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President Joe Biden signed 10 new executive orders on his second day in office that are designed to help roll out his broader plan to fight COVID-19.

Whitehouse.gov

“For the past year, we couldn’t rely on the federal government to act with the urgency and focus and coordination we needed, and we have seen the tragic cost of that failure,” Mr. Biden said in remarks from the White House, unveiling his 198-page National Strategy for the COVID-19 Response and Pandemic Preparedness.

He said as many as 500,000 Americans will have died by February. “It’s going to take months for us to turn things around,” he said.

“Our national strategy is comprehensive – it’s based on science, not politics; it’s based on truth, not denial,” Mr. Biden said. He also promised to restore public trust, in part by having scientists and public health experts speak to the public. “That’s why you’ll be hearing a lot more from Dr. Fauci again, not from the president,” he said, adding that the experts will be “free from political interference.”

While the president’s executive orders can help accomplish some of the plan’s proposals, the majority will require new funding from Congress and will be included in the $1.9 trillion American Rescue package that Mr. Biden hopes legislators will approve.
 

Ten new orders

The 10 new pandemic-related orders Biden signed on Jan. 21 follow two he signed on his first day in office.

One establishes a COVID-19 Response Office responsible for coordinating the pandemic response across all federal departments and agencies and also reestablishes the White House Directorate on Global Health Security and Biodefense, which was disabled by the Trump administration.

The other order requires masks and physical distancing in all federal buildings, on all federal lands, and by federal employees and contractors.

Among the new orders will be directives that:

• Require individuals to also wear masks in airports and planes, and when using other modes of public transportation including trains, boats, and intercity buses, and also require international travelers to produce proof of a recent negative COVID-19 test prior to entry and to quarantine after entry.
• Federal agencies use all powers, including the Defense Production Act, to accelerate manufacturing and delivery of supplies such as N95 masks, gowns, gloves, swabs, reagents, pipette tips, rapid test kits, and nitrocellulose material for rapid antigen tests, and all equipment and material needed to accelerate manufacture, delivery, and administration of COVID-19 vaccine.
• Create a Pandemic Testing Board to expand supply and access, to promote more surge capacity, and to ensure equitable access to tests.
• Facilitate discovery, development, and trials of potential COVID-19 treatments, as well as expand access to programs that can meet the long-term health needs of those recovering from the disease.
• Facilitate more and better data sharing that will allow businesses, schools, hospitals, and individuals to make real-time decisions based on spread in their community.
• Direct the Education and Health & Human Services departments to provide schools and child-care operations guidance on how to reopen and operate safely.
• Direct the Occupational Safety and Health Administration (OSHA) to immediately release clear guidance for employers to help keep workers safe and to enforce health and safety requirements.

The plan also sets goals for vaccination – including 100 million shots in the administration’s first 100 days. President Biden had already previewed his goals for vaccination, including setting up mass vaccination sites and mobile vaccination sites. During his remarks, Mr. Biden said that he had already directed the Federal Emergency Management Agency (FEMA) to begin setting up the vaccination centers.

The administration is also going to look into improving reimbursement for giving vaccines. As a start, the HHS will ask the Centers for Medicare & Medicaid Services to consider if a higher rate “may more accurately compensate providers,” according to the Biden plan.

“But the brutal truth is it will take months before we can get the majority of Americans vaccinated,” said Mr. Biden.

As part of the goal of ensuring an equitable pandemic response, the president will sign an order that establishes a COVID-19 Health Equity Task Force. The task force is charged with providing recommendations for allocating resources and funding in communities with inequities in COVID-19 outcomes by race, ethnicity, geography, disability, and other considerations.

Finally, the administration has committed to being more transparent and sharing more information. The national plan calls for the federal government to conduct regular, expert-led, science-based public briefings and to release regular reports on the pandemic. The administration said it will launch massive science-based public information campaigns – in multiple languages – to educate Americans on masks, testing, and vaccines, and also work to counter misinformation and disinformation.

The American Academy of Family Physicians (AAFP) applauded Mr. Biden’s initiative. “If enacted, this bold legislative agenda will provide much-needed support to American families struggling during the pandemic – especially communities of color and those hardest hit by the virus,” Ada D. Stewart, MD, AAFP president, said in a statement.

Dr. Stewart also noted that family physicians “are uniquely positioned in their communities to educate patients, prioritize access, and coordinate administration of the COVID-19 vaccines,” and urged the administration to ensure that family physicians and staff be vaccinated as soon as possible, to help them “more safely provide care to their communities.”

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

President Joe Biden signed 10 new executive orders on his second day in office that are designed to help roll out his broader plan to fight COVID-19.

Whitehouse.gov

“For the past year, we couldn’t rely on the federal government to act with the urgency and focus and coordination we needed, and we have seen the tragic cost of that failure,” Mr. Biden said in remarks from the White House, unveiling his 198-page National Strategy for the COVID-19 Response and Pandemic Preparedness.

He said as many as 500,000 Americans will have died by February. “It’s going to take months for us to turn things around,” he said.

“Our national strategy is comprehensive – it’s based on science, not politics; it’s based on truth, not denial,” Mr. Biden said. He also promised to restore public trust, in part by having scientists and public health experts speak to the public. “That’s why you’ll be hearing a lot more from Dr. Fauci again, not from the president,” he said, adding that the experts will be “free from political interference.”

While the president’s executive orders can help accomplish some of the plan’s proposals, the majority will require new funding from Congress and will be included in the $1.9 trillion American Rescue package that Mr. Biden hopes legislators will approve.
 

Ten new orders

The 10 new pandemic-related orders Biden signed on Jan. 21 follow two he signed on his first day in office.

One establishes a COVID-19 Response Office responsible for coordinating the pandemic response across all federal departments and agencies and also reestablishes the White House Directorate on Global Health Security and Biodefense, which was disabled by the Trump administration.

The other order requires masks and physical distancing in all federal buildings, on all federal lands, and by federal employees and contractors.

Among the new orders will be directives that:

• Require individuals to also wear masks in airports and planes, and when using other modes of public transportation including trains, boats, and intercity buses, and also require international travelers to produce proof of a recent negative COVID-19 test prior to entry and to quarantine after entry.
• Federal agencies use all powers, including the Defense Production Act, to accelerate manufacturing and delivery of supplies such as N95 masks, gowns, gloves, swabs, reagents, pipette tips, rapid test kits, and nitrocellulose material for rapid antigen tests, and all equipment and material needed to accelerate manufacture, delivery, and administration of COVID-19 vaccine.
• Create a Pandemic Testing Board to expand supply and access, to promote more surge capacity, and to ensure equitable access to tests.
• Facilitate discovery, development, and trials of potential COVID-19 treatments, as well as expand access to programs that can meet the long-term health needs of those recovering from the disease.
• Facilitate more and better data sharing that will allow businesses, schools, hospitals, and individuals to make real-time decisions based on spread in their community.
• Direct the Education and Health & Human Services departments to provide schools and child-care operations guidance on how to reopen and operate safely.
• Direct the Occupational Safety and Health Administration (OSHA) to immediately release clear guidance for employers to help keep workers safe and to enforce health and safety requirements.

The plan also sets goals for vaccination – including 100 million shots in the administration’s first 100 days. President Biden had already previewed his goals for vaccination, including setting up mass vaccination sites and mobile vaccination sites. During his remarks, Mr. Biden said that he had already directed the Federal Emergency Management Agency (FEMA) to begin setting up the vaccination centers.

The administration is also going to look into improving reimbursement for giving vaccines. As a start, the HHS will ask the Centers for Medicare & Medicaid Services to consider if a higher rate “may more accurately compensate providers,” according to the Biden plan.

“But the brutal truth is it will take months before we can get the majority of Americans vaccinated,” said Mr. Biden.

As part of the goal of ensuring an equitable pandemic response, the president will sign an order that establishes a COVID-19 Health Equity Task Force. The task force is charged with providing recommendations for allocating resources and funding in communities with inequities in COVID-19 outcomes by race, ethnicity, geography, disability, and other considerations.

Finally, the administration has committed to being more transparent and sharing more information. The national plan calls for the federal government to conduct regular, expert-led, science-based public briefings and to release regular reports on the pandemic. The administration said it will launch massive science-based public information campaigns – in multiple languages – to educate Americans on masks, testing, and vaccines, and also work to counter misinformation and disinformation.

