple sclerosis came recently from a prospective study of 10 million military recruits that found a 32-fold increased risk of MS after EBV infection but no increase after infection with other viruses, Dr. Peluso and Dr. Henrich both noted.
 

Research needs, treatment trials

Research needs are vast: The need to learn more about the mechanisms of pathogen persistence and immune evasion, for instance, and the need for more biomarker studies, more imaging studies and tissue analyses, more study of microbiome composition and activity, and continued development and application of metagenomic next-generation sequencing.

Workshop participants also spoke of the need to better understand the molecular mimicry that can occur between pathogen-produced proteins and self-antigens, for instance, and the effects of inflammation and infection-related immune changes on neuronal and microglial function in the brain.

“We should perform similar forms of analysis [across] patients with different infection-associated chronic conditions,” said Amy Proal, PhD, president of the PolyBio Research Foundation, which funds research on infection-associated chronic infections. And within individual conditions and well-characterized study groups “we should perform many different forms of analysis … so we can define endotypes and get more solid biomarkers so that industry [will have more confidence] to run clinical trials.”

In the meantime, patients need fast-moving treatment trials for long COVID, long Lyme, and other infection-associated chronic illnesses, speakers emphasized. “We all agree that treatment trials are overdue,” said the NINDS’ Dr. Nath. “We can’t afford to wait for another decade until we understand all the mechanisms, but rather we can do clinical trials based on what we understand now and study the pathophysiology in the context of the clinical trials.”

Just as was done with HIV, said Steven G. Deeks, MD, professor of medicine at UCSF, researchers must “practice experimental medicine” and select pathways and mechanisms of interest, interrupt those pathways in a controlled manner, and assess impact. “Much of this can be done by repurposing existing drugs,” he said, like antivirals for persistent viral infection, EBV-directed therapies for EBV reactivation, anti-inflammatory drugs for inflammation, B–cell-directed therapies for autoantibodies, and antiplatelet drugs for microvascular disease.

When done correctly, he said, such “probe” studies can deepen mechanistic understandings, lead to biomarkers, and provide proof-of-concept that “will encourage massive investment in developing new therapies” for long COVID and other infection-associated chronic illnesses.

Trials of treatments for long COVID “are starting, so I’m optimistic,” said Dr. Deeks, an expert on HIV pathogenesis and treatment and a principal investigator of the Researching COVID to Enhance Recovery (RECOVER) study. Among the trials: A study of intravenous immunoglobulin (IVIG) for neurologic long COVID; a study of an anti-SARS-CoV-2 monoclonal antibody that can deplete tissue/cellular reservoirs of viral particles (replicating or not); and a study evaluating baricitinib (Olumiant), a Janus kinase inhibitor, for neurocognitive impairment and cardiopulmonary symptoms of long COVID.

Alessio Fasano, MD, professor of pediatrics at Harvard Medical School and professor of nutrition at the Harvard T.H. Chan School of Public Health, Boston, described at the workshop how he began investigating the use of larazotide acetate – an inhibitor of the protein zonulin, which increases intestinal permeability – in children with COVID-19 Multisystem Inflammatory Syndrome (MIS-C) after learning that SARS-CoV-2 viral particles persist in the gastrointestinal tract, causing dysbiosis and zonulin upregulation.

In an ongoing phase 2, double-blind, placebo-controlled trial, the agent thus far has expedited the resolution of gastrointestinal symptoms and clearance of spike protein from the circulation, he said. A phase 2 trial of the agent for pediatric patients with long COVID and SARS-CoV-2 antigenemia is underway. “What if we were to stop [chains of events] by stopping the passage of elements from the virus into circulation?’ he said.

In the realm of Lyme disease, a recently launched Clinical Trials Network for Lyme and Other Tick-Borne Diseases has awarded pilot study grants to evaluate treatments aimed at a variety of possible disease mechanisms that, notably, are similar to those of other chronic illnesses: persistence of infection or remnants of infection, immune dysregulation and autoimmune reactions, neural dysfunction, and gut microbiome changes. (Microclots and mitochondrial dysfunction have not been as well studied in Lyme.)

Current and upcoming studies include evaluations of transcutaneous auricular vagus nerve stimulation for those with persistent Lyme fatigue, transcranial direct current stimulation with cognitive retraining for Lyme brain fog, and tetracycline for PTLD, said Brian Fallon, MD, MPH, professor of clinical psychiatry at Columbia University, New York, who directs the Lyme & Tick-Borne Diseases Research Center and the coordinating center of the new network.

Columbia University Irving Medical Center

Calls for a new NIH center and patient involvement

Patients and patient advocacy organizations have played a vital role in research thus far: They’ve documented post-COVID symptoms that academic researchers said they would not otherwise have known of. Leaders of the Patient-Led Research Collaborative have coauthored published reviews with leading long COVID experts. And patients with tick-borne illnesses have enrolled in the MyLymeData patient registry run by LymeDisease.org, which has documented patient-experienced efficacy of alternative treatments and described antibiotic responders and nonresponders.

At the workshop, they shared findings alongside academic experts, and researchers called for their continued involvement. “Patient engagement at every step of the research process is critical,” Dr. Nath said.

“We need to ensure that research is reflective of lived experiences … and [that we’re] accelerating clinical trials of therapeutics that are of priority to the patient community,” said Lisa McCorkell, cofounder of the long COVID-focused Patient-Led Research Collaborative.

Ms. McCorkell also called for the creation of an office for infection-associated chronic illnesses in the NIH director’s office. Others voiced their support. “I think it’s a great idea to have an NIH center for infection-associated chronic illnesses,” said Dr. Fallon. “I think it would have a profound impact.”

The other great need, of course, is funding. “We have ideas, we have drugs that can be repurposed, we have a highly informed and engaged community that will enroll in and be retained in studies, and we have outcomes we can measure,” Dr. Deeks said. “What we’re missing is industry engagement and funding. We need massive engagement from the NIH.”
 

Real-world treatment needs

In the meantime, patients are seeking treatment, and “clinicians need to have uncertainty tolerance” and try multiple treatments simultaneously, said David Putrino, PT, PhD, director of rehabilitation innovation for the Mount Sinai Health System and professor of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai, New York. He oversees a multidisciplinary hybrid clinical care research center that has seen over 1,500 patients with long COVID and is beginning to see patients with other infection-associated chronic illnesses.

Claudia Paul

It’s a model that should be replicated to help fill the “enormous unmet clinical need” of patients with infection-associated chronic illness, said Peter Rowe, MD, professor of pediatrics at the Johns Hopkins School of Medicine and an expert on ME/CFS. And “as we request [more research funding], we will also need [financial] support for clinical care,” he emphasized, to provide equitable access for patients and to attract treating physicians.

Moreover, said Linda Geng, MD, PhD, the culture of stigma needs to change. Right now, patients with long COVID often feel dismissed not only by friends, families, and coworkers, but by clinicians who find it find it hard “to grasp that this is real and a biological condition.”

And it’s not just conditions such as long COVID that are stigmatized, but treatments as well, she said. For instance, some clinicians view low-dose naltrexone, a treatment increasingly being used for inflammation, with suspicion because it is used for opioid use disorder and alcohol use disorder – or because the “low-dose” label summons mistrust of homeopathy. “Even with therapies, there are preconceived notions and biases,” said Dr. Geng, cofounder and codirector of the Stanford (Calif.) Long COVID program.

“What almost killed me,” said Meghan O’Rourke, who has ongoing effects from long-undiagnosed tick-borne illness, “was the invisibility of the illness.” Ms. O’Rourke teaches at Yale University and is the author of “The Invisible Kingdom: Reimagining Chronic Illness.”

Teaching young physicians about these illnesses would help, she and others said. During a question and answer session, Dr. Putrino shared that the Icahn School of Medicine has recently committed to “create a complex chronic illness medical curriculum” that will impact medical education from the first year of medical school through residencies. Dr. Putrino said his team is also working on materials to help other clinics develop care models similar to those at his Mount Sinai clinic.

The NASEM workshop did not collect or require disclosures of its participants.

Three California nurse practitioners with doctorates (DNP) have sued the state over its law that only physicians can call themselves doctors, saying it violates their first amendment right to use the honorific title without fear of regulatory repercussions.

The case highlights ongoing scope-creep battles as the American Medical Association tries to preserve the physician-led team model and nursing organizations and some lawmakers push for greater autonomy for allied professionals.

In the complaint filed in district court in June, plaintiffs Jacqueline Palmer, DNP, Heather Lewis, DNP, and Rodolfo Jaravata-Hanson, DNP, say they fear the state will sanction them. They note that “Doctor Sarah,” another DNP, was fined nearly $20,000 by the state last November for false advertising and fraud after using the moniker in her online advertising and social media accounts.

The fine was part of a settlement that the DNP, Sarah Erny, reached with the state to resolve allegations that she failed to identify her supervising physician and inform the public that she was not a medical doctor.

Under California’s Medical Practice Act, individuals cannot refer to themselves as “doctor, physician, or any other terms or letters indicating or implying that he or she is a physician and surgeon ... without having ... a certificate as a physician and surgeon.”

Instead, nurse practitioners certified by the California Board of Registered Nursing may use titles like “Certified Nurse Practitioner” and “Advanced Practice Registered Nurse,” corresponding letters such as APRN-CNP, RN, and NP, and phrases like pediatric nurse practitioner to identify specialization.

Individuals who misrepresent themselves are subject to misdemeanor charges and civil penalties.

The nonprofit Pacific Legal Foundation represents the plaintiffs. In court records, its attorneys argue that after “years earning their advanced degrees and qualifications ... they should be able to speak truthfully about them in their workplaces, on their business cards, the Internet, and social media, so long as they clarify that they are nurse practitioners.”

State lawmakers’ attempts to clarify the roles of physicians and nurse practitioners have seen mixed results. Florida legislators recently passed a bill to prevent advanced practice nurses from using the honorific title, reserving it only for MDs and DOs. Gov. Ron DeSantis vetoed it last month.

In May, Georgia lawmakers passed the Health Care Practitioners Truth and Transparency Act. It requires advanced practice nurses and physician assistants with doctoral degrees who refer to themselves as doctors in a clinical setting to state they are not medical doctors or physicians.

Still, some health professionals say that the designation should only be used in academic settings or among peers, and that all doctoral degree holders should ditch the moniker at the bedside to ease patient communications.

Named as defendants in the suit are three state officials: California Attorney General Rob Bonta, state Medical Board President Kristina Lawson, and California Board of Registered Nursing Executive Officer Loretta Melby.

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

Three California nurse practitioners with doctorates (DNP) have sued the state over its law that only physicians can call themselves doctors, saying it violates their first amendment right to use the honorific title without fear of regulatory repercussions.

The case highlights ongoing scope-creep battles as the American Medical Association tries to preserve the physician-led team model and nursing organizations and some lawmakers push for greater autonomy for allied professionals.

In the complaint filed in district court in June, plaintiffs Jacqueline Palmer, DNP, Heather Lewis, DNP, and Rodolfo Jaravata-Hanson, DNP, say they fear the state will sanction them. They note that “Doctor Sarah,” another DNP, was fined nearly $20,000 by the state last November for false advertising and fraud after using the moniker in her online advertising and social media accounts.

The fine was part of a settlement that the DNP, Sarah Erny, reached with the state to resolve allegations that she failed to identify her supervising physician and inform the public that she was not a medical doctor.

Under California’s Medical Practice Act, individuals cannot refer to themselves as “doctor, physician, or any other terms or letters indicating or implying that he or she is a physician and surgeon ... without having ... a certificate as a physician and surgeon.”

Instead, nurse practitioners certified by the California Board of Registered Nursing may use titles like “Certified Nurse Practitioner” and “Advanced Practice Registered Nurse,” corresponding letters such as APRN-CNP, RN, and NP, and phrases like pediatric nurse practitioner to identify specialization.

Individuals who misrepresent themselves are subject to misdemeanor charges and civil penalties.

The nonprofit Pacific Legal Foundation represents the plaintiffs. In court records, its attorneys argue that after “years earning their advanced degrees and qualifications ... they should be able to speak truthfully about them in their workplaces, on their business cards, the Internet, and social media, so long as they clarify that they are nurse practitioners.”

State lawmakers’ attempts to clarify the roles of physicians and nurse practitioners have seen mixed results. Florida legislators recently passed a bill to prevent advanced practice nurses from using the honorific title, reserving it only for MDs and DOs. Gov. Ron DeSantis vetoed it last month.

In May, Georgia lawmakers passed the Health Care Practitioners Truth and Transparency Act. It requires advanced practice nurses and physician assistants with doctoral degrees who refer to themselves as doctors in a clinical setting to state they are not medical doctors or physicians.

Still, some health professionals say that the designation should only be used in academic settings or among peers, and that all doctoral degree holders should ditch the moniker at the bedside to ease patient communications.

Named as defendants in the suit are three state officials: California Attorney General Rob Bonta, state Medical Board President Kristina Lawson, and California Board of Registered Nursing Executive Officer Loretta Melby.

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

Three California nurse practitioners with doctorates (DNP) have sued the state over its law that only physicians can call themselves doctors, saying it violates their first amendment right to use the honorific title without fear of regulatory repercussions.

The case highlights ongoing scope-creep battles as the American Medical Association tries to preserve the physician-led team model and nursing organizations and some lawmakers push for greater autonomy for allied professionals.

In the complaint filed in district court in June, plaintiffs Jacqueline Palmer, DNP, Heather Lewis, DNP, and Rodolfo Jaravata-Hanson, DNP, say they fear the state will sanction them. They note that “Doctor Sarah,” another DNP, was fined nearly $20,000 by the state last November for false advertising and fraud after using the moniker in her online advertising and social media accounts.

The fine was part of a settlement that the DNP, Sarah Erny, reached with the state to resolve allegations that she failed to identify her supervising physician and inform the public that she was not a medical doctor.

Under California’s Medical Practice Act, individuals cannot refer to themselves as “doctor, physician, or any other terms or letters indicating or implying that he or she is a physician and surgeon ... without having ... a certificate as a physician and surgeon.”

Instead, nurse practitioners certified by the California Board of Registered Nursing may use titles like “Certified Nurse Practitioner” and “Advanced Practice Registered Nurse,” corresponding letters such as APRN-CNP, RN, and NP, and phrases like pediatric nurse practitioner to identify specialization.

Individuals who misrepresent themselves are subject to misdemeanor charges and civil penalties.

The nonprofit Pacific Legal Foundation represents the plaintiffs. In court records, its attorneys argue that after “years earning their advanced degrees and qualifications ... they should be able to speak truthfully about them in their workplaces, on their business cards, the Internet, and social media, so long as they clarify that they are nurse practitioners.”

State lawmakers’ attempts to clarify the roles of physicians and nurse practitioners have seen mixed results. Florida legislators recently passed a bill to prevent advanced practice nurses from using the honorific title, reserving it only for MDs and DOs. Gov. Ron DeSantis vetoed it last month.

In May, Georgia lawmakers passed the Health Care Practitioners Truth and Transparency Act. It requires advanced practice nurses and physician assistants with doctoral degrees who refer to themselves as doctors in a clinical setting to state they are not medical doctors or physicians.

Still, some health professionals say that the designation should only be used in academic settings or among peers, and that all doctoral degree holders should ditch the moniker at the bedside to ease patient communications.

Named as defendants in the suit are three state officials: California Attorney General Rob Bonta, state Medical Board President Kristina Lawson, and California Board of Registered Nursing Executive Officer Loretta Melby.

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

Several recent developments in Lyme disease treatment and diagnosis may pave the way forward for combating disease that persists following missed or delayed diagnoses or remains following standard treatment. These include combination therapy to address “persister” bacteria and diagnostic tests that test directly for the pathogen and/or indirectly test for host response, according to experts who presented at a 2-day National Academies of Science, Engineering and Medicine workshop on infection-associated chronic illnesses.

Research has shown that 60% of people who are infected and not treated during the early or early disseminated stages of Lyme disease go on to develop late Lyme arthritis, said John Aucott, MD, director of the Johns Hopkins Lyme Disease Clinical Research Center in Baltimore. And in the real world, there’s an additional category of patients: Those who are misdiagnosed and develop infection-related persistent symptoms – such as fatigue, brain fog/cognitive dysfunction, and musculoskeletal problems – that don’t match the “textbook schematic” involving late Lyme arthritis and late neurologic disease.

Moreover, of patients who are treated with protocols recommended by the Infectious Diseases Society of America (IDSA), about 15% go on to develop persistent symptoms at 6 months – again, symptoms that don’t match textbook manifestations and do match symptoms of other infection-associated chronic illnesses. As a “research construct,” this has been coined posttreatment Lyme disease (PTLD), he said at the workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”

(On a practical level, it is hard to know clinically who has early disseminated disease unless they have multiple erythema migrans rashes or neurologic or cardiac involvement, he said after the meeting.)

All this points to the need for tests that are sensitive and specific for diagnosis at all stages of infection and disease, he said in a talk on diagnostics. Currently available tests – those that fit into the widely used two-tiered enzyme-linked immunosorbent assay, Western Blot serology testing – have significant limitations in sensitivity and specificity, including for acute infection when the body has not generated enough antibodies, yet treatment is most likely to succeed.
 

Move toward combination therapy research

Lyme disease is most commonly treated with doxycycline, and that’s problematic because the antibiotic is a microstatic whose efficacy relies on immune clearance of static bacteria, said Monica E. Embers, PhD, director of vector-borne disease at the Tulane National Primate Research Center and associate professor of immunology at Tulane University, New Orleans.

courtesy Tulane University-Paula Burch-Celentano

“But we know that Borrelia burgdorferi has the capability to evade the host immune response in almost every way possible. Persistence is the norm in an immunocompetent host ... [and] dormant bacteria/persisters are more tolerant of microstatic antibiotics,” she said.

Other considerations for antibiotic efficacy include the fact that B. burgdorferi survives for many months inside ticks without nutrient replenishment or replication, “so dormancy is part of their life cycle,” she said. Moreover, the bacteria can be found deep in connective tissues and joints.

The efficacy of accepted regimens of antibiotic treatment has been “a very contentious issue,” she said, noting that guidelines from the International Lyme and Associated Diseases Society “leave open the possibility for antibiotic retreatment when a chronic infection is judged to be a possible cause [of ongoing symptoms].”

The development of persister B. burgdorferi in the presence of antibiotics has been well studied in vitro, which has limitations, Dr. Embers said. But her group specializes in animal models and has shown persistence of antimicrobial-tolerant B. burgdorferi in tick-inoculated rhesus macaques 8-9 months after treatment with oral doxycycline.

“We [also] saw persistence of mild-moderate inflammation in the brain, peripheral nerves, spinal cord, joints and skeletal muscle, and in the heart,” Dr. Embers said, who coauthored a 2022 review of B. burgdorferi antimicrobial-tolerant persistence in Lyme disease and PTLD.

