CHEST Physician

Editor’s Note: This piece was originally published in Dr. Glasser’s bimonthly column in The Jolt, a nonprofit online news organization based in Olympia, Washington. She was inspired to write her story after meeting Christine Laine, MD, one of three female physician presenters at the Sommer Lectures in Portland, Oregon, in May 2024. The article has been edited lightly from the original. 

Primary care internal medicine — the medical field I chose, loved, and practiced for four decades — is dead. 

The grief and shock I feel about this is personal and transpersonal. The loss of internists (internal medicine physicians) practicing primary care is a major loss to us all. 

From the 1970s to roughly 2020, there were three groups of primary care physicians: family practice, pediatricians, and internists. In their 3-year residencies (after 4 years of medical school), pediatricians trained to care for children and adolescents; internists for adults; and FPs for children, adults, and women and pregnancy. Family practitioners are the most general of the generalists, whereas the others’ training involves comprehensive care of complex patients in their age groups.

How and when the field of primary care internal medicine flourished is my story. 

I was one of those kids who was hyperfocused on science, math, and the human body. By the end of high school, I was considering medicine for my career. 

To learn more, I volunteered at the local hospital. In my typical style, I requested not to be one of those candy stripers serving drinks on the wards. Instead, they put me in the emergency department, where I would transport patients and clean the stretchers. There I was free to watch whatever was going on if I did not interfere with the staff. On my first shift, a 20-year-old drowning victim arrived by ambulance. I watched the entire unsuccessful resuscitation and as shocked and saddened as I was, I knew (in the way only a headstrong 18-year-old can) that medicine was for me. 

It was a fortuitous time to graduate as a female pre-med student. 

In 1975, our country was in the midst of the women’s movement and a national effort to train primary care physicians. I was accepted to my state medical school. The University of Massachusetts Medical School had been established a few years earlier, with its main purpose to train primary care physicians and spread them around the state (especially out of the Boston metropolitan area). The curriculum was designed to expose students to primary care from year one. I was assigned to shadow a general practice physician in inner-city Springfield who saw over 50 patients a day! The patients knew they could see and afford him, so they crammed into his waiting room until their name was called in order of their arrival. No appointments necessary. His chart notes were a few scribbled sentences. I didn’t see myself in that practice exactly, but his work ethic and dedication inspired me. 

Over half of our graduating class chose to train in primary care specialties, and most stayed in-state. It turned out to be a good bet on the part of the government of Massachusetts. 

When I applied for residency in 1980, several internal medicine programs had a focus on primary care, which was my goal. I matched at Providence St. Vincent Hospital in Portland, Oregon, and moved across the country to the Pacific Northwest, never to look back. There, my attendings were doctors like I wanted to be: primary care internists in the community, not in academia. It was the perfect choice and an excellent training program. 

In 1984, I hung out my private practice internal medicine shingle in Hillsboro, Oregon, across the street from the community hospital. My primary care internal medicine colleagues and I shared weekend calls and admitted and cared for our patients in the hospital, and when they were discharged. That is now called “continuity of care.” It was a time when we ate in the doctors’ lounge together, met in hallways, and informally consulted each other about our patients. These were called “curbside consults.” They were invaluable to our ability to provide comprehensive care to our patients in primary care, led to fewer specialty referrals, and were free. That would now be called interprofessional communication and collegiality. 

“Burnout” was not a word you heard. We were busy and happy doing what we had spent 12 years of our precious youth to prepare for. 

What did internists offer to primary care? That also is part of my story. 

When I moved to Olympia, I took a position in the women’s health clinic at the American Lake Veterans Administration Medical Center. 

We were a small group: two family practice doctors, three nurse practitioners, and me, the only internist. Many of our patients were sick and complex. Two of the nurse practitioners (NPs) asked me to take their most complicated patients. Being comfortable with complexity as an internist, I said yes. 

One of the NPs was inappropriately hired, as she had experience in women’s health. She came to me freaked out: “Oh my God, I have no idea how to manage COPD!” The other wanted simpler patients. I don’t blame them for the patient transfers. NPs typically have 3 years of training before they practice, in contrast to primary care physicians’ 8. 

Guess who made friends with the custodian, staying until 8 p.m. most evenings, and who left by 5:30 p.m. 

What was I doing in those extra hours? I was trudging through clerical, yet important, tasks my medical assistant and transcriptionist used to do in private practice. In the 30 minutes allotted for the patient, I needed to focus entirely on them and their multiple complex medical problems. 

What is lost with the death of primary care internal medicine? 

At the recent Sommer Memorial Lectures in Portland, Steven D. Freer, MD, the current director of the residency program where I trained, has not had a single of his eight annual internal medicine graduates choose primary care in several years. Half (two of four) of those in my year did: One went to Tillamook, an underserved area on the Oregon coast, and I to Hillsboro. 

What are internal medicine training graduates doing now? They are becoming hospitalists or, more often, specialists in cardiology, pulmonology, nephrology, oncology, and other more lucrative fields of medicine. 

Why are they not choosing primary care? As when the University of Massachusetts Medical School was established, a shortage of primary care physicians persists and probably is more severe than it was in the 1970s. Massachusetts was proactive. We are already years behind catching up. The shortage is no longer in rural areas alone. 

Christine Laine, MD, who is editor in chief of Annals of Internal Medicine and spoke at the Sommer Memorial Lectures, lives in Philadelphia. Even there, she has lost her own primary care internal medicine physician and cannot find another primary care physician (much less an internist) for herself. 

Washington State, where I live, scores a D grade for our primary care staffing statewide. 

Is there hope for the future of primary care in general? Or for the restoration of primary care internal medicine? 

Maybe. I was relieved to hear from Dr. Freer and Dr. Laine that efforts are beginning to revive the field. 

Just like internists’ patients, the potential restoration of the field will be complex and multilayered. It will require new laws, policies, residency programs, and incentives for students, including debt reduction. Administrative burdens will need to be reduced; de-corporatization and restoring healthcare leadership to those with in-depth medical training will need to be a part of the solution as well. 

Let’s all hope the new resuscitation efforts will be successful for the field of primary care in general and primary care internal medicine specifically. It will be good for healthcare and for your patients! 

Many work for large systems in which they feel powerless to effect change.

Dr. Glasser is a retired internal medicine physician in Olympia, Washington. She can be reached at [email protected].

A version of this article appeared on Medscape.com.

Editor’s Note: This piece was originally published in Dr. Glasser’s bimonthly column in The Jolt, a nonprofit online news organization based in Olympia, Washington. She was inspired to write her story after meeting Christine Laine, MD, one of three female physician presenters at the Sommer Lectures in Portland, Oregon, in May 2024. The article has been edited lightly from the original. 

Primary care internal medicine — the medical field I chose, loved, and practiced for four decades — is dead. 

The grief and shock I feel about this is personal and transpersonal. The loss of internists (internal medicine physicians) practicing primary care is a major loss to us all. 

From the 1970s to roughly 2020, there were three groups of primary care physicians: family practice, pediatricians, and internists. In their 3-year residencies (after 4 years of medical school), pediatricians trained to care for children and adolescents; internists for adults; and FPs for children, adults, and women and pregnancy. Family practitioners are the most general of the generalists, whereas the others’ training involves comprehensive care of complex patients in their age groups.

How and when the field of primary care internal medicine flourished is my story. 

I was one of those kids who was hyperfocused on science, math, and the human body. By the end of high school, I was considering medicine for my career. 

To learn more, I volunteered at the local hospital. In my typical style, I requested not to be one of those candy stripers serving drinks on the wards. Instead, they put me in the emergency department, where I would transport patients and clean the stretchers. There I was free to watch whatever was going on if I did not interfere with the staff. On my first shift, a 20-year-old drowning victim arrived by ambulance. I watched the entire unsuccessful resuscitation and as shocked and saddened as I was, I knew (in the way only a headstrong 18-year-old can) that medicine was for me. 

It was a fortuitous time to graduate as a female pre-med student. 

In 1975, our country was in the midst of the women’s movement and a national effort to train primary care physicians. I was accepted to my state medical school. The University of Massachusetts Medical School had been established a few years earlier, with its main purpose to train primary care physicians and spread them around the state (especially out of the Boston metropolitan area). The curriculum was designed to expose students to primary care from year one. I was assigned to shadow a general practice physician in inner-city Springfield who saw over 50 patients a day! The patients knew they could see and afford him, so they crammed into his waiting room until their name was called in order of their arrival. No appointments necessary. His chart notes were a few scribbled sentences. I didn’t see myself in that practice exactly, but his work ethic and dedication inspired me. 

Over half of our graduating class chose to train in primary care specialties, and most stayed in-state. It turned out to be a good bet on the part of the government of Massachusetts. 

When I applied for residency in 1980, several internal medicine programs had a focus on primary care, which was my goal. I matched at Providence St. Vincent Hospital in Portland, Oregon, and moved across the country to the Pacific Northwest, never to look back. There, my attendings were doctors like I wanted to be: primary care internists in the community, not in academia. It was the perfect choice and an excellent training program. 

In 1984, I hung out my private practice internal medicine shingle in Hillsboro, Oregon, across the street from the community hospital. My primary care internal medicine colleagues and I shared weekend calls and admitted and cared for our patients in the hospital, and when they were discharged. That is now called “continuity of care.” It was a time when we ate in the doctors’ lounge together, met in hallways, and informally consulted each other about our patients. These were called “curbside consults.” They were invaluable to our ability to provide comprehensive care to our patients in primary care, led to fewer specialty referrals, and were free. That would now be called interprofessional communication and collegiality. 

“Burnout” was not a word you heard. We were busy and happy doing what we had spent 12 years of our precious youth to prepare for. 

What did internists offer to primary care? That also is part of my story. 

When I moved to Olympia, I took a position in the women’s health clinic at the American Lake Veterans Administration Medical Center. 

We were a small group: two family practice doctors, three nurse practitioners, and me, the only internist. Many of our patients were sick and complex. Two of the nurse practitioners (NPs) asked me to take their most complicated patients. Being comfortable with complexity as an internist, I said yes. 

One of the NPs was inappropriately hired, as she had experience in women’s health. She came to me freaked out: “Oh my God, I have no idea how to manage COPD!” The other wanted simpler patients. I don’t blame them for the patient transfers. NPs typically have 3 years of training before they practice, in contrast to primary care physicians’ 8. 

Guess who made friends with the custodian, staying until 8 p.m. most evenings, and who left by 5:30 p.m. 

What was I doing in those extra hours? I was trudging through clerical, yet important, tasks my medical assistant and transcriptionist used to do in private practice. In the 30 minutes allotted for the patient, I needed to focus entirely on them and their multiple complex medical problems. 

What is lost with the death of primary care internal medicine? 

At the recent Sommer Memorial Lectures in Portland, Steven D. Freer, MD, the current director of the residency program where I trained, has not had a single of his eight annual internal medicine graduates choose primary care in several years. Half (two of four) of those in my year did: One went to Tillamook, an underserved area on the Oregon coast, and I to Hillsboro. 

What are internal medicine training graduates doing now? They are becoming hospitalists or, more often, specialists in cardiology, pulmonology, nephrology, oncology, and other more lucrative fields of medicine. 

Why are they not choosing primary care? As when the University of Massachusetts Medical School was established, a shortage of primary care physicians persists and probably is more severe than it was in the 1970s. Massachusetts was proactive. We are already years behind catching up. The shortage is no longer in rural areas alone. 

Christine Laine, MD, who is editor in chief of Annals of Internal Medicine and spoke at the Sommer Memorial Lectures, lives in Philadelphia. Even there, she has lost her own primary care internal medicine physician and cannot find another primary care physician (much less an internist) for herself. 

Washington State, where I live, scores a D grade for our primary care staffing statewide. 

Is there hope for the future of primary care in general? Or for the restoration of primary care internal medicine? 

Maybe. I was relieved to hear from Dr. Freer and Dr. Laine that efforts are beginning to revive the field. 

Just like internists’ patients, the potential restoration of the field will be complex and multilayered. It will require new laws, policies, residency programs, and incentives for students, including debt reduction. Administrative burdens will need to be reduced; de-corporatization and restoring healthcare leadership to those with in-depth medical training will need to be a part of the solution as well. 

Let’s all hope the new resuscitation efforts will be successful for the field of primary care in general and primary care internal medicine specifically. It will be good for healthcare and for your patients! 

Many work for large systems in which they feel powerless to effect change.

Dr. Glasser is a retired internal medicine physician in Olympia, Washington. She can be reached at [email protected].

A version of this article appeared on Medscape.com.

Editor’s Note: This piece was originally published in Dr. Glasser’s bimonthly column in The Jolt, a nonprofit online news organization based in Olympia, Washington. She was inspired to write her story after meeting Christine Laine, MD, one of three female physician presenters at the Sommer Lectures in Portland, Oregon, in May 2024. The article has been edited lightly from the original. 

Primary care internal medicine — the medical field I chose, loved, and practiced for four decades — is dead. 

The grief and shock I feel about this is personal and transpersonal. The loss of internists (internal medicine physicians) practicing primary care is a major loss to us all. 

From the 1970s to roughly 2020, there were three groups of primary care physicians: family practice, pediatricians, and internists. In their 3-year residencies (after 4 years of medical school), pediatricians trained to care for children and adolescents; internists for adults; and FPs for children, adults, and women and pregnancy. Family practitioners are the most general of the generalists, whereas the others’ training involves comprehensive care of complex patients in their age groups.

How and when the field of primary care internal medicine flourished is my story. 

I was one of those kids who was hyperfocused on science, math, and the human body. By the end of high school, I was considering medicine for my career. 

To learn more, I volunteered at the local hospital. In my typical style, I requested not to be one of those candy stripers serving drinks on the wards. Instead, they put me in the emergency department, where I would transport patients and clean the stretchers. There I was free to watch whatever was going on if I did not interfere with the staff. On my first shift, a 20-year-old drowning victim arrived by ambulance. I watched the entire unsuccessful resuscitation and as shocked and saddened as I was, I knew (in the way only a headstrong 18-year-old can) that medicine was for me. 

It was a fortuitous time to graduate as a female pre-med student. 

In 1975, our country was in the midst of the women’s movement and a national effort to train primary care physicians. I was accepted to my state medical school. The University of Massachusetts Medical School had been established a few years earlier, with its main purpose to train primary care physicians and spread them around the state (especially out of the Boston metropolitan area). The curriculum was designed to expose students to primary care from year one. I was assigned to shadow a general practice physician in inner-city Springfield who saw over 50 patients a day! The patients knew they could see and afford him, so they crammed into his waiting room until their name was called in order of their arrival. No appointments necessary. His chart notes were a few scribbled sentences. I didn’t see myself in that practice exactly, but his work ethic and dedication inspired me. 

Over half of our graduating class chose to train in primary care specialties, and most stayed in-state. It turned out to be a good bet on the part of the government of Massachusetts. 

When I applied for residency in 1980, several internal medicine programs had a focus on primary care, which was my goal. I matched at Providence St. Vincent Hospital in Portland, Oregon, and moved across the country to the Pacific Northwest, never to look back. There, my attendings were doctors like I wanted to be: primary care internists in the community, not in academia. It was the perfect choice and an excellent training program. 

In 1984, I hung out my private practice internal medicine shingle in Hillsboro, Oregon, across the street from the community hospital. My primary care internal medicine colleagues and I shared weekend calls and admitted and cared for our patients in the hospital, and when they were discharged. That is now called “continuity of care.” It was a time when we ate in the doctors’ lounge together, met in hallways, and informally consulted each other about our patients. These were called “curbside consults.” They were invaluable to our ability to provide comprehensive care to our patients in primary care, led to fewer specialty referrals, and were free. That would now be called interprofessional communication and collegiality. 

“Burnout” was not a word you heard. We were busy and happy doing what we had spent 12 years of our precious youth to prepare for. 

What did internists offer to primary care? That also is part of my story. 

When I moved to Olympia, I took a position in the women’s health clinic at the American Lake Veterans Administration Medical Center. 

We were a small group: two family practice doctors, three nurse practitioners, and me, the only internist. Many of our patients were sick and complex. Two of the nurse practitioners (NPs) asked me to take their most complicated patients. Being comfortable with complexity as an internist, I said yes. 

One of the NPs was inappropriately hired, as she had experience in women’s health. She came to me freaked out: “Oh my God, I have no idea how to manage COPD!” The other wanted simpler patients. I don’t blame them for the patient transfers. NPs typically have 3 years of training before they practice, in contrast to primary care physicians’ 8. 

Guess who made friends with the custodian, staying until 8 p.m. most evenings, and who left by 5:30 p.m. 

What was I doing in those extra hours? I was trudging through clerical, yet important, tasks my medical assistant and transcriptionist used to do in private practice. In the 30 minutes allotted for the patient, I needed to focus entirely on them and their multiple complex medical problems. 

What is lost with the death of primary care internal medicine? 

At the recent Sommer Memorial Lectures in Portland, Steven D. Freer, MD, the current director of the residency program where I trained, has not had a single of his eight annual internal medicine graduates choose primary care in several years. Half (two of four) of those in my year did: One went to Tillamook, an underserved area on the Oregon coast, and I to Hillsboro. 

What are internal medicine training graduates doing now? They are becoming hospitalists or, more often, specialists in cardiology, pulmonology, nephrology, oncology, and other more lucrative fields of medicine. 

Why are they not choosing primary care? As when the University of Massachusetts Medical School was established, a shortage of primary care physicians persists and probably is more severe than it was in the 1970s. Massachusetts was proactive. We are already years behind catching up. The shortage is no longer in rural areas alone. 

Christine Laine, MD, who is editor in chief of Annals of Internal Medicine and spoke at the Sommer Memorial Lectures, lives in Philadelphia. Even there, she has lost her own primary care internal medicine physician and cannot find another primary care physician (much less an internist) for herself. 

Washington State, where I live, scores a D grade for our primary care staffing statewide. 

Is there hope for the future of primary care in general? Or for the restoration of primary care internal medicine? 

Maybe. I was relieved to hear from Dr. Freer and Dr. Laine that efforts are beginning to revive the field. 

Just like internists’ patients, the potential restoration of the field will be complex and multilayered. It will require new laws, policies, residency programs, and incentives for students, including debt reduction. Administrative burdens will need to be reduced; de-corporatization and restoring healthcare leadership to those with in-depth medical training will need to be a part of the solution as well. 

Let’s all hope the new resuscitation efforts will be successful for the field of primary care in general and primary care internal medicine specifically. It will be good for healthcare and for your patients! 

Many work for large systems in which they feel powerless to effect change.

Dr. Glasser is a retired internal medicine physician in Olympia, Washington. She can be reached at [email protected].

A version of this article appeared on Medscape.com.

The link between influenza infection and a rise in short-term risk for acute myocardial infarction (MI) has been reaffirmed in a new study, which showed the risk appears to be particularly elevated in individuals with no prior diagnosis of coronary artery disease.

“Our study results confirm previous findings of an increased risk of MI during or immediately following acute severe flu infection and raises the idea of giving prophylactic anticoagulation to these patients,” reported Patricia Bruijning-Verhagen, MD, University Medical Center Utrecht, the Netherlands, who is the senior author of the study, which was published online in NEJM Evidence.

“Our results also change things — in that we now know the focus should be on people without a history of cardiovascular disease — and highlight the importance of flu vaccination, particularly for this group,” she pointed out.

The observational, self-controlled, case-series study linked laboratory records on respiratory virus polymerase chain reaction (PCR) testing from 16 laboratories in the Netherlands to national mortality, hospitalization, medication, and administrative registries. Investigators compared the incidence of acute MI during the risk period — days 1-7 after influenza infection — with that in the control period — 1 year before and 51 weeks after the risk period.

The researchers found 26,221 positive PCR tests for influenza, constituting 23,405 unique influenza illness episodes. Of the episodes of acute MI occurring in the year before or the year after confirmed influenza infection and included in the analysis, 25 cases of acute MI occurred on days 1-7 after influenza infection and 394 occurred during the control period.

The adjusted relative incidence of acute MI during the risk period compared with during the control period was 6.16 (95% CI, 4.11-9.24).

The relative incidence of acute MI in individuals with no previous hospitalization for coronary artery disease was 16.60 (95% CI, 10.45-26.37); for those with a previous hospital admission for coronary artery disease, the relative incidence was 1.43 (95% CI, 0.53-3.84).

A temporary increase in the risk for MI has been reported in several previous studies. A 2018 Canadian study by Kwong and colleagues showed a sixfold elevation in the risk for acute MI after influenza infection, which was subsequently confirmed in studies from the United States, Denmark, and Scotland.

In their study, Dr. Bruijning-Verhagen and colleagues aimed to further quantify the association between laboratory-confirmed influenza infection and acute MI and to look at specific subgroups that might have the potential to guide a more individualized approach to prevention.

They replicated the Canadian study using a self-controlled case-series design that corrects for time-invariant confounding and found very similar results: A sixfold increase in the risk for acute MI in the first week after laboratory-confirmed influenza infection.

“The fact that we found similar results to Kwong et al. strengthens the finding that acute flu infection is linked to increased MI risk. This is becoming more and more clear now. It also shows that this effect is generalizable to other countries,” Dr. Bruijning-Verhagen said.
 

People Without Cardiovascular Disease at Highest Risk 

The researchers moved the field ahead by also looking at whether there is a difference in risk between individuals with flu who already had cardiovascular disease and those who did not.

“Most previous studies of flu and MI didn’t stratify between individuals with and without existing cardiovascular disease. And the ones that did look at this weren’t able to show a difference with any confidence,” Dr. Bruijning-Verhagen explained. “There have been suggestions before of a higher risk of MI in individuals with acute flu infection who do not have existing known cardiovascular disease, but this was uncertain.” 

The current study showed a large difference between the two groups, with a much higher risk for MI linked to flu in individuals without any known cardiovascular disease.

“You would think patients with existing cardiovascular disease would be more at risk of MI with flu infection, so this was a surprising result,” reported Dr. Bruijning-Verhagen. “But I think the result is real. The difference between the two groups was too big for it not to be.”