The American Academy of Family Physicians (AAFP) applauded Mr. Biden’s initiative. “If enacted, this bold legislative agenda will provide much-needed support to American families struggling during the pandemic – especially communities of color and those hardest hit by the virus,” Ada D. Stewart, MD, AAFP president, said in a statement.

Dr. Stewart also noted that family physicians “are uniquely positioned in their communities to educate patients, prioritize access, and coordinate administration of the COVID-19 vaccines,” and urged the administration to ensure that family physicians and staff be vaccinated as soon as possible, to help them “more safely provide care to their communities.”

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

President Joe Biden signed 10 new executive orders on his second day in office that are designed to help roll out his broader plan to fight COVID-19.

Whitehouse.gov

“For the past year, we couldn’t rely on the federal government to act with the urgency and focus and coordination we needed, and we have seen the tragic cost of that failure,” Mr. Biden said in remarks from the White House, unveiling his 198-page National Strategy for the COVID-19 Response and Pandemic Preparedness.

He said as many as 500,000 Americans will have died by February. “It’s going to take months for us to turn things around,” he said.

“Our national strategy is comprehensive – it’s based on science, not politics; it’s based on truth, not denial,” Mr. Biden said. He also promised to restore public trust, in part by having scientists and public health experts speak to the public. “That’s why you’ll be hearing a lot more from Dr. Fauci again, not from the president,” he said, adding that the experts will be “free from political interference.”

While the president’s executive orders can help accomplish some of the plan’s proposals, the majority will require new funding from Congress and will be included in the $1.9 trillion American Rescue package that Mr. Biden hopes legislators will approve.
 

Ten new orders

The 10 new pandemic-related orders Biden signed on Jan. 21 follow two he signed on his first day in office.

One establishes a COVID-19 Response Office responsible for coordinating the pandemic response across all federal departments and agencies and also reestablishes the White House Directorate on Global Health Security and Biodefense, which was disabled by the Trump administration.

The other order requires masks and physical distancing in all federal buildings, on all federal lands, and by federal employees and contractors.

Among the new orders will be directives that:

• Require individuals to also wear masks in airports and planes, and when using other modes of public transportation including trains, boats, and intercity buses, and also require international travelers to produce proof of a recent negative COVID-19 test prior to entry and to quarantine after entry.
• Federal agencies use all powers, including the Defense Production Act, to accelerate manufacturing and delivery of supplies such as N95 masks, gowns, gloves, swabs, reagents, pipette tips, rapid test kits, and nitrocellulose material for rapid antigen tests, and all equipment and material needed to accelerate manufacture, delivery, and administration of COVID-19 vaccine.
• Create a Pandemic Testing Board to expand supply and access, to promote more surge capacity, and to ensure equitable access to tests.
• Facilitate discovery, development, and trials of potential COVID-19 treatments, as well as expand access to programs that can meet the long-term health needs of those recovering from the disease.
• Facilitate more and better data sharing that will allow businesses, schools, hospitals, and individuals to make real-time decisions based on spread in their community.
• Direct the Education and Health & Human Services departments to provide schools and child-care operations guidance on how to reopen and operate safely.
• Direct the Occupational Safety and Health Administration (OSHA) to immediately release clear guidance for employers to help keep workers safe and to enforce health and safety requirements.

The plan also sets goals for vaccination – including 100 million shots in the administration’s first 100 days. President Biden had already previewed his goals for vaccination, including setting up mass vaccination sites and mobile vaccination sites. During his remarks, Mr. Biden said that he had already directed the Federal Emergency Management Agency (FEMA) to begin setting up the vaccination centers.

The administration is also going to look into improving reimbursement for giving vaccines. As a start, the HHS will ask the Centers for Medicare & Medicaid Services to consider if a higher rate “may more accurately compensate providers,” according to the Biden plan.

“But the brutal truth is it will take months before we can get the majority of Americans vaccinated,” said Mr. Biden.

As part of the goal of ensuring an equitable pandemic response, the president will sign an order that establishes a COVID-19 Health Equity Task Force. The task force is charged with providing recommendations for allocating resources and funding in communities with inequities in COVID-19 outcomes by race, ethnicity, geography, disability, and other considerations.

Finally, the administration has committed to being more transparent and sharing more information. The national plan calls for the federal government to conduct regular, expert-led, science-based public briefings and to release regular reports on the pandemic. The administration said it will launch massive science-based public information campaigns – in multiple languages – to educate Americans on masks, testing, and vaccines, and also work to counter misinformation and disinformation.

The American Academy of Family Physicians (AAFP) applauded Mr. Biden’s initiative. “If enacted, this bold legislative agenda will provide much-needed support to American families struggling during the pandemic – especially communities of color and those hardest hit by the virus,” Ada D. Stewart, MD, AAFP president, said in a statement.

Dr. Stewart also noted that family physicians “are uniquely positioned in their communities to educate patients, prioritize access, and coordinate administration of the COVID-19 vaccines,” and urged the administration to ensure that family physicians and staff be vaccinated as soon as possible, to help them “more safely provide care to their communities.”

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

People with type 2 diabetes who develop COVID-19 show a substantially reduced risk of dying if they are taking metformin, shows a study that adds to prior research indicating the drug might somehow play a role in reducing the severity of infection.

“Unlike several previous analyses, this was a study in a racially diverse population with a high proportion of Blacks/African Americans and [it] revealed that metformin treatment of diabetes prior to diagnosis with COVID-19 was associated with a dramatic threefold reduced mortality in subjects with type 2 diabetes, even after correcting for multiple covariates,” first author Anath Shalev, MD, of the Comprehensive Diabetes Center at the University of Alabama at Birmingham, said in an interview.

But Anne Peters, MD, a professor of clinical medicine at the University of Southern California, Los Angeles, said caution is needed when interpreting these findings.

“It’s hard to tease out the true effects because, for instance, those treated with insulin may be a sicker subset of patients with diabetes than those on metformin, or those with comorbidities such as renal insufficiency may not be treated with metformin” she said in an interview.

“In general, though, treatment obviously matters and people who are better treated tend to do better, so while I think this study raises the question of what role metformin plays in the risk of mortality and COVID-19, I don’t think it necessarily proves the association,” Dr. Peters asserted.
 

Diverse population

The new study, published this month in Frontiers of Endocrinology, included 25,326 individuals who were tested for COVID-19 at the University of Alabama at Birmingham Hospital between February and June 2020.

Overall, 2.4% tested positive for COVID-19 (n = 604), which the authors note is likely a low figure because screening included asymptomatic hospital staff and patients having elective procedures.

Black/African American patients had a significantly higher risk of COVID-19 positivity, compared with White patients (odds ratio, 2.6; P < .0001). Rates were also higher among those with hypertension (OR, 2.46), diabetes (OR, 2.11), and obesity (OR, 1.93), compared with those without each condition (all P < .0001).

The overall mortality rate in COVID-19-positive patients was 11%. Diabetes was associated with a dramatically increased risk of death (OR, 3.62; P < .0001), and remained an independent risk factor even after adjusting for age, race, sex, obesity, and hypertension.

Notably, the reduction in mortality among those with diabetes taking metformin prior to COVID-19 diagnosis was significant: 11% of those patients died, compared with 23% of those with diabetes not taking metformin (OR, 0.33; P = .021).
 

Similar findings reported across varied populations

The study adds to mounting research suggesting metformin could have a protective effect on COVID-19 mortality, including an early report from Wuhan, China, findings from the French CORONADO study, and a U.S. study linking treatment with decreased mortality among women with COVID-19.

Of note, the effects of metformin on mortality in the current study were observed in men and women alike, as well as in high-risk subgroups including African Americans.

“The fact that such similar results were obtained in different populations from around the world suggests that the observed reduction in mortality risk, associated with metformin use in subjects with type 2 diabetes and COVID-19, might be generalizable,” the authors wrote.

“Furthermore, these findings underline the importance of following general diabetes treatment and prevention guidelines and not delaying or discontinuing any metformin treatment,” they add.
 

Speculation of mechanisms includes anti-inflammatory effects

While the mechanisms behind metformin’s potential role in reducing mortality risk in COVID-19 are unknown, the authors note that the most obvious assumption – that improved glycemic control may be a key factor – is disputed by the study’s finding that blood glucose levels and hemoglobin A1c were not significantly different among COVID-19 survivors taking versus not taking metformin.