Her work has also shown that ceftriaxone, which is recommended by IDSA for patients with clinically evident neurological and/or cardiac involvement, does not clear infection in mice. “In general, single drugs have not been capable of clearing the infection, yet combinations show promise,” she said.

Dr. Embers has combed large drug libraries looking for combinations of antibiotics that employ different mechanisms of action in hopes of eliminating persister spirochetes. Certain combinations have shown promise in mice and have been tested in her rhesus macaque model; data analyses are underway.

Other research teams, such as that of Ying Zhang, MD, PhD, at Johns Hopkins, have similarly been screening combinations of antibiotics and other compounds, identifying candidates for further testing.

During a question and answer period, Dr. Embers said her team is also investigating the pathophysiology and long-term effects of tick-borne coinfections, including Bartonella, and is pursuing a hypothesis that infection with Borrelia allows Bartonella to cause more extensive disease and persist longer. “I think Lyme is at the core because of its ability to evade and suppress the immune response so effectively.”
 

Diagnostic possibilities, biomarkers for PTLD

Direct diagnostic tests for microbial nucleic acid and proteins “are promising alternatives for indirect serologic tests,” Dr. Aucott said. For instance, in addition to polymerase chain reaction tests, which “are making advances,” it may be possible to target the B. burgdorferi peptidoglycan for antigen detection.

Researchers have shown that peptidoglycan, a component of the B. burgdorferi cell envelope, is a persistent antigen in the synovial fluid of patients with Lyme arthritis who have been treated with oral and intravenous antibiotics, and that it likely contributes to inflammation.

“Maybe the infection is gone but parts of the bacteria are still there that are driving inflammation,” said Dr. Aucott, also associate professor of medicine at John Hopkins.

Researchers have also been looking at the host response to B. burgdorferi – including cytokines, chemokines, and autoantibiodies – to identify biomarkers for PTLD and to identify patients during posttreatment follow-up who are at increased risk of developing PTLD, with the hope of someday intervening. Persistently high levels of interleukin-23, CCL19, and interferon-alpha have each been associated in different studies with persistent symptoms after treatment, Dr. Aucott said.

In addition, metabolomics research is showing that patients with PTLD have metabolic fingerprints that are different from those who return to good health after treatment, and it may be possible to identify an epigenetic signature for Lyme disease. A project sponsored by the Defense Advanced Research Projects Agency called ECHO (Epigenetic Characterization and Observation) aims to identify epigenetic signatures of exposures to various threats, including B. burgdorferi.

“At the very proximal end of [indirectly testing for host response], there are modifications of the DNA that can occur in response to infectious insults ... and that changed DNA changes RNA expression and protein synthesis,” Dr. Aucott explained. DARPA’s project is “exciting because their goal [at DARPA] is to have a diagnostic test quickly as a result of this epigenetics work.”

Imaging research is also fast offering diagnostic opportunities, Dr. Aucott said. Levels of microglial activation on brain PET imaging have been found to correlate with PTLD, and a study at Johns Hopkins of multimodal neuroimaging with functional MRI and diffusion tensor imaging has shown distinct changes to white matter activation within the frontal lobe of patients with PTLD, compared with controls.

The NASEM workshop did not collect or require disclosures of its participants.

Several recent developments in Lyme disease treatment and diagnosis may pave the way forward for combating disease that persists following missed or delayed diagnoses or remains following standard treatment. These include combination therapy to address “persister” bacteria and diagnostic tests that test directly for the pathogen and/or indirectly test for host response, according to experts who presented at a 2-day National Academies of Science, Engineering and Medicine workshop on infection-associated chronic illnesses.

Research has shown that 60% of people who are infected and not treated during the early or early disseminated stages of Lyme disease go on to develop late Lyme arthritis, said John Aucott, MD, director of the Johns Hopkins Lyme Disease Clinical Research Center in Baltimore. And in the real world, there’s an additional category of patients: Those who are misdiagnosed and develop infection-related persistent symptoms – such as fatigue, brain fog/cognitive dysfunction, and musculoskeletal problems – that don’t match the “textbook schematic” involving late Lyme arthritis and late neurologic disease.

Moreover, of patients who are treated with protocols recommended by the Infectious Diseases Society of America (IDSA), about 15% go on to develop persistent symptoms at 6 months – again, symptoms that don’t match textbook manifestations and do match symptoms of other infection-associated chronic illnesses. As a “research construct,” this has been coined posttreatment Lyme disease (PTLD), he said at the workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”

(On a practical level, it is hard to know clinically who has early disseminated disease unless they have multiple erythema migrans rashes or neurologic or cardiac involvement, he said after the meeting.)

All this points to the need for tests that are sensitive and specific for diagnosis at all stages of infection and disease, he said in a talk on diagnostics. Currently available tests – those that fit into the widely used two-tiered enzyme-linked immunosorbent assay, Western Blot serology testing – have significant limitations in sensitivity and specificity, including for acute infection when the body has not generated enough antibodies, yet treatment is most likely to succeed.
 

Move toward combination therapy research

Lyme disease is most commonly treated with doxycycline, and that’s problematic because the antibiotic is a microstatic whose efficacy relies on immune clearance of static bacteria, said Monica E. Embers, PhD, director of vector-borne disease at the Tulane National Primate Research Center and associate professor of immunology at Tulane University, New Orleans.

courtesy Tulane University-Paula Burch-Celentano

“But we know that Borrelia burgdorferi has the capability to evade the host immune response in almost every way possible. Persistence is the norm in an immunocompetent host ... [and] dormant bacteria/persisters are more tolerant of microstatic antibiotics,” she said.

Other considerations for antibiotic efficacy include the fact that B. burgdorferi survives for many months inside ticks without nutrient replenishment or replication, “so dormancy is part of their life cycle,” she said. Moreover, the bacteria can be found deep in connective tissues and joints.

The efficacy of accepted regimens of antibiotic treatment has been “a very contentious issue,” she said, noting that guidelines from the International Lyme and Associated Diseases Society “leave open the possibility for antibiotic retreatment when a chronic infection is judged to be a possible cause [of ongoing symptoms].”

The development of persister B. burgdorferi in the presence of antibiotics has been well studied in vitro, which has limitations, Dr. Embers said. But her group specializes in animal models and has shown persistence of antimicrobial-tolerant B. burgdorferi in tick-inoculated rhesus macaques 8-9 months after treatment with oral doxycycline.

“We [also] saw persistence of mild-moderate inflammation in the brain, peripheral nerves, spinal cord, joints and skeletal muscle, and in the heart,” Dr. Embers said, who coauthored a 2022 review of B. burgdorferi antimicrobial-tolerant persistence in Lyme disease and PTLD.

Her work has also shown that ceftriaxone, which is recommended by IDSA for patients with clinically evident neurological and/or cardiac involvement, does not clear infection in mice. “In general, single drugs have not been capable of clearing the infection, yet combinations show promise,” she said.

Dr. Embers has combed large drug libraries looking for combinations of antibiotics that employ different mechanisms of action in hopes of eliminating persister spirochetes. Certain combinations have shown promise in mice and have been tested in her rhesus macaque model; data analyses are underway.

Other research teams, such as that of Ying Zhang, MD, PhD, at Johns Hopkins, have similarly been screening combinations of antibiotics and other compounds, identifying candidates for further testing.

During a question and answer period, Dr. Embers said her team is also investigating the pathophysiology and long-term effects of tick-borne coinfections, including Bartonella, and is pursuing a hypothesis that infection with Borrelia allows Bartonella to cause more extensive disease and persist longer. “I think Lyme is at the core because of its ability to evade and suppress the immune response so effectively.”
 

Diagnostic possibilities, biomarkers for PTLD

Direct diagnostic tests for microbial nucleic acid and proteins “are promising alternatives for indirect serologic tests,” Dr. Aucott said. For instance, in addition to polymerase chain reaction tests, which “are making advances,” it may be possible to target the B. burgdorferi peptidoglycan for antigen detection.

Researchers have shown that peptidoglycan, a component of the B. burgdorferi cell envelope, is a persistent antigen in the synovial fluid of patients with Lyme arthritis who have been treated with oral and intravenous antibiotics, and that it likely contributes to inflammation.

“Maybe the infection is gone but parts of the bacteria are still there that are driving inflammation,” said Dr. Aucott, also associate professor of medicine at John Hopkins.

Researchers have also been looking at the host response to B. burgdorferi – including cytokines, chemokines, and autoantibiodies – to identify biomarkers for PTLD and to identify patients during posttreatment follow-up who are at increased risk of developing PTLD, with the hope of someday intervening. Persistently high levels of interleukin-23, CCL19, and interferon-alpha have each been associated in different studies with persistent symptoms after treatment, Dr. Aucott said.

In addition, metabolomics research is showing that patients with PTLD have metabolic fingerprints that are different from those who return to good health after treatment, and it may be possible to identify an epigenetic signature for Lyme disease. A project sponsored by the Defense Advanced Research Projects Agency called ECHO (Epigenetic Characterization and Observation) aims to identify epigenetic signatures of exposures to various threats, including B. burgdorferi.

“At the very proximal end of [indirectly testing for host response], there are modifications of the DNA that can occur in response to infectious insults ... and that changed DNA changes RNA expression and protein synthesis,” Dr. Aucott explained. DARPA’s project is “exciting because their goal [at DARPA] is to have a diagnostic test quickly as a result of this epigenetics work.”

Imaging research is also fast offering diagnostic opportunities, Dr. Aucott said. Levels of microglial activation on brain PET imaging have been found to correlate with PTLD, and a study at Johns Hopkins of multimodal neuroimaging with functional MRI and diffusion tensor imaging has shown distinct changes to white matter activation within the frontal lobe of patients with PTLD, compared with controls.

The NASEM workshop did not collect or require disclosures of its participants.

Several recent developments in Lyme disease treatment and diagnosis may pave the way forward for combating disease that persists following missed or delayed diagnoses or remains following standard treatment. These include combination therapy to address “persister” bacteria and diagnostic tests that test directly for the pathogen and/or indirectly test for host response, according to experts who presented at a 2-day National Academies of Science, Engineering and Medicine workshop on infection-associated chronic illnesses.

Research has shown that 60% of people who are infected and not treated during the early or early disseminated stages of Lyme disease go on to develop late Lyme arthritis, said John Aucott, MD, director of the Johns Hopkins Lyme Disease Clinical Research Center in Baltimore. And in the real world, there’s an additional category of patients: Those who are misdiagnosed and develop infection-related persistent symptoms – such as fatigue, brain fog/cognitive dysfunction, and musculoskeletal problems – that don’t match the “textbook schematic” involving late Lyme arthritis and late neurologic disease.

Moreover, of patients who are treated with protocols recommended by the Infectious Diseases Society of America (IDSA), about 15% go on to develop persistent symptoms at 6 months – again, symptoms that don’t match textbook manifestations and do match symptoms of other infection-associated chronic illnesses. As a “research construct,” this has been coined posttreatment Lyme disease (PTLD), he said at the workshop, “Toward a Common Research Agenda in Infection-Associated Chronic Illnesses.”

(On a practical level, it is hard to know clinically who has early disseminated disease unless they have multiple erythema migrans rashes or neurologic or cardiac involvement, he said after the meeting.)

All this points to the need for tests that are sensitive and specific for diagnosis at all stages of infection and disease, he said in a talk on diagnostics. Currently available tests – those that fit into the widely used two-tiered enzyme-linked immunosorbent assay, Western Blot serology testing – have significant limitations in sensitivity and specificity, including for acute infection when the body has not generated enough antibodies, yet treatment is most likely to succeed.
 

Move toward combination therapy research

Lyme disease is most commonly treated with doxycycline, and that’s problematic because the antibiotic is a microstatic whose efficacy relies on immune clearance of static bacteria, said Monica E. Embers, PhD, director of vector-borne disease at the Tulane National Primate Research Center and associate professor of immunology at Tulane University, New Orleans.

courtesy Tulane University-Paula Burch-Celentano

“But we know that Borrelia burgdorferi has the capability to evade the host immune response in almost every way possible. Persistence is the norm in an immunocompetent host ... [and] dormant bacteria/persisters are more tolerant of microstatic antibiotics,” she said.

Other considerations for antibiotic efficacy include the fact that B. burgdorferi survives for many months inside ticks without nutrient replenishment or replication, “so dormancy is part of their life cycle,” she said. Moreover, the bacteria can be found deep in connective tissues and joints.

The efficacy of accepted regimens of antibiotic treatment has been “a very contentious issue,” she said, noting that guidelines from the International Lyme and Associated Diseases Society “leave open the possibility for antibiotic retreatment when a chronic infection is judged to be a possible cause [of ongoing symptoms].”

The development of persister B. burgdorferi in the presence of antibiotics has been well studied in vitro, which has limitations, Dr. Embers said. But her group specializes in animal models and has shown persistence of antimicrobial-tolerant B. burgdorferi in tick-inoculated rhesus macaques 8-9 months after treatment with oral doxycycline.

“We [also] saw persistence of mild-moderate inflammation in the brain, peripheral nerves, spinal cord, joints and skeletal muscle, and in the heart,” Dr. Embers said, who coauthored a 2022 review of B. burgdorferi antimicrobial-tolerant persistence in Lyme disease and PTLD.

Her work has also shown that ceftriaxone, which is recommended by IDSA for patients with clinically evident neurological and/or cardiac involvement, does not clear infection in mice. “In general, single drugs have not been capable of clearing the infection, yet combinations show promise,” she said.

Dr. Embers has combed large drug libraries looking for combinations of antibiotics that employ different mechanisms of action in hopes of eliminating persister spirochetes. Certain combinations have shown promise in mice and have been tested in her rhesus macaque model; data analyses are underway.

Other research teams, such as that of Ying Zhang, MD, PhD, at Johns Hopkins, have similarly been screening combinations of antibiotics and other compounds, identifying candidates for further testing.

During a question and answer period, Dr. Embers said her team is also investigating the pathophysiology and long-term effects of tick-borne coinfections, including Bartonella, and is pursuing a hypothesis that infection with Borrelia allows Bartonella to cause more extensive disease and persist longer. “I think Lyme is at the core because of its ability to evade and suppress the immune response so effectively.”
 

Diagnostic possibilities, biomarkers for PTLD

Direct diagnostic tests for microbial nucleic acid and proteins “are promising alternatives for indirect serologic tests,” Dr. Aucott said. For instance, in addition to polymerase chain reaction tests, which “are making advances,” it may be possible to target the B. burgdorferi peptidoglycan for antigen detection.

Researchers have shown that peptidoglycan, a component of the B. burgdorferi cell envelope, is a persistent antigen in the synovial fluid of patients with Lyme arthritis who have been treated with oral and intravenous antibiotics, and that it likely contributes to inflammation.

“Maybe the infection is gone but parts of the bacteria are still there that are driving inflammation,” said Dr. Aucott, also associate professor of medicine at John Hopkins.

Researchers have also been looking at the host response to B. burgdorferi – including cytokines, chemokines, and autoantibiodies – to identify biomarkers for PTLD and to identify patients during posttreatment follow-up who are at increased risk of developing PTLD, with the hope of someday intervening. Persistently high levels of interleukin-23, CCL19, and interferon-alpha have each been associated in different studies with persistent symptoms after treatment, Dr. Aucott said.

In addition, metabolomics research is showing that patients with PTLD have metabolic fingerprints that are different from those who return to good health after treatment, and it may be possible to identify an epigenetic signature for Lyme disease. A project sponsored by the Defense Advanced Research Projects Agency called ECHO (Epigenetic Characterization and Observation) aims to identify epigenetic signatures of exposures to various threats, including B. burgdorferi.

“At the very proximal end of [indirectly testing for host response], there are modifications of the DNA that can occur in response to infectious insults ... and that changed DNA changes RNA expression and protein synthesis,” Dr. Aucott explained. DARPA’s project is “exciting because their goal [at DARPA] is to have a diagnostic test quickly as a result of this epigenetics work.”

Imaging research is also fast offering diagnostic opportunities, Dr. Aucott said. Levels of microglial activation on brain PET imaging have been found to correlate with PTLD, and a study at Johns Hopkins of multimodal neuroimaging with functional MRI and diffusion tensor imaging has shown distinct changes to white matter activation within the frontal lobe of patients with PTLD, compared with controls.

The NASEM workshop did not collect or require disclosures of its participants.

The best-selling drug Humira (adalimumab) now faces competition in the United States after a 20-year monopoly. The first adalimumab biosimilar, Amjevita, launched in the United States on January 31, and in July, seven additional biosimilars became available. These drugs have the potential to lower prescription drug prices, but when and by how much remains to be seen.

Here’s what you need to know about adalimumab biosimilars.
 

What Humira biosimilars are now available?

Eight different biosimilars have launched in 2023 with discounts as large at 85% from Humira’s list price of $6,922. A few companies also offer two price points.

Three of these biosimilars – Hadlima, Hyrimoz, and Yuflyma – are available in high concentration formulations. This high concentration formulation makes up 85% of Humira prescriptions, according to a report from Goodroot, a collection of companies focused on lowering health care costs.

Cyltezo is currently the only adalimumab biosimilar with an interchangeability designation, meaning that a pharmacist can substitute the biosimilar for an equivalent Humira prescription without the intervention of a clinician. A total of 47 states allow for these substitutions without prior approval from a clinician, according to Goodroot, and the clinician must be notified of the switch within a certain time frame. A total of 40 states require that patients be notified of the switch before substitution.

However, it’s not clear if this interchangeability designation will prove an advantage for Cyltezo, as it is interchangeable with the lower concentration version of Humira that makes up just 15% of prescriptions.

Most of the companies behind these biosimilars are pursuing interchangeability designations for their drugs, except for Fresenius Kabi (Idacio) and Coherus (Yusimry).

A ninth biosimilar, Pfizer’s adalimumab-afzb (Abrilada), is not yet on the market and is currently awaiting an approval decision from the Food and Drug Administration to add an interchangeability designation to its prior approval for a low-concentration formulation.
 

Why are they priced differently?

The two price points offer different deals to payers. Pharmacy benefit managers make confidential agreements with drug manufacturers to get a discount – called a rebate – to get the drug on the PBM’s formulary. The PBM keeps a portion of that rebate, and the rest is passed on to the insurance company and patients. Biosimilars at a higher price point will likely offer larger rebates. Biosimilars offered at lower price points incorporate this discount up front in their list pricing and likely will not offer large rebates.

Will biosimilars be covered by payers?

Currently, biosimilars are being offered on formularies at parity with Humira, meaning they are on the same tier. The PBM companies OptumRx and Cigna Group’s Express Scripts will offer Amjevita (at both price points), Cyltezo, and Hyrimoz (at both price points).

“This decision allows our clients flexibility to provide access to the lower list price, so members in high-deductible plans and benefit designs with coinsurance can experience lower out-of-pocket costs,” said OptumRx spokesperson Isaac Sorensen in an email.