Influenza can cause a hypercoagulable state, systemic inflammation, and vascular changes that can trigger MI, even in patients not thought to be at risk before, she pointed out. And this is on top of high cardiac demands because of the acute infection.

Patients who already have cardiovascular disease may be protected to some extent by the cardiovascular medications that they are taking, she added.

These results could justify the use of short-term anticoagulation in patients with severe flu infection to cover the high-risk period, Dr. Bruijning-Verhagen suggested. “We give short-term anticoagulation as prophylaxis to patients when they have surgery. This would not be that different. But obviously, this approach would have to be tested.”

Clinical studies looking at such a strategy are currently underway.
 

‘Get Your Flu Shot’

The results reinforce the need for anyone who is eligible to get the flu vaccine. “These results should give extra weight to the message to get your flu shot,” she said. “Even if you do not consider yourself someone at risk of cardiovascular disease, our study shows that you can still have an increased risk of MI as a result of severe flu infection.” 

In many countries, the flu vaccine is recommended for everyone older than 60 or 65 years and for younger people with a history of cardiovascular disease. Data on flu vaccination was not available in the current study, but the average age of patients infected with flu was 74 years, so most patients would have been eligible to receive vaccination, she said.

In the Netherlands where the research took place, flu vaccination is recommended for everyone older than 60 years, and uptake is about 60%.

“There will be some cases in younger people, but the number needed to vaccinate to show a benefit would be much larger in younger people, and that may not be cost-effective,” reported Dr. Bruijning-Verhagen.

Flu vaccination policies vary across the world, with many factors being taken into account; some countries already advocate for universal vaccination every year.
 

Extend Flu Vaccination to Prevent ACS 

This study “provides further impetus to policy makers to review and update guidelines on prevention of acute coronary syndromes,” Raina MacIntyre, MBBS, Zubair Akhtar, MPH, and Aye Moa, MPH, University of New South Wales, Sydney, Australia, wrote in an accompanying editorial.

“Although vaccination to prevent influenza is recommended and funded in many countries for people 65 years of age and older, the additional benefits of prevention of ACS [acute coronary syndromes] have not been adopted universally into policy and practice nor have recommendations considered prevention of ACS in people 50-64 years of age,” they added.

“Vaccination is low-hanging fruit for people at risk of acute myocardial infarction who have not yet had a first event. It is time that we viewed influenza vaccine as a routine preventive measure for ACS and for people with coronary artery disease risk factors, along with statins, blood pressure control, and smoking cessation,” she explained.

The question of whether the link found between elevated MI risk and severe flu infection might be the result of MI being more likely to be detected in patients hospitalized with severe flu infection, who would undergo a thorough workup, was raised in a second editorial by Lori E. Dodd, PhD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

“I think this would be very unlikely to account for the large effect we found,” responded Dr. Bruijning-Verhagen. “There may be the occasional silent MI that gets missed in patients who are not hospitalized, but, in general, acute MI is not something that goes undetected.”

A version of this article appeared on Medscape.com.

The link between influenza infection and a rise in short-term risk for acute myocardial infarction (MI) has been reaffirmed in a new study, which showed the risk appears to be particularly elevated in individuals with no prior diagnosis of coronary artery disease.

“Our study results confirm previous findings of an increased risk of MI during or immediately following acute severe flu infection and raises the idea of giving prophylactic anticoagulation to these patients,” reported Patricia Bruijning-Verhagen, MD, University Medical Center Utrecht, the Netherlands, who is the senior author of the study, which was published online in NEJM Evidence.

“Our results also change things — in that we now know the focus should be on people without a history of cardiovascular disease — and highlight the importance of flu vaccination, particularly for this group,” she pointed out.

The observational, self-controlled, case-series study linked laboratory records on respiratory virus polymerase chain reaction (PCR) testing from 16 laboratories in the Netherlands to national mortality, hospitalization, medication, and administrative registries. Investigators compared the incidence of acute MI during the risk period — days 1-7 after influenza infection — with that in the control period — 1 year before and 51 weeks after the risk period.

The researchers found 26,221 positive PCR tests for influenza, constituting 23,405 unique influenza illness episodes. Of the episodes of acute MI occurring in the year before or the year after confirmed influenza infection and included in the analysis, 25 cases of acute MI occurred on days 1-7 after influenza infection and 394 occurred during the control period.

The adjusted relative incidence of acute MI during the risk period compared with during the control period was 6.16 (95% CI, 4.11-9.24).

The relative incidence of acute MI in individuals with no previous hospitalization for coronary artery disease was 16.60 (95% CI, 10.45-26.37); for those with a previous hospital admission for coronary artery disease, the relative incidence was 1.43 (95% CI, 0.53-3.84).

A temporary increase in the risk for MI has been reported in several previous studies. A 2018 Canadian study by Kwong and colleagues showed a sixfold elevation in the risk for acute MI after influenza infection, which was subsequently confirmed in studies from the United States, Denmark, and Scotland.

In their study, Dr. Bruijning-Verhagen and colleagues aimed to further quantify the association between laboratory-confirmed influenza infection and acute MI and to look at specific subgroups that might have the potential to guide a more individualized approach to prevention.

They replicated the Canadian study using a self-controlled case-series design that corrects for time-invariant confounding and found very similar results: A sixfold increase in the risk for acute MI in the first week after laboratory-confirmed influenza infection.

“The fact that we found similar results to Kwong et al. strengthens the finding that acute flu infection is linked to increased MI risk. This is becoming more and more clear now. It also shows that this effect is generalizable to other countries,” Dr. Bruijning-Verhagen said.
 

People Without Cardiovascular Disease at Highest Risk 

The researchers moved the field ahead by also looking at whether there is a difference in risk between individuals with flu who already had cardiovascular disease and those who did not.

“Most previous studies of flu and MI didn’t stratify between individuals with and without existing cardiovascular disease. And the ones that did look at this weren’t able to show a difference with any confidence,” Dr. Bruijning-Verhagen explained. “There have been suggestions before of a higher risk of MI in individuals with acute flu infection who do not have existing known cardiovascular disease, but this was uncertain.” 

The current study showed a large difference between the two groups, with a much higher risk for MI linked to flu in individuals without any known cardiovascular disease.

“You would think patients with existing cardiovascular disease would be more at risk of MI with flu infection, so this was a surprising result,” reported Dr. Bruijning-Verhagen. “But I think the result is real. The difference between the two groups was too big for it not to be.”

Influenza can cause a hypercoagulable state, systemic inflammation, and vascular changes that can trigger MI, even in patients not thought to be at risk before, she pointed out. And this is on top of high cardiac demands because of the acute infection.

Patients who already have cardiovascular disease may be protected to some extent by the cardiovascular medications that they are taking, she added.

These results could justify the use of short-term anticoagulation in patients with severe flu infection to cover the high-risk period, Dr. Bruijning-Verhagen suggested. “We give short-term anticoagulation as prophylaxis to patients when they have surgery. This would not be that different. But obviously, this approach would have to be tested.”

Clinical studies looking at such a strategy are currently underway.
 

‘Get Your Flu Shot’

The results reinforce the need for anyone who is eligible to get the flu vaccine. “These results should give extra weight to the message to get your flu shot,” she said. “Even if you do not consider yourself someone at risk of cardiovascular disease, our study shows that you can still have an increased risk of MI as a result of severe flu infection.” 

In many countries, the flu vaccine is recommended for everyone older than 60 or 65 years and for younger people with a history of cardiovascular disease. Data on flu vaccination was not available in the current study, but the average age of patients infected with flu was 74 years, so most patients would have been eligible to receive vaccination, she said.

In the Netherlands where the research took place, flu vaccination is recommended for everyone older than 60 years, and uptake is about 60%.

“There will be some cases in younger people, but the number needed to vaccinate to show a benefit would be much larger in younger people, and that may not be cost-effective,” reported Dr. Bruijning-Verhagen.

Flu vaccination policies vary across the world, with many factors being taken into account; some countries already advocate for universal vaccination every year.
 

Extend Flu Vaccination to Prevent ACS 

This study “provides further impetus to policy makers to review and update guidelines on prevention of acute coronary syndromes,” Raina MacIntyre, MBBS, Zubair Akhtar, MPH, and Aye Moa, MPH, University of New South Wales, Sydney, Australia, wrote in an accompanying editorial.

“Although vaccination to prevent influenza is recommended and funded in many countries for people 65 years of age and older, the additional benefits of prevention of ACS [acute coronary syndromes] have not been adopted universally into policy and practice nor have recommendations considered prevention of ACS in people 50-64 years of age,” they added.

“Vaccination is low-hanging fruit for people at risk of acute myocardial infarction who have not yet had a first event. It is time that we viewed influenza vaccine as a routine preventive measure for ACS and for people with coronary artery disease risk factors, along with statins, blood pressure control, and smoking cessation,” she explained.

The question of whether the link found between elevated MI risk and severe flu infection might be the result of MI being more likely to be detected in patients hospitalized with severe flu infection, who would undergo a thorough workup, was raised in a second editorial by Lori E. Dodd, PhD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

“I think this would be very unlikely to account for the large effect we found,” responded Dr. Bruijning-Verhagen. “There may be the occasional silent MI that gets missed in patients who are not hospitalized, but, in general, acute MI is not something that goes undetected.”

A version of this article appeared on Medscape.com.

The link between influenza infection and a rise in short-term risk for acute myocardial infarction (MI) has been reaffirmed in a new study, which showed the risk appears to be particularly elevated in individuals with no prior diagnosis of coronary artery disease.

“Our study results confirm previous findings of an increased risk of MI during or immediately following acute severe flu infection and raises the idea of giving prophylactic anticoagulation to these patients,” reported Patricia Bruijning-Verhagen, MD, University Medical Center Utrecht, the Netherlands, who is the senior author of the study, which was published online in NEJM Evidence.

“Our results also change things — in that we now know the focus should be on people without a history of cardiovascular disease — and highlight the importance of flu vaccination, particularly for this group,” she pointed out.

The observational, self-controlled, case-series study linked laboratory records on respiratory virus polymerase chain reaction (PCR) testing from 16 laboratories in the Netherlands to national mortality, hospitalization, medication, and administrative registries. Investigators compared the incidence of acute MI during the risk period — days 1-7 after influenza infection — with that in the control period — 1 year before and 51 weeks after the risk period.

The researchers found 26,221 positive PCR tests for influenza, constituting 23,405 unique influenza illness episodes. Of the episodes of acute MI occurring in the year before or the year after confirmed influenza infection and included in the analysis, 25 cases of acute MI occurred on days 1-7 after influenza infection and 394 occurred during the control period.

The adjusted relative incidence of acute MI during the risk period compared with during the control period was 6.16 (95% CI, 4.11-9.24).

The relative incidence of acute MI in individuals with no previous hospitalization for coronary artery disease was 16.60 (95% CI, 10.45-26.37); for those with a previous hospital admission for coronary artery disease, the relative incidence was 1.43 (95% CI, 0.53-3.84).

A temporary increase in the risk for MI has been reported in several previous studies. A 2018 Canadian study by Kwong and colleagues showed a sixfold elevation in the risk for acute MI after influenza infection, which was subsequently confirmed in studies from the United States, Denmark, and Scotland.

In their study, Dr. Bruijning-Verhagen and colleagues aimed to further quantify the association between laboratory-confirmed influenza infection and acute MI and to look at specific subgroups that might have the potential to guide a more individualized approach to prevention.

They replicated the Canadian study using a self-controlled case-series design that corrects for time-invariant confounding and found very similar results: A sixfold increase in the risk for acute MI in the first week after laboratory-confirmed influenza infection.

“The fact that we found similar results to Kwong et al. strengthens the finding that acute flu infection is linked to increased MI risk. This is becoming more and more clear now. It also shows that this effect is generalizable to other countries,” Dr. Bruijning-Verhagen said.
 

People Without Cardiovascular Disease at Highest Risk 

The researchers moved the field ahead by also looking at whether there is a difference in risk between individuals with flu who already had cardiovascular disease and those who did not.

“Most previous studies of flu and MI didn’t stratify between individuals with and without existing cardiovascular disease. And the ones that did look at this weren’t able to show a difference with any confidence,” Dr. Bruijning-Verhagen explained. “There have been suggestions before of a higher risk of MI in individuals with acute flu infection who do not have existing known cardiovascular disease, but this was uncertain.” 

The current study showed a large difference between the two groups, with a much higher risk for MI linked to flu in individuals without any known cardiovascular disease.

“You would think patients with existing cardiovascular disease would be more at risk of MI with flu infection, so this was a surprising result,” reported Dr. Bruijning-Verhagen. “But I think the result is real. The difference between the two groups was too big for it not to be.”

Influenza can cause a hypercoagulable state, systemic inflammation, and vascular changes that can trigger MI, even in patients not thought to be at risk before, she pointed out. And this is on top of high cardiac demands because of the acute infection.

Patients who already have cardiovascular disease may be protected to some extent by the cardiovascular medications that they are taking, she added.

These results could justify the use of short-term anticoagulation in patients with severe flu infection to cover the high-risk period, Dr. Bruijning-Verhagen suggested. “We give short-term anticoagulation as prophylaxis to patients when they have surgery. This would not be that different. But obviously, this approach would have to be tested.”

Clinical studies looking at such a strategy are currently underway.
 

‘Get Your Flu Shot’

The results reinforce the need for anyone who is eligible to get the flu vaccine. “These results should give extra weight to the message to get your flu shot,” she said. “Even if you do not consider yourself someone at risk of cardiovascular disease, our study shows that you can still have an increased risk of MI as a result of severe flu infection.” 

In many countries, the flu vaccine is recommended for everyone older than 60 or 65 years and for younger people with a history of cardiovascular disease. Data on flu vaccination was not available in the current study, but the average age of patients infected with flu was 74 years, so most patients would have been eligible to receive vaccination, she said.

In the Netherlands where the research took place, flu vaccination is recommended for everyone older than 60 years, and uptake is about 60%.

“There will be some cases in younger people, but the number needed to vaccinate to show a benefit would be much larger in younger people, and that may not be cost-effective,” reported Dr. Bruijning-Verhagen.

Flu vaccination policies vary across the world, with many factors being taken into account; some countries already advocate for universal vaccination every year.
 

Extend Flu Vaccination to Prevent ACS 

This study “provides further impetus to policy makers to review and update guidelines on prevention of acute coronary syndromes,” Raina MacIntyre, MBBS, Zubair Akhtar, MPH, and Aye Moa, MPH, University of New South Wales, Sydney, Australia, wrote in an accompanying editorial.

“Although vaccination to prevent influenza is recommended and funded in many countries for people 65 years of age and older, the additional benefits of prevention of ACS [acute coronary syndromes] have not been adopted universally into policy and practice nor have recommendations considered prevention of ACS in people 50-64 years of age,” they added.

“Vaccination is low-hanging fruit for people at risk of acute myocardial infarction who have not yet had a first event. It is time that we viewed influenza vaccine as a routine preventive measure for ACS and for people with coronary artery disease risk factors, along with statins, blood pressure control, and smoking cessation,” she explained.

The question of whether the link found between elevated MI risk and severe flu infection might be the result of MI being more likely to be detected in patients hospitalized with severe flu infection, who would undergo a thorough workup, was raised in a second editorial by Lori E. Dodd, PhD, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

“I think this would be very unlikely to account for the large effect we found,” responded Dr. Bruijning-Verhagen. “There may be the occasional silent MI that gets missed in patients who are not hospitalized, but, in general, acute MI is not something that goes undetected.”

A version of this article appeared on Medscape.com.

Neurologic symptoms of long COVID are vast, common, hard to treat, disabling, and can mimic dozens of other syndromes, with some symptoms as serious as those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).

Now, recent evidence has suggested long COVID is primarily an autonomic nervous system disorder.

Patients with long COVID increasingly complain of extreme fatigue, brain fog, cognitive issues, dizziness, irregular heart rhythms, and high or low blood pressure, all features seen with dysautonomia — dysregulation of the autonomic nervous system.

Their lives may never be the same.

Lindsay S. McAlpine, MD, a specialist in the neurologic sequelae of COVID-19 at the Yale School of Medicine and director of the Yale NeuroCOVID Clinic, New Haven, Connecticut, treats patients who struggle with neurologic symptoms even after disease recovery.

“Some people have the brain fog and the shortness of breath; some have the palpitations and the headaches ... it’s kind of a mix and match,” she said.

Dr. McAlpine’s research has been slowly building up into what could bring about a significant breakthrough in treating some of the most misunderstood and difficult-to-treat symptoms of long COVID.
 

The Effect of Vascular Inflammation on Long COVID

The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”

Using advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, McAlpine hopes to unearth and better understand the pathophysiology behind neurologic issues post-COVID.

Dr. McAlpine said, “What we’re seeing is that there’s a unique signature of vascular inflammation in long COVID that is distinct from acute COVID. And it has to do with endothelial apathy and platelet dysfunction.”

She’s also looking into whether microvascular dysfunction could increase one’s risk for small vessel disease. Her research is quantitatively building an overall pathophysiology piece by piece.

“We’re quantifying cognitive dysfunction and using objective testing ... a very rigorous 3-hour protocol to really identify the patterns of weakness until we find deficits in memory working and declarative memory, deficits in executive functioning, and others. Those are the three pieces that I’m trying to piece together: The MRI, the blood work, and the cognitive testing,” she said.

Ultimately, Dr. McAlpine believes long COVID will eventually be classified as a peripheral autonomic disorder. The damage being wrought to the whole body also damages the brain’s vasculature, and Dr. McAlpine’s MRI techniques probe at this connection.

“Some of my MRI techniques are dependent on the very subtle changes in blood flow to different regions in response to demand. Brain fog has been a key symptom of POTS and ME/CFS. And it’s now a key symptom of long COVID ... what I’m looking at in some of my studies is how and in which parts of the brain are affected by this,” she said.

Dr. McAlpine’s interest in COVID’s effect on our nervous system goes back all the way to the first wave of patients with COVID, where she noticed an unusually high incidence of ischemic stroke.

“We recognized that COVID really has a huge impact on the vessels ... there’s quite a bit of vascular inflammation. In terms of neurology, we were seeing quite a bit of ischemic stroke, which is unusual,” she said.

Patients don’t normally present with stroke while infected with a virus. Seeking answers, she conducted a stroke study in patients with acute COVID and found profound endotheliopathy — damage to key cells in the lining of blood vessels — leading to a cascade of dysfunction and clotting.
 

A Constellation of Neuropsychiatric Symptoms

In early June, Dr. McAlpine gave a presentation of her research at the Demystifying Long COVID North American Conference 2024 in Boston. She’s been hard at work in extrapolating the causes of neuropsychiatric long COVID, a tangled web of symptoms seen in patients with long COVID that range from cognitive dysfunction to headaches, neuropathy, mental health, and the aforementioned dysautonomia.

Amid the sea of neurologic long COVID symptoms, she said “symptoms that are mixing and matching are very similar. So, I wanted to specifically look at a symptom that I could definitely isolate to the brain, and that is brain fog and cognitive dysfunction and impairment.”

In September 2021, the journal Translational Psychiatry published a study titled “Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions.”

Going back all the way to the first cases of COVID in March 2020, the initial symptoms most patients complained of during an acute viral infection were around the respiratory system. Yet delirium, confusion, and neurocognitive disorders were also reported, puzzling experts and inciting a well-founded fear among many.

Even worse, after recovery, these neuropsychiatric symptoms persisted. The study found that coronavirus was able to invade the central nervous system through blood vessels and neuronal retrograde pathways, leading to brain injury and dysfunction of the cardiorespiratory center in the brainstem.

The study concluded by reporting that neuroimaging and neurochemical evidence indicated neuroimmune dysfunction and brain injury in severe patients with COVID-19. Suggested treatments included immunosuppressive therapies, vaccines to target the coronavirus’ spike protein, and pharmacological agents to improve endothelial integrity.

But there was still much that was unknown, and the study’s authors stressed the need for multidisciplinary research going forward.
 

How Immune Dysfunction Plays a Role

Similarly, Dr. McAlpine and her research team are still trying to sift their way through this opaque web to see why long COVID can cause autoimmune flare-ups.

In a study published in April, Dr. McAlpine and others found that small fiber neuropathy (SFN) after COVID is autoimmune-mediated and a dysfunction of the immune system.

Notably, they found that SFN could be a key pathologic finding in long COVID. SFN before the pandemic had been linked to ME/CFS and POTS, and the basic hypothesis revolved around an inflammatory immune response during a viral illness that may lead to immune dysregulation (dysimmunity) and damage to small fiber nerves.

But much still remains to be answered.

“We’ve seen quite a bit of that, but we still haven’t figured it out,” Dr. McAlpine said. “My big question is, how is this autonomic dysfunction related to the immune dysfunction, and how is that related to the vascular inflammation? There’s quite a bit of overlap in individuals with autoimmune disease and those who go on to develop this long COVID,” she added.

Still, a large portion of patients with long COVID don’t show autoimmune dysfunction, and those patients lack common biomarkers for an autoimmune condition.

“When we look at the spinal fluid in those individuals [with multiple sclerosis or a neuroinfectious disease], there’s inflammation going on ... the white blood cell count is elevated, the protein is elevated, the antibodies, the bands are elevated. I’ve been seeing long COVID patients now for 4 years, and their presentation is so distinctly different compared to my individuals that I see my patients with MS, or a neuroinfectious disease,” she said.

The mechanisms behind how all of this is interlaced remain unclear, and there may not be a one-size-fits-all treatment or definite pathogenesis for everyone.

“It’s that intersection of the immune system and the vessel wall ... Next is to figure out what do we treat, what are the targets, all of that, but there’s so many different presentations, and everybody has kind of a unique case,” she said.
 

How Physician Can Treat Common Symptoms Now

Though a cure for symptoms still eludes the scientific community, recent evidence has suggested that a combination of N-acetyl cysteine (NAC) and guanfacine has been successful in easing neurologic symptoms.