They point instead to metformin’s known anti-inflammatory and antithrombotic properties.

“We therefore hypothesize that, by exerting some of these effects, metformin might improve outcomes and we are now in the process of investigating this possibility further,” Dr. Shalev said.

Dr. Peters noted that anti-inflammatory properties, themselves, are not necessarily unique to metformin in the treatment of diabetes.

“Many other agents, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors can reduce inflammation, so I don’t know if that would explain it, but it certainly could help,” she said. “[Reducing inflammation] is a hypothesis you see commonly with diabetes drugs, but I think there are also a lot of metabolic benefits from metformin.”

“It was fascinating that they had the A1c data and that survival with metformin didn’t appear to be as related to A1c levels as one might think,” she added.

Notably, a key advantage, should the effects and mechanisms be validated, is metformin’s high accessibility, Dr. Peters added.

“This doesn’t necessarily tell us what we can do to reduce the health care disparities surrounding COVID-19, but the fact that metformin is low cost and easily available is very important, so maybe it will help as we try to grapple with other risk factors.”

The authors have reported no relevant financial relationships.

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

People with type 2 diabetes who develop COVID-19 show a substantially reduced risk of dying if they are taking metformin, shows a study that adds to prior research indicating the drug might somehow play a role in reducing the severity of infection.

“Unlike several previous analyses, this was a study in a racially diverse population with a high proportion of Blacks/African Americans and [it] revealed that metformin treatment of diabetes prior to diagnosis with COVID-19 was associated with a dramatic threefold reduced mortality in subjects with type 2 diabetes, even after correcting for multiple covariates,” first author Anath Shalev, MD, of the Comprehensive Diabetes Center at the University of Alabama at Birmingham, said in an interview.

But Anne Peters, MD, a professor of clinical medicine at the University of Southern California, Los Angeles, said caution is needed when interpreting these findings.

“It’s hard to tease out the true effects because, for instance, those treated with insulin may be a sicker subset of patients with diabetes than those on metformin, or those with comorbidities such as renal insufficiency may not be treated with metformin” she said in an interview.

“In general, though, treatment obviously matters and people who are better treated tend to do better, so while I think this study raises the question of what role metformin plays in the risk of mortality and COVID-19, I don’t think it necessarily proves the association,” Dr. Peters asserted.
 

Diverse population

The new study, published this month in Frontiers of Endocrinology, included 25,326 individuals who were tested for COVID-19 at the University of Alabama at Birmingham Hospital between February and June 2020.

Overall, 2.4% tested positive for COVID-19 (n = 604), which the authors note is likely a low figure because screening included asymptomatic hospital staff and patients having elective procedures.

Black/African American patients had a significantly higher risk of COVID-19 positivity, compared with White patients (odds ratio, 2.6; P < .0001). Rates were also higher among those with hypertension (OR, 2.46), diabetes (OR, 2.11), and obesity (OR, 1.93), compared with those without each condition (all P < .0001).

The overall mortality rate in COVID-19-positive patients was 11%. Diabetes was associated with a dramatically increased risk of death (OR, 3.62; P < .0001), and remained an independent risk factor even after adjusting for age, race, sex, obesity, and hypertension.

Notably, the reduction in mortality among those with diabetes taking metformin prior to COVID-19 diagnosis was significant: 11% of those patients died, compared with 23% of those with diabetes not taking metformin (OR, 0.33; P = .021).
 

Similar findings reported across varied populations

The study adds to mounting research suggesting metformin could have a protective effect on COVID-19 mortality, including an early report from Wuhan, China, findings from the French CORONADO study, and a U.S. study linking treatment with decreased mortality among women with COVID-19.

Of note, the effects of metformin on mortality in the current study were observed in men and women alike, as well as in high-risk subgroups including African Americans.

“The fact that such similar results were obtained in different populations from around the world suggests that the observed reduction in mortality risk, associated with metformin use in subjects with type 2 diabetes and COVID-19, might be generalizable,” the authors wrote.

“Furthermore, these findings underline the importance of following general diabetes treatment and prevention guidelines and not delaying or discontinuing any metformin treatment,” they add.
 

Speculation of mechanisms includes anti-inflammatory effects

While the mechanisms behind metformin’s potential role in reducing mortality risk in COVID-19 are unknown, the authors note that the most obvious assumption – that improved glycemic control may be a key factor – is disputed by the study’s finding that blood glucose levels and hemoglobin A1c were not significantly different among COVID-19 survivors taking versus not taking metformin.

They point instead to metformin’s known anti-inflammatory and antithrombotic properties.

“We therefore hypothesize that, by exerting some of these effects, metformin might improve outcomes and we are now in the process of investigating this possibility further,” Dr. Shalev said.

Dr. Peters noted that anti-inflammatory properties, themselves, are not necessarily unique to metformin in the treatment of diabetes.

“Many other agents, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors can reduce inflammation, so I don’t know if that would explain it, but it certainly could help,” she said. “[Reducing inflammation] is a hypothesis you see commonly with diabetes drugs, but I think there are also a lot of metabolic benefits from metformin.”

“It was fascinating that they had the A1c data and that survival with metformin didn’t appear to be as related to A1c levels as one might think,” she added.

Notably, a key advantage, should the effects and mechanisms be validated, is metformin’s high accessibility, Dr. Peters added.

“This doesn’t necessarily tell us what we can do to reduce the health care disparities surrounding COVID-19, but the fact that metformin is low cost and easily available is very important, so maybe it will help as we try to grapple with other risk factors.”

The authors have reported no relevant financial relationships.

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

People with type 2 diabetes who develop COVID-19 show a substantially reduced risk of dying if they are taking metformin, shows a study that adds to prior research indicating the drug might somehow play a role in reducing the severity of infection.

“Unlike several previous analyses, this was a study in a racially diverse population with a high proportion of Blacks/African Americans and [it] revealed that metformin treatment of diabetes prior to diagnosis with COVID-19 was associated with a dramatic threefold reduced mortality in subjects with type 2 diabetes, even after correcting for multiple covariates,” first author Anath Shalev, MD, of the Comprehensive Diabetes Center at the University of Alabama at Birmingham, said in an interview.

But Anne Peters, MD, a professor of clinical medicine at the University of Southern California, Los Angeles, said caution is needed when interpreting these findings.

“It’s hard to tease out the true effects because, for instance, those treated with insulin may be a sicker subset of patients with diabetes than those on metformin, or those with comorbidities such as renal insufficiency may not be treated with metformin” she said in an interview.

“In general, though, treatment obviously matters and people who are better treated tend to do better, so while I think this study raises the question of what role metformin plays in the risk of mortality and COVID-19, I don’t think it necessarily proves the association,” Dr. Peters asserted.
 

Diverse population

The new study, published this month in Frontiers of Endocrinology, included 25,326 individuals who were tested for COVID-19 at the University of Alabama at Birmingham Hospital between February and June 2020.

Overall, 2.4% tested positive for COVID-19 (n = 604), which the authors note is likely a low figure because screening included asymptomatic hospital staff and patients having elective procedures.

Black/African American patients had a significantly higher risk of COVID-19 positivity, compared with White patients (odds ratio, 2.6; P < .0001). Rates were also higher among those with hypertension (OR, 2.46), diabetes (OR, 2.11), and obesity (OR, 1.93), compared with those without each condition (all P < .0001).

The overall mortality rate in COVID-19-positive patients was 11%. Diabetes was associated with a dramatically increased risk of death (OR, 3.62; P < .0001), and remained an independent risk factor even after adjusting for age, race, sex, obesity, and hypertension.

Notably, the reduction in mortality among those with diabetes taking metformin prior to COVID-19 diagnosis was significant: 11% of those patients died, compared with 23% of those with diabetes not taking metformin (OR, 0.33; P = .021).
 

Similar findings reported across varied populations

The study adds to mounting research suggesting metformin could have a protective effect on COVID-19 mortality, including an early report from Wuhan, China, findings from the French CORONADO study, and a U.S. study linking treatment with decreased mortality among women with COVID-19.

Of note, the effects of metformin on mortality in the current study were observed in men and women alike, as well as in high-risk subgroups including African Americans.

“The fact that such similar results were obtained in different populations from around the world suggests that the observed reduction in mortality risk, associated with metformin use in subjects with type 2 diabetes and COVID-19, might be generalizable,” the authors wrote.