Mark Cuban Cost Plus Drug Company, which uses a direct-to-consumer model, will offer Yusimry for $567.27 on its website. SmithRx, a PBM based in San Francisco, announced it would partner with Cost Plus Drugs to offer Yusimry, adding that SmithRx members can use their insurance benefits to further reduce out-of-pocket costs. RxPreferred, another PBM, will also offer Yusimry through its partnership with Cuban’s company.

The news website Formulary Watch previously reported that CVS Caremark, another of the biggest PBMs, will be offering Amjevita, but as a nonpreferred brand, while Humira remains the preferred brand. CVS Caremark did not respond to a request for comment.
 

Will patients pay less?

Biosimilars have been touted as a potential solution to lower spending on biologic drugs, but it’s unknown if patients will ultimately benefit with lower out-of-pocket costs. It’s “impossible to predict” if the discount that third-party payers pay will be passed on to consumers, said Mark Fendrick, MD, who directs the University of Michigan Center for Value-based Insurance Design in Ann Arbor.

Michigan Medicine

Generally, a consumer’s copay is a percentage of a drug’s list price, so it stands to reason that a low drug price would result in lower out-of-pocket payments. While this is mostly true, Humira has a successful copay assistance program to lower prescription costs for consumers. According to a 2022 IQVIA report, 82% of commercial prescriptions cost patients less than $10 for Humira because of this program.

To appeal to patients, biosimilar companies will need to offer similar savings, Dr. Fendrick added. “There will be some discontent if patients are actually asked to pay more out-of-pocket for a less expensive drug,” he said.

All eight companies behind these biosimilars are offering or will be launching copay saving programs, many which advertise copays as low as $0 per month for eligible patients.
 

How will Humira respond?

Marta Wosińska, PhD, a health care economist at the Brookings Institute, Washington, predicts payers will use these lower biosimilar prices to negotiate better deals with AbbVie, Humira’s manufacturer. “We have a lot of players coming into [the market] right now, so the competition is really fierce,” she said. In response, AbbVie will need to increase rebates on Humira and/or lower its price to compete with these biosimilars. 

“The ball is in AbbVie’s court,” she said. “If [the company] is not willing to drop price sufficiently, then payers will start switching to biosimilars.”

Dr. Fendrick reported past financial relationships and consulting arrangements with AbbVie, Amgen, Arnold Ventures, Bayer, CareFirst, BlueCross BlueShield, and many other companies. Dr. Wosińska has received funding from Arnold Ventures and serves as an expert witness on antitrust cases involving generic medication.

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

The best-selling drug Humira (adalimumab) now faces competition in the United States after a 20-year monopoly. The first adalimumab biosimilar, Amjevita, launched in the United States on January 31, and in July, seven additional biosimilars became available. These drugs have the potential to lower prescription drug prices, but when and by how much remains to be seen.

Here’s what you need to know about adalimumab biosimilars.
 

What Humira biosimilars are now available?

Eight different biosimilars have launched in 2023 with discounts as large at 85% from Humira’s list price of $6,922. A few companies also offer two price points.

Three of these biosimilars – Hadlima, Hyrimoz, and Yuflyma – are available in high concentration formulations. This high concentration formulation makes up 85% of Humira prescriptions, according to a report from Goodroot, a collection of companies focused on lowering health care costs.

Cyltezo is currently the only adalimumab biosimilar with an interchangeability designation, meaning that a pharmacist can substitute the biosimilar for an equivalent Humira prescription without the intervention of a clinician. A total of 47 states allow for these substitutions without prior approval from a clinician, according to Goodroot, and the clinician must be notified of the switch within a certain time frame. A total of 40 states require that patients be notified of the switch before substitution.

However, it’s not clear if this interchangeability designation will prove an advantage for Cyltezo, as it is interchangeable with the lower concentration version of Humira that makes up just 15% of prescriptions.

Most of the companies behind these biosimilars are pursuing interchangeability designations for their drugs, except for Fresenius Kabi (Idacio) and Coherus (Yusimry).

A ninth biosimilar, Pfizer’s adalimumab-afzb (Abrilada), is not yet on the market and is currently awaiting an approval decision from the Food and Drug Administration to add an interchangeability designation to its prior approval for a low-concentration formulation.
 

Why are they priced differently?

The two price points offer different deals to payers. Pharmacy benefit managers make confidential agreements with drug manufacturers to get a discount – called a rebate – to get the drug on the PBM’s formulary. The PBM keeps a portion of that rebate, and the rest is passed on to the insurance company and patients. Biosimilars at a higher price point will likely offer larger rebates. Biosimilars offered at lower price points incorporate this discount up front in their list pricing and likely will not offer large rebates.

Will biosimilars be covered by payers?

Currently, biosimilars are being offered on formularies at parity with Humira, meaning they are on the same tier. The PBM companies OptumRx and Cigna Group’s Express Scripts will offer Amjevita (at both price points), Cyltezo, and Hyrimoz (at both price points).

“This decision allows our clients flexibility to provide access to the lower list price, so members in high-deductible plans and benefit designs with coinsurance can experience lower out-of-pocket costs,” said OptumRx spokesperson Isaac Sorensen in an email.

Mark Cuban Cost Plus Drug Company, which uses a direct-to-consumer model, will offer Yusimry for $567.27 on its website. SmithRx, a PBM based in San Francisco, announced it would partner with Cost Plus Drugs to offer Yusimry, adding that SmithRx members can use their insurance benefits to further reduce out-of-pocket costs. RxPreferred, another PBM, will also offer Yusimry through its partnership with Cuban’s company.

The news website Formulary Watch previously reported that CVS Caremark, another of the biggest PBMs, will be offering Amjevita, but as a nonpreferred brand, while Humira remains the preferred brand. CVS Caremark did not respond to a request for comment.
 

Will patients pay less?

Biosimilars have been touted as a potential solution to lower spending on biologic drugs, but it’s unknown if patients will ultimately benefit with lower out-of-pocket costs. It’s “impossible to predict” if the discount that third-party payers pay will be passed on to consumers, said Mark Fendrick, MD, who directs the University of Michigan Center for Value-based Insurance Design in Ann Arbor.

Michigan Medicine

Generally, a consumer’s copay is a percentage of a drug’s list price, so it stands to reason that a low drug price would result in lower out-of-pocket payments. While this is mostly true, Humira has a successful copay assistance program to lower prescription costs for consumers. According to a 2022 IQVIA report, 82% of commercial prescriptions cost patients less than $10 for Humira because of this program.

To appeal to patients, biosimilar companies will need to offer similar savings, Dr. Fendrick added. “There will be some discontent if patients are actually asked to pay more out-of-pocket for a less expensive drug,” he said.

All eight companies behind these biosimilars are offering or will be launching copay saving programs, many which advertise copays as low as $0 per month for eligible patients.
 

How will Humira respond?

Marta Wosińska, PhD, a health care economist at the Brookings Institute, Washington, predicts payers will use these lower biosimilar prices to negotiate better deals with AbbVie, Humira’s manufacturer. “We have a lot of players coming into [the market] right now, so the competition is really fierce,” she said. In response, AbbVie will need to increase rebates on Humira and/or lower its price to compete with these biosimilars. 

“The ball is in AbbVie’s court,” she said. “If [the company] is not willing to drop price sufficiently, then payers will start switching to biosimilars.”

Dr. Fendrick reported past financial relationships and consulting arrangements with AbbVie, Amgen, Arnold Ventures, Bayer, CareFirst, BlueCross BlueShield, and many other companies. Dr. Wosińska has received funding from Arnold Ventures and serves as an expert witness on antitrust cases involving generic medication.

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

The best-selling drug Humira (adalimumab) now faces competition in the United States after a 20-year monopoly. The first adalimumab biosimilar, Amjevita, launched in the United States on January 31, and in July, seven additional biosimilars became available. These drugs have the potential to lower prescription drug prices, but when and by how much remains to be seen.

Here’s what you need to know about adalimumab biosimilars.
 

What Humira biosimilars are now available?

Eight different biosimilars have launched in 2023 with discounts as large at 85% from Humira’s list price of $6,922. A few companies also offer two price points.

Three of these biosimilars – Hadlima, Hyrimoz, and Yuflyma – are available in high concentration formulations. This high concentration formulation makes up 85% of Humira prescriptions, according to a report from Goodroot, a collection of companies focused on lowering health care costs.

Cyltezo is currently the only adalimumab biosimilar with an interchangeability designation, meaning that a pharmacist can substitute the biosimilar for an equivalent Humira prescription without the intervention of a clinician. A total of 47 states allow for these substitutions without prior approval from a clinician, according to Goodroot, and the clinician must be notified of the switch within a certain time frame. A total of 40 states require that patients be notified of the switch before substitution.

However, it’s not clear if this interchangeability designation will prove an advantage for Cyltezo, as it is interchangeable with the lower concentration version of Humira that makes up just 15% of prescriptions.

Most of the companies behind these biosimilars are pursuing interchangeability designations for their drugs, except for Fresenius Kabi (Idacio) and Coherus (Yusimry).

A ninth biosimilar, Pfizer’s adalimumab-afzb (Abrilada), is not yet on the market and is currently awaiting an approval decision from the Food and Drug Administration to add an interchangeability designation to its prior approval for a low-concentration formulation.
 

Why are they priced differently?

The two price points offer different deals to payers. Pharmacy benefit managers make confidential agreements with drug manufacturers to get a discount – called a rebate – to get the drug on the PBM’s formulary. The PBM keeps a portion of that rebate, and the rest is passed on to the insurance company and patients. Biosimilars at a higher price point will likely offer larger rebates. Biosimilars offered at lower price points incorporate this discount up front in their list pricing and likely will not offer large rebates.

Will biosimilars be covered by payers?

Currently, biosimilars are being offered on formularies at parity with Humira, meaning they are on the same tier. The PBM companies OptumRx and Cigna Group’s Express Scripts will offer Amjevita (at both price points), Cyltezo, and Hyrimoz (at both price points).

“This decision allows our clients flexibility to provide access to the lower list price, so members in high-deductible plans and benefit designs with coinsurance can experience lower out-of-pocket costs,” said OptumRx spokesperson Isaac Sorensen in an email.

Mark Cuban Cost Plus Drug Company, which uses a direct-to-consumer model, will offer Yusimry for $567.27 on its website. SmithRx, a PBM based in San Francisco, announced it would partner with Cost Plus Drugs to offer Yusimry, adding that SmithRx members can use their insurance benefits to further reduce out-of-pocket costs. RxPreferred, another PBM, will also offer Yusimry through its partnership with Cuban’s company.

The news website Formulary Watch previously reported that CVS Caremark, another of the biggest PBMs, will be offering Amjevita, but as a nonpreferred brand, while Humira remains the preferred brand. CVS Caremark did not respond to a request for comment.
 

Will patients pay less?

Biosimilars have been touted as a potential solution to lower spending on biologic drugs, but it’s unknown if patients will ultimately benefit with lower out-of-pocket costs. It’s “impossible to predict” if the discount that third-party payers pay will be passed on to consumers, said Mark Fendrick, MD, who directs the University of Michigan Center for Value-based Insurance Design in Ann Arbor.

Michigan Medicine

Generally, a consumer’s copay is a percentage of a drug’s list price, so it stands to reason that a low drug price would result in lower out-of-pocket payments. While this is mostly true, Humira has a successful copay assistance program to lower prescription costs for consumers. According to a 2022 IQVIA report, 82% of commercial prescriptions cost patients less than $10 for Humira because of this program.

To appeal to patients, biosimilar companies will need to offer similar savings, Dr. Fendrick added. “There will be some discontent if patients are actually asked to pay more out-of-pocket for a less expensive drug,” he said.

All eight companies behind these biosimilars are offering or will be launching copay saving programs, many which advertise copays as low as $0 per month for eligible patients.
 

How will Humira respond?

Marta Wosińska, PhD, a health care economist at the Brookings Institute, Washington, predicts payers will use these lower biosimilar prices to negotiate better deals with AbbVie, Humira’s manufacturer. “We have a lot of players coming into [the market] right now, so the competition is really fierce,” she said. In response, AbbVie will need to increase rebates on Humira and/or lower its price to compete with these biosimilars. 

“The ball is in AbbVie’s court,” she said. “If [the company] is not willing to drop price sufficiently, then payers will start switching to biosimilars.”

Dr. Fendrick reported past financial relationships and consulting arrangements with AbbVie, Amgen, Arnold Ventures, Bayer, CareFirst, BlueCross BlueShield, and many other companies. Dr. Wosińska has received funding from Arnold Ventures and serves as an expert witness on antitrust cases involving generic medication.

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

Indigenous children or children with new abnormal auscultatory findings were significantly more likely than children in other categories to respond to oral antibiotics for exacerbations related to bronchiectasis, based on data from more than 200 individuals in New Zealand.

Children and adolescents with bronchiectasis are often treated with antibiotics for respiratory exacerbations, but the effects of antibiotics can vary among individuals, and phenotypic features associated with greater symptom resolution have not been identified, wrote Vikas Goyal, PhD, of the Centre for Children’s Health Research, Brisbane, Australia, and colleagues.

Previous studies have suggested that nearly half of exacerbations in children and adolescents resolve spontaneously after 14 days, and more data are needed to identify which patients are mostly likely to benefit from antibiotics, they noted.

In a study published in the journal Chest, the researchers reviewed secondary data from 217 children and adolescents aged 1-18 years with bronchiectasis enrolled in a pair of randomized, controlled trials comparing oral antibiotics with placebo (known as BEST-1 and BEST-2). The median age of the participants was 6.6 years, 52% were boys, and 41% were Indigenous (defined as Australian First Nations, New Zealand Maori, or Pacific Islander). All participants in the analysis received at least 14 days of oral antibiotics for treatment of nonhospitalized respiratory exacerbations.

Overall, 130 children had resolution of symptoms by day 14, and 87 were nonresponders.

In a multivariate analysis, children who were Indigenous or who had new abnormal auscultatory findings were significantly more likely to respond than children in other categories (odds ratios, 3.59 and 3.85, respectively).

Patients with multiple bronchiectatic lobes at the time of diagnosis and those with higher cough scores at the start of treatment were significantly less likely to respond to antibiotics than patients without these features (OR, 0.66 and 0.55, respectively).

The researchers conducted a further analysis to examine the association between Indigenous ethnicity and treatment response. They found no differences in the other response variables of number of affected lobes at diagnosis and cough scores at the start of treatment between Indigenous and non-Indigenous children.

Given the strong response to antibiotics among Indigenous children, the researchers also conducted a mediation analysis. “Respiratory bacterial pathogens were mediated by Indigenous ethnicity and associated with being an antibiotic ‘responder,’ ” they wrote. For new abnormal chest auscultatory findings, both direct and indirect effects on day 14 response to oral antibiotics were mediated by Indigenous ethnicity. However, neither cough scores at the start of treatment nor the number of affected lobes at diagnosis showed a mediation effect from Indigenous ethnicity.

Among the nonresponders, 59 of 87 resolved symptoms with continuing oral antibiotics over the next 2-4 weeks, and 21 improved without antibiotics.

Additionally, the detection of a respiratory virus at the start of an exacerbation was not associated with antibiotic failure at 14 days, the researchers noted.

The findings were limited by several factors including the use of data from randomized trials that were not designed to address the question in the current study, the researchers noted. Other limitations included incomplete clinical data and lack of data on inflammatory indices, potential antibiotic-resistant pathogens in nonresponders, and the follow-up period of only 14 days, they said.

However, the results suggest a role for patient and exacerbation phenotypes in management of bronchiectasis in clinical practice and promoting antimicrobial stewardship, the researchers wrote. “Although there is benefit in treating exacerbations early to avoid treatment failure and subsequent intravenous antibiotics, future research also needs to identify exacerbations that can be managed without antibiotics,” they concluded.

The BEST-1 and BEST-2 studies were supported by the Australian National Health and Medical Research Council and the NHMRC Centre for Research Excellence in Lung Health of Aboriginal and Torres Strait Islander Children. Dr. Goyal had no financial conflicts to disclose.
 

Indigenous children or children with new abnormal auscultatory findings were significantly more likely than children in other categories to respond to oral antibiotics for exacerbations related to bronchiectasis, based on data from more than 200 individuals in New Zealand.

Children and adolescents with bronchiectasis are often treated with antibiotics for respiratory exacerbations, but the effects of antibiotics can vary among individuals, and phenotypic features associated with greater symptom resolution have not been identified, wrote Vikas Goyal, PhD, of the Centre for Children’s Health Research, Brisbane, Australia, and colleagues.

Previous studies have suggested that nearly half of exacerbations in children and adolescents resolve spontaneously after 14 days, and more data are needed to identify which patients are mostly likely to benefit from antibiotics, they noted.

In a study published in the journal Chest, the researchers reviewed secondary data from 217 children and adolescents aged 1-18 years with bronchiectasis enrolled in a pair of randomized, controlled trials comparing oral antibiotics with placebo (known as BEST-1 and BEST-2). The median age of the participants was 6.6 years, 52% were boys, and 41% were Indigenous (defined as Australian First Nations, New Zealand Maori, or Pacific Islander). All participants in the analysis received at least 14 days of oral antibiotics for treatment of nonhospitalized respiratory exacerbations.

Overall, 130 children had resolution of symptoms by day 14, and 87 were nonresponders.

In a multivariate analysis, children who were Indigenous or who had new abnormal auscultatory findings were significantly more likely to respond than children in other categories (odds ratios, 3.59 and 3.85, respectively).

Patients with multiple bronchiectatic lobes at the time of diagnosis and those with higher cough scores at the start of treatment were significantly less likely to respond to antibiotics than patients without these features (OR, 0.66 and 0.55, respectively).

The researchers conducted a further analysis to examine the association between Indigenous ethnicity and treatment response. They found no differences in the other response variables of number of affected lobes at diagnosis and cough scores at the start of treatment between Indigenous and non-Indigenous children.

Given the strong response to antibiotics among Indigenous children, the researchers also conducted a mediation analysis. “Respiratory bacterial pathogens were mediated by Indigenous ethnicity and associated with being an antibiotic ‘responder,’ ” they wrote. For new abnormal chest auscultatory findings, both direct and indirect effects on day 14 response to oral antibiotics were mediated by Indigenous ethnicity. However, neither cough scores at the start of treatment nor the number of affected lobes at diagnosis showed a mediation effect from Indigenous ethnicity.

Among the nonresponders, 59 of 87 resolved symptoms with continuing oral antibiotics over the next 2-4 weeks, and 21 improved without antibiotics.

Additionally, the detection of a respiratory virus at the start of an exacerbation was not associated with antibiotic failure at 14 days, the researchers noted.

The findings were limited by several factors including the use of data from randomized trials that were not designed to address the question in the current study, the researchers noted. Other limitations included incomplete clinical data and lack of data on inflammatory indices, potential antibiotic-resistant pathogens in nonresponders, and the follow-up period of only 14 days, they said.