In November 2023, Arman Fesharaki-Zadeh, MD, PhD, a Yale Medicine behavioral neurologist and neuropsychiatrist, published a small study in Neuroimmunology Reports with his colleague, Yale neuroscientist Amy Arnsten, PhD. The two researchers showed how among 12 patients given 600 mg NAC daily, along with 1 mg guanfacine (increased to 2 mg after a month if well-tolerated), eight demonstrated improved cognitive abilities.

In patients who stayed on guanfacine + NAC, improved working memory, concentration, and executive functions were seen.

Also, they resumed their normal work schedule. Interruption and inability to work has been a significant factor in the lower quality-of-life long COVID patients experience.

Placebo-controlled trials will be needed going forward, but their small study has established safety and could open up a larger study in the future. For the moment, NAC can be gotten over the counter, and patients could get a prescription off-label from their doctor.

Dr. McAlpine has seen this combination work well for her own patients at Yale’s NeuroCOVID clinic.

Additionally, lifestyle practices such as quitting tobacco, increased exercise, exercising the mind, lowering alcohol intake, and even vitamin D supplementation (1000-2000 IU daily) could prove beneficial in tamping down persistent brain fog.

Vitamin D supports brain and nerve function through its reduction of brain aging biomarkers, regulating genes important for brain function, activating and deactivating enzymes important for neurotransmitter synthesis, and supporting neuronal growth and survival.

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

Neurologic symptoms of long COVID are vast, common, hard to treat, disabling, and can mimic dozens of other syndromes, with some symptoms as serious as those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).

Now, recent evidence has suggested long COVID is primarily an autonomic nervous system disorder.

Patients with long COVID increasingly complain of extreme fatigue, brain fog, cognitive issues, dizziness, irregular heart rhythms, and high or low blood pressure, all features seen with dysautonomia — dysregulation of the autonomic nervous system.

Their lives may never be the same.

Lindsay S. McAlpine, MD, a specialist in the neurologic sequelae of COVID-19 at the Yale School of Medicine and director of the Yale NeuroCOVID Clinic, New Haven, Connecticut, treats patients who struggle with neurologic symptoms even after disease recovery.

“Some people have the brain fog and the shortness of breath; some have the palpitations and the headaches ... it’s kind of a mix and match,” she said.

Dr. McAlpine’s research has been slowly building up into what could bring about a significant breakthrough in treating some of the most misunderstood and difficult-to-treat symptoms of long COVID.
 

The Effect of Vascular Inflammation on Long COVID

The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”

Using advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, McAlpine hopes to unearth and better understand the pathophysiology behind neurologic issues post-COVID.

Dr. McAlpine said, “What we’re seeing is that there’s a unique signature of vascular inflammation in long COVID that is distinct from acute COVID. And it has to do with endothelial apathy and platelet dysfunction.”

She’s also looking into whether microvascular dysfunction could increase one’s risk for small vessel disease. Her research is quantitatively building an overall pathophysiology piece by piece.

“We’re quantifying cognitive dysfunction and using objective testing ... a very rigorous 3-hour protocol to really identify the patterns of weakness until we find deficits in memory working and declarative memory, deficits in executive functioning, and others. Those are the three pieces that I’m trying to piece together: The MRI, the blood work, and the cognitive testing,” she said.

Ultimately, Dr. McAlpine believes long COVID will eventually be classified as a peripheral autonomic disorder. The damage being wrought to the whole body also damages the brain’s vasculature, and Dr. McAlpine’s MRI techniques probe at this connection.

“Some of my MRI techniques are dependent on the very subtle changes in blood flow to different regions in response to demand. Brain fog has been a key symptom of POTS and ME/CFS. And it’s now a key symptom of long COVID ... what I’m looking at in some of my studies is how and in which parts of the brain are affected by this,” she said.

Dr. McAlpine’s interest in COVID’s effect on our nervous system goes back all the way to the first wave of patients with COVID, where she noticed an unusually high incidence of ischemic stroke.

“We recognized that COVID really has a huge impact on the vessels ... there’s quite a bit of vascular inflammation. In terms of neurology, we were seeing quite a bit of ischemic stroke, which is unusual,” she said.

Patients don’t normally present with stroke while infected with a virus. Seeking answers, she conducted a stroke study in patients with acute COVID and found profound endotheliopathy — damage to key cells in the lining of blood vessels — leading to a cascade of dysfunction and clotting.
 

A Constellation of Neuropsychiatric Symptoms

In early June, Dr. McAlpine gave a presentation of her research at the Demystifying Long COVID North American Conference 2024 in Boston. She’s been hard at work in extrapolating the causes of neuropsychiatric long COVID, a tangled web of symptoms seen in patients with long COVID that range from cognitive dysfunction to headaches, neuropathy, mental health, and the aforementioned dysautonomia.

Amid the sea of neurologic long COVID symptoms, she said “symptoms that are mixing and matching are very similar. So, I wanted to specifically look at a symptom that I could definitely isolate to the brain, and that is brain fog and cognitive dysfunction and impairment.”

In September 2021, the journal Translational Psychiatry published a study titled “Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions.”

Going back all the way to the first cases of COVID in March 2020, the initial symptoms most patients complained of during an acute viral infection were around the respiratory system. Yet delirium, confusion, and neurocognitive disorders were also reported, puzzling experts and inciting a well-founded fear among many.

Even worse, after recovery, these neuropsychiatric symptoms persisted. The study found that coronavirus was able to invade the central nervous system through blood vessels and neuronal retrograde pathways, leading to brain injury and dysfunction of the cardiorespiratory center in the brainstem.

The study concluded by reporting that neuroimaging and neurochemical evidence indicated neuroimmune dysfunction and brain injury in severe patients with COVID-19. Suggested treatments included immunosuppressive therapies, vaccines to target the coronavirus’ spike protein, and pharmacological agents to improve endothelial integrity.

But there was still much that was unknown, and the study’s authors stressed the need for multidisciplinary research going forward.
 

How Immune Dysfunction Plays a Role

Similarly, Dr. McAlpine and her research team are still trying to sift their way through this opaque web to see why long COVID can cause autoimmune flare-ups.

In a study published in April, Dr. McAlpine and others found that small fiber neuropathy (SFN) after COVID is autoimmune-mediated and a dysfunction of the immune system.

Notably, they found that SFN could be a key pathologic finding in long COVID. SFN before the pandemic had been linked to ME/CFS and POTS, and the basic hypothesis revolved around an inflammatory immune response during a viral illness that may lead to immune dysregulation (dysimmunity) and damage to small fiber nerves.

But much still remains to be answered.

“We’ve seen quite a bit of that, but we still haven’t figured it out,” Dr. McAlpine said. “My big question is, how is this autonomic dysfunction related to the immune dysfunction, and how is that related to the vascular inflammation? There’s quite a bit of overlap in individuals with autoimmune disease and those who go on to develop this long COVID,” she added.

Still, a large portion of patients with long COVID don’t show autoimmune dysfunction, and those patients lack common biomarkers for an autoimmune condition.

“When we look at the spinal fluid in those individuals [with multiple sclerosis or a neuroinfectious disease], there’s inflammation going on ... the white blood cell count is elevated, the protein is elevated, the antibodies, the bands are elevated. I’ve been seeing long COVID patients now for 4 years, and their presentation is so distinctly different compared to my individuals that I see my patients with MS, or a neuroinfectious disease,” she said.

The mechanisms behind how all of this is interlaced remain unclear, and there may not be a one-size-fits-all treatment or definite pathogenesis for everyone.

“It’s that intersection of the immune system and the vessel wall ... Next is to figure out what do we treat, what are the targets, all of that, but there’s so many different presentations, and everybody has kind of a unique case,” she said.
 

How Physician Can Treat Common Symptoms Now

Though a cure for symptoms still eludes the scientific community, recent evidence has suggested that a combination of N-acetyl cysteine (NAC) and guanfacine has been successful in easing neurologic symptoms.

In November 2023, Arman Fesharaki-Zadeh, MD, PhD, a Yale Medicine behavioral neurologist and neuropsychiatrist, published a small study in Neuroimmunology Reports with his colleague, Yale neuroscientist Amy Arnsten, PhD. The two researchers showed how among 12 patients given 600 mg NAC daily, along with 1 mg guanfacine (increased to 2 mg after a month if well-tolerated), eight demonstrated improved cognitive abilities.

In patients who stayed on guanfacine + NAC, improved working memory, concentration, and executive functions were seen.

Also, they resumed their normal work schedule. Interruption and inability to work has been a significant factor in the lower quality-of-life long COVID patients experience.

Placebo-controlled trials will be needed going forward, but their small study has established safety and could open up a larger study in the future. For the moment, NAC can be gotten over the counter, and patients could get a prescription off-label from their doctor.

Dr. McAlpine has seen this combination work well for her own patients at Yale’s NeuroCOVID clinic.

Additionally, lifestyle practices such as quitting tobacco, increased exercise, exercising the mind, lowering alcohol intake, and even vitamin D supplementation (1000-2000 IU daily) could prove beneficial in tamping down persistent brain fog.

Vitamin D supports brain and nerve function through its reduction of brain aging biomarkers, regulating genes important for brain function, activating and deactivating enzymes important for neurotransmitter synthesis, and supporting neuronal growth and survival.

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

Neurologic symptoms of long COVID are vast, common, hard to treat, disabling, and can mimic dozens of other syndromes, with some symptoms as serious as those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).

Now, recent evidence has suggested long COVID is primarily an autonomic nervous system disorder.

Patients with long COVID increasingly complain of extreme fatigue, brain fog, cognitive issues, dizziness, irregular heart rhythms, and high or low blood pressure, all features seen with dysautonomia — dysregulation of the autonomic nervous system.

Their lives may never be the same.

Lindsay S. McAlpine, MD, a specialist in the neurologic sequelae of COVID-19 at the Yale School of Medicine and director of the Yale NeuroCOVID Clinic, New Haven, Connecticut, treats patients who struggle with neurologic symptoms even after disease recovery.

“Some people have the brain fog and the shortness of breath; some have the palpitations and the headaches ... it’s kind of a mix and match,” she said.

Dr. McAlpine’s research has been slowly building up into what could bring about a significant breakthrough in treating some of the most misunderstood and difficult-to-treat symptoms of long COVID.
 

The Effect of Vascular Inflammation on Long COVID

The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”

Using advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, McAlpine hopes to unearth and better understand the pathophysiology behind neurologic issues post-COVID.

Dr. McAlpine said, “What we’re seeing is that there’s a unique signature of vascular inflammation in long COVID that is distinct from acute COVID. And it has to do with endothelial apathy and platelet dysfunction.”

She’s also looking into whether microvascular dysfunction could increase one’s risk for small vessel disease. Her research is quantitatively building an overall pathophysiology piece by piece.

“We’re quantifying cognitive dysfunction and using objective testing ... a very rigorous 3-hour protocol to really identify the patterns of weakness until we find deficits in memory working and declarative memory, deficits in executive functioning, and others. Those are the three pieces that I’m trying to piece together: The MRI, the blood work, and the cognitive testing,” she said.

Ultimately, Dr. McAlpine believes long COVID will eventually be classified as a peripheral autonomic disorder. The damage being wrought to the whole body also damages the brain’s vasculature, and Dr. McAlpine’s MRI techniques probe at this connection.

“Some of my MRI techniques are dependent on the very subtle changes in blood flow to different regions in response to demand. Brain fog has been a key symptom of POTS and ME/CFS. And it’s now a key symptom of long COVID ... what I’m looking at in some of my studies is how and in which parts of the brain are affected by this,” she said.

Dr. McAlpine’s interest in COVID’s effect on our nervous system goes back all the way to the first wave of patients with COVID, where she noticed an unusually high incidence of ischemic stroke.

“We recognized that COVID really has a huge impact on the vessels ... there’s quite a bit of vascular inflammation. In terms of neurology, we were seeing quite a bit of ischemic stroke, which is unusual,” she said.

Patients don’t normally present with stroke while infected with a virus. Seeking answers, she conducted a stroke study in patients with acute COVID and found profound endotheliopathy — damage to key cells in the lining of blood vessels — leading to a cascade of dysfunction and clotting.
 

A Constellation of Neuropsychiatric Symptoms

In early June, Dr. McAlpine gave a presentation of her research at the Demystifying Long COVID North American Conference 2024 in Boston. She’s been hard at work in extrapolating the causes of neuropsychiatric long COVID, a tangled web of symptoms seen in patients with long COVID that range from cognitive dysfunction to headaches, neuropathy, mental health, and the aforementioned dysautonomia.

Amid the sea of neurologic long COVID symptoms, she said “symptoms that are mixing and matching are very similar. So, I wanted to specifically look at a symptom that I could definitely isolate to the brain, and that is brain fog and cognitive dysfunction and impairment.”

In September 2021, the journal Translational Psychiatry published a study titled “Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions.”

Going back all the way to the first cases of COVID in March 2020, the initial symptoms most patients complained of during an acute viral infection were around the respiratory system. Yet delirium, confusion, and neurocognitive disorders were also reported, puzzling experts and inciting a well-founded fear among many.

Even worse, after recovery, these neuropsychiatric symptoms persisted. The study found that coronavirus was able to invade the central nervous system through blood vessels and neuronal retrograde pathways, leading to brain injury and dysfunction of the cardiorespiratory center in the brainstem.

The study concluded by reporting that neuroimaging and neurochemical evidence indicated neuroimmune dysfunction and brain injury in severe patients with COVID-19. Suggested treatments included immunosuppressive therapies, vaccines to target the coronavirus’ spike protein, and pharmacological agents to improve endothelial integrity.

But there was still much that was unknown, and the study’s authors stressed the need for multidisciplinary research going forward.
 

How Immune Dysfunction Plays a Role

Similarly, Dr. McAlpine and her research team are still trying to sift their way through this opaque web to see why long COVID can cause autoimmune flare-ups.

In a study published in April, Dr. McAlpine and others found that small fiber neuropathy (SFN) after COVID is autoimmune-mediated and a dysfunction of the immune system.

Notably, they found that SFN could be a key pathologic finding in long COVID. SFN before the pandemic had been linked to ME/CFS and POTS, and the basic hypothesis revolved around an inflammatory immune response during a viral illness that may lead to immune dysregulation (dysimmunity) and damage to small fiber nerves.

But much still remains to be answered.

“We’ve seen quite a bit of that, but we still haven’t figured it out,” Dr. McAlpine said. “My big question is, how is this autonomic dysfunction related to the immune dysfunction, and how is that related to the vascular inflammation? There’s quite a bit of overlap in individuals with autoimmune disease and those who go on to develop this long COVID,” she added.

Still, a large portion of patients with long COVID don’t show autoimmune dysfunction, and those patients lack common biomarkers for an autoimmune condition.

“When we look at the spinal fluid in those individuals [with multiple sclerosis or a neuroinfectious disease], there’s inflammation going on ... the white blood cell count is elevated, the protein is elevated, the antibodies, the bands are elevated. I’ve been seeing long COVID patients now for 4 years, and their presentation is so distinctly different compared to my individuals that I see my patients with MS, or a neuroinfectious disease,” she said.

The mechanisms behind how all of this is interlaced remain unclear, and there may not be a one-size-fits-all treatment or definite pathogenesis for everyone.

“It’s that intersection of the immune system and the vessel wall ... Next is to figure out what do we treat, what are the targets, all of that, but there’s so many different presentations, and everybody has kind of a unique case,” she said.
 

How Physician Can Treat Common Symptoms Now

Though a cure for symptoms still eludes the scientific community, recent evidence has suggested that a combination of N-acetyl cysteine (NAC) and guanfacine has been successful in easing neurologic symptoms.

In November 2023, Arman Fesharaki-Zadeh, MD, PhD, a Yale Medicine behavioral neurologist and neuropsychiatrist, published a small study in Neuroimmunology Reports with his colleague, Yale neuroscientist Amy Arnsten, PhD. The two researchers showed how among 12 patients given 600 mg NAC daily, along with 1 mg guanfacine (increased to 2 mg after a month if well-tolerated), eight demonstrated improved cognitive abilities.

In patients who stayed on guanfacine + NAC, improved working memory, concentration, and executive functions were seen.

Also, they resumed their normal work schedule. Interruption and inability to work has been a significant factor in the lower quality-of-life long COVID patients experience.

Placebo-controlled trials will be needed going forward, but their small study has established safety and could open up a larger study in the future. For the moment, NAC can be gotten over the counter, and patients could get a prescription off-label from their doctor.

Dr. McAlpine has seen this combination work well for her own patients at Yale’s NeuroCOVID clinic.

Additionally, lifestyle practices such as quitting tobacco, increased exercise, exercising the mind, lowering alcohol intake, and even vitamin D supplementation (1000-2000 IU daily) could prove beneficial in tamping down persistent brain fog.

Vitamin D supports brain and nerve function through its reduction of brain aging biomarkers, regulating genes important for brain function, activating and deactivating enzymes important for neurotransmitter synthesis, and supporting neuronal growth and survival.

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

An estimated two million people in England and Scotland were experiencing symptoms of long COVID as of March 2024, according to the Office for National Statistics. Of these, 1.5 million said the condition was adversely affecting their day-to-day activities.

As more research emerges about long COVID, some experts are noticing that its trigger factors, symptoms, and causative mechanisms overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

ME/CFS is characterized by severe fatigue that does not improve with rest, in addition to pain and cognitive problems. One in four patients are bed- or house-bound with severe forms of the condition, sometimes experiencing atypical seizures, and speech and swallowing difficulties.

Despite affecting around 250,000 people in the UK and around 2 million people in the European Union (EU), it is a relatively poorly funded disease research area. Increased research into long COVID is thus providing a much-needed boost to ME/CFS research.

“What we already know about the possible causation of ME/CFS is helping research into the causes of long COVID. At the same time, research into long COVID is opening up new avenues of research that may also be relevant to ME/CFS. It is becoming a two-way process,” Dr. Charles Shepherd, honorary medical adviser to the UK-based ME Association, told this news organization.

While funding remains an issue, promising research is currently underway in the UK to improve diagnosis, treatment, and understanding of the pathology of ME/CFS.
 

Viral Reactivation

Dr. David Newton is research director at ME Research UK. “Viral infection is commonly reported as a trigger for [ME/CFS, meaning that the disease] may be caused by reactivation of latent viruses, including human herpes viruses and enteroviruses,” he said.

Herpes viruses can lie dormant in their host’s immune system for long periods of time. They can be reactivated by factors including infections, stress, and a weakened immune system, and may cause temporary symptoms or persistent disease.

A 2021 pilot study found that people with ME/CFS have a higher concentration of human herpesvirus 6B (HHV-6B) DNA in their saliva, and that concentration correlates with symptom severity. HHV-6B is a common virus typically contracted during infancy and childhood.

A continuation of this research is now underway at Brunel University to improve understanding of HHV-6B’s role in the onset and progression of ME/CFS, and to support the development of diagnostic and prognostic markers, as well as therapeutics such as antiviral therapies.
 

Mitochondrial Dysfunction

Dr. Shepherd explained that there is now sound evidence demonstrating that biochemical abnormalities in ME/CFS affect how mitochondria produce energy after physical exertion. Research is thus underway to see if treating mitochondrial dysfunction improves ME/CFS symptoms.

A phase 2a placebo-controlled clinical trial from 2023 found that AXA1125, a drug that works by modulating energy metabolism, significantly improved symptoms of fatigue in patients with fatigue-dominant long COVID, although it did not improve mitochondrial respiration.

“[The findings suggest] that improving mitochondrial health may be one way to restore normal functioning among people with long COVID, and by extension CFS,” study author Betty Raman, associate professor of cardiovascular medicine at the University of Oxford, told this news organization. She noted, however, that plans for a phase III trial have stalled due to insufficient funding.

Meanwhile, researchers from the Quadram Institute in Norwich and the University of East Anglia are conducting a pilot study to see if red light therapy can relieve symptoms of ME/CFS. Red light can be absorbed by mitochondria and is used to boost energy production. The trial will monitor patients remotely from their homes and will assess cognitive function and physical activity levels.
 

Gut Dysbiosis

Many studies have found that people with ME/CFS have altered gut microbiota, which suggests that changes in gut bacteria may contribute to the condition. Researchers at the Quadram Institute will thus conduct a clinical trial called RESTORE-ME to see whether fecal microbiota transplants (FMT) can treat the condition.

Rik Haagmans is a research scientist and PhD candidate at the Quadram Institute. He told this news organization: “Our FMT studies, if effective, could provide a longer lasting or even permanent relief of ME/CFS, as restoring the gut microbial composition wouldn’t require continuous medication,” he said.
 

Biobank and Biomarkers

Europe’s first ME/CFS-specific biobank is in the UK and is called UKMEB. It now has more than 30,000 blood samples from patients with ME/CFS, multiple sclerosis, and healthy controls. Uniquely, it includes samples from people with ME/CFS who are house- and bed-bound. Caroline Kingdon, RN, MSc, a research fellow and biobank lead at the London School of Hygiene and Tropical Medicine, told this news organization that samples and data from the UKMEB have been provided to research groups all over the world and have contributed to widely cited literature.

One group making use of these samples is led by Fatima Labeed, PhD, senior lecturer in human biology at the University of Surrey. Dr. Labeed and her team are developing a diagnostic test for ME/CFS based on electrical properties in white blood cells.

“To date, studies of ME/CFS have focused on the biochemical behavior of cells: the amount and type of proteins that cells use. We have taken a different approach, studying the electrical properties,” she explained to this news organization.

Her research builds on initial observations from 2019 that found differences in the electrical impedance of white blood cells between people with ME/CFS and controls. While the biological implications remain unknown, the findings may represent a biomarker for the condition.

Using blood samples from the UKMEB, the researchers are now investigating this potential biomarker with improved techniques and a larger patient cohort, including those with mild/moderate and severe forms of ME/CFS. So far, they have received more than 100 blood samples and have analyzed the electrical properties of 42.

“Based on the results we have so far, we are very close to having a biomarker for diagnosis. Our results so far show a high degree of accuracy and are able to distinguish between ME/CFS and other diseases,” said Dr. Labeed.
 