“Furthermore, these findings underline the importance of following general diabetes treatment and prevention guidelines and not delaying or discontinuing any metformin treatment,” they add.
 

Speculation of mechanisms includes anti-inflammatory effects

While the mechanisms behind metformin’s potential role in reducing mortality risk in COVID-19 are unknown, the authors note that the most obvious assumption – that improved glycemic control may be a key factor – is disputed by the study’s finding that blood glucose levels and hemoglobin A1c were not significantly different among COVID-19 survivors taking versus not taking metformin.

They point instead to metformin’s known anti-inflammatory and antithrombotic properties.

“We therefore hypothesize that, by exerting some of these effects, metformin might improve outcomes and we are now in the process of investigating this possibility further,” Dr. Shalev said.

Dr. Peters noted that anti-inflammatory properties, themselves, are not necessarily unique to metformin in the treatment of diabetes.

“Many other agents, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors can reduce inflammation, so I don’t know if that would explain it, but it certainly could help,” she said. “[Reducing inflammation] is a hypothesis you see commonly with diabetes drugs, but I think there are also a lot of metabolic benefits from metformin.”

“It was fascinating that they had the A1c data and that survival with metformin didn’t appear to be as related to A1c levels as one might think,” she added.

Notably, a key advantage, should the effects and mechanisms be validated, is metformin’s high accessibility, Dr. Peters added.

“This doesn’t necessarily tell us what we can do to reduce the health care disparities surrounding COVID-19, but the fact that metformin is low cost and easily available is very important, so maybe it will help as we try to grapple with other risk factors.”

The authors have reported no relevant financial relationships.

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

President Joe Biden has come into office after an unexpected shift in Congress. On Jan. 5, Democrats scored an upset by winning two U.S. Senate seats in runoff elections in Georgia, giving them control of the Senate.

Now the Democrats have control of all three levers of power – the Senate, the House, and the presidency – for the first time since the early years of the Obama administration.

How will President Biden use this new concentration of power to shape health care policy?

Democrats’ small majorities in both houses of Congress suggest that moderation and bipartisanship will be necessary to get things done. Moreover, Mr. Biden himself is calling for bipartisanship. “On this January day,” he said in his inauguration speech, “my whole soul is in this: Bringing America together, uniting our people, uniting our nation.”

Key health care actions that Mr. Biden could pursue include the following.
 

1. Passing a new COVID-19 relief bill

Above all, Mr. Biden is focused on overcoming the COVID-19 pandemic, which has been registering record deaths recently, and getting newly released vaccines to Americans.

“Dealing with the coronavirus pandemic is one of the most important battles our administration will face, and I will be informed by science and by experts,” the president said.

“There is no question that the pandemic is the highest priority for the Biden administration,” said Larry Levitt, executive vice president for health policy at the Henry J. Kaiser Family Foundation. “COVID will dominate the early weeks and months of this administration. His success rests, in particular, on improving the rollout of vaccines.”

Five days before his inauguration, the president-elect unveiled the American Rescue Plan, a massive, $1.9 trillion legislative package intended to hasten rollout of COVID-19 vaccines, improve COVID-19 testing, and provide financial help to businesses and individuals, among many other things.

The bill would add $1,400 to the recently passed $600 government relief payments for each American, amounting to a $2,000 check. It would also enact many non-COVID-19 measures, such as a $15-an-hour minimum wage and measures to bolster the Affordable Care Act (ACA).

If Democrats cannot reach a deal with the Republicans, they might turn the proposal into a reconciliation bill, which could then be passed with a simple majority. However, drafting a reconciliation bill is a long, complicated process that would require removing provisions that don’t meet the requirements of reconciliation, said Hazen Marshall, a Washington lobbyist and former staffer for Sen. Mitch McConnell.

Most importantly, Mr. Marshall said, reconciliation bills bring out diehard partisanship. “They involve a sledgehammer mentality,” he says. “You’re telling the other side that their views aren’t going to matter.” The final version of the ACA, for example, was passed as a reconciliation bill, with not one Republican vote.

In the Trump years, “the last four reconciliation bills did not get any votes from the minority,” added Rodney Whitlock, PhD, a political consultant at McDermott+Consulting, who worked 21 years for Republicans in the House. “When the majority chooses to use reconciliation, it is an admission that it has no interest in working with the minority.”

Hammering out a compromise will be tough, but Robert Pearl MD, former CEO of the Permanente Medical Group and a professor at Stanford (Calif.) University, said that if anyone can do it, it would be President Biden. Having served in the Senate for 36 years, “Biden knows Congress better than any president since Lyndon Johnson,” he said. “He can reach across the aisle and get legislation passed as much as anyone could these days.”
 

2. Restoring Obamacare

Mr. Biden has vowed to undo a gradual dismantling of the ACA that went on during the Trump administration through executive orders, rule-making, and new laws. “Reinvigorating the ACA was a central part of Biden’s platform as a candidate,” Mr. Levitt said.

Each Trump action against the ACA must be undone in the same way. Presidential orders must be met with presidential orders, regulations with regulations, and legislation with legislation.

The ACA is also being challenged in the Supreme Court. Republicans under Trump passed a law that reduced the penalty for not buying health insurance under the ACA to zero. Then a group of 20 states, led by Texas, filed a lawsuit asserting that this change makes the ACA unconstitutional.

The lawsuit was heard by the Supreme Court in November. From remarks made by the justices then, it appears that the court might well uphold the law when a verdict comes down in June.

But just in case, Mr. Biden wants Congress to enact a small penalty for not buying health insurance, which would remove the basis of the lawsuit.

Mr. Biden’s choice for secretary of Health and Human Services shows his level of commitment to protecting the ACA. His HHS nominee is California Attorney General Xavier Becerra, who led a group of 17 states defending the ACA in the current lawsuit.

In addition to undoing Trump’s changes, Mr. Biden plans to expand the ACA beyond the original legislation. The new COVID-19 bill contains provisions that would expand subsidies to buy insurance on the exchanges and would lower the maximum percentage of income that anyone has to pay for health insurance to 8.5%.

Dealing with Medicaid is also related to the ACA. In 2012, the Supreme Court struck down a mandate that states expand their Medicaid programs, with substantial funding from the federal government.

To date, 12 states still do not participate in the Medicaid expansion. To lure them into the expansion, the Democrat-controlled House last session passed a bill that would offer to pay the entire bill for the first 3 years of Medicaid expansion if they chose to enact an expansion.
 

3. Undoing other Trump actions in health care

In addition to changes in the ACA, Trump also enacted a number of other changes in health care that President Biden could undo. For example, Mr. Biden says he will reenter the World Health Organization (WHO) so that the United States could better coordinate a COVID-19 response with other nations. Trump exited the WHO with the stroke of a pen, and Mr. Biden can do the same in reverse.

Under Trump, the Centers for Medicare & Medicaid Services used waivers to weaken the ACA and allow states to alter their Medicaid programs. One waiver allows Georgia to leave the ACA exchanges and put brokers in charge of buying coverage. Other waivers allow states to transform federal Medicaid payments into block grants, which several states are planning to do.

The Trump CMS has allowed several states to use Medicaid waivers to add work requirements for Medicaid recipients. The courts have blocked the work rules so far, and the Biden CMS may decide to reverse these waivers or modify them.

“Undoing waivers is normally a fairly simple thing,” Mr. Levitt said. In January, however, the Trump CMS asked some waiver states to sign new contracts in which the CMS pledges not to end a waiver without 9 months’ notice. It’s unclear how many states signed such contracts and what obligation the Biden CMS has to enforce them.

The Trump CMS also stopped reimbursing insurers for waiving deductibles and copayments for low-income customers, as directed by the ACA. Without federal reimbursement, some insurers raised premiums by as much as 20% to cover the costs. It is unclear how the Biden CMS would tackle this change.
 

4. Negotiating lower drug prices

Allowing Medicare to negotiate drug prices, a major plank in Mr. Biden’s campaign, would seem like a slam dunk for the Democrats. This approach is backed by 89% of Americans, including 84% of Republicans, according to a Kaiser Family Foundation survey in December.

“With that level of support, it’s hard to go wrong politically on this issue,” Mr. Levitt said.

Many Republicans, however, do not favor negotiating drug prices, and the two parties continue to be far apart on how to control drug prices. Trump signed an action that allows Americans to buy cheaper drugs abroad, an approach that Mr. Biden also supports, but it is now tied up in the courts.