However, the results suggest a role for patient and exacerbation phenotypes in management of bronchiectasis in clinical practice and promoting antimicrobial stewardship, the researchers wrote. “Although there is benefit in treating exacerbations early to avoid treatment failure and subsequent intravenous antibiotics, future research also needs to identify exacerbations that can be managed without antibiotics,” they concluded.

The BEST-1 and BEST-2 studies were supported by the Australian National Health and Medical Research Council and the NHMRC Centre for Research Excellence in Lung Health of Aboriginal and Torres Strait Islander Children. Dr. Goyal had no financial conflicts to disclose.
 

Indigenous children or children with new abnormal auscultatory findings were significantly more likely than children in other categories to respond to oral antibiotics for exacerbations related to bronchiectasis, based on data from more than 200 individuals in New Zealand.

Children and adolescents with bronchiectasis are often treated with antibiotics for respiratory exacerbations, but the effects of antibiotics can vary among individuals, and phenotypic features associated with greater symptom resolution have not been identified, wrote Vikas Goyal, PhD, of the Centre for Children’s Health Research, Brisbane, Australia, and colleagues.

Previous studies have suggested that nearly half of exacerbations in children and adolescents resolve spontaneously after 14 days, and more data are needed to identify which patients are mostly likely to benefit from antibiotics, they noted.

In a study published in the journal Chest, the researchers reviewed secondary data from 217 children and adolescents aged 1-18 years with bronchiectasis enrolled in a pair of randomized, controlled trials comparing oral antibiotics with placebo (known as BEST-1 and BEST-2). The median age of the participants was 6.6 years, 52% were boys, and 41% were Indigenous (defined as Australian First Nations, New Zealand Maori, or Pacific Islander). All participants in the analysis received at least 14 days of oral antibiotics for treatment of nonhospitalized respiratory exacerbations.

Overall, 130 children had resolution of symptoms by day 14, and 87 were nonresponders.

In a multivariate analysis, children who were Indigenous or who had new abnormal auscultatory findings were significantly more likely to respond than children in other categories (odds ratios, 3.59 and 3.85, respectively).

Patients with multiple bronchiectatic lobes at the time of diagnosis and those with higher cough scores at the start of treatment were significantly less likely to respond to antibiotics than patients without these features (OR, 0.66 and 0.55, respectively).

The researchers conducted a further analysis to examine the association between Indigenous ethnicity and treatment response. They found no differences in the other response variables of number of affected lobes at diagnosis and cough scores at the start of treatment between Indigenous and non-Indigenous children.

Given the strong response to antibiotics among Indigenous children, the researchers also conducted a mediation analysis. “Respiratory bacterial pathogens were mediated by Indigenous ethnicity and associated with being an antibiotic ‘responder,’ ” they wrote. For new abnormal chest auscultatory findings, both direct and indirect effects on day 14 response to oral antibiotics were mediated by Indigenous ethnicity. However, neither cough scores at the start of treatment nor the number of affected lobes at diagnosis showed a mediation effect from Indigenous ethnicity.

Among the nonresponders, 59 of 87 resolved symptoms with continuing oral antibiotics over the next 2-4 weeks, and 21 improved without antibiotics.

Additionally, the detection of a respiratory virus at the start of an exacerbation was not associated with antibiotic failure at 14 days, the researchers noted.

The findings were limited by several factors including the use of data from randomized trials that were not designed to address the question in the current study, the researchers noted. Other limitations included incomplete clinical data and lack of data on inflammatory indices, potential antibiotic-resistant pathogens in nonresponders, and the follow-up period of only 14 days, they said.

However, the results suggest a role for patient and exacerbation phenotypes in management of bronchiectasis in clinical practice and promoting antimicrobial stewardship, the researchers wrote. “Although there is benefit in treating exacerbations early to avoid treatment failure and subsequent intravenous antibiotics, future research also needs to identify exacerbations that can be managed without antibiotics,” they concluded.

The BEST-1 and BEST-2 studies were supported by the Australian National Health and Medical Research Council and the NHMRC Centre for Research Excellence in Lung Health of Aboriginal and Torres Strait Islander Children. Dr. Goyal had no financial conflicts to disclose.
 

Nearly 90% of diabetes management in the United States is provided by primary care clinicians; diabetes is the fifth most common reason for a primary care visit. State-of-the-art technology such as continuous glucose monitors (CGMs) will inevitably transform the management of diabetes in primary care. Clinicians and staff must be ready to educate, counsel, and support primary care patients in the use of CGMs.

CGMs (also called glucose sensors) are small, minimally invasive devices that attach to the skin of the upper arm or trunk. A tiny electrode in the subcutaneous space prompts an enzyme reaction that measures the interstitial (rather than blood) glucose concentration, typically every 5 minutes. The results are displayed on an accompanying reader or transmitted to an app on the user’s mobile phone.

CGMs could eliminate the need for finger-stick blood glucose testing, which until now, has been the much-despised gold standard for self-monitoring of glucose levels in diabetes. Despite being relatively inexpensive and accurate, finger-stick glucose tests are inconvenient and often painful. But of greater significance is this downside: Finger-stick monitoring reveals the patient’s blood glucose concentration at a single point in time, which can be difficult to interpret. Is the blood glucose rising or falling? Multiple finger-stick tests are required to determine the trend of a patient’s glucose levels or the response to food or exercise.

In contrast, the graphic display from a CGM sensor is more like a movie, telling a story as it unfolds. Uninterrupted data provide valuable feedback to patients about the effects of diet, physical activity, stress, or pain on their glucose levels. And for the first time, it’s easy to determine the proportion of time the patient spends in or out of the target glucose range.

Incorporating new technology into your practice may seem like a burden, but the reward is better information that leads to better management of diabetes. If you’re new to glucose sensors, many excellent resources are available to learn how to use them.

I recommend starting with a website called diabeteswise.org, which has both a patient-facing and clinician-facing version. This unbranded site serves as a kind of Consumer Reports for diabetes technology, allowing both patients and professionals to compare and contrast currently available CGM devices.

DiabetesWisePro  has information ranging from CGM device fundamentals and best practices to CGM prescribing and reimbursement.

Clinical Diabetes also provides multiple tools to help incorporate these devices into primary care clinical practice, including:

• Continuous Glucose Monitoring: Optimizing Diabetes Care (CME course).

• Diabetes Technology in Primary Care.

The next article in this series will cover two types of CGMs used in primary care: professional and personal devices.

Dr. Shubrook is a professor in the department of primary care, Touro University California College of Osteopathic Medicine, Vallejo, Calif., and director of diabetes services, Solano County Family Health Services, Fairfield, Calif. He disclosed ties with Abbott, Astra Zeneca, Bayer, Nevro, and Novo Nordisk.

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

Nearly 90% of diabetes management in the United States is provided by primary care clinicians; diabetes is the fifth most common reason for a primary care visit. State-of-the-art technology such as continuous glucose monitors (CGMs) will inevitably transform the management of diabetes in primary care. Clinicians and staff must be ready to educate, counsel, and support primary care patients in the use of CGMs.

CGMs (also called glucose sensors) are small, minimally invasive devices that attach to the skin of the upper arm or trunk. A tiny electrode in the subcutaneous space prompts an enzyme reaction that measures the interstitial (rather than blood) glucose concentration, typically every 5 minutes. The results are displayed on an accompanying reader or transmitted to an app on the user’s mobile phone.

CGMs could eliminate the need for finger-stick blood glucose testing, which until now, has been the much-despised gold standard for self-monitoring of glucose levels in diabetes. Despite being relatively inexpensive and accurate, finger-stick glucose tests are inconvenient and often painful. But of greater significance is this downside: Finger-stick monitoring reveals the patient’s blood glucose concentration at a single point in time, which can be difficult to interpret. Is the blood glucose rising or falling? Multiple finger-stick tests are required to determine the trend of a patient’s glucose levels or the response to food or exercise.

In contrast, the graphic display from a CGM sensor is more like a movie, telling a story as it unfolds. Uninterrupted data provide valuable feedback to patients about the effects of diet, physical activity, stress, or pain on their glucose levels. And for the first time, it’s easy to determine the proportion of time the patient spends in or out of the target glucose range.

Incorporating new technology into your practice may seem like a burden, but the reward is better information that leads to better management of diabetes. If you’re new to glucose sensors, many excellent resources are available to learn how to use them.

I recommend starting with a website called diabeteswise.org, which has both a patient-facing and clinician-facing version. This unbranded site serves as a kind of Consumer Reports for diabetes technology, allowing both patients and professionals to compare and contrast currently available CGM devices.

DiabetesWisePro  has information ranging from CGM device fundamentals and best practices to CGM prescribing and reimbursement.

Clinical Diabetes also provides multiple tools to help incorporate these devices into primary care clinical practice, including:

• Continuous Glucose Monitoring: Optimizing Diabetes Care (CME course).

• Diabetes Technology in Primary Care.

The next article in this series will cover two types of CGMs used in primary care: professional and personal devices.

Dr. Shubrook is a professor in the department of primary care, Touro University California College of Osteopathic Medicine, Vallejo, Calif., and director of diabetes services, Solano County Family Health Services, Fairfield, Calif. He disclosed ties with Abbott, Astra Zeneca, Bayer, Nevro, and Novo Nordisk.

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

Nearly 90% of diabetes management in the United States is provided by primary care clinicians; diabetes is the fifth most common reason for a primary care visit. State-of-the-art technology such as continuous glucose monitors (CGMs) will inevitably transform the management of diabetes in primary care. Clinicians and staff must be ready to educate, counsel, and support primary care patients in the use of CGMs.

CGMs (also called glucose sensors) are small, minimally invasive devices that attach to the skin of the upper arm or trunk. A tiny electrode in the subcutaneous space prompts an enzyme reaction that measures the interstitial (rather than blood) glucose concentration, typically every 5 minutes. The results are displayed on an accompanying reader or transmitted to an app on the user’s mobile phone.

CGMs could eliminate the need for finger-stick blood glucose testing, which until now, has been the much-despised gold standard for self-monitoring of glucose levels in diabetes. Despite being relatively inexpensive and accurate, finger-stick glucose tests are inconvenient and often painful. But of greater significance is this downside: Finger-stick monitoring reveals the patient’s blood glucose concentration at a single point in time, which can be difficult to interpret. Is the blood glucose rising or falling? Multiple finger-stick tests are required to determine the trend of a patient’s glucose levels or the response to food or exercise.

In contrast, the graphic display from a CGM sensor is more like a movie, telling a story as it unfolds. Uninterrupted data provide valuable feedback to patients about the effects of diet, physical activity, stress, or pain on their glucose levels. And for the first time, it’s easy to determine the proportion of time the patient spends in or out of the target glucose range.

Incorporating new technology into your practice may seem like a burden, but the reward is better information that leads to better management of diabetes. If you’re new to glucose sensors, many excellent resources are available to learn how to use them.

I recommend starting with a website called diabeteswise.org, which has both a patient-facing and clinician-facing version. This unbranded site serves as a kind of Consumer Reports for diabetes technology, allowing both patients and professionals to compare and contrast currently available CGM devices.

DiabetesWisePro  has information ranging from CGM device fundamentals and best practices to CGM prescribing and reimbursement.

Clinical Diabetes also provides multiple tools to help incorporate these devices into primary care clinical practice, including:

• Continuous Glucose Monitoring: Optimizing Diabetes Care (CME course).

• Diabetes Technology in Primary Care.

The next article in this series will cover two types of CGMs used in primary care: professional and personal devices.

Dr. Shubrook is a professor in the department of primary care, Touro University California College of Osteopathic Medicine, Vallejo, Calif., and director of diabetes services, Solano County Family Health Services, Fairfield, Calif. He disclosed ties with Abbott, Astra Zeneca, Bayer, Nevro, and Novo Nordisk.

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

In Colorado and Wyoming, nearly every baby born since 2020 is tested for signs of a mutation in the SMN1 gene, an indicator of spinal muscular atrophy (SMA). And in 4 years, genetic counselor Melissa Gibbons has seen 24 positive results. She has prepped 24 different pediatricians and family doctors to deliver the news: A seemingly perfect newborn likely has a lethal genetic disease.

Most of these clinicians had never cared for a child with SMA before, nor did they know that lifesaving gene therapy for the condition now exists. Still, the physicians were foundational to getting babies emergency treatment and monitoring the child’s safety after the fact.

“They are boots on the ground for this kind of [work],” Ms. Gibbons, who is the newborn screen coordinator for SMA in both states, told this news organization. “I’m not even sure they realize it.” As of today, the U.S. Food and Drug Administration has approved 16 gene therapies for the treatment of rare and debilitating diseases once considered lethal, such as SMA and cerebral adrenoleukodystrophy.

The newest addition to the list of approvals is Elevidys, Sarepta’s gene therapy for Duchenne muscular dystrophy (DMD). These conditions can now be mitigated, abated for years at a time, and even cured using treatments that tweak a patient’s DNA or RNA.

Hundreds of treatments are under development using the same mechanism. Viruses, liposomes, and other vectors of all kinds are being used to usher new genes into cells, correcting faulty copies or equipping a cell to fight disease. Cells gain the ability to make lifesaving proteins – proteins that heal wounds, restore muscle function, and fight cancer.

Within the decade, a significant fraction of the pediatric population will have gone through gene therapy, experts told this news organization. And primary care stands to be a linchpin in the scale-up of this kind of precision genetic medicine. Pediatricians and general practitioners will be central to finding and monitoring the patients that need these treatments. But the time and support doctors will need to fill that role remain scarce.

“This is a world we are creating right now, quite literally,” said Stanley Nelson, MD, director of the center for Duchenne muscular dystrophy at the University of California, Los Angeles. These cases – some before gene therapy and some after – will show up in primary care offices before the textbook is written.
 

Unknown side effects, new diseases

Even now, gene therapy is sequestered away in large academic medical research centers. The diagnosis, decision-making, and aftercare are handled by subspecialists working on clinical trials. While the research is ongoing, trial sponsors are keeping a close eye on enrolled patients. But that’s only until these drugs get market approval, Phil Beales, MD, chief medical officer at Congenica, a digital health company specializing in genome analysis support, said. Afterward, “the trialists will no longer have a role in looking after those patients.”

At that point, the role of primary care clinicians will be critically important. Although they probably will not manage gene-therapy patients on their own – comanaging them instead with subspecialists – they will be involved in the ordering and monitoring of safety labs and other tests.

General practitioners “need to know side effects because they are going to deal with side effects when someone calls them in the middle of the night,” said Dr. Beales, who also is chief executive officer of Axovia Therapeutics, a biotech company developing gene therapies.

Some of the side effects that come with gene therapy are established. Adeno-associated virus (AAV) or AAV-mediated gene therapies carry an increased risk for damage to the heart and liver, Dr. Nelson said. Other side effects are less well known and could be specific to the treatment and the tissue it targets. Primary care will be critical in detecting these unexpected side effects and expediting visits with subspecialists, he said.

In rural Wyoming, pediatricians and family doctors are especially important, Ms. Gibbons said. In the 30-90 days after gene therapy, patients need a lot of follow-up for safety reasons.

But aftercare for gene therapy will be more than just monitoring and managing side effects. The diseases themselves will change. Patients will be living with conditions that once were lethal.

In some cases, gene therapy may largely eliminate the disease. The data suggest that thalassemia, for example, can be largely cured for decades with one infusion of a patient’s genetically modified hematopoietic stem cells made using bluebird bio’s Zynteglo, according to Christy Duncan, MD, medical director of clinical research at the gene therapy program at Boston Children’s Hospital.

But other gene therapies, like the one for DMD, will offer a “spectrum of benefits,” Dr. Nelson said. They will be lifesaving, but the signs of the disease will linger. Clinicians will be learning alongside specialists what the new disease state for DMD and other rare diseases looks like after gene therapy.

“As we get hundreds of such therapies, [post–gene therapy] will amount to a substantial part of the pediatric population,” Dr. Nelson said.
 

Finding patients

Many of these rare diseases that plague young patients are unmistakable. Children with moderate or severe dystrophic epidermolysis bullosa, for instance, carry a mutation that prevents them from making type VII collagen. The babies suffer wounds and excessive bleeding and tend to receive a quick diagnosis within the first 6 months of life, according to Andy Orth, chief commercial officer at Krystal Bio, manufacturer of a new wound-healing gene therapy, Vyjuvek, for the disorder.

Other rare neurologic or muscular diseases can go undiagnosed for years. Until recently, drug companies and researchers have had little motivation to speed up the timeline because early diagnosis of a disease like DMD would not change the outcome, Dr. Nelson said.

But with gene therapy, prognoses are changing. And finding diseases early could soon mean preserving muscular function or preventing neurologic damage, Dr. Duncan said.

Newborn sequencing “is not standard of care yet, but it’s certainly coming,” Josh Peterson, MD, MPH, director of the center for precision medicine at Vanderbilt University Medical Center, in Nashville, Tenn., told this news organization.

A recent survey of 238 specialists in rare diseases found that roughly 90% believe whole-genome sequencing should be available to all newborns. And 80% of those experts endorse 42 genes as disease predictors. Screening for rare diseases at birth could reveal a host of conditions in the first week of life and expedite treatment. But this strategy will often rely on primary care and pediatricians interpreting the results.

Most pediatricians think sequencing is a great idea, but they do not feel comfortable doing it themselves, Dr. Peterson said. The good news, he said, is that manufacturers have made screening tests straightforward. Some drug companies even offer free screenings for gene therapy candidates.

Dr. Peterson predicts pediatricians will need to be equipped to deliver negative results on their own, which will be the case for around 97%-99% of patients. They also will need to be clear on whether a negative result is definitive or if more testing is warranted.

Positive results are more nuanced. Genetic counseling is the ideal resource when delivering this kind of news to patients, but counselors are a scarce resource nationally – and particularly in rural areas, Dr. Nelson said. Physicians likely will have to rely on their own counseling training to some degree.

“I feel very strongly that genetic counselors are in short supply,” Ms. Gibbons in Colorado said. Patients need a friendly resource who can talk them through the disease and how it works. And that discussion is not a one-off, she said.

The number of board-certified genetic counselors in the United States has doubled to more than 6,000 in the past 10 years – a pace that is expected to continue, according to the National Society of Genetic Counselors. “However, the geographical distribution of genetic counselors is most concentrated in urban centers.”

Equally important to the counseling experience, according to Dr. Duncan at Boston Children’s, is a primary care physician’s network of connections. The best newborn screening rollouts across the country have succeeded because clinicians knew where to send people next and how to get families the help they needed, she said.

But she also cautioned that this learning curve will soon be overwhelming. As gene therapy expands, it may be difficult for primary care doctors to keep up with the science, treatment studies, and commercially available therapies. “It’s asking too much,” Dr. Duncan said.