Genetic Test

Another promising avenue for diagnostics comes from a research team at the University of Edinburgh led by Professor Chris Ponting at the university’s Institute of Genetics and Cancer. They are currently working on DecodeMe, a large genetic study of ME using data from more than 26,000 people.

“We are studying blood-based biomarkers that distinguish people with ME from population controls. We’ve found a large number — including some found previously in other studies — and are writing these results up for publication,” said Ponting. The results should be published in early 2025.
 

The Future

While research into ME/CFS has picked up pace in recent years, funding remains a key bottleneck.

“Over the last 10 years, only £8.05m has been spent on ME research,” Sonya Chowdhury, chief executive of UK charity Action for ME told this news organization. She believes this amount is not equitably comparable to research funding allocated to other diseases.

In 2022, the UK government announced its intention to develop a cross-government interim delivery plan on ME/CFS for England, however publication of the final plan has been delayed numerous times.

Dr. Shepherd agreed that increased funding is crucial for progress to be made. He said the biggest help to ME/CFS research would be to end the disparity in government research funding for the disease, and match what is given for many other disabling long-term conditions.

“It’s not fair to continue to rely on the charity sector to fund almost all of the biomedical research into ME/CFS here in the UK,” he said.

A version of this article appeared on Medscape.com.

An estimated two million people in England and Scotland were experiencing symptoms of long COVID as of March 2024, according to the Office for National Statistics. Of these, 1.5 million said the condition was adversely affecting their day-to-day activities.

As more research emerges about long COVID, some experts are noticing that its trigger factors, symptoms, and causative mechanisms overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

ME/CFS is characterized by severe fatigue that does not improve with rest, in addition to pain and cognitive problems. One in four patients are bed- or house-bound with severe forms of the condition, sometimes experiencing atypical seizures, and speech and swallowing difficulties.

Despite affecting around 250,000 people in the UK and around 2 million people in the European Union (EU), it is a relatively poorly funded disease research area. Increased research into long COVID is thus providing a much-needed boost to ME/CFS research.

“What we already know about the possible causation of ME/CFS is helping research into the causes of long COVID. At the same time, research into long COVID is opening up new avenues of research that may also be relevant to ME/CFS. It is becoming a two-way process,” Dr. Charles Shepherd, honorary medical adviser to the UK-based ME Association, told this news organization.

While funding remains an issue, promising research is currently underway in the UK to improve diagnosis, treatment, and understanding of the pathology of ME/CFS.
 

Viral Reactivation

Dr. David Newton is research director at ME Research UK. “Viral infection is commonly reported as a trigger for [ME/CFS, meaning that the disease] may be caused by reactivation of latent viruses, including human herpes viruses and enteroviruses,” he said.

Herpes viruses can lie dormant in their host’s immune system for long periods of time. They can be reactivated by factors including infections, stress, and a weakened immune system, and may cause temporary symptoms or persistent disease.

A 2021 pilot study found that people with ME/CFS have a higher concentration of human herpesvirus 6B (HHV-6B) DNA in their saliva, and that concentration correlates with symptom severity. HHV-6B is a common virus typically contracted during infancy and childhood.

A continuation of this research is now underway at Brunel University to improve understanding of HHV-6B’s role in the onset and progression of ME/CFS, and to support the development of diagnostic and prognostic markers, as well as therapeutics such as antiviral therapies.
 

Mitochondrial Dysfunction

Dr. Shepherd explained that there is now sound evidence demonstrating that biochemical abnormalities in ME/CFS affect how mitochondria produce energy after physical exertion. Research is thus underway to see if treating mitochondrial dysfunction improves ME/CFS symptoms.

A phase 2a placebo-controlled clinical trial from 2023 found that AXA1125, a drug that works by modulating energy metabolism, significantly improved symptoms of fatigue in patients with fatigue-dominant long COVID, although it did not improve mitochondrial respiration.

“[The findings suggest] that improving mitochondrial health may be one way to restore normal functioning among people with long COVID, and by extension CFS,” study author Betty Raman, associate professor of cardiovascular medicine at the University of Oxford, told this news organization. She noted, however, that plans for a phase III trial have stalled due to insufficient funding.

Meanwhile, researchers from the Quadram Institute in Norwich and the University of East Anglia are conducting a pilot study to see if red light therapy can relieve symptoms of ME/CFS. Red light can be absorbed by mitochondria and is used to boost energy production. The trial will monitor patients remotely from their homes and will assess cognitive function and physical activity levels.
 

Gut Dysbiosis

Many studies have found that people with ME/CFS have altered gut microbiota, which suggests that changes in gut bacteria may contribute to the condition. Researchers at the Quadram Institute will thus conduct a clinical trial called RESTORE-ME to see whether fecal microbiota transplants (FMT) can treat the condition.

Rik Haagmans is a research scientist and PhD candidate at the Quadram Institute. He told this news organization: “Our FMT studies, if effective, could provide a longer lasting or even permanent relief of ME/CFS, as restoring the gut microbial composition wouldn’t require continuous medication,” he said.
 

Biobank and Biomarkers

Europe’s first ME/CFS-specific biobank is in the UK and is called UKMEB. It now has more than 30,000 blood samples from patients with ME/CFS, multiple sclerosis, and healthy controls. Uniquely, it includes samples from people with ME/CFS who are house- and bed-bound. Caroline Kingdon, RN, MSc, a research fellow and biobank lead at the London School of Hygiene and Tropical Medicine, told this news organization that samples and data from the UKMEB have been provided to research groups all over the world and have contributed to widely cited literature.

One group making use of these samples is led by Fatima Labeed, PhD, senior lecturer in human biology at the University of Surrey. Dr. Labeed and her team are developing a diagnostic test for ME/CFS based on electrical properties in white blood cells.

“To date, studies of ME/CFS have focused on the biochemical behavior of cells: the amount and type of proteins that cells use. We have taken a different approach, studying the electrical properties,” she explained to this news organization.

Her research builds on initial observations from 2019 that found differences in the electrical impedance of white blood cells between people with ME/CFS and controls. While the biological implications remain unknown, the findings may represent a biomarker for the condition.

Using blood samples from the UKMEB, the researchers are now investigating this potential biomarker with improved techniques and a larger patient cohort, including those with mild/moderate and severe forms of ME/CFS. So far, they have received more than 100 blood samples and have analyzed the electrical properties of 42.

“Based on the results we have so far, we are very close to having a biomarker for diagnosis. Our results so far show a high degree of accuracy and are able to distinguish between ME/CFS and other diseases,” said Dr. Labeed.
 

Genetic Test

Another promising avenue for diagnostics comes from a research team at the University of Edinburgh led by Professor Chris Ponting at the university’s Institute of Genetics and Cancer. They are currently working on DecodeMe, a large genetic study of ME using data from more than 26,000 people.

“We are studying blood-based biomarkers that distinguish people with ME from population controls. We’ve found a large number — including some found previously in other studies — and are writing these results up for publication,” said Ponting. The results should be published in early 2025.
 

The Future

While research into ME/CFS has picked up pace in recent years, funding remains a key bottleneck.

“Over the last 10 years, only £8.05m has been spent on ME research,” Sonya Chowdhury, chief executive of UK charity Action for ME told this news organization. She believes this amount is not equitably comparable to research funding allocated to other diseases.

In 2022, the UK government announced its intention to develop a cross-government interim delivery plan on ME/CFS for England, however publication of the final plan has been delayed numerous times.

Dr. Shepherd agreed that increased funding is crucial for progress to be made. He said the biggest help to ME/CFS research would be to end the disparity in government research funding for the disease, and match what is given for many other disabling long-term conditions.

“It’s not fair to continue to rely on the charity sector to fund almost all of the biomedical research into ME/CFS here in the UK,” he said.

A version of this article appeared on Medscape.com.

An estimated two million people in England and Scotland were experiencing symptoms of long COVID as of March 2024, according to the Office for National Statistics. Of these, 1.5 million said the condition was adversely affecting their day-to-day activities.

As more research emerges about long COVID, some experts are noticing that its trigger factors, symptoms, and causative mechanisms overlap with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

ME/CFS is characterized by severe fatigue that does not improve with rest, in addition to pain and cognitive problems. One in four patients are bed- or house-bound with severe forms of the condition, sometimes experiencing atypical seizures, and speech and swallowing difficulties.

Despite affecting around 250,000 people in the UK and around 2 million people in the European Union (EU), it is a relatively poorly funded disease research area. Increased research into long COVID is thus providing a much-needed boost to ME/CFS research.

“What we already know about the possible causation of ME/CFS is helping research into the causes of long COVID. At the same time, research into long COVID is opening up new avenues of research that may also be relevant to ME/CFS. It is becoming a two-way process,” Dr. Charles Shepherd, honorary medical adviser to the UK-based ME Association, told this news organization.

While funding remains an issue, promising research is currently underway in the UK to improve diagnosis, treatment, and understanding of the pathology of ME/CFS.
 

Viral Reactivation

Dr. David Newton is research director at ME Research UK. “Viral infection is commonly reported as a trigger for [ME/CFS, meaning that the disease] may be caused by reactivation of latent viruses, including human herpes viruses and enteroviruses,” he said.

Herpes viruses can lie dormant in their host’s immune system for long periods of time. They can be reactivated by factors including infections, stress, and a weakened immune system, and may cause temporary symptoms or persistent disease.

A 2021 pilot study found that people with ME/CFS have a higher concentration of human herpesvirus 6B (HHV-6B) DNA in their saliva, and that concentration correlates with symptom severity. HHV-6B is a common virus typically contracted during infancy and childhood.

A continuation of this research is now underway at Brunel University to improve understanding of HHV-6B’s role in the onset and progression of ME/CFS, and to support the development of diagnostic and prognostic markers, as well as therapeutics such as antiviral therapies.
 

Mitochondrial Dysfunction

Dr. Shepherd explained that there is now sound evidence demonstrating that biochemical abnormalities in ME/CFS affect how mitochondria produce energy after physical exertion. Research is thus underway to see if treating mitochondrial dysfunction improves ME/CFS symptoms.

A phase 2a placebo-controlled clinical trial from 2023 found that AXA1125, a drug that works by modulating energy metabolism, significantly improved symptoms of fatigue in patients with fatigue-dominant long COVID, although it did not improve mitochondrial respiration.

“[The findings suggest] that improving mitochondrial health may be one way to restore normal functioning among people with long COVID, and by extension CFS,” study author Betty Raman, associate professor of cardiovascular medicine at the University of Oxford, told this news organization. She noted, however, that plans for a phase III trial have stalled due to insufficient funding.

Meanwhile, researchers from the Quadram Institute in Norwich and the University of East Anglia are conducting a pilot study to see if red light therapy can relieve symptoms of ME/CFS. Red light can be absorbed by mitochondria and is used to boost energy production. The trial will monitor patients remotely from their homes and will assess cognitive function and physical activity levels.
 

Gut Dysbiosis

Many studies have found that people with ME/CFS have altered gut microbiota, which suggests that changes in gut bacteria may contribute to the condition. Researchers at the Quadram Institute will thus conduct a clinical trial called RESTORE-ME to see whether fecal microbiota transplants (FMT) can treat the condition.

Rik Haagmans is a research scientist and PhD candidate at the Quadram Institute. He told this news organization: “Our FMT studies, if effective, could provide a longer lasting or even permanent relief of ME/CFS, as restoring the gut microbial composition wouldn’t require continuous medication,” he said.
 

Biobank and Biomarkers

Europe’s first ME/CFS-specific biobank is in the UK and is called UKMEB. It now has more than 30,000 blood samples from patients with ME/CFS, multiple sclerosis, and healthy controls. Uniquely, it includes samples from people with ME/CFS who are house- and bed-bound. Caroline Kingdon, RN, MSc, a research fellow and biobank lead at the London School of Hygiene and Tropical Medicine, told this news organization that samples and data from the UKMEB have been provided to research groups all over the world and have contributed to widely cited literature.

One group making use of these samples is led by Fatima Labeed, PhD, senior lecturer in human biology at the University of Surrey. Dr. Labeed and her team are developing a diagnostic test for ME/CFS based on electrical properties in white blood cells.

“To date, studies of ME/CFS have focused on the biochemical behavior of cells: the amount and type of proteins that cells use. We have taken a different approach, studying the electrical properties,” she explained to this news organization.

Her research builds on initial observations from 2019 that found differences in the electrical impedance of white blood cells between people with ME/CFS and controls. While the biological implications remain unknown, the findings may represent a biomarker for the condition.

Using blood samples from the UKMEB, the researchers are now investigating this potential biomarker with improved techniques and a larger patient cohort, including those with mild/moderate and severe forms of ME/CFS. So far, they have received more than 100 blood samples and have analyzed the electrical properties of 42.

“Based on the results we have so far, we are very close to having a biomarker for diagnosis. Our results so far show a high degree of accuracy and are able to distinguish between ME/CFS and other diseases,” said Dr. Labeed.
 

Genetic Test

Another promising avenue for diagnostics comes from a research team at the University of Edinburgh led by Professor Chris Ponting at the university’s Institute of Genetics and Cancer. They are currently working on DecodeMe, a large genetic study of ME using data from more than 26,000 people.

“We are studying blood-based biomarkers that distinguish people with ME from population controls. We’ve found a large number — including some found previously in other studies — and are writing these results up for publication,” said Ponting. The results should be published in early 2025.
 

The Future

While research into ME/CFS has picked up pace in recent years, funding remains a key bottleneck.

“Over the last 10 years, only £8.05m has been spent on ME research,” Sonya Chowdhury, chief executive of UK charity Action for ME told this news organization. She believes this amount is not equitably comparable to research funding allocated to other diseases.

In 2022, the UK government announced its intention to develop a cross-government interim delivery plan on ME/CFS for England, however publication of the final plan has been delayed numerous times.

Dr. Shepherd agreed that increased funding is crucial for progress to be made. He said the biggest help to ME/CFS research would be to end the disparity in government research funding for the disease, and match what is given for many other disabling long-term conditions.

“It’s not fair to continue to rely on the charity sector to fund almost all of the biomedical research into ME/CFS here in the UK,” he said.

A version of this article appeared on Medscape.com.

It’s the difference between running a marathon and taking a leisurely stroll. That’s how recent pediatrics resident Joey Whelihan, MD, compared an 11-hour inpatient hospital day with an 8-hour outpatient shift where residents see patients in a clinic.

With inpatient training, “you are lucky if you have time to cook dinner, go to bed, and get ready for the next day,” said Dr. Whelihan, who recently started his adolescent medicine fellowship at Children’s Hospital of Philadelphia after 3 years of residency there. Some residents have call every fourth day during inpatient rotations, working 24-28 hours at a time. They come in one morning and go home the next, he told this news organization.

“Outpatient blocks give you more time to catch your breath and feel somewhat refreshed and ready to take care of patients.”

Longer stretches of inpatient rotations are not sustainable, Dr. Whelihan added, and residents are likely to become exhausted. Fatigue is a leading cause of burnout, a mental, physical, and emotional challenge that residency programs and national medical organizations have been struggling to address.

In recent years, there has been a movement to reduce the maximum consecutive duration of resident duty hours in residency programs across the country. Fueled by resident health and patient safety concerns, the movement is a shift from the previous 24- to 36-hour call duty schedules.
 

Improved Call Systems = Better Residents

The connection between burnout, well-being, and work schedules appears regularly in national program standards. “Residents and faculty members are at risk for burnout and depression,” according to the current Accreditation Council for Graduate Medical Education’s standard residency program requirements.

“Programs, in partnership with their sponsoring institutions, have the same responsibility to address well-being as other aspects of resident competence,” the guidelines state. That charge includes “attention to scheduling, work intensity, and work compression that impacts resident well-being.”

In Medscape’s Residents Lifestyle & Happiness Report 2023, a third of residents surveyed rarely or never paid attention to their well-being, which closely mirrors the 31% who rarely or never had time for a social life. Slightly more residents (37%) said their work-life balance was “somewhat worse” or “much worse” than they expected.

“I think everyone has burnout as a resident, regardless of the type of program they are in,” Dr. Whelihan said. He described the experience as when you lack fulfillment and empathy and feel exhausted, callous, and removed from interactions with colleagues and patients.

The American Medical Association’s recently released report on the state of residency well-being in 2023 also found that about 43% of residents and fellows had at least one symptom of burnout, about a 2% increase from 2022.
 

Efforts to Combat Burnout

One residency program found a way to reduce burnout by changing its block scheduling from 4 inpatient weeks followed by 1 outpatient week (4 + 1) to 4 inpatient call-based weeks and 4 outpatient ambulatory, non-call weeks (4 + 4), according to a survey study published recently in JAMA Network Open. The initiative drew praise from some residents and a med school professor who studies wellness issues.

In the survey of postgraduate year (PGY) 1 and PGY-2 hospitalist and primary care residents from the University of Colorado’s Internal Medicine Residency Program, Aurora, between June 2019 and June 2021, the schedule change resulted in improved burnout scores and self-reported professional, educational, and health benefits.

As part of the survey, residents rated symptoms on a 7-point scale on the basis of how frequently they experienced emotional exhaustion, depersonalization, and personal accomplishment.

Investigators also used a questionnaire to evaluate how participants perceived the rotation structure with various outcomes, including the ability to acquire clinical skills, access educational and scholarly opportunities, job satisfaction, and health.

The study concluded that the schedule change improved burnout, health, wellness, and professional development without weakening residents perceived clinical skills or standardized exam scores.

Still, the study authors acknowledged that several factors, including the pandemic, may have limited the findings. During that time, the study transitioned from in-person to electronic submissions, resulting in reduced response rates because of changes in staffing needs and fewer research and scholarly activities.

“One of the things we worried about was that the pandemic would make [burnout findings] look worse,” said lead author Dan Heppe, MD, a hospitalist and associate director of the CU Internal Medicine Residency Program. “Anecdotally, residents may have had more support in our program than perhaps some other programs. Though they had long hours with very sick patients, we tried to keep going in a positive direction.”

Dr. Heppe said in an interview that the purpose of the schedule change was to space out more intense rotations and build in more time for research, leadership, teaching, and professional development. He suggested the new schedule could help with other aspects of residents’ careers, exposing them to alternate avenues earlier in their training and in a more structured way.

Like most of the study authors, Dr. Heppe is a graduate of the residency program. He recalled how the program changed from multiple inpatient months in a row with clinic half days during those rotations to a 4 + 1 schedule. But the 1 week between inpatient rotations wasn’t enough time to recover or catch up on clinical work, said Dr. Heppe, who is also an associate professor of medicine at CU.

“It was too erratic,” he said of his former residency schedule. “There was a month of research here or there and clinic and then right back to the ICU for a couple of months without a break, and it was less predictable.”

Dr. Heppe said other residency programs have expressed interest in duplicating CU’s schedule change. He admits it may be difficult because of intensive schedule coordination, and some hospitals may not want to reduce clinical services.

The Yale Internal Medicine Traditional Residency Program also recently ended its 28-hour call, during which residents worked 24 hours with an additional 4 hours to transfer the patient to the incoming team. The move was made in response to residents’ requests, saying that the grueling call rotation’s time had come. The reaction has been overwhelmingly positive.

Proponents of alternate scheduling blocks [4 + 4 or 6 + 2] say that they improve residents’ educational experience, patient care, and continuity of care, reduce burnout, and guarantee residents time off.
 

Advancing Resident Well-Being

“The premise of looking at scheduling in a more intentional way is a sound one in the process of trying to support and advance resident well-being,” said Mark Greenawald, MD, vice chair of academic affairs, well-being, and professional development for the Virginia Tech Carilion School of Medicine’s Department of Family and Community Medicine in Roanoke.

He said it’s up to residency program directors or graduate medical education departments within a specialty to determine whether such scheduling changes fit their requirements for inpatient and outpatient care and training electives. Requirements may limit some scheduling changes, but within the specialty, there’s some flexibility to be creative with rotations. The CU study considered how to create a residency rhythm without stacking inpatient rotations so there’s recovery time.

“Human beings need a break. If residents work 80 hours continually, they will start to experience greater distress, which for many leads to burnout,” he said

Still, the study includes design flaws because it doesn’t explain how call times and hours differ between inpatient and outpatient rotations. “My own [family medicine] program also does outpatient clinics when we have inpatient service. We have half days in the clinic, which ensures better continuity care with the patient.”

Dr. Greenawald has yet to see much research published about the impact of resident schedule changes. By taking an experimental approach, the CU study showed that their particular change positively affected burnout. If the study leads to improvements in rotation schedules or encourages other programs to experiment with their schedules, it will be a step in the right direction.
 

How Residents Respond

Haidn Foster, MD, a third-year internal medicine resident at Penn State Health Milton S. Hershey Medical Center, Hershey, remembered experiencing burnout as an intern. At that time, he occasionally dealt with poor patient outcomes and sick patients while working long hours with only 1 day off each week. During a particularly challenging rotation, he felt overwhelmed and numb, which was exacerbated if a patient’s condition worsened or they passed away, he said.

His program follows a schedule of 6 weeks of inpatient training and 2 weeks of outpatient rotations (6 + 2). He said that restructuring residents’ schedules may be more effective than commonly used individual wellness modules, referring to the CU study. “The authors tried out a novel systematic way to tackle the epidemic of physician burnout overwhelming people in the medical community.”

Although the study found that schedule changes don’t affect standardized exam scores, Dr. Foster wondered about preceptor ratings, another marker for clinical competency.

He said future studies should attempt to change the structure of medical training delivery by evaluating models that best reduce burnout, are consistent with residents’ career goals, and produce competent physicians. “Burnout plagues our medical system and leads to too many physicians and physicians-in-training leaving the field or taking their lives. I’m not sure this particular mechanism gets us there, but it’s a step, and so that’s very important.”

Like Dr. Foster, Dr. Whelihan follows a 6 + 2 schedule. He said he would have welcomed a schedule that included more outpatient and less inpatient training and can see how changes in scheduling could reduce burnout. “More outpatient time gives you an opportunity to breathe. You get a little more time off working in clinic with less sick people at a slower pace.”