“A drug pricing bill has always been difficult to pass,” Dr. Whitlock said. “The issue is popular with the public, but change does not come easily. The drug lobby is one the strongest in Washington, and now it may be even stronger, since it was the drug companies that gave us the COVID vaccines.”

Dr. Whitlock said Republicans will want Democrats to compromise on drug pricing, but he doubts they will do so. The House passed a bill to negotiate drug prices last year, which never was voted on in the Senate. “It is difficult to imagine that the Democrats will be able to move rightward from that House bill,” Dr. Whitlock said. “Democrats are likely to stand pat on drug pricing.”
 

5. Introducing a public option

President Biden’s campaign proposal for a public option – health insurance offered by the federal government – and to lower the age for Medicare eligibility from 65 years to 60 years, resulted from a compromise between two factions of the Democratic party on how to expand coverage.

Although Mr. Biden and other moderates wanted to focus on fixing the ACA, Democrats led by Sen. Bernie Sanders of Vermont called for a single-payer system, dubbed “Medicare for all.” A public option was seen as the middle ground between the two camps.

“A public option would be a very controversial,” Dr. Whitlock said. Critics say it would pay at Medicare rates, which would reduce doctors’ reimbursements, and save very little money compared with a single-payer system.

Dr. Pearl sees similar problems with lowering the Medicare age. “This would be an expensive change that the federal government could not afford, particularly with all the spending on the pandemic,” he said. “And it would be tough on doctors and hospitals, because Medicare pays less than the private insurance payment they are now getting.”

“The public option is likely to get serious discussion within the Democratic caucus and get onto the Senate floor,” Mr. Levitt said. “The party won’t ignore it.” He notes that in the new Senate, Sen. Sanders chairs the budget committee, and from that position he is likely to push for expanding access to care.

Mr. Levitt says the Biden CMS might allow states to experiment with a statewide public option or even a single-payer model, but he concedes that states, with their budgets ravaged by COVID-19, do not currently have the money to launch such programs.
 

6. Reviving the CMS

Under President Obama, the CMS was the engine that implemented the ACA and shepherded wider use of value-based reimbursements, which reward providers for quality and outcomes rather than volume.

Under the Trump administration, CMS leadership continued to uphold value-based reimbursement, Dr. Pearl observed. “CMS leadership championed value-based payments, but they encountered a lot of pushback from doctors and hospitals and had to scale back their goals,” he said.

On the other hand, the Trump CMS took a 180-degree turn on the ACA and worked to take it apart. This took a toll on staff morale, according to Donald M. Berwick, MD, who ran the CMS under President Obama. “Many people in CMS did not feel supported during the Trump administration, and some of them left,” Dr. Berwick said.

The CMS needs experienced staff on board to write comprehensible rules and regulations that can overcome court challenges.

Having a fully functioning CMS also requires consistent leadership, which was a problem for Obama. When Mr. Obama nominated Dr. Berwick, 60 Senate votes were needed to confirm him, and Republicans would not vote for him. Mr. Obama eventually brought Dr. Berwick in as a recess appointment, but it meant he could serve for only 17 months.

Since then, Senate confirmation rules have changed so that only a simple majority is needed to confirm appointments. This is important for Biden’s nominees, Dr. Berwick said. “For a president, having your team in place means you are able to execute the policies you want,” he said. “You need to have consistent leadership.”
 

7. Potentially changing health care without Congress

Even with their newly won control of the Senate, the Democrats’ thin majorities in both houses of Congress may not be enough to pass much legislation if Republicans are solidly opposed.

Democrats in the House also have a narrow path this session in which to pass legislation. The Democratic leadership has an 11-vote majority, but it must contend with 15 moderate representatives in purple districts (where Democrats and Republicans have about equal support).

A bigger problem looms before the Democrats. In 2022, the party may well lose its majorities in both houses. Mr. Whitlock notes that the party of an incoming president normally loses seats in the first midterm election. “The last incoming president to keep both houses of Congress in his first midterm was Jimmy Carter,” he said.

If this happens, President Biden would have to govern without the support of Congress, which is what Barack Obama had to do through most of his presidency. As Mr. Obama’s vice president, Mr. Biden is well aware how that goes. Governing without Congress means relying on presidential orders and decrees.

In health care, Mr. Biden has a powerful policy-making tool, the Center for Medicare & Medicaid Innovation (CMMI). The CMMI was empowered by the ACA to initiate pilot programs for new payment models.

So far, the CMMI’s work has been mainly limited to accountable care organizations, bundled payments, and patient-centered medical homes, but it could also be used to enact new federal policies that would normally require Congressional action, Mr. Levitt said.
 

Conclusion

Expectations have been very high for what President Joe Biden can do in health care. He needs to unite a very divided political system to defeat a deadly pandemic, restore Obamacare, and sign landmark legislation, such as a drug-pricing bill.

But shepherding bills through Congress will be a challenge. “You need to have accountability, unity, and civility, which is a Herculean task,” Mr. Whitlock said. “You have to keep policies off the table that could blow up the bipartisanship.”

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

President Joe Biden has come into office after an unexpected shift in Congress. On Jan. 5, Democrats scored an upset by winning two U.S. Senate seats in runoff elections in Georgia, giving them control of the Senate.

Now the Democrats have control of all three levers of power – the Senate, the House, and the presidency – for the first time since the early years of the Obama administration.

How will President Biden use this new concentration of power to shape health care policy?

Democrats’ small majorities in both houses of Congress suggest that moderation and bipartisanship will be necessary to get things done. Moreover, Mr. Biden himself is calling for bipartisanship. “On this January day,” he said in his inauguration speech, “my whole soul is in this: Bringing America together, uniting our people, uniting our nation.”

Key health care actions that Mr. Biden could pursue include the following.
 

1. Passing a new COVID-19 relief bill

Above all, Mr. Biden is focused on overcoming the COVID-19 pandemic, which has been registering record deaths recently, and getting newly released vaccines to Americans.

“Dealing with the coronavirus pandemic is one of the most important battles our administration will face, and I will be informed by science and by experts,” the president said.

“There is no question that the pandemic is the highest priority for the Biden administration,” said Larry Levitt, executive vice president for health policy at the Henry J. Kaiser Family Foundation. “COVID will dominate the early weeks and months of this administration. His success rests, in particular, on improving the rollout of vaccines.”

Five days before his inauguration, the president-elect unveiled the American Rescue Plan, a massive, $1.9 trillion legislative package intended to hasten rollout of COVID-19 vaccines, improve COVID-19 testing, and provide financial help to businesses and individuals, among many other things.

The bill would add $1,400 to the recently passed $600 government relief payments for each American, amounting to a $2,000 check. It would also enact many non-COVID-19 measures, such as a $15-an-hour minimum wage and measures to bolster the Affordable Care Act (ACA).

If Democrats cannot reach a deal with the Republicans, they might turn the proposal into a reconciliation bill, which could then be passed with a simple majority. However, drafting a reconciliation bill is a long, complicated process that would require removing provisions that don’t meet the requirements of reconciliation, said Hazen Marshall, a Washington lobbyist and former staffer for Sen. Mitch McConnell.

Most importantly, Mr. Marshall said, reconciliation bills bring out diehard partisanship. “They involve a sledgehammer mentality,” he says. “You’re telling the other side that their views aren’t going to matter.” The final version of the ACA, for example, was passed as a reconciliation bill, with not one Republican vote.

In the Trump years, “the last four reconciliation bills did not get any votes from the minority,” added Rodney Whitlock, PhD, a political consultant at McDermott+Consulting, who worked 21 years for Republicans in the House. “When the majority chooses to use reconciliation, it is an admission that it has no interest in working with the minority.”

Hammering out a compromise will be tough, but Robert Pearl MD, former CEO of the Permanente Medical Group and a professor at Stanford (Calif.) University, said that if anyone can do it, it would be President Biden. Having served in the Senate for 36 years, “Biden knows Congress better than any president since Lyndon Johnson,” he said. “He can reach across the aisle and get legislation passed as much as anyone could these days.”
 

2. Restoring Obamacare

Mr. Biden has vowed to undo a gradual dismantling of the ACA that went on during the Trump administration through executive orders, rule-making, and new laws. “Reinvigorating the ACA was a central part of Biden’s platform as a candidate,” Mr. Levitt said.