The structure of primary care already stretches practitioners thin and will “affect how well precision medicine can be adopted and disseminated,” Dr. Peterson said. “I think that is a key issue.”

Artificial intelligence may offer a partial solution. Some genetic counseling models already exist, but their utility for clinicians so far is limited, Dr. Beales said. But he said he expects these tools to improve rapidly to help clinicians and patients. On the patient’s end, they may be able to answer questions and supplement basic genetic counseling. On the physician’s end, algorithms could help triage patients and help move them along to the next steps in the care pathway for these rare diseases.
 

The whole patient

Primary care physicians will not be expected to be experts in gene therapy or solely in charge of patient safety. They will have support from industry and subspecialists leading the development of these treatments, experts agreed.

But generalists should expect to be drawn into multidisciplinary care teams, be the sounding boards for patients making decisions about gene therapy, help arrange insurance coverage, and be the recipients of late-night phone calls about side effects.

All that, while never losing sight of the child’s holistic health. In children so sick, specialists, subspecialists, and even parents tend to focus only on the rare disease. The team can “get distracted from good normal routine care,” Dr. Nelson said. But these children aren’t exempt from check-ups, vaccine regimens, or the other diseases of childhood.

“In a world where we mitigate that core disease,” he said, “we need a partner in the general pediatrics community” investing in their long-term health.

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

In Colorado and Wyoming, nearly every baby born since 2020 is tested for signs of a mutation in the SMN1 gene, an indicator of spinal muscular atrophy (SMA). And in 4 years, genetic counselor Melissa Gibbons has seen 24 positive results. She has prepped 24 different pediatricians and family doctors to deliver the news: A seemingly perfect newborn likely has a lethal genetic disease.

Most of these clinicians had never cared for a child with SMA before, nor did they know that lifesaving gene therapy for the condition now exists. Still, the physicians were foundational to getting babies emergency treatment and monitoring the child’s safety after the fact.

“They are boots on the ground for this kind of [work],” Ms. Gibbons, who is the newborn screen coordinator for SMA in both states, told this news organization. “I’m not even sure they realize it.” As of today, the U.S. Food and Drug Administration has approved 16 gene therapies for the treatment of rare and debilitating diseases once considered lethal, such as SMA and cerebral adrenoleukodystrophy.

The newest addition to the list of approvals is Elevidys, Sarepta’s gene therapy for Duchenne muscular dystrophy (DMD). These conditions can now be mitigated, abated for years at a time, and even cured using treatments that tweak a patient’s DNA or RNA.

Hundreds of treatments are under development using the same mechanism. Viruses, liposomes, and other vectors of all kinds are being used to usher new genes into cells, correcting faulty copies or equipping a cell to fight disease. Cells gain the ability to make lifesaving proteins – proteins that heal wounds, restore muscle function, and fight cancer.

Within the decade, a significant fraction of the pediatric population will have gone through gene therapy, experts told this news organization. And primary care stands to be a linchpin in the scale-up of this kind of precision genetic medicine. Pediatricians and general practitioners will be central to finding and monitoring the patients that need these treatments. But the time and support doctors will need to fill that role remain scarce.

“This is a world we are creating right now, quite literally,” said Stanley Nelson, MD, director of the center for Duchenne muscular dystrophy at the University of California, Los Angeles. These cases – some before gene therapy and some after – will show up in primary care offices before the textbook is written.
 

Unknown side effects, new diseases

Even now, gene therapy is sequestered away in large academic medical research centers. The diagnosis, decision-making, and aftercare are handled by subspecialists working on clinical trials. While the research is ongoing, trial sponsors are keeping a close eye on enrolled patients. But that’s only until these drugs get market approval, Phil Beales, MD, chief medical officer at Congenica, a digital health company specializing in genome analysis support, said. Afterward, “the trialists will no longer have a role in looking after those patients.”

At that point, the role of primary care clinicians will be critically important. Although they probably will not manage gene-therapy patients on their own – comanaging them instead with subspecialists – they will be involved in the ordering and monitoring of safety labs and other tests.

General practitioners “need to know side effects because they are going to deal with side effects when someone calls them in the middle of the night,” said Dr. Beales, who also is chief executive officer of Axovia Therapeutics, a biotech company developing gene therapies.

Some of the side effects that come with gene therapy are established. Adeno-associated virus (AAV) or AAV-mediated gene therapies carry an increased risk for damage to the heart and liver, Dr. Nelson said. Other side effects are less well known and could be specific to the treatment and the tissue it targets. Primary care will be critical in detecting these unexpected side effects and expediting visits with subspecialists, he said.

In rural Wyoming, pediatricians and family doctors are especially important, Ms. Gibbons said. In the 30-90 days after gene therapy, patients need a lot of follow-up for safety reasons.

But aftercare for gene therapy will be more than just monitoring and managing side effects. The diseases themselves will change. Patients will be living with conditions that once were lethal.

In some cases, gene therapy may largely eliminate the disease. The data suggest that thalassemia, for example, can be largely cured for decades with one infusion of a patient’s genetically modified hematopoietic stem cells made using bluebird bio’s Zynteglo, according to Christy Duncan, MD, medical director of clinical research at the gene therapy program at Boston Children’s Hospital.

But other gene therapies, like the one for DMD, will offer a “spectrum of benefits,” Dr. Nelson said. They will be lifesaving, but the signs of the disease will linger. Clinicians will be learning alongside specialists what the new disease state for DMD and other rare diseases looks like after gene therapy.

“As we get hundreds of such therapies, [post–gene therapy] will amount to a substantial part of the pediatric population,” Dr. Nelson said.
 

Finding patients

Many of these rare diseases that plague young patients are unmistakable. Children with moderate or severe dystrophic epidermolysis bullosa, for instance, carry a mutation that prevents them from making type VII collagen. The babies suffer wounds and excessive bleeding and tend to receive a quick diagnosis within the first 6 months of life, according to Andy Orth, chief commercial officer at Krystal Bio, manufacturer of a new wound-healing gene therapy, Vyjuvek, for the disorder.

Other rare neurologic or muscular diseases can go undiagnosed for years. Until recently, drug companies and researchers have had little motivation to speed up the timeline because early diagnosis of a disease like DMD would not change the outcome, Dr. Nelson said.

But with gene therapy, prognoses are changing. And finding diseases early could soon mean preserving muscular function or preventing neurologic damage, Dr. Duncan said.

Newborn sequencing “is not standard of care yet, but it’s certainly coming,” Josh Peterson, MD, MPH, director of the center for precision medicine at Vanderbilt University Medical Center, in Nashville, Tenn., told this news organization.

A recent survey of 238 specialists in rare diseases found that roughly 90% believe whole-genome sequencing should be available to all newborns. And 80% of those experts endorse 42 genes as disease predictors. Screening for rare diseases at birth could reveal a host of conditions in the first week of life and expedite treatment. But this strategy will often rely on primary care and pediatricians interpreting the results.

Most pediatricians think sequencing is a great idea, but they do not feel comfortable doing it themselves, Dr. Peterson said. The good news, he said, is that manufacturers have made screening tests straightforward. Some drug companies even offer free screenings for gene therapy candidates.

Dr. Peterson predicts pediatricians will need to be equipped to deliver negative results on their own, which will be the case for around 97%-99% of patients. They also will need to be clear on whether a negative result is definitive or if more testing is warranted.

Positive results are more nuanced. Genetic counseling is the ideal resource when delivering this kind of news to patients, but counselors are a scarce resource nationally – and particularly in rural areas, Dr. Nelson said. Physicians likely will have to rely on their own counseling training to some degree.

“I feel very strongly that genetic counselors are in short supply,” Ms. Gibbons in Colorado said. Patients need a friendly resource who can talk them through the disease and how it works. And that discussion is not a one-off, she said.

The number of board-certified genetic counselors in the United States has doubled to more than 6,000 in the past 10 years – a pace that is expected to continue, according to the National Society of Genetic Counselors. “However, the geographical distribution of genetic counselors is most concentrated in urban centers.”

Equally important to the counseling experience, according to Dr. Duncan at Boston Children’s, is a primary care physician’s network of connections. The best newborn screening rollouts across the country have succeeded because clinicians knew where to send people next and how to get families the help they needed, she said.

But she also cautioned that this learning curve will soon be overwhelming. As gene therapy expands, it may be difficult for primary care doctors to keep up with the science, treatment studies, and commercially available therapies. “It’s asking too much,” Dr. Duncan said.

The structure of primary care already stretches practitioners thin and will “affect how well precision medicine can be adopted and disseminated,” Dr. Peterson said. “I think that is a key issue.”

Artificial intelligence may offer a partial solution. Some genetic counseling models already exist, but their utility for clinicians so far is limited, Dr. Beales said. But he said he expects these tools to improve rapidly to help clinicians and patients. On the patient’s end, they may be able to answer questions and supplement basic genetic counseling. On the physician’s end, algorithms could help triage patients and help move them along to the next steps in the care pathway for these rare diseases.
 

The whole patient

Primary care physicians will not be expected to be experts in gene therapy or solely in charge of patient safety. They will have support from industry and subspecialists leading the development of these treatments, experts agreed.

But generalists should expect to be drawn into multidisciplinary care teams, be the sounding boards for patients making decisions about gene therapy, help arrange insurance coverage, and be the recipients of late-night phone calls about side effects.

All that, while never losing sight of the child’s holistic health. In children so sick, specialists, subspecialists, and even parents tend to focus only on the rare disease. The team can “get distracted from good normal routine care,” Dr. Nelson said. But these children aren’t exempt from check-ups, vaccine regimens, or the other diseases of childhood.

“In a world where we mitigate that core disease,” he said, “we need a partner in the general pediatrics community” investing in their long-term health.

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

In Colorado and Wyoming, nearly every baby born since 2020 is tested for signs of a mutation in the SMN1 gene, an indicator of spinal muscular atrophy (SMA). And in 4 years, genetic counselor Melissa Gibbons has seen 24 positive results. She has prepped 24 different pediatricians and family doctors to deliver the news: A seemingly perfect newborn likely has a lethal genetic disease.

Most of these clinicians had never cared for a child with SMA before, nor did they know that lifesaving gene therapy for the condition now exists. Still, the physicians were foundational to getting babies emergency treatment and monitoring the child’s safety after the fact.

“They are boots on the ground for this kind of [work],” Ms. Gibbons, who is the newborn screen coordinator for SMA in both states, told this news organization. “I’m not even sure they realize it.” As of today, the U.S. Food and Drug Administration has approved 16 gene therapies for the treatment of rare and debilitating diseases once considered lethal, such as SMA and cerebral adrenoleukodystrophy.

The newest addition to the list of approvals is Elevidys, Sarepta’s gene therapy for Duchenne muscular dystrophy (DMD). These conditions can now be mitigated, abated for years at a time, and even cured using treatments that tweak a patient’s DNA or RNA.

Hundreds of treatments are under development using the same mechanism. Viruses, liposomes, and other vectors of all kinds are being used to usher new genes into cells, correcting faulty copies or equipping a cell to fight disease. Cells gain the ability to make lifesaving proteins – proteins that heal wounds, restore muscle function, and fight cancer.

Within the decade, a significant fraction of the pediatric population will have gone through gene therapy, experts told this news organization. And primary care stands to be a linchpin in the scale-up of this kind of precision genetic medicine. Pediatricians and general practitioners will be central to finding and monitoring the patients that need these treatments. But the time and support doctors will need to fill that role remain scarce.

“This is a world we are creating right now, quite literally,” said Stanley Nelson, MD, director of the center for Duchenne muscular dystrophy at the University of California, Los Angeles. These cases – some before gene therapy and some after – will show up in primary care offices before the textbook is written.
 

Unknown side effects, new diseases

Even now, gene therapy is sequestered away in large academic medical research centers. The diagnosis, decision-making, and aftercare are handled by subspecialists working on clinical trials. While the research is ongoing, trial sponsors are keeping a close eye on enrolled patients. But that’s only until these drugs get market approval, Phil Beales, MD, chief medical officer at Congenica, a digital health company specializing in genome analysis support, said. Afterward, “the trialists will no longer have a role in looking after those patients.”

At that point, the role of primary care clinicians will be critically important. Although they probably will not manage gene-therapy patients on their own – comanaging them instead with subspecialists – they will be involved in the ordering and monitoring of safety labs and other tests.

General practitioners “need to know side effects because they are going to deal with side effects when someone calls them in the middle of the night,” said Dr. Beales, who also is chief executive officer of Axovia Therapeutics, a biotech company developing gene therapies.

Some of the side effects that come with gene therapy are established. Adeno-associated virus (AAV) or AAV-mediated gene therapies carry an increased risk for damage to the heart and liver, Dr. Nelson said. Other side effects are less well known and could be specific to the treatment and the tissue it targets. Primary care will be critical in detecting these unexpected side effects and expediting visits with subspecialists, he said.

In rural Wyoming, pediatricians and family doctors are especially important, Ms. Gibbons said. In the 30-90 days after gene therapy, patients need a lot of follow-up for safety reasons.

But aftercare for gene therapy will be more than just monitoring and managing side effects. The diseases themselves will change. Patients will be living with conditions that once were lethal.

In some cases, gene therapy may largely eliminate the disease. The data suggest that thalassemia, for example, can be largely cured for decades with one infusion of a patient’s genetically modified hematopoietic stem cells made using bluebird bio’s Zynteglo, according to Christy Duncan, MD, medical director of clinical research at the gene therapy program at Boston Children’s Hospital.

But other gene therapies, like the one for DMD, will offer a “spectrum of benefits,” Dr. Nelson said. They will be lifesaving, but the signs of the disease will linger. Clinicians will be learning alongside specialists what the new disease state for DMD and other rare diseases looks like after gene therapy.

“As we get hundreds of such therapies, [post–gene therapy] will amount to a substantial part of the pediatric population,” Dr. Nelson said.
 

Finding patients

Many of these rare diseases that plague young patients are unmistakable. Children with moderate or severe dystrophic epidermolysis bullosa, for instance, carry a mutation that prevents them from making type VII collagen. The babies suffer wounds and excessive bleeding and tend to receive a quick diagnosis within the first 6 months of life, according to Andy Orth, chief commercial officer at Krystal Bio, manufacturer of a new wound-healing gene therapy, Vyjuvek, for the disorder.

Other rare neurologic or muscular diseases can go undiagnosed for years. Until recently, drug companies and researchers have had little motivation to speed up the timeline because early diagnosis of a disease like DMD would not change the outcome, Dr. Nelson said.

But with gene therapy, prognoses are changing. And finding diseases early could soon mean preserving muscular function or preventing neurologic damage, Dr. Duncan said.

Newborn sequencing “is not standard of care yet, but it’s certainly coming,” Josh Peterson, MD, MPH, director of the center for precision medicine at Vanderbilt University Medical Center, in Nashville, Tenn., told this news organization.

A recent survey of 238 specialists in rare diseases found that roughly 90% believe whole-genome sequencing should be available to all newborns. And 80% of those experts endorse 42 genes as disease predictors. Screening for rare diseases at birth could reveal a host of conditions in the first week of life and expedite treatment. But this strategy will often rely on primary care and pediatricians interpreting the results.

Most pediatricians think sequencing is a great idea, but they do not feel comfortable doing it themselves, Dr. Peterson said. The good news, he said, is that manufacturers have made screening tests straightforward. Some drug companies even offer free screenings for gene therapy candidates.

Dr. Peterson predicts pediatricians will need to be equipped to deliver negative results on their own, which will be the case for around 97%-99% of patients. They also will need to be clear on whether a negative result is definitive or if more testing is warranted.

Positive results are more nuanced. Genetic counseling is the ideal resource when delivering this kind of news to patients, but counselors are a scarce resource nationally – and particularly in rural areas, Dr. Nelson said. Physicians likely will have to rely on their own counseling training to some degree.

“I feel very strongly that genetic counselors are in short supply,” Ms. Gibbons in Colorado said. Patients need a friendly resource who can talk them through the disease and how it works. And that discussion is not a one-off, she said.

The number of board-certified genetic counselors in the United States has doubled to more than 6,000 in the past 10 years – a pace that is expected to continue, according to the National Society of Genetic Counselors. “However, the geographical distribution of genetic counselors is most concentrated in urban centers.”

Equally important to the counseling experience, according to Dr. Duncan at Boston Children’s, is a primary care physician’s network of connections. The best newborn screening rollouts across the country have succeeded because clinicians knew where to send people next and how to get families the help they needed, she said.

But she also cautioned that this learning curve will soon be overwhelming. As gene therapy expands, it may be difficult for primary care doctors to keep up with the science, treatment studies, and commercially available therapies. “It’s asking too much,” Dr. Duncan said.

The structure of primary care already stretches practitioners thin and will “affect how well precision medicine can be adopted and disseminated,” Dr. Peterson said. “I think that is a key issue.”

Artificial intelligence may offer a partial solution. Some genetic counseling models already exist, but their utility for clinicians so far is limited, Dr. Beales said. But he said he expects these tools to improve rapidly to help clinicians and patients. On the patient’s end, they may be able to answer questions and supplement basic genetic counseling. On the physician’s end, algorithms could help triage patients and help move them along to the next steps in the care pathway for these rare diseases.
 

The whole patient

Primary care physicians will not be expected to be experts in gene therapy or solely in charge of patient safety. They will have support from industry and subspecialists leading the development of these treatments, experts agreed.

But generalists should expect to be drawn into multidisciplinary care teams, be the sounding boards for patients making decisions about gene therapy, help arrange insurance coverage, and be the recipients of late-night phone calls about side effects.

All that, while never losing sight of the child’s holistic health. In children so sick, specialists, subspecialists, and even parents tend to focus only on the rare disease. The team can “get distracted from good normal routine care,” Dr. Nelson said. But these children aren’t exempt from check-ups, vaccine regimens, or the other diseases of childhood.

“In a world where we mitigate that core disease,” he said, “we need a partner in the general pediatrics community” investing in their long-term health.

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

Like hundreds of other medical experts, Leana Wen, MD, an emergency physician and former Baltimore health commissioner, was an early and avid supporter of COVID vaccines and their ability to prevent severe disease, hospitalization, and death from SARS-CoV-2 infections.

When 51-year-old Scott Eli Harris, of Aubrey, Tex., heard of Dr. Wen’s stance in July 2021, the self-described “fifth-generation U.S. Army veteran and a sniper” sent Dr. Wen an electronic invective laden with racist language and very specific threats to shoot her.

Mr. Harris pled guilty to transmitting threats via interstate commerce last February and began serving 6 months in federal prison in the fall of 2022, but his threats wouldn’t be the last for Dr. Wen. Just 2 days after Mr. Harris was sentenced, charges were unsealed against another man in Massachusetts, who threatened that Dr. Wen would “end up in pieces” if she continued “pushing” her thoughts publicly.’