Ally Fuher, MD, said she chose CU’s Internal Medicine Residency Program 4 years ago largely because of its innovative schedule. Now the program’s chief medical resident, she knew the structure would give her more time to pursue other nonclinical interests including research and medical education, meet regularly with mentors, visit family in another state, and attend important life events.

She acknowledged that the alternative would have meant a more irregular schedule with the possibility of working as many as 80 hours a week on back-to-back inpatient rotations with only 1 day off a week, leaving minimal time to plan other activities, let alone rest and recover.

Dr. Fuher said a balanced schedule made her a more well-rounded person excited to engage in her profession. While she hasn’t personally experienced burnout, she realizes a schedule change may not completely solve the issue for others. However, it shows what progress programs can make when they create systemic structural change.

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

It’s the difference between running a marathon and taking a leisurely stroll. That’s how recent pediatrics resident Joey Whelihan, MD, compared an 11-hour inpatient hospital day with an 8-hour outpatient shift where residents see patients in a clinic.

With inpatient training, “you are lucky if you have time to cook dinner, go to bed, and get ready for the next day,” said Dr. Whelihan, who recently started his adolescent medicine fellowship at Children’s Hospital of Philadelphia after 3 years of residency there. Some residents have call every fourth day during inpatient rotations, working 24-28 hours at a time. They come in one morning and go home the next, he told this news organization.

“Outpatient blocks give you more time to catch your breath and feel somewhat refreshed and ready to take care of patients.”

Longer stretches of inpatient rotations are not sustainable, Dr. Whelihan added, and residents are likely to become exhausted. Fatigue is a leading cause of burnout, a mental, physical, and emotional challenge that residency programs and national medical organizations have been struggling to address.

In recent years, there has been a movement to reduce the maximum consecutive duration of resident duty hours in residency programs across the country. Fueled by resident health and patient safety concerns, the movement is a shift from the previous 24- to 36-hour call duty schedules.
 

Improved Call Systems = Better Residents

The connection between burnout, well-being, and work schedules appears regularly in national program standards. “Residents and faculty members are at risk for burnout and depression,” according to the current Accreditation Council for Graduate Medical Education’s standard residency program requirements.

“Programs, in partnership with their sponsoring institutions, have the same responsibility to address well-being as other aspects of resident competence,” the guidelines state. That charge includes “attention to scheduling, work intensity, and work compression that impacts resident well-being.”

In Medscape’s Residents Lifestyle & Happiness Report 2023, a third of residents surveyed rarely or never paid attention to their well-being, which closely mirrors the 31% who rarely or never had time for a social life. Slightly more residents (37%) said their work-life balance was “somewhat worse” or “much worse” than they expected.

“I think everyone has burnout as a resident, regardless of the type of program they are in,” Dr. Whelihan said. He described the experience as when you lack fulfillment and empathy and feel exhausted, callous, and removed from interactions with colleagues and patients.

The American Medical Association’s recently released report on the state of residency well-being in 2023 also found that about 43% of residents and fellows had at least one symptom of burnout, about a 2% increase from 2022.
 

Efforts to Combat Burnout

One residency program found a way to reduce burnout by changing its block scheduling from 4 inpatient weeks followed by 1 outpatient week (4 + 1) to 4 inpatient call-based weeks and 4 outpatient ambulatory, non-call weeks (4 + 4), according to a survey study published recently in JAMA Network Open. The initiative drew praise from some residents and a med school professor who studies wellness issues.

In the survey of postgraduate year (PGY) 1 and PGY-2 hospitalist and primary care residents from the University of Colorado’s Internal Medicine Residency Program, Aurora, between June 2019 and June 2021, the schedule change resulted in improved burnout scores and self-reported professional, educational, and health benefits.

As part of the survey, residents rated symptoms on a 7-point scale on the basis of how frequently they experienced emotional exhaustion, depersonalization, and personal accomplishment.

Investigators also used a questionnaire to evaluate how participants perceived the rotation structure with various outcomes, including the ability to acquire clinical skills, access educational and scholarly opportunities, job satisfaction, and health.

The study concluded that the schedule change improved burnout, health, wellness, and professional development without weakening residents perceived clinical skills or standardized exam scores.

Still, the study authors acknowledged that several factors, including the pandemic, may have limited the findings. During that time, the study transitioned from in-person to electronic submissions, resulting in reduced response rates because of changes in staffing needs and fewer research and scholarly activities.

“One of the things we worried about was that the pandemic would make [burnout findings] look worse,” said lead author Dan Heppe, MD, a hospitalist and associate director of the CU Internal Medicine Residency Program. “Anecdotally, residents may have had more support in our program than perhaps some other programs. Though they had long hours with very sick patients, we tried to keep going in a positive direction.”

Dr. Heppe said in an interview that the purpose of the schedule change was to space out more intense rotations and build in more time for research, leadership, teaching, and professional development. He suggested the new schedule could help with other aspects of residents’ careers, exposing them to alternate avenues earlier in their training and in a more structured way.

Like most of the study authors, Dr. Heppe is a graduate of the residency program. He recalled how the program changed from multiple inpatient months in a row with clinic half days during those rotations to a 4 + 1 schedule. But the 1 week between inpatient rotations wasn’t enough time to recover or catch up on clinical work, said Dr. Heppe, who is also an associate professor of medicine at CU.

“It was too erratic,” he said of his former residency schedule. “There was a month of research here or there and clinic and then right back to the ICU for a couple of months without a break, and it was less predictable.”

Dr. Heppe said other residency programs have expressed interest in duplicating CU’s schedule change. He admits it may be difficult because of intensive schedule coordination, and some hospitals may not want to reduce clinical services.

The Yale Internal Medicine Traditional Residency Program also recently ended its 28-hour call, during which residents worked 24 hours with an additional 4 hours to transfer the patient to the incoming team. The move was made in response to residents’ requests, saying that the grueling call rotation’s time had come. The reaction has been overwhelmingly positive.

Proponents of alternate scheduling blocks [4 + 4 or 6 + 2] say that they improve residents’ educational experience, patient care, and continuity of care, reduce burnout, and guarantee residents time off.
 

Advancing Resident Well-Being

“The premise of looking at scheduling in a more intentional way is a sound one in the process of trying to support and advance resident well-being,” said Mark Greenawald, MD, vice chair of academic affairs, well-being, and professional development for the Virginia Tech Carilion School of Medicine’s Department of Family and Community Medicine in Roanoke.

He said it’s up to residency program directors or graduate medical education departments within a specialty to determine whether such scheduling changes fit their requirements for inpatient and outpatient care and training electives. Requirements may limit some scheduling changes, but within the specialty, there’s some flexibility to be creative with rotations. The CU study considered how to create a residency rhythm without stacking inpatient rotations so there’s recovery time.

“Human beings need a break. If residents work 80 hours continually, they will start to experience greater distress, which for many leads to burnout,” he said

Still, the study includes design flaws because it doesn’t explain how call times and hours differ between inpatient and outpatient rotations. “My own [family medicine] program also does outpatient clinics when we have inpatient service. We have half days in the clinic, which ensures better continuity care with the patient.”

Dr. Greenawald has yet to see much research published about the impact of resident schedule changes. By taking an experimental approach, the CU study showed that their particular change positively affected burnout. If the study leads to improvements in rotation schedules or encourages other programs to experiment with their schedules, it will be a step in the right direction.
 

How Residents Respond

Haidn Foster, MD, a third-year internal medicine resident at Penn State Health Milton S. Hershey Medical Center, Hershey, remembered experiencing burnout as an intern. At that time, he occasionally dealt with poor patient outcomes and sick patients while working long hours with only 1 day off each week. During a particularly challenging rotation, he felt overwhelmed and numb, which was exacerbated if a patient’s condition worsened or they passed away, he said.

His program follows a schedule of 6 weeks of inpatient training and 2 weeks of outpatient rotations (6 + 2). He said that restructuring residents’ schedules may be more effective than commonly used individual wellness modules, referring to the CU study. “The authors tried out a novel systematic way to tackle the epidemic of physician burnout overwhelming people in the medical community.”

Although the study found that schedule changes don’t affect standardized exam scores, Dr. Foster wondered about preceptor ratings, another marker for clinical competency.

He said future studies should attempt to change the structure of medical training delivery by evaluating models that best reduce burnout, are consistent with residents’ career goals, and produce competent physicians. “Burnout plagues our medical system and leads to too many physicians and physicians-in-training leaving the field or taking their lives. I’m not sure this particular mechanism gets us there, but it’s a step, and so that’s very important.”

Like Dr. Foster, Dr. Whelihan follows a 6 + 2 schedule. He said he would have welcomed a schedule that included more outpatient and less inpatient training and can see how changes in scheduling could reduce burnout. “More outpatient time gives you an opportunity to breathe. You get a little more time off working in clinic with less sick people at a slower pace.”

Ally Fuher, MD, said she chose CU’s Internal Medicine Residency Program 4 years ago largely because of its innovative schedule. Now the program’s chief medical resident, she knew the structure would give her more time to pursue other nonclinical interests including research and medical education, meet regularly with mentors, visit family in another state, and attend important life events.

She acknowledged that the alternative would have meant a more irregular schedule with the possibility of working as many as 80 hours a week on back-to-back inpatient rotations with only 1 day off a week, leaving minimal time to plan other activities, let alone rest and recover.

Dr. Fuher said a balanced schedule made her a more well-rounded person excited to engage in her profession. While she hasn’t personally experienced burnout, she realizes a schedule change may not completely solve the issue for others. However, it shows what progress programs can make when they create systemic structural change.

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

It’s the difference between running a marathon and taking a leisurely stroll. That’s how recent pediatrics resident Joey Whelihan, MD, compared an 11-hour inpatient hospital day with an 8-hour outpatient shift where residents see patients in a clinic.

With inpatient training, “you are lucky if you have time to cook dinner, go to bed, and get ready for the next day,” said Dr. Whelihan, who recently started his adolescent medicine fellowship at Children’s Hospital of Philadelphia after 3 years of residency there. Some residents have call every fourth day during inpatient rotations, working 24-28 hours at a time. They come in one morning and go home the next, he told this news organization.

“Outpatient blocks give you more time to catch your breath and feel somewhat refreshed and ready to take care of patients.”

Longer stretches of inpatient rotations are not sustainable, Dr. Whelihan added, and residents are likely to become exhausted. Fatigue is a leading cause of burnout, a mental, physical, and emotional challenge that residency programs and national medical organizations have been struggling to address.

In recent years, there has been a movement to reduce the maximum consecutive duration of resident duty hours in residency programs across the country. Fueled by resident health and patient safety concerns, the movement is a shift from the previous 24- to 36-hour call duty schedules.
 

Improved Call Systems = Better Residents

The connection between burnout, well-being, and work schedules appears regularly in national program standards. “Residents and faculty members are at risk for burnout and depression,” according to the current Accreditation Council for Graduate Medical Education’s standard residency program requirements.

“Programs, in partnership with their sponsoring institutions, have the same responsibility to address well-being as other aspects of resident competence,” the guidelines state. That charge includes “attention to scheduling, work intensity, and work compression that impacts resident well-being.”

In Medscape’s Residents Lifestyle & Happiness Report 2023, a third of residents surveyed rarely or never paid attention to their well-being, which closely mirrors the 31% who rarely or never had time for a social life. Slightly more residents (37%) said their work-life balance was “somewhat worse” or “much worse” than they expected.

“I think everyone has burnout as a resident, regardless of the type of program they are in,” Dr. Whelihan said. He described the experience as when you lack fulfillment and empathy and feel exhausted, callous, and removed from interactions with colleagues and patients.

The American Medical Association’s recently released report on the state of residency well-being in 2023 also found that about 43% of residents and fellows had at least one symptom of burnout, about a 2% increase from 2022.
 

Efforts to Combat Burnout

One residency program found a way to reduce burnout by changing its block scheduling from 4 inpatient weeks followed by 1 outpatient week (4 + 1) to 4 inpatient call-based weeks and 4 outpatient ambulatory, non-call weeks (4 + 4), according to a survey study published recently in JAMA Network Open. The initiative drew praise from some residents and a med school professor who studies wellness issues.

In the survey of postgraduate year (PGY) 1 and PGY-2 hospitalist and primary care residents from the University of Colorado’s Internal Medicine Residency Program, Aurora, between June 2019 and June 2021, the schedule change resulted in improved burnout scores and self-reported professional, educational, and health benefits.

As part of the survey, residents rated symptoms on a 7-point scale on the basis of how frequently they experienced emotional exhaustion, depersonalization, and personal accomplishment.

Investigators also used a questionnaire to evaluate how participants perceived the rotation structure with various outcomes, including the ability to acquire clinical skills, access educational and scholarly opportunities, job satisfaction, and health.

The study concluded that the schedule change improved burnout, health, wellness, and professional development without weakening residents perceived clinical skills or standardized exam scores.

Still, the study authors acknowledged that several factors, including the pandemic, may have limited the findings. During that time, the study transitioned from in-person to electronic submissions, resulting in reduced response rates because of changes in staffing needs and fewer research and scholarly activities.

“One of the things we worried about was that the pandemic would make [burnout findings] look worse,” said lead author Dan Heppe, MD, a hospitalist and associate director of the CU Internal Medicine Residency Program. “Anecdotally, residents may have had more support in our program than perhaps some other programs. Though they had long hours with very sick patients, we tried to keep going in a positive direction.”

Dr. Heppe said in an interview that the purpose of the schedule change was to space out more intense rotations and build in more time for research, leadership, teaching, and professional development. He suggested the new schedule could help with other aspects of residents’ careers, exposing them to alternate avenues earlier in their training and in a more structured way.

Like most of the study authors, Dr. Heppe is a graduate of the residency program. He recalled how the program changed from multiple inpatient months in a row with clinic half days during those rotations to a 4 + 1 schedule. But the 1 week between inpatient rotations wasn’t enough time to recover or catch up on clinical work, said Dr. Heppe, who is also an associate professor of medicine at CU.

“It was too erratic,” he said of his former residency schedule. “There was a month of research here or there and clinic and then right back to the ICU for a couple of months without a break, and it was less predictable.”

Dr. Heppe said other residency programs have expressed interest in duplicating CU’s schedule change. He admits it may be difficult because of intensive schedule coordination, and some hospitals may not want to reduce clinical services.

The Yale Internal Medicine Traditional Residency Program also recently ended its 28-hour call, during which residents worked 24 hours with an additional 4 hours to transfer the patient to the incoming team. The move was made in response to residents’ requests, saying that the grueling call rotation’s time had come. The reaction has been overwhelmingly positive.

Proponents of alternate scheduling blocks [4 + 4 or 6 + 2] say that they improve residents’ educational experience, patient care, and continuity of care, reduce burnout, and guarantee residents time off.
 

Advancing Resident Well-Being

“The premise of looking at scheduling in a more intentional way is a sound one in the process of trying to support and advance resident well-being,” said Mark Greenawald, MD, vice chair of academic affairs, well-being, and professional development for the Virginia Tech Carilion School of Medicine’s Department of Family and Community Medicine in Roanoke.

He said it’s up to residency program directors or graduate medical education departments within a specialty to determine whether such scheduling changes fit their requirements for inpatient and outpatient care and training electives. Requirements may limit some scheduling changes, but within the specialty, there’s some flexibility to be creative with rotations. The CU study considered how to create a residency rhythm without stacking inpatient rotations so there’s recovery time.

“Human beings need a break. If residents work 80 hours continually, they will start to experience greater distress, which for many leads to burnout,” he said

Still, the study includes design flaws because it doesn’t explain how call times and hours differ between inpatient and outpatient rotations. “My own [family medicine] program also does outpatient clinics when we have inpatient service. We have half days in the clinic, which ensures better continuity care with the patient.”

Dr. Greenawald has yet to see much research published about the impact of resident schedule changes. By taking an experimental approach, the CU study showed that their particular change positively affected burnout. If the study leads to improvements in rotation schedules or encourages other programs to experiment with their schedules, it will be a step in the right direction.
 

How Residents Respond

Haidn Foster, MD, a third-year internal medicine resident at Penn State Health Milton S. Hershey Medical Center, Hershey, remembered experiencing burnout as an intern. At that time, he occasionally dealt with poor patient outcomes and sick patients while working long hours with only 1 day off each week. During a particularly challenging rotation, he felt overwhelmed and numb, which was exacerbated if a patient’s condition worsened or they passed away, he said.

His program follows a schedule of 6 weeks of inpatient training and 2 weeks of outpatient rotations (6 + 2). He said that restructuring residents’ schedules may be more effective than commonly used individual wellness modules, referring to the CU study. “The authors tried out a novel systematic way to tackle the epidemic of physician burnout overwhelming people in the medical community.”

Although the study found that schedule changes don’t affect standardized exam scores, Dr. Foster wondered about preceptor ratings, another marker for clinical competency.

He said future studies should attempt to change the structure of medical training delivery by evaluating models that best reduce burnout, are consistent with residents’ career goals, and produce competent physicians. “Burnout plagues our medical system and leads to too many physicians and physicians-in-training leaving the field or taking their lives. I’m not sure this particular mechanism gets us there, but it’s a step, and so that’s very important.”

Like Dr. Foster, Dr. Whelihan follows a 6 + 2 schedule. He said he would have welcomed a schedule that included more outpatient and less inpatient training and can see how changes in scheduling could reduce burnout. “More outpatient time gives you an opportunity to breathe. You get a little more time off working in clinic with less sick people at a slower pace.”

Ally Fuher, MD, said she chose CU’s Internal Medicine Residency Program 4 years ago largely because of its innovative schedule. Now the program’s chief medical resident, she knew the structure would give her more time to pursue other nonclinical interests including research and medical education, meet regularly with mentors, visit family in another state, and attend important life events.

She acknowledged that the alternative would have meant a more irregular schedule with the possibility of working as many as 80 hours a week on back-to-back inpatient rotations with only 1 day off a week, leaving minimal time to plan other activities, let alone rest and recover.

Dr. Fuher said a balanced schedule made her a more well-rounded person excited to engage in her profession. While she hasn’t personally experienced burnout, she realizes a schedule change may not completely solve the issue for others. However, it shows what progress programs can make when they create systemic structural change.

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

This transcript has been edited for clarity. 

ACIP, the CDC’s Advisory Committee on Immunization Practices, met for 3 days in June. New vaccines and new recommendations for respiratory syncytial virus (RSV), flu, COVID, and a new pneumococcal vaccine were revealed.

RSV Protection

We’ll begin with RSV vaccines for adults aged 60 or older. For this group, shared clinical decision-making is out; it no longer applies. New, more specific recommendations from ACIP for RSV vaccines are both age based and risk based. The age-based recommendation applies to those aged 75 or older, who should receive a single RSV vaccine dose. If they have already received a dose under the old recommendation, they don’t need another one, at least for now.

The risk-based recommendation applies to adults from age 60 up to 75, but only for those with risk factors for severe RSV. These risk factors include lung disease, heart disease, immunocompromise, diabetes, obesity with a BMI of 40 or more, neurologic conditions, neuromuscular conditions, chronic kidney disease, liver disorders, hematologic disorders, frailty, and living in a nursing home or other long-term care facility. Those aged 60-75 with these risk factors should receive the RSV vaccine, and those without them should not receive it. The best time to get the RSV vaccine is late summer, but early fall administration with other adult vaccines is allowed and is acceptable.

Vaccine safety concerns were top of mind as ACIP members began their deliberations. Possible safety concerns for RSV vaccines have been detected for Guillain-Barré syndrome, atrial fibrillation, and idiopathic thrombocytopenic purpura. Safety surveillance updates are still interim and inconclusive. These signals still need further study and clarification. 

Two RSV vaccines have been on the market: one by Pfizer, called Abrysvo, which does not contain an adjuvant; and another one by GSK, called Arexvy, which does contain an adjuvant. With the recent FDA approval of Moderna’s new mRNA RSV vaccine, mRESVIA, there are now three RSV vaccines licensed for those 60 or older. Arexvy is now FDA approved for adults in their 50s. That just happened in early June, but ACIP doesn’t currently recommend it for this fifty-something age group, even for those at high risk for severe RSV disease. This may change with greater clarification of potential vaccine safety concerns.

There is also news about protecting babies from RSV. RSV is the most common cause of hospitalization for infants in the United States, and most hospitalizations for RSV are in healthy, full-term infants. We now have two ways to protect babies: a dose of RSV vaccine given to mom, or a dose of the long-acting monoclonal antibody nirsevimab given to the baby. ACIP clarified that those who received a dose of maternal RSV vaccine during a previous pregnancy are not recommended to receive additional doses during future pregnancies, but infants born to those who were vaccinated for RSV during a prior pregnancy can receive nirsevimab, which is recommended for infants up to 8 months of age during their first RSV season, and for high-risk infants and toddlers aged 8-19 months during their second RSV season.

Last RSV season, supplies of nirsevimab were limited and doses had to be prioritized. No supply problems are anticipated for the upcoming season. A study published in March showed that nirsevimab was 90% effective at preventing RSV-associated hospitalization for infants in their first RSV season.
 

COVID

Here’s what’s new for COVID vaccines. A new-formula COVID vaccine will be ready for fall. ACIP voted unanimously to recommend a dose of the updated 2024-2025 COVID vaccine for everyone aged 6 months or older. This is a universal recommendation, just like the one we have for flu. But understand that even though COVID has waned, it’s still more deadly than flu. Most Americans now have some immunity against COVID, but this immunity wanes with time, and it also wanes as the virus keeps changing. These updated vaccines provide an incremental boost to our immunity for the new formula for fall. FDA has directed manufacturers to use a monovalent JN.1 lineage formula, with a preference for the KP.2 strain.

Older adults (aged 75 or older) and children under 6 months old are hit hardest by COVID. The littlest ones are too young to be vaccinated, but they can get protection from maternal vaccination. The uptake for last year’s COVID vaccine has been disappointing. Only 22.5% of adults and 14% of children received a dose of the updated shot. Focus-group discussions highlight the importance of a physician recommendation. Adults and children who receive a healthcare provider’s recommendation to get the COVID vaccine are more likely to get vaccinated. 
 