Each Trump action against the ACA must be undone in the same way. Presidential orders must be met with presidential orders, regulations with regulations, and legislation with legislation.

The ACA is also being challenged in the Supreme Court. Republicans under Trump passed a law that reduced the penalty for not buying health insurance under the ACA to zero. Then a group of 20 states, led by Texas, filed a lawsuit asserting that this change makes the ACA unconstitutional.

The lawsuit was heard by the Supreme Court in November. From remarks made by the justices then, it appears that the court might well uphold the law when a verdict comes down in June.

But just in case, Mr. Biden wants Congress to enact a small penalty for not buying health insurance, which would remove the basis of the lawsuit.

Mr. Biden’s choice for secretary of Health and Human Services shows his level of commitment to protecting the ACA. His HHS nominee is California Attorney General Xavier Becerra, who led a group of 17 states defending the ACA in the current lawsuit.

In addition to undoing Trump’s changes, Mr. Biden plans to expand the ACA beyond the original legislation. The new COVID-19 bill contains provisions that would expand subsidies to buy insurance on the exchanges and would lower the maximum percentage of income that anyone has to pay for health insurance to 8.5%.

Dealing with Medicaid is also related to the ACA. In 2012, the Supreme Court struck down a mandate that states expand their Medicaid programs, with substantial funding from the federal government.

To date, 12 states still do not participate in the Medicaid expansion. To lure them into the expansion, the Democrat-controlled House last session passed a bill that would offer to pay the entire bill for the first 3 years of Medicaid expansion if they chose to enact an expansion.
 

3. Undoing other Trump actions in health care

In addition to changes in the ACA, Trump also enacted a number of other changes in health care that President Biden could undo. For example, Mr. Biden says he will reenter the World Health Organization (WHO) so that the United States could better coordinate a COVID-19 response with other nations. Trump exited the WHO with the stroke of a pen, and Mr. Biden can do the same in reverse.

Under Trump, the Centers for Medicare & Medicaid Services used waivers to weaken the ACA and allow states to alter their Medicaid programs. One waiver allows Georgia to leave the ACA exchanges and put brokers in charge of buying coverage. Other waivers allow states to transform federal Medicaid payments into block grants, which several states are planning to do.

The Trump CMS has allowed several states to use Medicaid waivers to add work requirements for Medicaid recipients. The courts have blocked the work rules so far, and the Biden CMS may decide to reverse these waivers or modify them.

“Undoing waivers is normally a fairly simple thing,” Mr. Levitt said. In January, however, the Trump CMS asked some waiver states to sign new contracts in which the CMS pledges not to end a waiver without 9 months’ notice. It’s unclear how many states signed such contracts and what obligation the Biden CMS has to enforce them.

The Trump CMS also stopped reimbursing insurers for waiving deductibles and copayments for low-income customers, as directed by the ACA. Without federal reimbursement, some insurers raised premiums by as much as 20% to cover the costs. It is unclear how the Biden CMS would tackle this change.
 

4. Negotiating lower drug prices

Allowing Medicare to negotiate drug prices, a major plank in Mr. Biden’s campaign, would seem like a slam dunk for the Democrats. This approach is backed by 89% of Americans, including 84% of Republicans, according to a Kaiser Family Foundation survey in December.

“With that level of support, it’s hard to go wrong politically on this issue,” Mr. Levitt said.

Many Republicans, however, do not favor negotiating drug prices, and the two parties continue to be far apart on how to control drug prices. Trump signed an action that allows Americans to buy cheaper drugs abroad, an approach that Mr. Biden also supports, but it is now tied up in the courts.

“A drug pricing bill has always been difficult to pass,” Dr. Whitlock said. “The issue is popular with the public, but change does not come easily. The drug lobby is one the strongest in Washington, and now it may be even stronger, since it was the drug companies that gave us the COVID vaccines.”

Dr. Whitlock said Republicans will want Democrats to compromise on drug pricing, but he doubts they will do so. The House passed a bill to negotiate drug prices last year, which never was voted on in the Senate. “It is difficult to imagine that the Democrats will be able to move rightward from that House bill,” Dr. Whitlock said. “Democrats are likely to stand pat on drug pricing.”
 

5. Introducing a public option

President Biden’s campaign proposal for a public option – health insurance offered by the federal government – and to lower the age for Medicare eligibility from 65 years to 60 years, resulted from a compromise between two factions of the Democratic party on how to expand coverage.

Although Mr. Biden and other moderates wanted to focus on fixing the ACA, Democrats led by Sen. Bernie Sanders of Vermont called for a single-payer system, dubbed “Medicare for all.” A public option was seen as the middle ground between the two camps.

“A public option would be a very controversial,” Dr. Whitlock said. Critics say it would pay at Medicare rates, which would reduce doctors’ reimbursements, and save very little money compared with a single-payer system.

Dr. Pearl sees similar problems with lowering the Medicare age. “This would be an expensive change that the federal government could not afford, particularly with all the spending on the pandemic,” he said. “And it would be tough on doctors and hospitals, because Medicare pays less than the private insurance payment they are now getting.”

“The public option is likely to get serious discussion within the Democratic caucus and get onto the Senate floor,” Mr. Levitt said. “The party won’t ignore it.” He notes that in the new Senate, Sen. Sanders chairs the budget committee, and from that position he is likely to push for expanding access to care.

Mr. Levitt says the Biden CMS might allow states to experiment with a statewide public option or even a single-payer model, but he concedes that states, with their budgets ravaged by COVID-19, do not currently have the money to launch such programs.
 

6. Reviving the CMS

Under President Obama, the CMS was the engine that implemented the ACA and shepherded wider use of value-based reimbursements, which reward providers for quality and outcomes rather than volume.

Under the Trump administration, CMS leadership continued to uphold value-based reimbursement, Dr. Pearl observed. “CMS leadership championed value-based payments, but they encountered a lot of pushback from doctors and hospitals and had to scale back their goals,” he said.

On the other hand, the Trump CMS took a 180-degree turn on the ACA and worked to take it apart. This took a toll on staff morale, according to Donald M. Berwick, MD, who ran the CMS under President Obama. “Many people in CMS did not feel supported during the Trump administration, and some of them left,” Dr. Berwick said.

The CMS needs experienced staff on board to write comprehensible rules and regulations that can overcome court challenges.

Having a fully functioning CMS also requires consistent leadership, which was a problem for Obama. When Mr. Obama nominated Dr. Berwick, 60 Senate votes were needed to confirm him, and Republicans would not vote for him. Mr. Obama eventually brought Dr. Berwick in as a recess appointment, but it meant he could serve for only 17 months.

Since then, Senate confirmation rules have changed so that only a simple majority is needed to confirm appointments. This is important for Biden’s nominees, Dr. Berwick said. “For a president, having your team in place means you are able to execute the policies you want,” he said. “You need to have consistent leadership.”
 

7. Potentially changing health care without Congress

Even with their newly won control of the Senate, the Democrats’ thin majorities in both houses of Congress may not be enough to pass much legislation if Republicans are solidly opposed.

Democrats in the House also have a narrow path this session in which to pass legislation. The Democratic leadership has an 11-vote majority, but it must contend with 15 moderate representatives in purple districts (where Democrats and Republicans have about equal support).

A bigger problem looms before the Democrats. In 2022, the party may well lose its majorities in both houses. Mr. Whitlock notes that the party of an incoming president normally loses seats in the first midterm election. “The last incoming president to keep both houses of Congress in his first midterm was Jimmy Carter,” he said.

If this happens, President Biden would have to govern without the support of Congress, which is what Barack Obama had to do through most of his presidency. As Mr. Obama’s vice president, Mr. Biden is well aware how that goes. Governing without Congress means relying on presidential orders and decrees.

In health care, Mr. Biden has a powerful policy-making tool, the Center for Medicare & Medicaid Innovation (CMMI). The CMMI was empowered by the ACA to initiate pilot programs for new payment models.

So far, the CMMI’s work has been mainly limited to accountable care organizations, bundled payments, and patient-centered medical homes, but it could also be used to enact new federal policies that would normally require Congressional action, Mr. Levitt said.
 

Conclusion

Expectations have been very high for what President Joe Biden can do in health care. He needs to unite a very divided political system to defeat a deadly pandemic, restore Obamacare, and sign landmark legislation, such as a drug-pricing bill.