Dr. Wen has plenty of company. In an August 2022 survey of emergency doctors conducted by the American College of Emergency Physicians, 85% of respondents said violence against them is increasing. One in four doctors said they’re being assaulted by patients and their family and friends multiple times a week, compared with just 8% of doctors who said as much in 2018. About 64% of emergency physicians reported receiving verbal assaults and threats of violence; 40% reported being hit or slapped, and 26% were kicked.

This uptick of violence and threats against physicians didn’t come out of nowhere; violence against health care workers has been gradually increasing over the past decade. Health care providers can attest to the hostility that particular topics have sparked for years: vaccines in pediatrics, abortion in ob.gyn., and gender-affirming care in endocrinology.

But the pandemic fueled the fire. While there have always been hot-button issues in medicine, the ire they arouse today is more intense than ever before. The proliferation of misinformation (often via social media) and the politicization of public health and medicine are at the center of the problem.
 

‘The people attacking are themselves victims’

The misinformation problem first came to a head in one area of public health: vaccines. The pandemic accelerated antagonism in medicine – thanks, in part, to decades of antivaccine activism.

The antivaccine movement, which has ebbed and flowed in the United States and across the globe since the first vaccine, experienced a new wave in the early 2000s with the combination of concerns about thimerosal in vaccines and a now disproven link between autism and the MMR vaccine. But that movement grew. It picked up steam when activists gained political clout after a 2014 measles outbreak at Disneyland led California schools to tighten up policies regarding vaccinations for kids who enrolled. These stronger public school vaccination laws ran up against religious freedom arguments from antivaccine advocates.

Use of social media continues to grow, and with it, the spread of misinformation. A recent study found that Facebook “users’ social media habits doubled, and in some cases, tripled the amount of fake news they shared.”

In the face of growing confusion, health care providers and public health experts have often struggled to treat their patients – and communicate to the public – without appearing political.

“The people that are doing the attacking are in some ways themselves victims,” said Peter Hotez, MD, PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine, Houston. “They’re victims of the antiscience, antihealth ecosystem coming out of Fox News, the House Freedom Caucus, the CPAC conference, coming out of contrarian intellectuals.”

Many of Dr. Hotez’s colleagues don’t want to talk about the political right as an enabler of scientific disinformation, he said, but that doesn’t change what the evidence shows. The vast majority of state and national bills opposing vaccination, gender-affirming care, comprehensive reproductive care, and other evidence-based medical care often come from Republican legislators.
 

When politics and health care collide

“We’re in an incredible status quo,” said William Schaffner, MD, the previous director of the Infectious Diseases Society of America and a professor of infectious diseases and preventive medicine at Vanderbilt University, Nashville, Tenn. “You can’t get away from the politics, because you have [political] candidates espousing certain concepts that are antithetical to good public health.”

In March 2023, Florida Gov. Ron DeSantis’s surgeon general, Joseph Ladapo, MD, PhD, warned that COVID vaccines are harmful to young men, prompting rebukes from federal health authorities. It later came out that Dr. Ladapo had changed some of the results of the study before issuing his warning. But long before 2023, there emerged an increasing gap in COVID deaths between red states and blue states, mirroring the vaccination rates in those states. The redder the state, the higher the death toll.

It’s not just Republican Party culture warriors; medical misinformation is also finding increasing purchase on the far left. Robert F. Kennedy Jr. and Marianne Williamson, both of whom have launched long-shot challenges to President Biden for the 2024 Democratic nomination, had promoted antivaccine ideas long before the COVID pandemic. Mr. Kennedy continues to spread misinformation.

In June 2023, Joe Rogan hosted Mr. Kennedy, on his podcast. During the episode, Mr. Rogan listened uncritically as Mr. Kennedy told his millions of listeners that vaccines cause autism and that 5G causes cancer, among other fringe, often-debunked theories.

Dr. Hotez, a prominent misinformation debunker who was also part of a team that designed a low-cost COVID-19 vaccine, wrote on Twitter that the episode was “just awful.”

The backlash began almost immediately. Mr. Rogan, who has over 11 million followers on Twitter, responded with a public challenge for Dr. Hotez to debate Mr. Kennedy on Mr. Rogan’s show, with a reward of $100,000 to the charity of Dr. Hotez’s choice. More offers streamed in, including from Elon Musk, who tweeted that Dr. Hotez was “afraid of a public debate, because he knows he’s wrong.” More supporters of Mr. Kennedy and Mr. Rogan piled on.

Vaccine skeptics even showed up at Dr. Hotez’s house, filming him as he was returning from buying a Father’s Day cake and taunting him to debate Mr. Kennedy.
 

A turn in the pandemic

For a precious few weeks at the start of the pandemic, it felt as though the country was all in this together. There were arguments against closing schools and shutting down businesses, but for the most part, the nation had about 4 solid weeks of solidarity.

As masking mandates changed and the public health establishment lost the confidence of Americans, the veneer of solidarity began to chip away.

“Things were changing so rapidly during the pandemic that it was very hard for staff and patients to understand the changing guidelines, whether it was visitor constraints or masking,” said Carrie Nelson, the chief medical officer at the telehealth company AmWell, who worked as a supervisor at a large health care system in the Midwest until 2021.

In the midst of the public health crisis, former President Trump was downplaying the severity of the disease and was silencing officials from the Centers for Disease Control and Prevention, such as Nancy Messonier, who warned from the very beginning of the pandemic’s potential.

When the vaccines came out, the latent antivaccine movement flared up once again. And this time – unlike in decades past – the debate over vaccines had become partisan.

“Before the pandemic,” said Christopher Thomas, an emergency physician on the West Coast who requested that a pseudonym be used because of personal threats he has received, “patients wouldn’t really challenge me or throw out weird questions.” It’s not that he never encountered pushback, but the stakes felt lower, and people largely deferred to his medical expertise. “If we got a parent who had not vaccinated their child, I would totally engage back then,” Dr. Thomas said.

But the pandemic – and America’s response to it – changed the conversation. “The rhetoric ... switched from downplaying the virus to demonizing the vaccines,” Dr. Thomas said.
 

The toll on health care professionals

By the time vaccines were available, the public had begun to conflate doctors with public health experts, since both were “pushing” the vaccine.

“Most people probably don’t really know the difference between clinical medicine and public health,” said Richard Pan, MD, MPH, a pediatrician and California legislator who sponsored two bills – now laws – that strengthened state childhood vaccination requirements.

At first, it was clearly public health officials, such as Anthony Fauci, MD, who were the face of measures to mitigate the virus. But as doctors became the enforcers of those measures, the line between physicians and public health officials blurred.

A lot of the anger then shifted toward doctors, nurses, and other health care professionals, Dr. Pan said, “because we were, of course, the ones who would be administering the vaccines. They don’t really think of their doctor as a government person until your doctor is carrying a [government] message.”

Given the pressures and struggles of the past few years, it’s no surprise that burnout among health care professionals is high. According to an April 2023 study by the National Council of State Boards of Nursing and the National Forum of State Nursing Workforce Centers, an estimated 800,000 nurses expect to leave the profession by 2027, driven first and foremost by “stress and burnout.”

All of these departures in medicine’s “great resignation” have left hospitals and health care organizations even more short staffed, thereby increasing even more the pressure and burnout on those left.

The pandemic had already badly exacerbated the already widespread problem of burnout in the medical field, which Ms. Nelson said has contributed to the tension.

“The burnout problem that we have in health care is not a good basis for the development of a good therapeutic relationship,” Ms. Nelson said. “Burnout is fraught with apathy and desensitization to human emotions. It takes away the empathy that we once had for people that we see.”
 

What comes next?

Almost exactly 3 years after the world learned about SARS-CoV-2, Biden declared an end to the coronavirus public health emergency in April 2023. Yet, Americans continue to die from COVID, and the anger that bloomed and spread has not abated.

“I think we’re in a new steady state of violence in health care settings,” Ms. Nelson said. “It’s not gone down, because people are still very distressed.” That’s evident from the high prevalence of mental health conditions, the financial strain of first the pandemic and then inflation, and the overall traumatic impact the pandemic had on people, whether they recognize it or not.

The first step to solving any problem is, as the saying goes, to admit that there is a problem.

“I think people need to start stepping out of their comfort bubbles and start to look at things that make them uncomfortable,” Dr. Thomas said, but he doesn’t see that happening any time soon. “I’ve been very let down by physicians and embarrassed by the American physician organizations.”

The medical board in his state, he said, has stood by as some doctors continue misrepresenting medical evidence. “That’s been really, really hard on me. I didn’t think that the medical boards would go so far as to look the other way for something that was this tremendously bad.”

There are others who can take the lead – if they’re willing.

“There are some things the medical societies and academic health centers can do,” Dr. Hotez said, “starting with building up a culture of physicians and health care providers feeling comfortable in the public domain.” He said the messaging when he was getting his degrees was not to engage the public and not to talk to journalists because that was “self-promotion” or “grandstanding.” But the world is different now. Health care professionals need training in public engagement and communication, he said, and the culture needs to change so that health care providers feel comfortable speaking out without feeling “the sword of Damocles over their heads” every time they talk to a reporter, Dr. Hotez said.

There may be no silver bullet to solve the big-picture trust problem in medicine and public health. No TV appearance or quote in an article can solve it. But on an individual level — through careful relationship building with patients – doctors can strengthen that trust.

Telehealth may help with that, but there’s a fine balance there, Ms. Nelson cautioned. On the one hand, with the doctor and the patient each in their own private spaces, where they feel safe and comfortable, the overall experience can be more therapeutic and less stressful. At the same time, telehealth can pile on change-management tasks that can exacerbate burnout, “so it’s a delicate thing we have to approach.”

One very thin silver lining that could emerge from the way in which patients have begun to try to take charge of their care.

“They should fully understand the reasoning behind the recommendations that physicians are making,” Ms. Nelson said. “I’d like to see us get to a happy medium where it’s a partnership. We can’t go back to the old school where the doctor knows best and you don’t ever question him.

“What we need is the partnership, and I would love to see that as the silver lining, but the anger has got to settle down in order for that kind of productive thing to happen.”

As for the big picture? There’s a limit to what even society’s “miracle workers” can do. “The biggest priority right now for the health system is to protect their staff whatever way they can and do some training in deescalation,” Ms. Nelson said. “But I don’t think health care can solve the societal issues that seem to be creating this.”

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

Like hundreds of other medical experts, Leana Wen, MD, an emergency physician and former Baltimore health commissioner, was an early and avid supporter of COVID vaccines and their ability to prevent severe disease, hospitalization, and death from SARS-CoV-2 infections.

When 51-year-old Scott Eli Harris, of Aubrey, Tex., heard of Dr. Wen’s stance in July 2021, the self-described “fifth-generation U.S. Army veteran and a sniper” sent Dr. Wen an electronic invective laden with racist language and very specific threats to shoot her.

Mr. Harris pled guilty to transmitting threats via interstate commerce last February and began serving 6 months in federal prison in the fall of 2022, but his threats wouldn’t be the last for Dr. Wen. Just 2 days after Mr. Harris was sentenced, charges were unsealed against another man in Massachusetts, who threatened that Dr. Wen would “end up in pieces” if she continued “pushing” her thoughts publicly.’

Dr. Wen has plenty of company. In an August 2022 survey of emergency doctors conducted by the American College of Emergency Physicians, 85% of respondents said violence against them is increasing. One in four doctors said they’re being assaulted by patients and their family and friends multiple times a week, compared with just 8% of doctors who said as much in 2018. About 64% of emergency physicians reported receiving verbal assaults and threats of violence; 40% reported being hit or slapped, and 26% were kicked.

This uptick of violence and threats against physicians didn’t come out of nowhere; violence against health care workers has been gradually increasing over the past decade. Health care providers can attest to the hostility that particular topics have sparked for years: vaccines in pediatrics, abortion in ob.gyn., and gender-affirming care in endocrinology.

But the pandemic fueled the fire. While there have always been hot-button issues in medicine, the ire they arouse today is more intense than ever before. The proliferation of misinformation (often via social media) and the politicization of public health and medicine are at the center of the problem.
 

‘The people attacking are themselves victims’

The misinformation problem first came to a head in one area of public health: vaccines. The pandemic accelerated antagonism in medicine – thanks, in part, to decades of antivaccine activism.

The antivaccine movement, which has ebbed and flowed in the United States and across the globe since the first vaccine, experienced a new wave in the early 2000s with the combination of concerns about thimerosal in vaccines and a now disproven link between autism and the MMR vaccine. But that movement grew. It picked up steam when activists gained political clout after a 2014 measles outbreak at Disneyland led California schools to tighten up policies regarding vaccinations for kids who enrolled. These stronger public school vaccination laws ran up against religious freedom arguments from antivaccine advocates.

Use of social media continues to grow, and with it, the spread of misinformation. A recent study found that Facebook “users’ social media habits doubled, and in some cases, tripled the amount of fake news they shared.”

In the face of growing confusion, health care providers and public health experts have often struggled to treat their patients – and communicate to the public – without appearing political.

“The people that are doing the attacking are in some ways themselves victims,” said Peter Hotez, MD, PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine, Houston. “They’re victims of the antiscience, antihealth ecosystem coming out of Fox News, the House Freedom Caucus, the CPAC conference, coming out of contrarian intellectuals.”

Many of Dr. Hotez’s colleagues don’t want to talk about the political right as an enabler of scientific disinformation, he said, but that doesn’t change what the evidence shows. The vast majority of state and national bills opposing vaccination, gender-affirming care, comprehensive reproductive care, and other evidence-based medical care often come from Republican legislators.
 

When politics and health care collide

“We’re in an incredible status quo,” said William Schaffner, MD, the previous director of the Infectious Diseases Society of America and a professor of infectious diseases and preventive medicine at Vanderbilt University, Nashville, Tenn. “You can’t get away from the politics, because you have [political] candidates espousing certain concepts that are antithetical to good public health.”

In March 2023, Florida Gov. Ron DeSantis’s surgeon general, Joseph Ladapo, MD, PhD, warned that COVID vaccines are harmful to young men, prompting rebukes from federal health authorities. It later came out that Dr. Ladapo had changed some of the results of the study before issuing his warning. But long before 2023, there emerged an increasing gap in COVID deaths between red states and blue states, mirroring the vaccination rates in those states. The redder the state, the higher the death toll.

It’s not just Republican Party culture warriors; medical misinformation is also finding increasing purchase on the far left. Robert F. Kennedy Jr. and Marianne Williamson, both of whom have launched long-shot challenges to President Biden for the 2024 Democratic nomination, had promoted antivaccine ideas long before the COVID pandemic. Mr. Kennedy continues to spread misinformation.

In June 2023, Joe Rogan hosted Mr. Kennedy, on his podcast. During the episode, Mr. Rogan listened uncritically as Mr. Kennedy told his millions of listeners that vaccines cause autism and that 5G causes cancer, among other fringe, often-debunked theories.

Dr. Hotez, a prominent misinformation debunker who was also part of a team that designed a low-cost COVID-19 vaccine, wrote on Twitter that the episode was “just awful.”

The backlash began almost immediately. Mr. Rogan, who has over 11 million followers on Twitter, responded with a public challenge for Dr. Hotez to debate Mr. Kennedy on Mr. Rogan’s show, with a reward of $100,000 to the charity of Dr. Hotez’s choice. More offers streamed in, including from Elon Musk, who tweeted that Dr. Hotez was “afraid of a public debate, because he knows he’s wrong.” More supporters of Mr. Kennedy and Mr. Rogan piled on.

Vaccine skeptics even showed up at Dr. Hotez’s house, filming him as he was returning from buying a Father’s Day cake and taunting him to debate Mr. Kennedy.
 

A turn in the pandemic

For a precious few weeks at the start of the pandemic, it felt as though the country was all in this together. There were arguments against closing schools and shutting down businesses, but for the most part, the nation had about 4 solid weeks of solidarity.

As masking mandates changed and the public health establishment lost the confidence of Americans, the veneer of solidarity began to chip away.

“Things were changing so rapidly during the pandemic that it was very hard for staff and patients to understand the changing guidelines, whether it was visitor constraints or masking,” said Carrie Nelson, the chief medical officer at the telehealth company AmWell, who worked as a supervisor at a large health care system in the Midwest until 2021.

In the midst of the public health crisis, former President Trump was downplaying the severity of the disease and was silencing officials from the Centers for Disease Control and Prevention, such as Nancy Messonier, who warned from the very beginning of the pandemic’s potential.

When the vaccines came out, the latent antivaccine movement flared up once again. And this time – unlike in decades past – the debate over vaccines had become partisan.

“Before the pandemic,” said Christopher Thomas, an emergency physician on the West Coast who requested that a pseudonym be used because of personal threats he has received, “patients wouldn’t really challenge me or throw out weird questions.” It’s not that he never encountered pushback, but the stakes felt lower, and people largely deferred to his medical expertise. “If we got a parent who had not vaccinated their child, I would totally engage back then,” Dr. Thomas said.

But the pandemic – and America’s response to it – changed the conversation. “The rhetoric ... switched from downplaying the virus to demonizing the vaccines,” Dr. Thomas said.
 

The toll on health care professionals

By the time vaccines were available, the public had begun to conflate doctors with public health experts, since both were “pushing” the vaccine.

“Most people probably don’t really know the difference between clinical medicine and public health,” said Richard Pan, MD, MPH, a pediatrician and California legislator who sponsored two bills – now laws – that strengthened state childhood vaccination requirements.

At first, it was clearly public health officials, such as Anthony Fauci, MD, who were the face of measures to mitigate the virus. But as doctors became the enforcers of those measures, the line between physicians and public health officials blurred.

A lot of the anger then shifted toward doctors, nurses, and other health care professionals, Dr. Pan said, “because we were, of course, the ones who would be administering the vaccines. They don’t really think of their doctor as a government person until your doctor is carrying a [government] message.”

Given the pressures and struggles of the past few years, it’s no surprise that burnout among health care professionals is high. According to an April 2023 study by the National Council of State Boards of Nursing and the National Forum of State Nursing Workforce Centers, an estimated 800,000 nurses expect to leave the profession by 2027, driven first and foremost by “stress and burnout.”

All of these departures in medicine’s “great resignation” have left hospitals and health care organizations even more short staffed, thereby increasing even more the pressure and burnout on those left.

The pandemic had already badly exacerbated the already widespread problem of burnout in the medical field, which Ms. Nelson said has contributed to the tension.

“The burnout problem that we have in health care is not a good basis for the development of a good therapeutic relationship,” Ms. Nelson said. “Burnout is fraught with apathy and desensitization to human emotions. It takes away the empathy that we once had for people that we see.”
 

What comes next?

Almost exactly 3 years after the world learned about SARS-CoV-2, Biden declared an end to the coronavirus public health emergency in April 2023. Yet, Americans continue to die from COVID, and the anger that bloomed and spread has not abated.