Pneumococcal Vaccines

On June 17, 2024, a new pneumococcal vaccine, PCV21, was FDA approved for those aged 18 or older under an accelerated-approval pathway. ACIP voted to keep it simple and recommends PCV21 as an option for adults aged 19 or older who currently have an indication to receive a dose of PCV. This new PCV21 vaccine is indicated for prevention of both invasive pneumococcal disease (IPD) and pneumococcal pneumonia. Its brand name is Capvaxive and it’s made by Merck. IPD includes bacteremia, pneumonia, pneumococcal bacteremia, and meningitis.

There are two basic types of pneumococcal vaccines: polysaccharide vaccines (PPSV), which do not produce memory B cells; and PCV conjugate vaccines, which do trigger memory B-cell production and therefore induce greater long-term immunity. PCV21 covers 11 unique serotypes not in PCV20. This is important because many cases of adult disease are caused by subtypes not covered by other FDA-approved pneumococcal vaccines. PCV21 has greater coverage of the serotypes that cause invasive disease in adults as compared with PCV20. PCV20 covers up to 58% of those strains, while PCV21 covers up to 84% of strains responsible for invasive disease in adults. But there’s one serotype missing in PCV21, which may limit the groups who receive it. PCV21 does not cover serotype 4, a major cause of IPD in certain populations. Adults experiencing homelessness are 100-300 times more likely to develop IPD due to serotype 4. So are adults in Alaska, especially Alaska Natives. They have an 88-fold increase in serotype 4 invasive disease. Serotype 4 is covered by other pneumococcal vaccines, so for these patients, PCV20 is likely a better high-valent conjugate vaccine option than PCV21.
 

Flu Vaccines

What’s new for flu? Everyone aged 6 months or older needs a seasonal flu vaccination every year. That’s not new, but there are two new things coming this fall: (1) The seasonal flu vaccine is going trivalent. FDA has removed the Yamagata flu B strain because it no longer appears to be circulating. (2) ACIP made a special off-label recommendation to boost flu protection for solid organ transplant recipients ages 18-64 who are on immunosuppressive medications. These high-risk patients now have the off-label option of receiving one of the higher-dose flu vaccines, including high-dose and adjuvanted flu vaccines, which are FDA approved only for those 65 or older.

Sandra Adamson Fryhofer, Adjunct Clinical Associate Professor of Medicine, Emory University School of Medicine, Atlanta, Georgia, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for American Medical Association; Medical Association of Atlanta; ACIP liaison. Received income in an amount equal to or greater than $250 from American College of Physicians; Medscape; American Medical Association.

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

This transcript has been edited for clarity. 

ACIP, the CDC’s Advisory Committee on Immunization Practices, met for 3 days in June. New vaccines and new recommendations for respiratory syncytial virus (RSV), flu, COVID, and a new pneumococcal vaccine were revealed.

RSV Protection

We’ll begin with RSV vaccines for adults aged 60 or older. For this group, shared clinical decision-making is out; it no longer applies. New, more specific recommendations from ACIP for RSV vaccines are both age based and risk based. The age-based recommendation applies to those aged 75 or older, who should receive a single RSV vaccine dose. If they have already received a dose under the old recommendation, they don’t need another one, at least for now.

The risk-based recommendation applies to adults from age 60 up to 75, but only for those with risk factors for severe RSV. These risk factors include lung disease, heart disease, immunocompromise, diabetes, obesity with a BMI of 40 or more, neurologic conditions, neuromuscular conditions, chronic kidney disease, liver disorders, hematologic disorders, frailty, and living in a nursing home or other long-term care facility. Those aged 60-75 with these risk factors should receive the RSV vaccine, and those without them should not receive it. The best time to get the RSV vaccine is late summer, but early fall administration with other adult vaccines is allowed and is acceptable.

Vaccine safety concerns were top of mind as ACIP members began their deliberations. Possible safety concerns for RSV vaccines have been detected for Guillain-Barré syndrome, atrial fibrillation, and idiopathic thrombocytopenic purpura. Safety surveillance updates are still interim and inconclusive. These signals still need further study and clarification. 

Two RSV vaccines have been on the market: one by Pfizer, called Abrysvo, which does not contain an adjuvant; and another one by GSK, called Arexvy, which does contain an adjuvant. With the recent FDA approval of Moderna’s new mRNA RSV vaccine, mRESVIA, there are now three RSV vaccines licensed for those 60 or older. Arexvy is now FDA approved for adults in their 50s. That just happened in early June, but ACIP doesn’t currently recommend it for this fifty-something age group, even for those at high risk for severe RSV disease. This may change with greater clarification of potential vaccine safety concerns.

There is also news about protecting babies from RSV. RSV is the most common cause of hospitalization for infants in the United States, and most hospitalizations for RSV are in healthy, full-term infants. We now have two ways to protect babies: a dose of RSV vaccine given to mom, or a dose of the long-acting monoclonal antibody nirsevimab given to the baby. ACIP clarified that those who received a dose of maternal RSV vaccine during a previous pregnancy are not recommended to receive additional doses during future pregnancies, but infants born to those who were vaccinated for RSV during a prior pregnancy can receive nirsevimab, which is recommended for infants up to 8 months of age during their first RSV season, and for high-risk infants and toddlers aged 8-19 months during their second RSV season.

Last RSV season, supplies of nirsevimab were limited and doses had to be prioritized. No supply problems are anticipated for the upcoming season. A study published in March showed that nirsevimab was 90% effective at preventing RSV-associated hospitalization for infants in their first RSV season.
 

COVID

Here’s what’s new for COVID vaccines. A new-formula COVID vaccine will be ready for fall. ACIP voted unanimously to recommend a dose of the updated 2024-2025 COVID vaccine for everyone aged 6 months or older. This is a universal recommendation, just like the one we have for flu. But understand that even though COVID has waned, it’s still more deadly than flu. Most Americans now have some immunity against COVID, but this immunity wanes with time, and it also wanes as the virus keeps changing. These updated vaccines provide an incremental boost to our immunity for the new formula for fall. FDA has directed manufacturers to use a monovalent JN.1 lineage formula, with a preference for the KP.2 strain.

Older adults (aged 75 or older) and children under 6 months old are hit hardest by COVID. The littlest ones are too young to be vaccinated, but they can get protection from maternal vaccination. The uptake for last year’s COVID vaccine has been disappointing. Only 22.5% of adults and 14% of children received a dose of the updated shot. Focus-group discussions highlight the importance of a physician recommendation. Adults and children who receive a healthcare provider’s recommendation to get the COVID vaccine are more likely to get vaccinated. 
 

Pneumococcal Vaccines

On June 17, 2024, a new pneumococcal vaccine, PCV21, was FDA approved for those aged 18 or older under an accelerated-approval pathway. ACIP voted to keep it simple and recommends PCV21 as an option for adults aged 19 or older who currently have an indication to receive a dose of PCV. This new PCV21 vaccine is indicated for prevention of both invasive pneumococcal disease (IPD) and pneumococcal pneumonia. Its brand name is Capvaxive and it’s made by Merck. IPD includes bacteremia, pneumonia, pneumococcal bacteremia, and meningitis.

There are two basic types of pneumococcal vaccines: polysaccharide vaccines (PPSV), which do not produce memory B cells; and PCV conjugate vaccines, which do trigger memory B-cell production and therefore induce greater long-term immunity. PCV21 covers 11 unique serotypes not in PCV20. This is important because many cases of adult disease are caused by subtypes not covered by other FDA-approved pneumococcal vaccines. PCV21 has greater coverage of the serotypes that cause invasive disease in adults as compared with PCV20. PCV20 covers up to 58% of those strains, while PCV21 covers up to 84% of strains responsible for invasive disease in adults. But there’s one serotype missing in PCV21, which may limit the groups who receive it. PCV21 does not cover serotype 4, a major cause of IPD in certain populations. Adults experiencing homelessness are 100-300 times more likely to develop IPD due to serotype 4. So are adults in Alaska, especially Alaska Natives. They have an 88-fold increase in serotype 4 invasive disease. Serotype 4 is covered by other pneumococcal vaccines, so for these patients, PCV20 is likely a better high-valent conjugate vaccine option than PCV21.
 

Flu Vaccines

What’s new for flu? Everyone aged 6 months or older needs a seasonal flu vaccination every year. That’s not new, but there are two new things coming this fall: (1) The seasonal flu vaccine is going trivalent. FDA has removed the Yamagata flu B strain because it no longer appears to be circulating. (2) ACIP made a special off-label recommendation to boost flu protection for solid organ transplant recipients ages 18-64 who are on immunosuppressive medications. These high-risk patients now have the off-label option of receiving one of the higher-dose flu vaccines, including high-dose and adjuvanted flu vaccines, which are FDA approved only for those 65 or older.

Sandra Adamson Fryhofer, Adjunct Clinical Associate Professor of Medicine, Emory University School of Medicine, Atlanta, Georgia, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for American Medical Association; Medical Association of Atlanta; ACIP liaison. Received income in an amount equal to or greater than $250 from American College of Physicians; Medscape; American Medical Association.

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

This transcript has been edited for clarity. 

ACIP, the CDC’s Advisory Committee on Immunization Practices, met for 3 days in June. New vaccines and new recommendations for respiratory syncytial virus (RSV), flu, COVID, and a new pneumococcal vaccine were revealed.

RSV Protection

We’ll begin with RSV vaccines for adults aged 60 or older. For this group, shared clinical decision-making is out; it no longer applies. New, more specific recommendations from ACIP for RSV vaccines are both age based and risk based. The age-based recommendation applies to those aged 75 or older, who should receive a single RSV vaccine dose. If they have already received a dose under the old recommendation, they don’t need another one, at least for now.

The risk-based recommendation applies to adults from age 60 up to 75, but only for those with risk factors for severe RSV. These risk factors include lung disease, heart disease, immunocompromise, diabetes, obesity with a BMI of 40 or more, neurologic conditions, neuromuscular conditions, chronic kidney disease, liver disorders, hematologic disorders, frailty, and living in a nursing home or other long-term care facility. Those aged 60-75 with these risk factors should receive the RSV vaccine, and those without them should not receive it. The best time to get the RSV vaccine is late summer, but early fall administration with other adult vaccines is allowed and is acceptable.

Vaccine safety concerns were top of mind as ACIP members began their deliberations. Possible safety concerns for RSV vaccines have been detected for Guillain-Barré syndrome, atrial fibrillation, and idiopathic thrombocytopenic purpura. Safety surveillance updates are still interim and inconclusive. These signals still need further study and clarification. 

Two RSV vaccines have been on the market: one by Pfizer, called Abrysvo, which does not contain an adjuvant; and another one by GSK, called Arexvy, which does contain an adjuvant. With the recent FDA approval of Moderna’s new mRNA RSV vaccine, mRESVIA, there are now three RSV vaccines licensed for those 60 or older. Arexvy is now FDA approved for adults in their 50s. That just happened in early June, but ACIP doesn’t currently recommend it for this fifty-something age group, even for those at high risk for severe RSV disease. This may change with greater clarification of potential vaccine safety concerns.

There is also news about protecting babies from RSV. RSV is the most common cause of hospitalization for infants in the United States, and most hospitalizations for RSV are in healthy, full-term infants. We now have two ways to protect babies: a dose of RSV vaccine given to mom, or a dose of the long-acting monoclonal antibody nirsevimab given to the baby. ACIP clarified that those who received a dose of maternal RSV vaccine during a previous pregnancy are not recommended to receive additional doses during future pregnancies, but infants born to those who were vaccinated for RSV during a prior pregnancy can receive nirsevimab, which is recommended for infants up to 8 months of age during their first RSV season, and for high-risk infants and toddlers aged 8-19 months during their second RSV season.

Last RSV season, supplies of nirsevimab were limited and doses had to be prioritized. No supply problems are anticipated for the upcoming season. A study published in March showed that nirsevimab was 90% effective at preventing RSV-associated hospitalization for infants in their first RSV season.
 

COVID

Here’s what’s new for COVID vaccines. A new-formula COVID vaccine will be ready for fall. ACIP voted unanimously to recommend a dose of the updated 2024-2025 COVID vaccine for everyone aged 6 months or older. This is a universal recommendation, just like the one we have for flu. But understand that even though COVID has waned, it’s still more deadly than flu. Most Americans now have some immunity against COVID, but this immunity wanes with time, and it also wanes as the virus keeps changing. These updated vaccines provide an incremental boost to our immunity for the new formula for fall. FDA has directed manufacturers to use a monovalent JN.1 lineage formula, with a preference for the KP.2 strain.

Older adults (aged 75 or older) and children under 6 months old are hit hardest by COVID. The littlest ones are too young to be vaccinated, but they can get protection from maternal vaccination. The uptake for last year’s COVID vaccine has been disappointing. Only 22.5% of adults and 14% of children received a dose of the updated shot. Focus-group discussions highlight the importance of a physician recommendation. Adults and children who receive a healthcare provider’s recommendation to get the COVID vaccine are more likely to get vaccinated. 
 

Pneumococcal Vaccines

On June 17, 2024, a new pneumococcal vaccine, PCV21, was FDA approved for those aged 18 or older under an accelerated-approval pathway. ACIP voted to keep it simple and recommends PCV21 as an option for adults aged 19 or older who currently have an indication to receive a dose of PCV. This new PCV21 vaccine is indicated for prevention of both invasive pneumococcal disease (IPD) and pneumococcal pneumonia. Its brand name is Capvaxive and it’s made by Merck. IPD includes bacteremia, pneumonia, pneumococcal bacteremia, and meningitis.

There are two basic types of pneumococcal vaccines: polysaccharide vaccines (PPSV), which do not produce memory B cells; and PCV conjugate vaccines, which do trigger memory B-cell production and therefore induce greater long-term immunity. PCV21 covers 11 unique serotypes not in PCV20. This is important because many cases of adult disease are caused by subtypes not covered by other FDA-approved pneumococcal vaccines. PCV21 has greater coverage of the serotypes that cause invasive disease in adults as compared with PCV20. PCV20 covers up to 58% of those strains, while PCV21 covers up to 84% of strains responsible for invasive disease in adults. But there’s one serotype missing in PCV21, which may limit the groups who receive it. PCV21 does not cover serotype 4, a major cause of IPD in certain populations. Adults experiencing homelessness are 100-300 times more likely to develop IPD due to serotype 4. So are adults in Alaska, especially Alaska Natives. They have an 88-fold increase in serotype 4 invasive disease. Serotype 4 is covered by other pneumococcal vaccines, so for these patients, PCV20 is likely a better high-valent conjugate vaccine option than PCV21.
 

Flu Vaccines

What’s new for flu? Everyone aged 6 months or older needs a seasonal flu vaccination every year. That’s not new, but there are two new things coming this fall: (1) The seasonal flu vaccine is going trivalent. FDA has removed the Yamagata flu B strain because it no longer appears to be circulating. (2) ACIP made a special off-label recommendation to boost flu protection for solid organ transplant recipients ages 18-64 who are on immunosuppressive medications. These high-risk patients now have the off-label option of receiving one of the higher-dose flu vaccines, including high-dose and adjuvanted flu vaccines, which are FDA approved only for those 65 or older.

Sandra Adamson Fryhofer, Adjunct Clinical Associate Professor of Medicine, Emory University School of Medicine, Atlanta, Georgia, has disclosed the following relevant financial relationships: Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for American Medical Association; Medical Association of Atlanta; ACIP liaison. Received income in an amount equal to or greater than $250 from American College of Physicians; Medscape; American Medical Association.

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

Recently I was in Wyoming. As I rode down the Snake River, the guide pointed out tree trunks that had been chewed on by beavers. Days later I joined a local friend for a hike to Taggart Lake. Upon reaching the end of the trail as I began to cast my eyes on the magnificent scenery, I could not help but notice several children, including toddlers, playing in the fresh warm water. The next thing out of my friend’s mouth was “You know there is Giardia in there.” Little did she know, she and the guide had just helped me select a topic for ID Consult.

Giardia, aka ”beaver fever,” was discussed in detail in this column as part of the differential of a diarrheal illness by Christopher J. Harrison, MD. However, it is the perfect time of year to revisit other recreational water–associated illnesses.

Infections acquired during recreational water activity can lead to illnesses involving the gastrointestinal tract, central nervous system, respiratory tract, skin, eyes, and ears. Pathogens, chemicals, and toxins are transmitted by ingestion, contact with contaminated water or a sick individual or animal, and inhalation of aerosols. The National Waterborne Disease and Outbreak Surveillance System (WBDOSS) collects data on waterborne disease and outbreaks associated with recreational water, drinking water, and environmental and undetermined exposures to water. All reporting to the Centers for Disease Control and Prevention (CDC) is voluntary. However, mandatory pathogen reporting requirements can vary by state. Ideally, once an agency has completed the outbreak investigation, the definitive cause and source will be determined, and interventions to prevent future outbreaks implemented.

Treated Versus Untreated Water

One useful way to help narrow the etiology of a patient’s symptoms is to consider those illnesses associated with treated water venues (e.g., pools, hot tubs, water parks) versus untreated water venues (e.g., rivers, lakes, oceans). Parents may forget to offer that information since they may not perceive a connection between water exposure and the illness, especially if they traveled within the US.

In 2021, the CDC reported results of data submitted between 2015 and 2019 from treated recreational water facilities. Of the 208 outbreaks, most (96%) were associated with public pools, hot tubs, or water playgrounds. These outbreaks resulted in at least 3,646 cases of illness, 286 hospitalizations, and 13 deaths. Overall infectious etiologies were the primary cause of illness. Of the 155 outbreaks with a confirmed etiology, Cryptosporidium was the causative pathogen in 49% of the outbreaks and accounted for 84% (2,492) of cases, while Legionella caused 42% of outbreaks, accounted for 13% (354) of cases, and was responsible for all 13 deaths. Slightly more than half (107 of 208) of the outbreaks started between June-August with Cryptosporidium accounting for 63 of the outbreaks during that period. A little more than one-third were associated with a hotel or resort. The majority of hotel recreational water–associated illnesses was associated with hot tubs. Of the 53 outbreaks without a confirmed etiology, 20 were suspected to have a chemical related etiology (excess chlorine, altered pool chemistry).

In contrast, there were 140 untreated recreational water outbreaks reported between 2000 and 2014 from 35 states and Guam involving 4,958 cases and 2 deaths. The etiology was confirmed for 103 (74%) outbreaks including 5 that had multiple etiologies and 8 due to toxins or chemicals; 7 of 8 toxins were from harmful algal blooms. Enteric pathogens were the etiology in 84% of outbreaks including: Norovirus (n = 1459), Shigella (n = 362) Avian schistosomes (n = 345), Cryptosporidium (n = 314) and Escherichia coli (n = 155).There were 24 cases of Giardia. The two deaths were due to Naegleria fowleri. The top 2 settings for these outbreaks were public parks (36%) and beaches (32%) with most outbreaks (n = 117) being associated with a lake /pond venue. Most outbreaks began between June and August.

The major differences between the two types of recreational water–associated illnesses are their most common settings and etiologies. With that in mind, let us briefly review the most common etiology from each venue.
 

Treated Water Venue: Cryptosporidiosis

Cryptosporidium is an oocyst-forming protozoa that causes a self-limited watery, nonbloody diarrhea which usually resolves within 10-14 days. Most patients have associated abdominal cramps, fever, and vomiting although infected persons can be asymptomatic. Infection in the immunocompromised potentially can lead to profuse and prolonged diarrhea. Oocysts are excreted in the feces of infected hosts and as little as 10 can cause infection. They can survive extreme environmental conditions in water and soil for several months and even survive up to 7 days in a properly chlorinated pool. Transmission occurs between humans via contaminated food and water or from infected animals. Oocysts have been isolated in raw or unpasteurized milk and apple cider. Incidence is highest in children 1 through 4 years of age.

Diagnosis today is usually via molecular methods (nucleic acid amplification tests, aka NAATs), due to their high sensitivity and specificity and is the preferred method. These tests can identify multiple gastrointestinal tract pathogens with a single assay. Diagnosis by microscopy or fecal immunoassay antigens are still available. Treatment is supportive in most cases. If needed, a 3-day course of nitazoxanide can be prescribed. Immunocompromised patients should be managed in consultation with an infectious disease specialist.
 

Untreated Water Venue: Norovirus

Norovirus is a viral illness characterized by the abrupt onset of vomiting and/or watery diarrhea, usually associated with nausea and abdominal cramps. Symptoms persist 24-72 hours, however they may be prolonged in the immunocompromised and persons at the extremes of the age spectrum. Norovirus has replaced rotavirus as the major cause of medically attended gastroenteritis. While a major cause of recreational water–associated illnesses, high attack rates also occur in semi closed communities including cruise ships, childcare centers, and schools. Transmission is fecal-oral, vomitus oral, person to person, by ingestion of contaminated food and water or touching contaminated surfaces with subsequent touching of the mouth. Asymptomatic viral shedding may occur, especially in children. Prolonged shedding (> 6 mos.) has been reported in immunocompromised hosts.

Molecular diagnosis with stool is utilized most often. Treatment is supportive.
 

Take Home Message

When evaluating your patients for an acute gastrointestinal illness, consider water-related activities and their potential for being the source. Encourage patients not to ignore posted advisories on beaches, to not swim if they have diarrhea, not to swallow the water they swim in and to minimize water entering their nose while swimming in warm freshwater. If you start seeing several patients with similar symptoms and/or etiology, consider contacting your local or state health department. It could be the beginning of an outbreak.
 

Dr. Word is a pediatric infectious disease specialist and director of the Houston Travel Medicine Clinic. She has no relevant financial disclosures.

Suggested Readings

Graciaa DS et al. Outbreaks Associated with Untreated Recreational Water — United States, 2000–2014. MMWR Morb Mortal Wkly Rep. 2018 Jun 29;67(25):701-706. doi: 10.15585/mmwr.mm6725a1.