But shepherding bills through Congress will be a challenge. “You need to have accountability, unity, and civility, which is a Herculean task,” Mr. Whitlock said. “You have to keep policies off the table that could blow up the bipartisanship.”

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

President Joe Biden has come into office after an unexpected shift in Congress. On Jan. 5, Democrats scored an upset by winning two U.S. Senate seats in runoff elections in Georgia, giving them control of the Senate.

Now the Democrats have control of all three levers of power – the Senate, the House, and the presidency – for the first time since the early years of the Obama administration.

How will President Biden use this new concentration of power to shape health care policy?

Democrats’ small majorities in both houses of Congress suggest that moderation and bipartisanship will be necessary to get things done. Moreover, Mr. Biden himself is calling for bipartisanship. “On this January day,” he said in his inauguration speech, “my whole soul is in this: Bringing America together, uniting our people, uniting our nation.”

Key health care actions that Mr. Biden could pursue include the following.
 

1. Passing a new COVID-19 relief bill

Above all, Mr. Biden is focused on overcoming the COVID-19 pandemic, which has been registering record deaths recently, and getting newly released vaccines to Americans.

“Dealing with the coronavirus pandemic is one of the most important battles our administration will face, and I will be informed by science and by experts,” the president said.

“There is no question that the pandemic is the highest priority for the Biden administration,” said Larry Levitt, executive vice president for health policy at the Henry J. Kaiser Family Foundation. “COVID will dominate the early weeks and months of this administration. His success rests, in particular, on improving the rollout of vaccines.”

Five days before his inauguration, the president-elect unveiled the American Rescue Plan, a massive, $1.9 trillion legislative package intended to hasten rollout of COVID-19 vaccines, improve COVID-19 testing, and provide financial help to businesses and individuals, among many other things.

The bill would add $1,400 to the recently passed $600 government relief payments for each American, amounting to a $2,000 check. It would also enact many non-COVID-19 measures, such as a $15-an-hour minimum wage and measures to bolster the Affordable Care Act (ACA).

If Democrats cannot reach a deal with the Republicans, they might turn the proposal into a reconciliation bill, which could then be passed with a simple majority. However, drafting a reconciliation bill is a long, complicated process that would require removing provisions that don’t meet the requirements of reconciliation, said Hazen Marshall, a Washington lobbyist and former staffer for Sen. Mitch McConnell.

Most importantly, Mr. Marshall said, reconciliation bills bring out diehard partisanship. “They involve a sledgehammer mentality,” he says. “You’re telling the other side that their views aren’t going to matter.” The final version of the ACA, for example, was passed as a reconciliation bill, with not one Republican vote.

In the Trump years, “the last four reconciliation bills did not get any votes from the minority,” added Rodney Whitlock, PhD, a political consultant at McDermott+Consulting, who worked 21 years for Republicans in the House. “When the majority chooses to use reconciliation, it is an admission that it has no interest in working with the minority.”

Hammering out a compromise will be tough, but Robert Pearl MD, former CEO of the Permanente Medical Group and a professor at Stanford (Calif.) University, said that if anyone can do it, it would be President Biden. Having served in the Senate for 36 years, “Biden knows Congress better than any president since Lyndon Johnson,” he said. “He can reach across the aisle and get legislation passed as much as anyone could these days.”
 

2. Restoring Obamacare

Mr. Biden has vowed to undo a gradual dismantling of the ACA that went on during the Trump administration through executive orders, rule-making, and new laws. “Reinvigorating the ACA was a central part of Biden’s platform as a candidate,” Mr. Levitt said.

Each Trump action against the ACA must be undone in the same way. Presidential orders must be met with presidential orders, regulations with regulations, and legislation with legislation.

The ACA is also being challenged in the Supreme Court. Republicans under Trump passed a law that reduced the penalty for not buying health insurance under the ACA to zero. Then a group of 20 states, led by Texas, filed a lawsuit asserting that this change makes the ACA unconstitutional.

The lawsuit was heard by the Supreme Court in November. From remarks made by the justices then, it appears that the court might well uphold the law when a verdict comes down in June.

But just in case, Mr. Biden wants Congress to enact a small penalty for not buying health insurance, which would remove the basis of the lawsuit.

Mr. Biden’s choice for secretary of Health and Human Services shows his level of commitment to protecting the ACA. His HHS nominee is California Attorney General Xavier Becerra, who led a group of 17 states defending the ACA in the current lawsuit.

In addition to undoing Trump’s changes, Mr. Biden plans to expand the ACA beyond the original legislation. The new COVID-19 bill contains provisions that would expand subsidies to buy insurance on the exchanges and would lower the maximum percentage of income that anyone has to pay for health insurance to 8.5%.

Dealing with Medicaid is also related to the ACA. In 2012, the Supreme Court struck down a mandate that states expand their Medicaid programs, with substantial funding from the federal government.

To date, 12 states still do not participate in the Medicaid expansion. To lure them into the expansion, the Democrat-controlled House last session passed a bill that would offer to pay the entire bill for the first 3 years of Medicaid expansion if they chose to enact an expansion.
 

3. Undoing other Trump actions in health care

In addition to changes in the ACA, Trump also enacted a number of other changes in health care that President Biden could undo. For example, Mr. Biden says he will reenter the World Health Organization (WHO) so that the United States could better coordinate a COVID-19 response with other nations. Trump exited the WHO with the stroke of a pen, and Mr. Biden can do the same in reverse.

Under Trump, the Centers for Medicare & Medicaid Services used waivers to weaken the ACA and allow states to alter their Medicaid programs. One waiver allows Georgia to leave the ACA exchanges and put brokers in charge of buying coverage. Other waivers allow states to transform federal Medicaid payments into block grants, which several states are planning to do.

The Trump CMS has allowed several states to use Medicaid waivers to add work requirements for Medicaid recipients. The courts have blocked the work rules so far, and the Biden CMS may decide to reverse these waivers or modify them.

“Undoing waivers is normally a fairly simple thing,” Mr. Levitt said. In January, however, the Trump CMS asked some waiver states to sign new contracts in which the CMS pledges not to end a waiver without 9 months’ notice. It’s unclear how many states signed such contracts and what obligation the Biden CMS has to enforce them.

The Trump CMS also stopped reimbursing insurers for waiving deductibles and copayments for low-income customers, as directed by the ACA. Without federal reimbursement, some insurers raised premiums by as much as 20% to cover the costs. It is unclear how the Biden CMS would tackle this change.
 

4. Negotiating lower drug prices

Allowing Medicare to negotiate drug prices, a major plank in Mr. Biden’s campaign, would seem like a slam dunk for the Democrats. This approach is backed by 89% of Americans, including 84% of Republicans, according to a Kaiser Family Foundation survey in December.

“With that level of support, it’s hard to go wrong politically on this issue,” Mr. Levitt said.

Many Republicans, however, do not favor negotiating drug prices, and the two parties continue to be far apart on how to control drug prices. Trump signed an action that allows Americans to buy cheaper drugs abroad, an approach that Mr. Biden also supports, but it is now tied up in the courts.

“A drug pricing bill has always been difficult to pass,” Dr. Whitlock said. “The issue is popular with the public, but change does not come easily. The drug lobby is one the strongest in Washington, and now it may be even stronger, since it was the drug companies that gave us the COVID vaccines.”

Dr. Whitlock said Republicans will want Democrats to compromise on drug pricing, but he doubts they will do so. The House passed a bill to negotiate drug prices last year, which never was voted on in the Senate. “It is difficult to imagine that the Democrats will be able to move rightward from that House bill,” Dr. Whitlock said. “Democrats are likely to stand pat on drug pricing.”
 

5. Introducing a public option

President Biden’s campaign proposal for a public option – health insurance offered by the federal government – and to lower the age for Medicare eligibility from 65 years to 60 years, resulted from a compromise between two factions of the Democratic party on how to expand coverage.

Although Mr. Biden and other moderates wanted to focus on fixing the ACA, Democrats led by Sen. Bernie Sanders of Vermont called for a single-payer system, dubbed “Medicare for all.” A public option was seen as the middle ground between the two camps.

“A public option would be a very controversial,” Dr. Whitlock said. Critics say it would pay at Medicare rates, which would reduce doctors’ reimbursements, and save very little money compared with a single-payer system.