“I think we’re in a new steady state of violence in health care settings,” Ms. Nelson said. “It’s not gone down, because people are still very distressed.” That’s evident from the high prevalence of mental health conditions, the financial strain of first the pandemic and then inflation, and the overall traumatic impact the pandemic had on people, whether they recognize it or not.

The first step to solving any problem is, as the saying goes, to admit that there is a problem.

“I think people need to start stepping out of their comfort bubbles and start to look at things that make them uncomfortable,” Dr. Thomas said, but he doesn’t see that happening any time soon. “I’ve been very let down by physicians and embarrassed by the American physician organizations.”

The medical board in his state, he said, has stood by as some doctors continue misrepresenting medical evidence. “That’s been really, really hard on me. I didn’t think that the medical boards would go so far as to look the other way for something that was this tremendously bad.”

There are others who can take the lead – if they’re willing.

“There are some things the medical societies and academic health centers can do,” Dr. Hotez said, “starting with building up a culture of physicians and health care providers feeling comfortable in the public domain.” He said the messaging when he was getting his degrees was not to engage the public and not to talk to journalists because that was “self-promotion” or “grandstanding.” But the world is different now. Health care professionals need training in public engagement and communication, he said, and the culture needs to change so that health care providers feel comfortable speaking out without feeling “the sword of Damocles over their heads” every time they talk to a reporter, Dr. Hotez said.

There may be no silver bullet to solve the big-picture trust problem in medicine and public health. No TV appearance or quote in an article can solve it. But on an individual level — through careful relationship building with patients – doctors can strengthen that trust.

Telehealth may help with that, but there’s a fine balance there, Ms. Nelson cautioned. On the one hand, with the doctor and the patient each in their own private spaces, where they feel safe and comfortable, the overall experience can be more therapeutic and less stressful. At the same time, telehealth can pile on change-management tasks that can exacerbate burnout, “so it’s a delicate thing we have to approach.”

One very thin silver lining that could emerge from the way in which patients have begun to try to take charge of their care.

“They should fully understand the reasoning behind the recommendations that physicians are making,” Ms. Nelson said. “I’d like to see us get to a happy medium where it’s a partnership. We can’t go back to the old school where the doctor knows best and you don’t ever question him.

“What we need is the partnership, and I would love to see that as the silver lining, but the anger has got to settle down in order for that kind of productive thing to happen.”

As for the big picture? There’s a limit to what even society’s “miracle workers” can do. “The biggest priority right now for the health system is to protect their staff whatever way they can and do some training in deescalation,” Ms. Nelson said. “But I don’t think health care can solve the societal issues that seem to be creating this.”

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

Like hundreds of other medical experts, Leana Wen, MD, an emergency physician and former Baltimore health commissioner, was an early and avid supporter of COVID vaccines and their ability to prevent severe disease, hospitalization, and death from SARS-CoV-2 infections.

When 51-year-old Scott Eli Harris, of Aubrey, Tex., heard of Dr. Wen’s stance in July 2021, the self-described “fifth-generation U.S. Army veteran and a sniper” sent Dr. Wen an electronic invective laden with racist language and very specific threats to shoot her.

Mr. Harris pled guilty to transmitting threats via interstate commerce last February and began serving 6 months in federal prison in the fall of 2022, but his threats wouldn’t be the last for Dr. Wen. Just 2 days after Mr. Harris was sentenced, charges were unsealed against another man in Massachusetts, who threatened that Dr. Wen would “end up in pieces” if she continued “pushing” her thoughts publicly.’

Dr. Wen has plenty of company. In an August 2022 survey of emergency doctors conducted by the American College of Emergency Physicians, 85% of respondents said violence against them is increasing. One in four doctors said they’re being assaulted by patients and their family and friends multiple times a week, compared with just 8% of doctors who said as much in 2018. About 64% of emergency physicians reported receiving verbal assaults and threats of violence; 40% reported being hit or slapped, and 26% were kicked.

This uptick of violence and threats against physicians didn’t come out of nowhere; violence against health care workers has been gradually increasing over the past decade. Health care providers can attest to the hostility that particular topics have sparked for years: vaccines in pediatrics, abortion in ob.gyn., and gender-affirming care in endocrinology.

But the pandemic fueled the fire. While there have always been hot-button issues in medicine, the ire they arouse today is more intense than ever before. The proliferation of misinformation (often via social media) and the politicization of public health and medicine are at the center of the problem.
 

‘The people attacking are themselves victims’

The misinformation problem first came to a head in one area of public health: vaccines. The pandemic accelerated antagonism in medicine – thanks, in part, to decades of antivaccine activism.

The antivaccine movement, which has ebbed and flowed in the United States and across the globe since the first vaccine, experienced a new wave in the early 2000s with the combination of concerns about thimerosal in vaccines and a now disproven link between autism and the MMR vaccine. But that movement grew. It picked up steam when activists gained political clout after a 2014 measles outbreak at Disneyland led California schools to tighten up policies regarding vaccinations for kids who enrolled. These stronger public school vaccination laws ran up against religious freedom arguments from antivaccine advocates.

Use of social media continues to grow, and with it, the spread of misinformation. A recent study found that Facebook “users’ social media habits doubled, and in some cases, tripled the amount of fake news they shared.”

In the face of growing confusion, health care providers and public health experts have often struggled to treat their patients – and communicate to the public – without appearing political.

“The people that are doing the attacking are in some ways themselves victims,” said Peter Hotez, MD, PhD, dean of the National School of Tropical Medicine at Baylor College of Medicine, Houston. “They’re victims of the antiscience, antihealth ecosystem coming out of Fox News, the House Freedom Caucus, the CPAC conference, coming out of contrarian intellectuals.”

Many of Dr. Hotez’s colleagues don’t want to talk about the political right as an enabler of scientific disinformation, he said, but that doesn’t change what the evidence shows. The vast majority of state and national bills opposing vaccination, gender-affirming care, comprehensive reproductive care, and other evidence-based medical care often come from Republican legislators.
 

When politics and health care collide

“We’re in an incredible status quo,” said William Schaffner, MD, the previous director of the Infectious Diseases Society of America and a professor of infectious diseases and preventive medicine at Vanderbilt University, Nashville, Tenn. “You can’t get away from the politics, because you have [political] candidates espousing certain concepts that are antithetical to good public health.”

In March 2023, Florida Gov. Ron DeSantis’s surgeon general, Joseph Ladapo, MD, PhD, warned that COVID vaccines are harmful to young men, prompting rebukes from federal health authorities. It later came out that Dr. Ladapo had changed some of the results of the study before issuing his warning. But long before 2023, there emerged an increasing gap in COVID deaths between red states and blue states, mirroring the vaccination rates in those states. The redder the state, the higher the death toll.

It’s not just Republican Party culture warriors; medical misinformation is also finding increasing purchase on the far left. Robert F. Kennedy Jr. and Marianne Williamson, both of whom have launched long-shot challenges to President Biden for the 2024 Democratic nomination, had promoted antivaccine ideas long before the COVID pandemic. Mr. Kennedy continues to spread misinformation.

In June 2023, Joe Rogan hosted Mr. Kennedy, on his podcast. During the episode, Mr. Rogan listened uncritically as Mr. Kennedy told his millions of listeners that vaccines cause autism and that 5G causes cancer, among other fringe, often-debunked theories.

Dr. Hotez, a prominent misinformation debunker who was also part of a team that designed a low-cost COVID-19 vaccine, wrote on Twitter that the episode was “just awful.”

The backlash began almost immediately. Mr. Rogan, who has over 11 million followers on Twitter, responded with a public challenge for Dr. Hotez to debate Mr. Kennedy on Mr. Rogan’s show, with a reward of $100,000 to the charity of Dr. Hotez’s choice. More offers streamed in, including from Elon Musk, who tweeted that Dr. Hotez was “afraid of a public debate, because he knows he’s wrong.” More supporters of Mr. Kennedy and Mr. Rogan piled on.

Vaccine skeptics even showed up at Dr. Hotez’s house, filming him as he was returning from buying a Father’s Day cake and taunting him to debate Mr. Kennedy.
 

A turn in the pandemic

For a precious few weeks at the start of the pandemic, it felt as though the country was all in this together. There were arguments against closing schools and shutting down businesses, but for the most part, the nation had about 4 solid weeks of solidarity.

As masking mandates changed and the public health establishment lost the confidence of Americans, the veneer of solidarity began to chip away.

“Things were changing so rapidly during the pandemic that it was very hard for staff and patients to understand the changing guidelines, whether it was visitor constraints or masking,” said Carrie Nelson, the chief medical officer at the telehealth company AmWell, who worked as a supervisor at a large health care system in the Midwest until 2021.

In the midst of the public health crisis, former President Trump was downplaying the severity of the disease and was silencing officials from the Centers for Disease Control and Prevention, such as Nancy Messonier, who warned from the very beginning of the pandemic’s potential.

When the vaccines came out, the latent antivaccine movement flared up once again. And this time – unlike in decades past – the debate over vaccines had become partisan.

“Before the pandemic,” said Christopher Thomas, an emergency physician on the West Coast who requested that a pseudonym be used because of personal threats he has received, “patients wouldn’t really challenge me or throw out weird questions.” It’s not that he never encountered pushback, but the stakes felt lower, and people largely deferred to his medical expertise. “If we got a parent who had not vaccinated their child, I would totally engage back then,” Dr. Thomas said.

But the pandemic – and America’s response to it – changed the conversation. “The rhetoric ... switched from downplaying the virus to demonizing the vaccines,” Dr. Thomas said.
 

The toll on health care professionals

By the time vaccines were available, the public had begun to conflate doctors with public health experts, since both were “pushing” the vaccine.

“Most people probably don’t really know the difference between clinical medicine and public health,” said Richard Pan, MD, MPH, a pediatrician and California legislator who sponsored two bills – now laws – that strengthened state childhood vaccination requirements.

At first, it was clearly public health officials, such as Anthony Fauci, MD, who were the face of measures to mitigate the virus. But as doctors became the enforcers of those measures, the line between physicians and public health officials blurred.

A lot of the anger then shifted toward doctors, nurses, and other health care professionals, Dr. Pan said, “because we were, of course, the ones who would be administering the vaccines. They don’t really think of their doctor as a government person until your doctor is carrying a [government] message.”

Given the pressures and struggles of the past few years, it’s no surprise that burnout among health care professionals is high. According to an April 2023 study by the National Council of State Boards of Nursing and the National Forum of State Nursing Workforce Centers, an estimated 800,000 nurses expect to leave the profession by 2027, driven first and foremost by “stress and burnout.”

All of these departures in medicine’s “great resignation” have left hospitals and health care organizations even more short staffed, thereby increasing even more the pressure and burnout on those left.

The pandemic had already badly exacerbated the already widespread problem of burnout in the medical field, which Ms. Nelson said has contributed to the tension.

“The burnout problem that we have in health care is not a good basis for the development of a good therapeutic relationship,” Ms. Nelson said. “Burnout is fraught with apathy and desensitization to human emotions. It takes away the empathy that we once had for people that we see.”
 

What comes next?

Almost exactly 3 years after the world learned about SARS-CoV-2, Biden declared an end to the coronavirus public health emergency in April 2023. Yet, Americans continue to die from COVID, and the anger that bloomed and spread has not abated.

“I think we’re in a new steady state of violence in health care settings,” Ms. Nelson said. “It’s not gone down, because people are still very distressed.” That’s evident from the high prevalence of mental health conditions, the financial strain of first the pandemic and then inflation, and the overall traumatic impact the pandemic had on people, whether they recognize it or not.

The first step to solving any problem is, as the saying goes, to admit that there is a problem.

“I think people need to start stepping out of their comfort bubbles and start to look at things that make them uncomfortable,” Dr. Thomas said, but he doesn’t see that happening any time soon. “I’ve been very let down by physicians and embarrassed by the American physician organizations.”

The medical board in his state, he said, has stood by as some doctors continue misrepresenting medical evidence. “That’s been really, really hard on me. I didn’t think that the medical boards would go so far as to look the other way for something that was this tremendously bad.”

There are others who can take the lead – if they’re willing.

“There are some things the medical societies and academic health centers can do,” Dr. Hotez said, “starting with building up a culture of physicians and health care providers feeling comfortable in the public domain.” He said the messaging when he was getting his degrees was not to engage the public and not to talk to journalists because that was “self-promotion” or “grandstanding.” But the world is different now. Health care professionals need training in public engagement and communication, he said, and the culture needs to change so that health care providers feel comfortable speaking out without feeling “the sword of Damocles over their heads” every time they talk to a reporter, Dr. Hotez said.

There may be no silver bullet to solve the big-picture trust problem in medicine and public health. No TV appearance or quote in an article can solve it. But on an individual level — through careful relationship building with patients – doctors can strengthen that trust.

Telehealth may help with that, but there’s a fine balance there, Ms. Nelson cautioned. On the one hand, with the doctor and the patient each in their own private spaces, where they feel safe and comfortable, the overall experience can be more therapeutic and less stressful. At the same time, telehealth can pile on change-management tasks that can exacerbate burnout, “so it’s a delicate thing we have to approach.”

One very thin silver lining that could emerge from the way in which patients have begun to try to take charge of their care.

“They should fully understand the reasoning behind the recommendations that physicians are making,” Ms. Nelson said. “I’d like to see us get to a happy medium where it’s a partnership. We can’t go back to the old school where the doctor knows best and you don’t ever question him.

“What we need is the partnership, and I would love to see that as the silver lining, but the anger has got to settle down in order for that kind of productive thing to happen.”

As for the big picture? There’s a limit to what even society’s “miracle workers” can do. “The biggest priority right now for the health system is to protect their staff whatever way they can and do some training in deescalation,” Ms. Nelson said. “But I don’t think health care can solve the societal issues that seem to be creating this.”

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

Choosing the right partner to add to your practice takes planning and strategic decision-making. When the match is right, the benefits can be significant: more hands to share the load of running a medical practice, and increased revenue and expanded patient population. A partner can bring in new, complementary strengths and skills. Adding a partner is also a way to prepare for the future by setting your practice up for a smooth transition if you or another partner is looking toward retirement.

But a mismatched partnership can cost you time and money, not to mention endless amount of conflict, dysfunction, and liability. Mutual trust and a long-term commitment on both sides are critical.

“Just like with marriage, it can be very difficult, traumatic, and expensive to break up with a partner,” said Clifton Straughn, MD, partner at Direct Access MD, a concierge-service model family practice in Anderson, S.C. “So, do your due diligence and take your time.” Picking the right partner is essential.
 

The basics

Before you begin the process of partnership with a physician, be sure you know what you need, the skill sets you’re looking for to complement your practice, and the personality characteristics and values that are important to you so the person you choose can check all the boxes and not just add a name to the letterhead.

“A lot of times, doctors go into this with just a general idea that they need more doctors or that they would like to be bigger or have more clout,” said Tim Boden, a certified medical practice executive with over 40 years of experience. “But you have to understand that to a certain degree, if you’re bringing somebody in who has basically an identical clinical profile to yours, you’re going to be sacrificing a bit of your lunch for a while until that person builds a name for himself or herself. A new partner’s skill set should match the need that you’re trying to fill.”

Figure out and discuss with your current partners how much it will cost to bring in a partner between their compensation and additional practice expenses. How much revenue will you expect the partner to generate? Will your practice break even the first year or the second? And how will you cover any shortfall?

It’s also essential to understand how the day-to-day operation of your practice will change after you add another partner.

• Will the new partner’s percentage of ownership be the same as that of the other partners?
• Will their ownership include a percentage of the facility, equipment, supplies, and accounts receivable?
• How will you split call and work hours?
• How will decision-making work?
• How would buyout work if a partner were to leave the practice, and is there a minimum obligation, such as a 5-year commitment?

As a team, you may also want to discuss “soft skills,” or the way you’d hope a partner would represent your practice to patients and the community.

“These can be harder to quantify,” said Dr. Straughn. “Evaluating them can take artful questions and simple observation over time.”
 

It’s a slow process

Many practices offer paths to partnership rather than bringing in a partner straight away. With this process, an incoming physician works toward that goal. If you’re going this route, discuss this during the hiring process, so that both sides are clear about the process. Rule No. 1 is to make sure that new hires understand that partnership is possible, although it’s not a given. The typical partnership track is 2-3 years, but you can set the timeline that works best for your practice.

Mr. Boden recommends at least a year for this period so as to allow you the opportunity to evaluate the new member, how they work, and how they fit with your team. The partnership track method is typically for young or fairly new physicians.

“I would avoid ever promising an ownership position to a recruit,” said Mr. Boden. “I would only show them how it can happen and what it would look like if they qualify.”
 

Consider professional help

If you want to be sure you weigh all the pros and cons of your new partner, a medical practice consultant may be the way to go. A consultant can identify many situations that you might overlook.

Some services offer a medical practice assessment to help you see where you need the most help and what skills might be best to bring to the table. They might also be able to take over some of the administrative work of a new hire if you like, so you and the other partners can focus solely on interacting with and observing the clinical abilities of a potential partner.

A health care attorney can help you build a sound agreement regarding decision-making and how the fees/costs will be divided and can put legal protections in place for everyone involved.

You’ll need a buy-sell agreement (also called a partnership or shareholder agreement) that spells out the terms and conditions, including buying into and selling out of the practice. A fair agreement respects all parties, while a poor one that offers the new partner a minority share or lessor profit may favor the practice’s current partners but could breed resentment, undermining the practice’s culture and morale.
 

Takeaway

Ideally, you’ll select someone with excellent credentials and experience with similar goals for the practice who blends well with your staff. It’s best to find someone who fits well culturally with your office and who practices medicine with a similar patient philosophy.

To that end, Mr. Boden encourages out-of-the-box questions for interviews, such as what a potential partner wants to make sure they have room for in their life, or what their ideal work and family life looks like. The more you can assess components such as emotional intelligence, =the fuller picture you’ll get.

“You’re going to be spending major hours every week with this person, and your destiny is going to be tied up with theirs to some degree,” said Mr. Boden. You can teach somebody the job, but if you don’t genuinely like and respect them and want to work with them daily, it may not be the right fit.

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

Choosing the right partner to add to your practice takes planning and strategic decision-making. When the match is right, the benefits can be significant: more hands to share the load of running a medical practice, and increased revenue and expanded patient population. A partner can bring in new, complementary strengths and skills. Adding a partner is also a way to prepare for the future by setting your practice up for a smooth transition if you or another partner is looking toward retirement.

But a mismatched partnership can cost you time and money, not to mention endless amount of conflict, dysfunction, and liability. Mutual trust and a long-term commitment on both sides are critical.

“Just like with marriage, it can be very difficult, traumatic, and expensive to break up with a partner,” said Clifton Straughn, MD, partner at Direct Access MD, a concierge-service model family practice in Anderson, S.C. “So, do your due diligence and take your time.” Picking the right partner is essential.
 

The basics

Before you begin the process of partnership with a physician, be sure you know what you need, the skill sets you’re looking for to complement your practice, and the personality characteristics and values that are important to you so the person you choose can check all the boxes and not just add a name to the letterhead.