Hlavsa MC et al. Outbreaks Associated with Treated Recreational Water — United States, 2015–2019. MMWR Morb Mortal Wkly Rep. 2021;70:733–738. doi: 10.15585/mmwr.mm7020a1.

Kimberlin DW et al., eds. Red Book Report of the Committee on Infectious Diseases. 33rd ed. American Academy of Pediatrics. 2024. Cryptosporidiosis, p 338-40 and Norovirus, p 622-624.Waterborne Outbreaks Summary Reports. CDC. 2024 April 18.

Recently I was in Wyoming. As I rode down the Snake River, the guide pointed out tree trunks that had been chewed on by beavers. Days later I joined a local friend for a hike to Taggart Lake. Upon reaching the end of the trail as I began to cast my eyes on the magnificent scenery, I could not help but notice several children, including toddlers, playing in the fresh warm water. The next thing out of my friend’s mouth was “You know there is Giardia in there.” Little did she know, she and the guide had just helped me select a topic for ID Consult.

Giardia, aka ”beaver fever,” was discussed in detail in this column as part of the differential of a diarrheal illness by Christopher J. Harrison, MD. However, it is the perfect time of year to revisit other recreational water–associated illnesses.

Infections acquired during recreational water activity can lead to illnesses involving the gastrointestinal tract, central nervous system, respiratory tract, skin, eyes, and ears. Pathogens, chemicals, and toxins are transmitted by ingestion, contact with contaminated water or a sick individual or animal, and inhalation of aerosols. The National Waterborne Disease and Outbreak Surveillance System (WBDOSS) collects data on waterborne disease and outbreaks associated with recreational water, drinking water, and environmental and undetermined exposures to water. All reporting to the Centers for Disease Control and Prevention (CDC) is voluntary. However, mandatory pathogen reporting requirements can vary by state. Ideally, once an agency has completed the outbreak investigation, the definitive cause and source will be determined, and interventions to prevent future outbreaks implemented.

Treated Versus Untreated Water

One useful way to help narrow the etiology of a patient’s symptoms is to consider those illnesses associated with treated water venues (e.g., pools, hot tubs, water parks) versus untreated water venues (e.g., rivers, lakes, oceans). Parents may forget to offer that information since they may not perceive a connection between water exposure and the illness, especially if they traveled within the US.

In 2021, the CDC reported results of data submitted between 2015 and 2019 from treated recreational water facilities. Of the 208 outbreaks, most (96%) were associated with public pools, hot tubs, or water playgrounds. These outbreaks resulted in at least 3,646 cases of illness, 286 hospitalizations, and 13 deaths. Overall infectious etiologies were the primary cause of illness. Of the 155 outbreaks with a confirmed etiology, Cryptosporidium was the causative pathogen in 49% of the outbreaks and accounted for 84% (2,492) of cases, while Legionella caused 42% of outbreaks, accounted for 13% (354) of cases, and was responsible for all 13 deaths. Slightly more than half (107 of 208) of the outbreaks started between June-August with Cryptosporidium accounting for 63 of the outbreaks during that period. A little more than one-third were associated with a hotel or resort. The majority of hotel recreational water–associated illnesses was associated with hot tubs. Of the 53 outbreaks without a confirmed etiology, 20 were suspected to have a chemical related etiology (excess chlorine, altered pool chemistry).

In contrast, there were 140 untreated recreational water outbreaks reported between 2000 and 2014 from 35 states and Guam involving 4,958 cases and 2 deaths. The etiology was confirmed for 103 (74%) outbreaks including 5 that had multiple etiologies and 8 due to toxins or chemicals; 7 of 8 toxins were from harmful algal blooms. Enteric pathogens were the etiology in 84% of outbreaks including: Norovirus (n = 1459), Shigella (n = 362) Avian schistosomes (n = 345), Cryptosporidium (n = 314) and Escherichia coli (n = 155).There were 24 cases of Giardia. The two deaths were due to Naegleria fowleri. The top 2 settings for these outbreaks were public parks (36%) and beaches (32%) with most outbreaks (n = 117) being associated with a lake /pond venue. Most outbreaks began between June and August.

The major differences between the two types of recreational water–associated illnesses are their most common settings and etiologies. With that in mind, let us briefly review the most common etiology from each venue.
 

Treated Water Venue: Cryptosporidiosis

Cryptosporidium is an oocyst-forming protozoa that causes a self-limited watery, nonbloody diarrhea which usually resolves within 10-14 days. Most patients have associated abdominal cramps, fever, and vomiting although infected persons can be asymptomatic. Infection in the immunocompromised potentially can lead to profuse and prolonged diarrhea. Oocysts are excreted in the feces of infected hosts and as little as 10 can cause infection. They can survive extreme environmental conditions in water and soil for several months and even survive up to 7 days in a properly chlorinated pool. Transmission occurs between humans via contaminated food and water or from infected animals. Oocysts have been isolated in raw or unpasteurized milk and apple cider. Incidence is highest in children 1 through 4 years of age.

Diagnosis today is usually via molecular methods (nucleic acid amplification tests, aka NAATs), due to their high sensitivity and specificity and is the preferred method. These tests can identify multiple gastrointestinal tract pathogens with a single assay. Diagnosis by microscopy or fecal immunoassay antigens are still available. Treatment is supportive in most cases. If needed, a 3-day course of nitazoxanide can be prescribed. Immunocompromised patients should be managed in consultation with an infectious disease specialist.
 

Untreated Water Venue: Norovirus

Norovirus is a viral illness characterized by the abrupt onset of vomiting and/or watery diarrhea, usually associated with nausea and abdominal cramps. Symptoms persist 24-72 hours, however they may be prolonged in the immunocompromised and persons at the extremes of the age spectrum. Norovirus has replaced rotavirus as the major cause of medically attended gastroenteritis. While a major cause of recreational water–associated illnesses, high attack rates also occur in semi closed communities including cruise ships, childcare centers, and schools. Transmission is fecal-oral, vomitus oral, person to person, by ingestion of contaminated food and water or touching contaminated surfaces with subsequent touching of the mouth. Asymptomatic viral shedding may occur, especially in children. Prolonged shedding (> 6 mos.) has been reported in immunocompromised hosts.

Molecular diagnosis with stool is utilized most often. Treatment is supportive.
 

Take Home Message

When evaluating your patients for an acute gastrointestinal illness, consider water-related activities and their potential for being the source. Encourage patients not to ignore posted advisories on beaches, to not swim if they have diarrhea, not to swallow the water they swim in and to minimize water entering their nose while swimming in warm freshwater. If you start seeing several patients with similar symptoms and/or etiology, consider contacting your local or state health department. It could be the beginning of an outbreak.
 

Dr. Word is a pediatric infectious disease specialist and director of the Houston Travel Medicine Clinic. She has no relevant financial disclosures.

Suggested Readings

Graciaa DS et al. Outbreaks Associated with Untreated Recreational Water — United States, 2000–2014. MMWR Morb Mortal Wkly Rep. 2018 Jun 29;67(25):701-706. doi: 10.15585/mmwr.mm6725a1.

Hlavsa MC et al. Outbreaks Associated with Treated Recreational Water — United States, 2015–2019. MMWR Morb Mortal Wkly Rep. 2021;70:733–738. doi: 10.15585/mmwr.mm7020a1.

Kimberlin DW et al., eds. Red Book Report of the Committee on Infectious Diseases. 33rd ed. American Academy of Pediatrics. 2024. Cryptosporidiosis, p 338-40 and Norovirus, p 622-624.Waterborne Outbreaks Summary Reports. CDC. 2024 April 18.

Recently I was in Wyoming. As I rode down the Snake River, the guide pointed out tree trunks that had been chewed on by beavers. Days later I joined a local friend for a hike to Taggart Lake. Upon reaching the end of the trail as I began to cast my eyes on the magnificent scenery, I could not help but notice several children, including toddlers, playing in the fresh warm water. The next thing out of my friend’s mouth was “You know there is Giardia in there.” Little did she know, she and the guide had just helped me select a topic for ID Consult.

Giardia, aka ”beaver fever,” was discussed in detail in this column as part of the differential of a diarrheal illness by Christopher J. Harrison, MD. However, it is the perfect time of year to revisit other recreational water–associated illnesses.

Infections acquired during recreational water activity can lead to illnesses involving the gastrointestinal tract, central nervous system, respiratory tract, skin, eyes, and ears. Pathogens, chemicals, and toxins are transmitted by ingestion, contact with contaminated water or a sick individual or animal, and inhalation of aerosols. The National Waterborne Disease and Outbreak Surveillance System (WBDOSS) collects data on waterborne disease and outbreaks associated with recreational water, drinking water, and environmental and undetermined exposures to water. All reporting to the Centers for Disease Control and Prevention (CDC) is voluntary. However, mandatory pathogen reporting requirements can vary by state. Ideally, once an agency has completed the outbreak investigation, the definitive cause and source will be determined, and interventions to prevent future outbreaks implemented.

Treated Versus Untreated Water

One useful way to help narrow the etiology of a patient’s symptoms is to consider those illnesses associated with treated water venues (e.g., pools, hot tubs, water parks) versus untreated water venues (e.g., rivers, lakes, oceans). Parents may forget to offer that information since they may not perceive a connection between water exposure and the illness, especially if they traveled within the US.

In 2021, the CDC reported results of data submitted between 2015 and 2019 from treated recreational water facilities. Of the 208 outbreaks, most (96%) were associated with public pools, hot tubs, or water playgrounds. These outbreaks resulted in at least 3,646 cases of illness, 286 hospitalizations, and 13 deaths. Overall infectious etiologies were the primary cause of illness. Of the 155 outbreaks with a confirmed etiology, Cryptosporidium was the causative pathogen in 49% of the outbreaks and accounted for 84% (2,492) of cases, while Legionella caused 42% of outbreaks, accounted for 13% (354) of cases, and was responsible for all 13 deaths. Slightly more than half (107 of 208) of the outbreaks started between June-August with Cryptosporidium accounting for 63 of the outbreaks during that period. A little more than one-third were associated with a hotel or resort. The majority of hotel recreational water–associated illnesses was associated with hot tubs. Of the 53 outbreaks without a confirmed etiology, 20 were suspected to have a chemical related etiology (excess chlorine, altered pool chemistry).

In contrast, there were 140 untreated recreational water outbreaks reported between 2000 and 2014 from 35 states and Guam involving 4,958 cases and 2 deaths. The etiology was confirmed for 103 (74%) outbreaks including 5 that had multiple etiologies and 8 due to toxins or chemicals; 7 of 8 toxins were from harmful algal blooms. Enteric pathogens were the etiology in 84% of outbreaks including: Norovirus (n = 1459), Shigella (n = 362) Avian schistosomes (n = 345), Cryptosporidium (n = 314) and Escherichia coli (n = 155).There were 24 cases of Giardia. The two deaths were due to Naegleria fowleri. The top 2 settings for these outbreaks were public parks (36%) and beaches (32%) with most outbreaks (n = 117) being associated with a lake /pond venue. Most outbreaks began between June and August.

The major differences between the two types of recreational water–associated illnesses are their most common settings and etiologies. With that in mind, let us briefly review the most common etiology from each venue.
 

Treated Water Venue: Cryptosporidiosis

Cryptosporidium is an oocyst-forming protozoa that causes a self-limited watery, nonbloody diarrhea which usually resolves within 10-14 days. Most patients have associated abdominal cramps, fever, and vomiting although infected persons can be asymptomatic. Infection in the immunocompromised potentially can lead to profuse and prolonged diarrhea. Oocysts are excreted in the feces of infected hosts and as little as 10 can cause infection. They can survive extreme environmental conditions in water and soil for several months and even survive up to 7 days in a properly chlorinated pool. Transmission occurs between humans via contaminated food and water or from infected animals. Oocysts have been isolated in raw or unpasteurized milk and apple cider. Incidence is highest in children 1 through 4 years of age.

Diagnosis today is usually via molecular methods (nucleic acid amplification tests, aka NAATs), due to their high sensitivity and specificity and is the preferred method. These tests can identify multiple gastrointestinal tract pathogens with a single assay. Diagnosis by microscopy or fecal immunoassay antigens are still available. Treatment is supportive in most cases. If needed, a 3-day course of nitazoxanide can be prescribed. Immunocompromised patients should be managed in consultation with an infectious disease specialist.
 

Untreated Water Venue: Norovirus

Norovirus is a viral illness characterized by the abrupt onset of vomiting and/or watery diarrhea, usually associated with nausea and abdominal cramps. Symptoms persist 24-72 hours, however they may be prolonged in the immunocompromised and persons at the extremes of the age spectrum. Norovirus has replaced rotavirus as the major cause of medically attended gastroenteritis. While a major cause of recreational water–associated illnesses, high attack rates also occur in semi closed communities including cruise ships, childcare centers, and schools. Transmission is fecal-oral, vomitus oral, person to person, by ingestion of contaminated food and water or touching contaminated surfaces with subsequent touching of the mouth. Asymptomatic viral shedding may occur, especially in children. Prolonged shedding (> 6 mos.) has been reported in immunocompromised hosts.

Molecular diagnosis with stool is utilized most often. Treatment is supportive.
 

Take Home Message

When evaluating your patients for an acute gastrointestinal illness, consider water-related activities and their potential for being the source. Encourage patients not to ignore posted advisories on beaches, to not swim if they have diarrhea, not to swallow the water they swim in and to minimize water entering their nose while swimming in warm freshwater. If you start seeing several patients with similar symptoms and/or etiology, consider contacting your local or state health department. It could be the beginning of an outbreak.
 

Dr. Word is a pediatric infectious disease specialist and director of the Houston Travel Medicine Clinic. She has no relevant financial disclosures.

Suggested Readings

Graciaa DS et al. Outbreaks Associated with Untreated Recreational Water — United States, 2000–2014. MMWR Morb Mortal Wkly Rep. 2018 Jun 29;67(25):701-706. doi: 10.15585/mmwr.mm6725a1.

Hlavsa MC et al. Outbreaks Associated with Treated Recreational Water — United States, 2015–2019. MMWR Morb Mortal Wkly Rep. 2021;70:733–738. doi: 10.15585/mmwr.mm7020a1.

Kimberlin DW et al., eds. Red Book Report of the Committee on Infectious Diseases. 33rd ed. American Academy of Pediatrics. 2024. Cryptosporidiosis, p 338-40 and Norovirus, p 622-624.Waterborne Outbreaks Summary Reports. CDC. 2024 April 18.

TOPLINE:

Lowering the dose of edoxaban to 30 mg in patients 80 years of age and older with atrial fibrillation (AF) reduces major bleeding events without increasing ischemic events.

METHODOLOGY:

• Researchers conducted a parallel design, double-blind clinical trial of 21,105 patients with AF.
• Nearly 3000 patients aged 80 years and older were included in the secondary analysis, focusing on edoxaban, 60 mg vs 30 mg, and edoxaban 30 mg vs warfarin.
• The primary outcome was a composite of death, stroke or systemic embolism, and major bleeding, with secondary outcomes including ischemic stroke and all-cause death.
• People were excluded from the study if they had moderate or severe mitral stenosis, a mechanical heart valve, a high risk for bleeding, or were on antiplatelet drugs.

TAKEAWAY:

• Participants without dose-reduction criteria who received edoxaban 30 mg had lower rates of major bleeding than those who received 60 mg (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38; P = .03).
• Rates of major gastrointestinal hemorrhage were higher with edoxaban 60 mg than with 30 mg (HR, 2.24; 95% CI, 1.29-3.90; P = .004).
• People who took edoxaban 30 mg had a 17% lower risk for all-cause death than those who received warfarin (HR, 0.83; 95% CI, 0.70-1.00; P = .046).
• In a little over 2400 participants with or without dose-reduction criteria, those receiving edoxaban 30 mg had the lower risk for major bleeding (HR, 0.59; 95% CI, 0.45-0.77; P < .001) and death (HR, 0.83; 95% CI, 0.70-1.00; P = .046); risk for stroke or systemic embolism was comparable between the two drugs.

IN PRACTICE:

“These data suggest that lower-dose anticoagulants, such as edoxaban, 30 mg once daily, may be considered in all patients 80 years and older with AF irrespective of dose-reduction criteria,” the study authors wrote.

SOURCE:

The study was led by André Zimerman, MD, PhD, of Brigham and Women’s Hospital and the Department of Medicine at Harvard Medical School in Boston. It was published online in JAMA Cardiology. The study was funded by Daiichi Sankyo for the TIMI Study Group.

LIMITATIONS:

The study did not adjust for multiple comparisons, increasing the risk for type I and type II errors. Additionally, the trial participants may represent a more compliant subset of the target population, which could influence the results.

DISCLOSURES:

Various authors reported receiving grants, consultant fees, and consulting fees from AstraZeneca, Merck, Novartis, Amgen, Boehringer Ingelheim/Lilly, and Cardurion Pharmaceuticals, among others.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Lowering the dose of edoxaban to 30 mg in patients 80 years of age and older with atrial fibrillation (AF) reduces major bleeding events without increasing ischemic events.

METHODOLOGY:

• Researchers conducted a parallel design, double-blind clinical trial of 21,105 patients with AF.
• Nearly 3000 patients aged 80 years and older were included in the secondary analysis, focusing on edoxaban, 60 mg vs 30 mg, and edoxaban 30 mg vs warfarin.
• The primary outcome was a composite of death, stroke or systemic embolism, and major bleeding, with secondary outcomes including ischemic stroke and all-cause death.
• People were excluded from the study if they had moderate or severe mitral stenosis, a mechanical heart valve, a high risk for bleeding, or were on antiplatelet drugs.

TAKEAWAY:

• Participants without dose-reduction criteria who received edoxaban 30 mg had lower rates of major bleeding than those who received 60 mg (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38; P = .03).
• Rates of major gastrointestinal hemorrhage were higher with edoxaban 60 mg than with 30 mg (HR, 2.24; 95% CI, 1.29-3.90; P = .004).
• People who took edoxaban 30 mg had a 17% lower risk for all-cause death than those who received warfarin (HR, 0.83; 95% CI, 0.70-1.00; P = .046).
• In a little over 2400 participants with or without dose-reduction criteria, those receiving edoxaban 30 mg had the lower risk for major bleeding (HR, 0.59; 95% CI, 0.45-0.77; P < .001) and death (HR, 0.83; 95% CI, 0.70-1.00; P = .046); risk for stroke or systemic embolism was comparable between the two drugs.

IN PRACTICE:

“These data suggest that lower-dose anticoagulants, such as edoxaban, 30 mg once daily, may be considered in all patients 80 years and older with AF irrespective of dose-reduction criteria,” the study authors wrote.

SOURCE:

The study was led by André Zimerman, MD, PhD, of Brigham and Women’s Hospital and the Department of Medicine at Harvard Medical School in Boston. It was published online in JAMA Cardiology. The study was funded by Daiichi Sankyo for the TIMI Study Group.

LIMITATIONS:

The study did not adjust for multiple comparisons, increasing the risk for type I and type II errors. Additionally, the trial participants may represent a more compliant subset of the target population, which could influence the results.

DISCLOSURES:

Various authors reported receiving grants, consultant fees, and consulting fees from AstraZeneca, Merck, Novartis, Amgen, Boehringer Ingelheim/Lilly, and Cardurion Pharmaceuticals, among others.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

Lowering the dose of edoxaban to 30 mg in patients 80 years of age and older with atrial fibrillation (AF) reduces major bleeding events without increasing ischemic events.

METHODOLOGY:

• Researchers conducted a parallel design, double-blind clinical trial of 21,105 patients with AF.
• Nearly 3000 patients aged 80 years and older were included in the secondary analysis, focusing on edoxaban, 60 mg vs 30 mg, and edoxaban 30 mg vs warfarin.
• The primary outcome was a composite of death, stroke or systemic embolism, and major bleeding, with secondary outcomes including ischemic stroke and all-cause death.
• People were excluded from the study if they had moderate or severe mitral stenosis, a mechanical heart valve, a high risk for bleeding, or were on antiplatelet drugs.

TAKEAWAY:

• Participants without dose-reduction criteria who received edoxaban 30 mg had lower rates of major bleeding than those who received 60 mg (hazard ratio [HR], 1.57; 95% CI, 1.04-2.38; P = .03).
• Rates of major gastrointestinal hemorrhage were higher with edoxaban 60 mg than with 30 mg (HR, 2.24; 95% CI, 1.29-3.90; P = .004).
• People who took edoxaban 30 mg had a 17% lower risk for all-cause death than those who received warfarin (HR, 0.83; 95% CI, 0.70-1.00; P = .046).
• In a little over 2400 participants with or without dose-reduction criteria, those receiving edoxaban 30 mg had the lower risk for major bleeding (HR, 0.59; 95% CI, 0.45-0.77; P < .001) and death (HR, 0.83; 95% CI, 0.70-1.00; P = .046); risk for stroke or systemic embolism was comparable between the two drugs.

IN PRACTICE:

“These data suggest that lower-dose anticoagulants, such as edoxaban, 30 mg once daily, may be considered in all patients 80 years and older with AF irrespective of dose-reduction criteria,” the study authors wrote.

SOURCE:

The study was led by André Zimerman, MD, PhD, of Brigham and Women’s Hospital and the Department of Medicine at Harvard Medical School in Boston. It was published online in JAMA Cardiology. The study was funded by Daiichi Sankyo for the TIMI Study Group.

LIMITATIONS:

The study did not adjust for multiple comparisons, increasing the risk for type I and type II errors. Additionally, the trial participants may represent a more compliant subset of the target population, which could influence the results.

DISCLOSURES:

Various authors reported receiving grants, consultant fees, and consulting fees from AstraZeneca, Merck, Novartis, Amgen, Boehringer Ingelheim/Lilly, and Cardurion Pharmaceuticals, among others.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article first appeared on Medscape.com.

TOPLINE:

New-onset atrial fibrillation (AF) is associated with a substantially higher risk for all-cause dementia in patients with type 2 diabetes (T2D).

METHODOLOGY:

• Studies suggest a potential link between AF and dementia in the broader population, but evidence is scarce in people with diabetes, who are at increased risk for both conditions.
• This longitudinal observational study assessed the association between new-onset AF and dementia in 22,989 patients with T2D (median age at enrollment, 61.0 years; 62.3% men; 86.3% White individuals).
• New-onset AF was identified through hospital admission records using the International Classification of Diseases – 9th Revision (ICD-9) and ICD-10 codes, and dementia cases were identified using an algorithm developed by the UK Biobank.
• Time-varying Cox proportional hazard regression models were used to determine the association between incident dementia and new-onset AF.

TAKEAWAY:

• Over a median follow-up duration of about 12 years, 844 patients developed all-cause dementia, 342 were diagnosed with Alzheimer’s disease, and 246 had vascular dementia.
• Patients with incident AF had a higher risk of developing all-cause dementia (hazard ratio [HR], 2.15; 95% CI, 1.80-2.57), Alzheimer’s disease (HR, 1.44; 95% CI, 1.06-1.96), and vascular dementia (HR, 3.11; 95% CI, 2.32-4.17) than those without incident AF.
• The results are independent of common dementia risk factors, such as sociodemographic characteristics and lifestyle factors.
• The mean time intervals from the onset of AF to all-cause dementia, Alzheimer’s disease and vascular dementia were 2.95, 2.81, and 3.37 years, respectively.

IN PRACTICE:

“AF is a significant risk factor for dementia in patients with type 2 diabetes, suggesting the importance of timely and effective treatment of AF, such as early rhythm control strategies and anticoagulant use, in preventing dementia among this demographic,” the authors wrote.
 

SOURCE:

The study, led by Ying Zhou, PhD, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, was published online in Diabetes, Obesity and Metabolism.

LIMITATIONS:

The study could not explore the link between different AF subtypes and dementia owing to its small sample size. The effects of AF treatment on the risk for dementia in patients with type 2 diabetes were not considered because of lack of information. The mostly White study population limits the generalizability of the findings to other races and ethnicities.

DISCLOSURES:

The study was supported by the National Social Science Fund of China. The authors declared no conflicts of interest.

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

TOPLINE:

New-onset atrial fibrillation (AF) is associated with a substantially higher risk for all-cause dementia in patients with type 2 diabetes (T2D).

METHODOLOGY:

• Studies suggest a potential link between AF and dementia in the broader population, but evidence is scarce in people with diabetes, who are at increased risk for both conditions.
• This longitudinal observational study assessed the association between new-onset AF and dementia in 22,989 patients with T2D (median age at enrollment, 61.0 years; 62.3% men; 86.3% White individuals).
• New-onset AF was identified through hospital admission records using the International Classification of Diseases – 9th Revision (ICD-9) and ICD-10 codes, and dementia cases were identified using an algorithm developed by the UK Biobank.
• Time-varying Cox proportional hazard regression models were used to determine the association between incident dementia and new-onset AF.

TAKEAWAY:

• Over a median follow-up duration of about 12 years, 844 patients developed all-cause dementia, 342 were diagnosed with Alzheimer’s disease, and 246 had vascular dementia.
• Patients with incident AF had a higher risk of developing all-cause dementia (hazard ratio [HR], 2.15; 95% CI, 1.80-2.57), Alzheimer’s disease (HR, 1.44; 95% CI, 1.06-1.96), and vascular dementia (HR, 3.11; 95% CI, 2.32-4.17) than those without incident AF.
• The results are independent of common dementia risk factors, such as sociodemographic characteristics and lifestyle factors.
• The mean time intervals from the onset of AF to all-cause dementia, Alzheimer’s disease and vascular dementia were 2.95, 2.81, and 3.37 years, respectively.

IN PRACTICE:

“AF is a significant risk factor for dementia in patients with type 2 diabetes, suggesting the importance of timely and effective treatment of AF, such as early rhythm control strategies and anticoagulant use, in preventing dementia among this demographic,” the authors wrote.
 

SOURCE:

The study, led by Ying Zhou, PhD, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, was published online in Diabetes, Obesity and Metabolism.

LIMITATIONS:

The study could not explore the link between different AF subtypes and dementia owing to its small sample size. The effects of AF treatment on the risk for dementia in patients with type 2 diabetes were not considered because of lack of information. The mostly White study population limits the generalizability of the findings to other races and ethnicities.

DISCLOSURES:

The study was supported by the National Social Science Fund of China. The authors declared no conflicts of interest.

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

TOPLINE:

New-onset atrial fibrillation (AF) is associated with a substantially higher risk for all-cause dementia in patients with type 2 diabetes (T2D).

METHODOLOGY:

• Studies suggest a potential link between AF and dementia in the broader population, but evidence is scarce in people with diabetes, who are at increased risk for both conditions.
• This longitudinal observational study assessed the association between new-onset AF and dementia in 22,989 patients with T2D (median age at enrollment, 61.0 years; 62.3% men; 86.3% White individuals).
• New-onset AF was identified through hospital admission records using the International Classification of Diseases – 9th Revision (ICD-9) and ICD-10 codes, and dementia cases were identified using an algorithm developed by the UK Biobank.
• Time-varying Cox proportional hazard regression models were used to determine the association between incident dementia and new-onset AF.

TAKEAWAY:

• Over a median follow-up duration of about 12 years, 844 patients developed all-cause dementia, 342 were diagnosed with Alzheimer’s disease, and 246 had vascular dementia.
• Patients with incident AF had a higher risk of developing all-cause dementia (hazard ratio [HR], 2.15; 95% CI, 1.80-2.57), Alzheimer’s disease (HR, 1.44; 95% CI, 1.06-1.96), and vascular dementia (HR, 3.11; 95% CI, 2.32-4.17) than those without incident AF.
• The results are independent of common dementia risk factors, such as sociodemographic characteristics and lifestyle factors.
• The mean time intervals from the onset of AF to all-cause dementia, Alzheimer’s disease and vascular dementia were 2.95, 2.81, and 3.37 years, respectively.

IN PRACTICE:

“AF is a significant risk factor for dementia in patients with type 2 diabetes, suggesting the importance of timely and effective treatment of AF, such as early rhythm control strategies and anticoagulant use, in preventing dementia among this demographic,” the authors wrote.
 

SOURCE:

The study, led by Ying Zhou, PhD, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China, was published online in Diabetes, Obesity and Metabolism.

LIMITATIONS:

The study could not explore the link between different AF subtypes and dementia owing to its small sample size. The effects of AF treatment on the risk for dementia in patients with type 2 diabetes were not considered because of lack of information. The mostly White study population limits the generalizability of the findings to other races and ethnicities.

DISCLOSURES:

The study was supported by the National Social Science Fund of China. The authors declared no conflicts of interest.

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

An international trial of the Impella heart pump in patients with ST elevation myocardial infarction (STEMI) and cardiogenic shock has been stopped by the sponsor, Abiomed Inc. The termination followed news that another international trial, DanGer Shock, found that the pump improved survival in these patients.

Abiomed Inc., which manufactures the Impella microaxial flow pump, said in a statement that the trial’s Data and Safety Monitoring Board recommended stopping RECOVER IV.

“I was convinced that the study could not continue,” one of the principal investigators William O’Neill, MD, an interventional cardiologist with the Henry Ford Health in Detroit, said in an interview. After 3.5 years of work and thousands of person-hours, he added, “It’s not a decision that people took lightly.”

The trial already had three sites in Europe and one in the United States up and running, with two more US sites slated to join the trial. It had started enrolling patients, although few to date.

DanGer Shock trial results were expected to have a serious effect on how RECOVER IV would unfold. It was previously uncertain whether the Impella heart pump would save lives vs existing approaches, said O’Neill and co-principal investigator Navin Kapur, MD, an interventional cardiologist at Tufts Medical Center in Boston. Once the DanGer Shock trial showed the benefits of using the heart pump, that equipoise vanished.
 

Loss of Clinical Equipoise

“The clinicians were challenged in getting consent from patients where they had to say, ‘If you are randomized to the control arm, we are not able to use an Impella,’ ” said Dr. Kapur. He pointed out that patients would be unlikely to agree to participate in a trial where they might not get the treatment already shown to improve survival.

Dr. Kapur and Dr. O’Neill said the clinicians participating in the trial expressed discomfort at continuing. The RECOVER IV trial was expected to take many years to enroll the targeted number of patients. To participate, hospitals had to have the equipment and expertise to use the Impella heart pump, as well as the control treatments — balloon-pump support and extracorporeal membrane oxygenation (ECMO), Dr. Kapur explained. He said most patients with STEMI and cardiogenic shock would present to their nearest community hospitals, many of which would not have these treatments and would be unable to participate in the study.

Patients with STEMI and cardiogenic shock are uncommon. About 80,000 patients in the United States each year present with cardiogenic shock, of whom about 40% are not experiencing a STEMI, said Dr. O’Neill.

But those who do fit into the population of both STEMI and cardiogenic shock are at very high risk, said Dr. Kapur. “One in three or one in two patients with STEMI and cardiogenic shock will die in hospital.”
 

Getting Hearts Pumping

The Impella heart pump was originally developed by Impella Cardiosystems in Aachen, Germany, which was acquired by Abiomed in 2005, according to the Abiomed website. And Abiomed was acquired by Johnson & Johnson MedTech in 2022. The company has developed a series of models over the years and said that Impella CP — the model used in DanGer Shock and RECOVER IV trials — is the world’s smallest heart pump.

“Impella is the only heart pump that can be introduced percutaneously through the leg,” said Dr. O’Neill, whereas other pumps available are used only in open-heart surgery. While Impella is the first pump to be used this way, he said it won’t be the last. Other, more powerful pumps are being developed.
 

DanGer Shock: A Leap Forward

Despite leading to the halt of another trial, the DanGer Shock results are a good news story, said the RECOVER IV investigators.

“The DanGer trial is a huge advance,” said Dr. O’Neill. “It’s the first study this century that shows something that improves survival in cardiogenic shock. You treat eight patients, and you save one life.” Dr. O’Neill said this is one of the best outcomes he has seen during his long career.

Dr. Kapur said the DanGer trial is also a leap forward in designing trials for cardiogenic shock. He said previous trials of mechanical support in cardiogenic shock had neutral results, probably due to broad inclusion criteria for patients.

“The DanGer trial was selective in its inclusion and exclusion criteria. That made it more difficult to enroll the population, so it took a lot longer. But it used the right device at the right time in the right patient, and it was successful,” he said.

“The DanGer investigators need to be applauded,” he added. “The lesson is, we have to design the right trials.”
 

New Cardiogenic Shock Trials

Dr. O’Neill and Dr. Kapur said the groundwork they laid for RECOVER IV can be used for new trials.

“We have 50 sites in the US, Germany, and Denmark. They’re interested, and they’re waiting,” said Dr. O’Neill. The researchers are poised to begin new trials once protocols are developed.

What will the next trials investigate?

DanGer Shock results showed higher rates of adverse events following Impella use than after standard care. “We need to come up with strategies to decrease bleeding problems and renal failure,” said Dr. O’Neill, and these could be tested in trials.

Other questions he would like to see investigated are using the Impella heart pump before or after angioplasty, and multi-vessel vs culprit-vessel percutaneous coronary intervention in cardiogenic shock with Impella support.

Dr. Kapur mentioned studying patients excluded from the DanGer Shock trial — such as those needing right ventricular support — because DanGer Shock covered only left ventricular support and those suffering cardiac arrest outside hospital. He said trials could compare differences between models of Impella and investigate the role of ECMO.

“I’m optimistic that we can design more randomized controlled trials with the right patient population and right treatment algorithm,” Dr. Kapur said. This is a critical step toward better outcomes for patients, he added. Another step is optimizing the design of heart pumps, which should decrease the rates of adverse events, he said. “I have a lot of optimism for the future of device design.”

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

An international trial of the Impella heart pump in patients with ST elevation myocardial infarction (STEMI) and cardiogenic shock has been stopped by the sponsor, Abiomed Inc. The termination followed news that another international trial, DanGer Shock, found that the pump improved survival in these patients.

Abiomed Inc., which manufactures the Impella microaxial flow pump, said in a statement that the trial’s Data and Safety Monitoring Board recommended stopping RECOVER IV.

“I was convinced that the study could not continue,” one of the principal investigators William O’Neill, MD, an interventional cardiologist with the Henry Ford Health in Detroit, said in an interview. After 3.5 years of work and thousands of person-hours, he added, “It’s not a decision that people took lightly.”

The trial already had three sites in Europe and one in the United States up and running, with two more US sites slated to join the trial. It had started enrolling patients, although few to date.

DanGer Shock trial results were expected to have a serious effect on how RECOVER IV would unfold. It was previously uncertain whether the Impella heart pump would save lives vs existing approaches, said O’Neill and co-principal investigator Navin Kapur, MD, an interventional cardiologist at Tufts Medical Center in Boston. Once the DanGer Shock trial showed the benefits of using the heart pump, that equipoise vanished.
 

Loss of Clinical Equipoise

“The clinicians were challenged in getting consent from patients where they had to say, ‘If you are randomized to the control arm, we are not able to use an Impella,’ ” said Dr. Kapur. He pointed out that patients would be unlikely to agree to participate in a trial where they might not get the treatment already shown to improve survival.

Dr. Kapur and Dr. O’Neill said the clinicians participating in the trial expressed discomfort at continuing. The RECOVER IV trial was expected to take many years to enroll the targeted number of patients. To participate, hospitals had to have the equipment and expertise to use the Impella heart pump, as well as the control treatments — balloon-pump support and extracorporeal membrane oxygenation (ECMO), Dr. Kapur explained. He said most patients with STEMI and cardiogenic shock would present to their nearest community hospitals, many of which would not have these treatments and would be unable to participate in the study.

Patients with STEMI and cardiogenic shock are uncommon. About 80,000 patients in the United States each year present with cardiogenic shock, of whom about 40% are not experiencing a STEMI, said Dr. O’Neill.

But those who do fit into the population of both STEMI and cardiogenic shock are at very high risk, said Dr. Kapur. “One in three or one in two patients with STEMI and cardiogenic shock will die in hospital.”
 

Getting Hearts Pumping

The Impella heart pump was originally developed by Impella Cardiosystems in Aachen, Germany, which was acquired by Abiomed in 2005, according to the Abiomed website. And Abiomed was acquired by Johnson & Johnson MedTech in 2022. The company has developed a series of models over the years and said that Impella CP — the model used in DanGer Shock and RECOVER IV trials — is the world’s smallest heart pump.

“Impella is the only heart pump that can be introduced percutaneously through the leg,” said Dr. O’Neill, whereas other pumps available are used only in open-heart surgery. While Impella is the first pump to be used this way, he said it won’t be the last. Other, more powerful pumps are being developed.
 

DanGer Shock: A Leap Forward

Despite leading to the halt of another trial, the DanGer Shock results are a good news story, said the RECOVER IV investigators.

“The DanGer trial is a huge advance,” said Dr. O’Neill. “It’s the first study this century that shows something that improves survival in cardiogenic shock. You treat eight patients, and you save one life.” Dr. O’Neill said this is one of the best outcomes he has seen during his long career.

Dr. Kapur said the DanGer trial is also a leap forward in designing trials for cardiogenic shock. He said previous trials of mechanical support in cardiogenic shock had neutral results, probably due to broad inclusion criteria for patients.

“The DanGer trial was selective in its inclusion and exclusion criteria. That made it more difficult to enroll the population, so it took a lot longer. But it used the right device at the right time in the right patient, and it was successful,” he said.

“The DanGer investigators need to be applauded,” he added. “The lesson is, we have to design the right trials.”
 

New Cardiogenic Shock Trials

Dr. O’Neill and Dr. Kapur said the groundwork they laid for RECOVER IV can be used for new trials.

“We have 50 sites in the US, Germany, and Denmark. They’re interested, and they’re waiting,” said Dr. O’Neill. The researchers are poised to begin new trials once protocols are developed.

What will the next trials investigate?

DanGer Shock results showed higher rates of adverse events following Impella use than after standard care. “We need to come up with strategies to decrease bleeding problems and renal failure,” said Dr. O’Neill, and these could be tested in trials.

Other questions he would like to see investigated are using the Impella heart pump before or after angioplasty, and multi-vessel vs culprit-vessel percutaneous coronary intervention in cardiogenic shock with Impella support.

Dr. Kapur mentioned studying patients excluded from the DanGer Shock trial — such as those needing right ventricular support — because DanGer Shock covered only left ventricular support and those suffering cardiac arrest outside hospital. He said trials could compare differences between models of Impella and investigate the role of ECMO.

“I’m optimistic that we can design more randomized controlled trials with the right patient population and right treatment algorithm,” Dr. Kapur said. This is a critical step toward better outcomes for patients, he added. Another step is optimizing the design of heart pumps, which should decrease the rates of adverse events, he said. “I have a lot of optimism for the future of device design.”

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

An international trial of the Impella heart pump in patients with ST elevation myocardial infarction (STEMI) and cardiogenic shock has been stopped by the sponsor, Abiomed Inc. The termination followed news that another international trial, DanGer Shock, found that the pump improved survival in these patients.

Abiomed Inc., which manufactures the Impella microaxial flow pump, said in a statement that the trial’s Data and Safety Monitoring Board recommended stopping RECOVER IV.

“I was convinced that the study could not continue,” one of the principal investigators William O’Neill, MD, an interventional cardiologist with the Henry Ford Health in Detroit, said in an interview. After 3.5 years of work and thousands of person-hours, he added, “It’s not a decision that people took lightly.”

The trial already had three sites in Europe and one in the United States up and running, with two more US sites slated to join the trial. It had started enrolling patients, although few to date.

DanGer Shock trial results were expected to have a serious effect on how RECOVER IV would unfold. It was previously uncertain whether the Impella heart pump would save lives vs existing approaches, said O’Neill and co-principal investigator Navin Kapur, MD, an interventional cardiologist at Tufts Medical Center in Boston. Once the DanGer Shock trial showed the benefits of using the heart pump, that equipoise vanished.
 

Loss of Clinical Equipoise

“The clinicians were challenged in getting consent from patients where they had to say, ‘If you are randomized to the control arm, we are not able to use an Impella,’ ” said Dr. Kapur. He pointed out that patients would be unlikely to agree to participate in a trial where they might not get the treatment already shown to improve survival.

Dr. Kapur and Dr. O’Neill said the clinicians participating in the trial expressed discomfort at continuing. The RECOVER IV trial was expected to take many years to enroll the targeted number of patients. To participate, hospitals had to have the equipment and expertise to use the Impella heart pump, as well as the control treatments — balloon-pump support and extracorporeal membrane oxygenation (ECMO), Dr. Kapur explained. He said most patients with STEMI and cardiogenic shock would present to their nearest community hospitals, many of which would not have these treatments and would be unable to participate in the study.

Patients with STEMI and cardiogenic shock are uncommon. About 80,000 patients in the United States each year present with cardiogenic shock, of whom about 40% are not experiencing a STEMI, said Dr. O’Neill.

But those who do fit into the population of both STEMI and cardiogenic shock are at very high risk, said Dr. Kapur. “One in three or one in two patients with STEMI and cardiogenic shock will die in hospital.”
 

Getting Hearts Pumping

The Impella heart pump was originally developed by Impella Cardiosystems in Aachen, Germany, which was acquired by Abiomed in 2005, according to the Abiomed website. And Abiomed was acquired by Johnson & Johnson MedTech in 2022. The company has developed a series of models over the years and said that Impella CP — the model used in DanGer Shock and RECOVER IV trials — is the world’s smallest heart pump.

“Impella is the only heart pump that can be introduced percutaneously through the leg,” said Dr. O’Neill, whereas other pumps available are used only in open-heart surgery. While Impella is the first pump to be used this way, he said it won’t be the last. Other, more powerful pumps are being developed.
 

DanGer Shock: A Leap Forward

Despite leading to the halt of another trial, the DanGer Shock results are a good news story, said the RECOVER IV investigators.

“The DanGer trial is a huge advance,” said Dr. O’Neill. “It’s the first study this century that shows something that improves survival in cardiogenic shock. You treat eight patients, and you save one life.” Dr. O’Neill said this is one of the best outcomes he has seen during his long career.

Dr. Kapur said the DanGer trial is also a leap forward in designing trials for cardiogenic shock. He said previous trials of mechanical support in cardiogenic shock had neutral results, probably due to broad inclusion criteria for patients.

“The DanGer trial was selective in its inclusion and exclusion criteria. That made it more difficult to enroll the population, so it took a lot longer. But it used the right device at the right time in the right patient, and it was successful,” he said.

“The DanGer investigators need to be applauded,” he added. “The lesson is, we have to design the right trials.”
 

New Cardiogenic Shock Trials

Dr. O’Neill and Dr. Kapur said the groundwork they laid for RECOVER IV can be used for new trials.

“We have 50 sites in the US, Germany, and Denmark. They’re interested, and they’re waiting,” said Dr. O’Neill. The researchers are poised to begin new trials once protocols are developed.

What will the next trials investigate?

DanGer Shock results showed higher rates of adverse events following Impella use than after standard care. “We need to come up with strategies to decrease bleeding problems and renal failure,” said Dr. O’Neill, and these could be tested in trials.

Other questions he would like to see investigated are using the Impella heart pump before or after angioplasty, and multi-vessel vs culprit-vessel percutaneous coronary intervention in cardiogenic shock with Impella support.

Dr. Kapur mentioned studying patients excluded from the DanGer Shock trial — such as those needing right ventricular support — because DanGer Shock covered only left ventricular support and those suffering cardiac arrest outside hospital. He said trials could compare differences between models of Impella and investigate the role of ECMO.

“I’m optimistic that we can design more randomized controlled trials with the right patient population and right treatment algorithm,” Dr. Kapur said. This is a critical step toward better outcomes for patients, he added. Another step is optimizing the design of heart pumps, which should decrease the rates of adverse events, he said. “I have a lot of optimism for the future of device design.”

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