“A lot of times, doctors go into this with just a general idea that they need more doctors or that they would like to be bigger or have more clout,” said Tim Boden, a certified medical practice executive with over 40 years of experience. “But you have to understand that to a certain degree, if you’re bringing somebody in who has basically an identical clinical profile to yours, you’re going to be sacrificing a bit of your lunch for a while until that person builds a name for himself or herself. A new partner’s skill set should match the need that you’re trying to fill.”

Figure out and discuss with your current partners how much it will cost to bring in a partner between their compensation and additional practice expenses. How much revenue will you expect the partner to generate? Will your practice break even the first year or the second? And how will you cover any shortfall?

It’s also essential to understand how the day-to-day operation of your practice will change after you add another partner.

• Will the new partner’s percentage of ownership be the same as that of the other partners?
• Will their ownership include a percentage of the facility, equipment, supplies, and accounts receivable?
• How will you split call and work hours?
• How will decision-making work?
• How would buyout work if a partner were to leave the practice, and is there a minimum obligation, such as a 5-year commitment?

As a team, you may also want to discuss “soft skills,” or the way you’d hope a partner would represent your practice to patients and the community.

“These can be harder to quantify,” said Dr. Straughn. “Evaluating them can take artful questions and simple observation over time.”
 

It’s a slow process

Many practices offer paths to partnership rather than bringing in a partner straight away. With this process, an incoming physician works toward that goal. If you’re going this route, discuss this during the hiring process, so that both sides are clear about the process. Rule No. 1 is to make sure that new hires understand that partnership is possible, although it’s not a given. The typical partnership track is 2-3 years, but you can set the timeline that works best for your practice.

Mr. Boden recommends at least a year for this period so as to allow you the opportunity to evaluate the new member, how they work, and how they fit with your team. The partnership track method is typically for young or fairly new physicians.

“I would avoid ever promising an ownership position to a recruit,” said Mr. Boden. “I would only show them how it can happen and what it would look like if they qualify.”
 

Consider professional help

If you want to be sure you weigh all the pros and cons of your new partner, a medical practice consultant may be the way to go. A consultant can identify many situations that you might overlook.

Some services offer a medical practice assessment to help you see where you need the most help and what skills might be best to bring to the table. They might also be able to take over some of the administrative work of a new hire if you like, so you and the other partners can focus solely on interacting with and observing the clinical abilities of a potential partner.

A health care attorney can help you build a sound agreement regarding decision-making and how the fees/costs will be divided and can put legal protections in place for everyone involved.

You’ll need a buy-sell agreement (also called a partnership or shareholder agreement) that spells out the terms and conditions, including buying into and selling out of the practice. A fair agreement respects all parties, while a poor one that offers the new partner a minority share or lessor profit may favor the practice’s current partners but could breed resentment, undermining the practice’s culture and morale.
 

Takeaway

Ideally, you’ll select someone with excellent credentials and experience with similar goals for the practice who blends well with your staff. It’s best to find someone who fits well culturally with your office and who practices medicine with a similar patient philosophy.

To that end, Mr. Boden encourages out-of-the-box questions for interviews, such as what a potential partner wants to make sure they have room for in their life, or what their ideal work and family life looks like. The more you can assess components such as emotional intelligence, =the fuller picture you’ll get.

“You’re going to be spending major hours every week with this person, and your destiny is going to be tied up with theirs to some degree,” said Mr. Boden. You can teach somebody the job, but if you don’t genuinely like and respect them and want to work with them daily, it may not be the right fit.

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

Choosing the right partner to add to your practice takes planning and strategic decision-making. When the match is right, the benefits can be significant: more hands to share the load of running a medical practice, and increased revenue and expanded patient population. A partner can bring in new, complementary strengths and skills. Adding a partner is also a way to prepare for the future by setting your practice up for a smooth transition if you or another partner is looking toward retirement.

But a mismatched partnership can cost you time and money, not to mention endless amount of conflict, dysfunction, and liability. Mutual trust and a long-term commitment on both sides are critical.

“Just like with marriage, it can be very difficult, traumatic, and expensive to break up with a partner,” said Clifton Straughn, MD, partner at Direct Access MD, a concierge-service model family practice in Anderson, S.C. “So, do your due diligence and take your time.” Picking the right partner is essential.
 

The basics

Before you begin the process of partnership with a physician, be sure you know what you need, the skill sets you’re looking for to complement your practice, and the personality characteristics and values that are important to you so the person you choose can check all the boxes and not just add a name to the letterhead.

“A lot of times, doctors go into this with just a general idea that they need more doctors or that they would like to be bigger or have more clout,” said Tim Boden, a certified medical practice executive with over 40 years of experience. “But you have to understand that to a certain degree, if you’re bringing somebody in who has basically an identical clinical profile to yours, you’re going to be sacrificing a bit of your lunch for a while until that person builds a name for himself or herself. A new partner’s skill set should match the need that you’re trying to fill.”

Figure out and discuss with your current partners how much it will cost to bring in a partner between their compensation and additional practice expenses. How much revenue will you expect the partner to generate? Will your practice break even the first year or the second? And how will you cover any shortfall?

It’s also essential to understand how the day-to-day operation of your practice will change after you add another partner.

• Will the new partner’s percentage of ownership be the same as that of the other partners?
• Will their ownership include a percentage of the facility, equipment, supplies, and accounts receivable?
• How will you split call and work hours?
• How will decision-making work?
• How would buyout work if a partner were to leave the practice, and is there a minimum obligation, such as a 5-year commitment?

As a team, you may also want to discuss “soft skills,” or the way you’d hope a partner would represent your practice to patients and the community.

“These can be harder to quantify,” said Dr. Straughn. “Evaluating them can take artful questions and simple observation over time.”
 

It’s a slow process

Many practices offer paths to partnership rather than bringing in a partner straight away. With this process, an incoming physician works toward that goal. If you’re going this route, discuss this during the hiring process, so that both sides are clear about the process. Rule No. 1 is to make sure that new hires understand that partnership is possible, although it’s not a given. The typical partnership track is 2-3 years, but you can set the timeline that works best for your practice.

Mr. Boden recommends at least a year for this period so as to allow you the opportunity to evaluate the new member, how they work, and how they fit with your team. The partnership track method is typically for young or fairly new physicians.

“I would avoid ever promising an ownership position to a recruit,” said Mr. Boden. “I would only show them how it can happen and what it would look like if they qualify.”
 

Consider professional help

If you want to be sure you weigh all the pros and cons of your new partner, a medical practice consultant may be the way to go. A consultant can identify many situations that you might overlook.

Some services offer a medical practice assessment to help you see where you need the most help and what skills might be best to bring to the table. They might also be able to take over some of the administrative work of a new hire if you like, so you and the other partners can focus solely on interacting with and observing the clinical abilities of a potential partner.

A health care attorney can help you build a sound agreement regarding decision-making and how the fees/costs will be divided and can put legal protections in place for everyone involved.

You’ll need a buy-sell agreement (also called a partnership or shareholder agreement) that spells out the terms and conditions, including buying into and selling out of the practice. A fair agreement respects all parties, while a poor one that offers the new partner a minority share or lessor profit may favor the practice’s current partners but could breed resentment, undermining the practice’s culture and morale.
 

Takeaway

Ideally, you’ll select someone with excellent credentials and experience with similar goals for the practice who blends well with your staff. It’s best to find someone who fits well culturally with your office and who practices medicine with a similar patient philosophy.

To that end, Mr. Boden encourages out-of-the-box questions for interviews, such as what a potential partner wants to make sure they have room for in their life, or what their ideal work and family life looks like. The more you can assess components such as emotional intelligence, =the fuller picture you’ll get.

“You’re going to be spending major hours every week with this person, and your destiny is going to be tied up with theirs to some degree,” said Mr. Boden. You can teach somebody the job, but if you don’t genuinely like and respect them and want to work with them daily, it may not be the right fit.

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

In a test of one of the nation’s most restrictive laws limiting noncompete clauses in medicine, an Indiana pediatric critical-care physician is suing to stop his former hospital employer from controlling his future employment prospects.

David Lankford, DO, acknowledges that he signed a contract with the Lutheran Health Network that included a noncompete clause. However, he claims in a lawsuit filed July 5 in Allen County Superior Court that an Indiana law that took effect 4 days earlier nullifies the clause because he quit his job with cause. 

Indiana’s law is notable among states because if a physician terminates his/her job for cause, the noncompete may be considered unenforceable.

“When you have physicians who are unable to work in their community, it creates a barrier for access to care for patients,” Dr. Lankford said in an interview. “I’m fighting to decrease barriers and continue to have patients be able to see their doctors in their own hometown or their own county.”

Lutheran Health’s media relations department did not respond to requests for comment.
 

Noncompete clauses ‘extremely common’

Non-compete clauses – which typically restrict when and where employees can take future jobs – are common in physician contracts, Anu Murthy, JD, who reviews employee contracts for a firm called Contract Diagnostics, said in an interview.

However, the tide has been turning against them.

About a dozen states and the District of Columbia have enacted legislation to limit the use of noncompetes in employment contracts, and about half of states have pending legislation that could dilute noncompete clauses, Ms. Murthy said. In June, the state of New York sent a noncompete ban bill to the governor’s desk.

For more about state-by-state restrictions on noncompete clauses, check this chart.

In his lawsuit, Dr. Lankford said he was hired in 2017 to work at Lutheran Hospital in Fort Wayne.

Dr. Lankford signed an employee renewal contract in 2020 that included a noncompete clause; his attorneys declined to provide details about the clause because of confidentiality restrictions. 

In 2022, the lawsuit says, Lutheran Hospital told Dr. Lankford that he’d need to take on more work due to layoffs of pediatric hospitalists. His patient load subsequently grew by 4-5 times, and he quit as of Jan. 7, 2023. 

Dr. Lankford wrote that he found a new job at Parkview Regional Medical Center in Fort Wayne, but his former employer threatened to take action under the noncompete clause, and Parkview withdrew its offer.

Among other things, the new Indiana law says that the clauses are not enforceable “if physician terminates the physician’s employment for cause.”

The lawsuit asks for a judge to prevent Lutheran Health Network from enforcing the clause.
 

Impact on patients

The new Indiana law also bans noncompete clauses for primary care physicians. Kathleen A. DeLaney, JD, one of Dr. Lankford’s attorneys, said in an interview that this provision came about because rural legislators didn’t want to add to the challenges of attracting primary care doctors to move to their communities.  

State legislators have become less friendly to noncompete clauses in medicine because they’re wary of the negative effects on patients, Evan Starr, PhD, said in an interview. The clauses prevent doctors from taking new jobs where they could continue to treat their previous patients, said Dr. Starr, associate professor in the department of management and organization at the University of Maryland.

However, he said, hospitals are fighting to preserve the clauses, arguing that they provide a base of patients to physicians in return for their agreement not to go work for a competitor.

The legal landscape may change even more. The Federal Trade Commission has proposed banning the clauses nationally, and a decision is expected in 2024. However, it’s an election year, which may delay a decision, attorney Ms. Murthy said, “and there is also language in the proposed rule that could exempt nonprofit hospitals, which further complicates the issues.”

For now, Ms. Murthy said, “we are still seeing noncompetes and other restrictive covenants in almost every contract we review in all 50 states and across all specialties. We explicitly explain to every client that they should only sign the agreement with the expectation that their specific noncompete will be enforced as written. Large employer groups, including hospital systems, will likely fight any kind of restriction or dilution of noncompetes, and these types of legal challenges could be tied up in court for many years.”
 

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

In a test of one of the nation’s most restrictive laws limiting noncompete clauses in medicine, an Indiana pediatric critical-care physician is suing to stop his former hospital employer from controlling his future employment prospects.

David Lankford, DO, acknowledges that he signed a contract with the Lutheran Health Network that included a noncompete clause. However, he claims in a lawsuit filed July 5 in Allen County Superior Court that an Indiana law that took effect 4 days earlier nullifies the clause because he quit his job with cause. 

Indiana’s law is notable among states because if a physician terminates his/her job for cause, the noncompete may be considered unenforceable.

“When you have physicians who are unable to work in their community, it creates a barrier for access to care for patients,” Dr. Lankford said in an interview. “I’m fighting to decrease barriers and continue to have patients be able to see their doctors in their own hometown or their own county.”

Lutheran Health’s media relations department did not respond to requests for comment.
 

Noncompete clauses ‘extremely common’

Non-compete clauses – which typically restrict when and where employees can take future jobs – are common in physician contracts, Anu Murthy, JD, who reviews employee contracts for a firm called Contract Diagnostics, said in an interview.

However, the tide has been turning against them.

About a dozen states and the District of Columbia have enacted legislation to limit the use of noncompetes in employment contracts, and about half of states have pending legislation that could dilute noncompete clauses, Ms. Murthy said. In June, the state of New York sent a noncompete ban bill to the governor’s desk.

For more about state-by-state restrictions on noncompete clauses, check this chart.

In his lawsuit, Dr. Lankford said he was hired in 2017 to work at Lutheran Hospital in Fort Wayne.

Dr. Lankford signed an employee renewal contract in 2020 that included a noncompete clause; his attorneys declined to provide details about the clause because of confidentiality restrictions. 

In 2022, the lawsuit says, Lutheran Hospital told Dr. Lankford that he’d need to take on more work due to layoffs of pediatric hospitalists. His patient load subsequently grew by 4-5 times, and he quit as of Jan. 7, 2023. 

Dr. Lankford wrote that he found a new job at Parkview Regional Medical Center in Fort Wayne, but his former employer threatened to take action under the noncompete clause, and Parkview withdrew its offer.

Among other things, the new Indiana law says that the clauses are not enforceable “if physician terminates the physician’s employment for cause.”

The lawsuit asks for a judge to prevent Lutheran Health Network from enforcing the clause.
 

Impact on patients

The new Indiana law also bans noncompete clauses for primary care physicians. Kathleen A. DeLaney, JD, one of Dr. Lankford’s attorneys, said in an interview that this provision came about because rural legislators didn’t want to add to the challenges of attracting primary care doctors to move to their communities.  

State legislators have become less friendly to noncompete clauses in medicine because they’re wary of the negative effects on patients, Evan Starr, PhD, said in an interview. The clauses prevent doctors from taking new jobs where they could continue to treat their previous patients, said Dr. Starr, associate professor in the department of management and organization at the University of Maryland.

However, he said, hospitals are fighting to preserve the clauses, arguing that they provide a base of patients to physicians in return for their agreement not to go work for a competitor.

The legal landscape may change even more. The Federal Trade Commission has proposed banning the clauses nationally, and a decision is expected in 2024. However, it’s an election year, which may delay a decision, attorney Ms. Murthy said, “and there is also language in the proposed rule that could exempt nonprofit hospitals, which further complicates the issues.”

For now, Ms. Murthy said, “we are still seeing noncompetes and other restrictive covenants in almost every contract we review in all 50 states and across all specialties. We explicitly explain to every client that they should only sign the agreement with the expectation that their specific noncompete will be enforced as written. Large employer groups, including hospital systems, will likely fight any kind of restriction or dilution of noncompetes, and these types of legal challenges could be tied up in court for many years.”
 

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

In a test of one of the nation’s most restrictive laws limiting noncompete clauses in medicine, an Indiana pediatric critical-care physician is suing to stop his former hospital employer from controlling his future employment prospects.

David Lankford, DO, acknowledges that he signed a contract with the Lutheran Health Network that included a noncompete clause. However, he claims in a lawsuit filed July 5 in Allen County Superior Court that an Indiana law that took effect 4 days earlier nullifies the clause because he quit his job with cause. 

Indiana’s law is notable among states because if a physician terminates his/her job for cause, the noncompete may be considered unenforceable.

“When you have physicians who are unable to work in their community, it creates a barrier for access to care for patients,” Dr. Lankford said in an interview. “I’m fighting to decrease barriers and continue to have patients be able to see their doctors in their own hometown or their own county.”

Lutheran Health’s media relations department did not respond to requests for comment.
 

Noncompete clauses ‘extremely common’

Non-compete clauses – which typically restrict when and where employees can take future jobs – are common in physician contracts, Anu Murthy, JD, who reviews employee contracts for a firm called Contract Diagnostics, said in an interview.

However, the tide has been turning against them.

About a dozen states and the District of Columbia have enacted legislation to limit the use of noncompetes in employment contracts, and about half of states have pending legislation that could dilute noncompete clauses, Ms. Murthy said. In June, the state of New York sent a noncompete ban bill to the governor’s desk.

For more about state-by-state restrictions on noncompete clauses, check this chart.

In his lawsuit, Dr. Lankford said he was hired in 2017 to work at Lutheran Hospital in Fort Wayne.

Dr. Lankford signed an employee renewal contract in 2020 that included a noncompete clause; his attorneys declined to provide details about the clause because of confidentiality restrictions. 

In 2022, the lawsuit says, Lutheran Hospital told Dr. Lankford that he’d need to take on more work due to layoffs of pediatric hospitalists. His patient load subsequently grew by 4-5 times, and he quit as of Jan. 7, 2023. 

Dr. Lankford wrote that he found a new job at Parkview Regional Medical Center in Fort Wayne, but his former employer threatened to take action under the noncompete clause, and Parkview withdrew its offer.

Among other things, the new Indiana law says that the clauses are not enforceable “if physician terminates the physician’s employment for cause.”

The lawsuit asks for a judge to prevent Lutheran Health Network from enforcing the clause.
 

Impact on patients

The new Indiana law also bans noncompete clauses for primary care physicians. Kathleen A. DeLaney, JD, one of Dr. Lankford’s attorneys, said in an interview that this provision came about because rural legislators didn’t want to add to the challenges of attracting primary care doctors to move to their communities.  

State legislators have become less friendly to noncompete clauses in medicine because they’re wary of the negative effects on patients, Evan Starr, PhD, said in an interview. The clauses prevent doctors from taking new jobs where they could continue to treat their previous patients, said Dr. Starr, associate professor in the department of management and organization at the University of Maryland.

However, he said, hospitals are fighting to preserve the clauses, arguing that they provide a base of patients to physicians in return for their agreement not to go work for a competitor.

The legal landscape may change even more. The Federal Trade Commission has proposed banning the clauses nationally, and a decision is expected in 2024. However, it’s an election year, which may delay a decision, attorney Ms. Murthy said, “and there is also language in the proposed rule that could exempt nonprofit hospitals, which further complicates the issues.”

For now, Ms. Murthy said, “we are still seeing noncompetes and other restrictive covenants in almost every contract we review in all 50 states and across all specialties. We explicitly explain to every client that they should only sign the agreement with the expectation that their specific noncompete will be enforced as written. Large employer groups, including hospital systems, will likely fight any kind of restriction or dilution of noncompetes, and these types of legal challenges could be tied up in court for many years.”
 

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