Dr. Pearl sees similar problems with lowering the Medicare age. “This would be an expensive change that the federal government could not afford, particularly with all the spending on the pandemic,” he said. “And it would be tough on doctors and hospitals, because Medicare pays less than the private insurance payment they are now getting.”

“The public option is likely to get serious discussion within the Democratic caucus and get onto the Senate floor,” Mr. Levitt said. “The party won’t ignore it.” He notes that in the new Senate, Sen. Sanders chairs the budget committee, and from that position he is likely to push for expanding access to care.

Mr. Levitt says the Biden CMS might allow states to experiment with a statewide public option or even a single-payer model, but he concedes that states, with their budgets ravaged by COVID-19, do not currently have the money to launch such programs.
 

6. Reviving the CMS

Under President Obama, the CMS was the engine that implemented the ACA and shepherded wider use of value-based reimbursements, which reward providers for quality and outcomes rather than volume.

Under the Trump administration, CMS leadership continued to uphold value-based reimbursement, Dr. Pearl observed. “CMS leadership championed value-based payments, but they encountered a lot of pushback from doctors and hospitals and had to scale back their goals,” he said.

On the other hand, the Trump CMS took a 180-degree turn on the ACA and worked to take it apart. This took a toll on staff morale, according to Donald M. Berwick, MD, who ran the CMS under President Obama. “Many people in CMS did not feel supported during the Trump administration, and some of them left,” Dr. Berwick said.

The CMS needs experienced staff on board to write comprehensible rules and regulations that can overcome court challenges.

Having a fully functioning CMS also requires consistent leadership, which was a problem for Obama. When Mr. Obama nominated Dr. Berwick, 60 Senate votes were needed to confirm him, and Republicans would not vote for him. Mr. Obama eventually brought Dr. Berwick in as a recess appointment, but it meant he could serve for only 17 months.

Since then, Senate confirmation rules have changed so that only a simple majority is needed to confirm appointments. This is important for Biden’s nominees, Dr. Berwick said. “For a president, having your team in place means you are able to execute the policies you want,” he said. “You need to have consistent leadership.”
 

7. Potentially changing health care without Congress

Even with their newly won control of the Senate, the Democrats’ thin majorities in both houses of Congress may not be enough to pass much legislation if Republicans are solidly opposed.

Democrats in the House also have a narrow path this session in which to pass legislation. The Democratic leadership has an 11-vote majority, but it must contend with 15 moderate representatives in purple districts (where Democrats and Republicans have about equal support).

A bigger problem looms before the Democrats. In 2022, the party may well lose its majorities in both houses. Mr. Whitlock notes that the party of an incoming president normally loses seats in the first midterm election. “The last incoming president to keep both houses of Congress in his first midterm was Jimmy Carter,” he said.

If this happens, President Biden would have to govern without the support of Congress, which is what Barack Obama had to do through most of his presidency. As Mr. Obama’s vice president, Mr. Biden is well aware how that goes. Governing without Congress means relying on presidential orders and decrees.

In health care, Mr. Biden has a powerful policy-making tool, the Center for Medicare & Medicaid Innovation (CMMI). The CMMI was empowered by the ACA to initiate pilot programs for new payment models.

So far, the CMMI’s work has been mainly limited to accountable care organizations, bundled payments, and patient-centered medical homes, but it could also be used to enact new federal policies that would normally require Congressional action, Mr. Levitt said.
 

Conclusion

Expectations have been very high for what President Joe Biden can do in health care. He needs to unite a very divided political system to defeat a deadly pandemic, restore Obamacare, and sign landmark legislation, such as a drug-pricing bill.

But shepherding bills through Congress will be a challenge. “You need to have accountability, unity, and civility, which is a Herculean task,” Mr. Whitlock said. “You have to keep policies off the table that could blow up the bipartisanship.”

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

Primary care physicians (PCPs) generate only a small part of the $75 billion to $100 billion wasted every year on low-value care, according to a brief report published online Jan. 18 in Annals of Internal Medicine.

However, one expert said there are better ways to curb low-value care than focusing on which specialties are guilty of the practice.

Analyzing a 20% random sample of Medicare Part B claims, Aaron Baum, PhD, with the Icahn School of Medicine at Mount Sinai, New York, and colleagues found that the services primary care physicians performed or ordered made up on average 8.3% of the low-value care their patients received (interquartile range, 3.9%-15.1%; 95th percentile, 35.6%) and their referrals made up 15.4% (IQR, 6.3%-26.4%; 95th percentile, 44.6%).

By specialty, cardiology had the worst record with 27% of all spending on low-value services ($1.8 billion) attributed to that specialty. Yet, of the 25 highest-spending specialties in the report, 12 of them were associated with 1% or less than 1% each of all low-value spending, indicating the waste was widely distributed.

Dr. Baum said in an interview that though there are some PCPs guilty of high spending on low-value services, overall, most primary care physicians’ low-value services add up to only 0.3% of Part B spending. He noted that Part B spending is about one-third of all Medicare spending.

Primary care is often thought to be at the core of care management and spending and PCPs are often seen as the gatekeepers, but this analysis suggests that efforts to make big differences in curtailing low-value spending might be more effective elsewhere.

“There’s only so much spending you can reduce by changing primary care physicians’ services that they directly perform,” Dr. Baum said.
 

Low-value care is costly, can be harmful

Mark Fendrick, MD, director of the University of Michigan’s Center for Value-Based Insurance Design in Ann Arbor, said in an interview that the report adds confirmation to previous research that has consistently shown low-value care is “extremely common, very costly, and provided by primary care providers and specialists alike.” He noted that it can also be harmful.

“The math is simple,” he said. “If we want to improve coverage and lower patient costs for essential services like visits, diagnostic tests, and drugs, we have to reduce spending on those services that do not make Americans any healthier.”

The study ranked 31 clinical services judged to be low value by physician societies, Medicare and clinical guidelines, and their use among beneficiaries enrolled between 2007 and 2014. Here’s how the top six low-value services compare.

Dr. Fendrick said a weakness of the paper is the years of the data (2007-2014). Some of the criteria around low-value care have changed since then. The age that a prostate-specific antigen test becomes low-value is now 70 years, for instance, instead of 75. He added that some of the figures attributed to non-PCP providers appear out of date.

Dr. Fendrick said, “I understand that there are Medicare patients who end up at a gastroenterologist or surgeon’s office to get colorectal cancer screening, but it would be very hard for me to believe that half of stress tests and over half of colon cancer screening over [age] 85 [years] and half of PSA for people over 75 did not have some type of referring clinicians involved. I certainly don’t think that would be the case in 2020-2021.”

Dr. Baum said those years were the latest years available for the data points needed for this analysis, but he and his colleagues were working to update the data for future publication.

Dr. Fendrick said not much has changed in recent years in terms of waste on low-value care, even with campaigns such as Choosing Wisely dedicated to identifying low-value services or procedures in each specialty.

“I believe there’s not a particular group of clinicians one way or the other who are actually doing any better now than they were 7 years ago,” he said. He would rather focus less on which specialties are associated with the most low-value care and more on the underlying policies that encourage low-value care.

“If you’re going to get paid for doing a stress test and get paid nothing or significantly less if you don’t, the incentives are in the wrong direction,” he said.

Dr. Fendrick said the pandemic era provides an opportunity to eliminate low-value care because use of those services has dropped drastically as resources have been diverted to COVID-19 patients and many services have been delayed or canceled.

He said he has been pushing an approach that providers should be paid more after the pandemic “to do the things we want them to do.”

As an example, he said, instead of paying $886 million on colonoscopies for people over the age of 85, “why don’t we put a policy in place that would make it better for patients by lowering cost sharing and better for providers by paying them more to do the service on the people who need it as opposed to the people who don’t?”

The research was funded by the American Board of Family Medicine Foundation. Dr. Baum and a coauthor reported receiving personal fees from American Board of Family Medicine Foundation during the conduct of the study. Another coauthor reported receiving personal fees from Collective Health, HealthRight 360, PLOS Medicine, and the New England Journal of Medicine, outside the submitted work. Dr. Fendrick disclosed no relevant financial relationships.

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

Primary care physicians (PCPs) generate only a small part of the $75 billion to $100 billion wasted every year on low-value care, according to a brief report published online Jan. 18 in Annals of Internal Medicine.

However, one expert said there are better ways to curb low-value care than focusing on which specialties are guilty of the practice.

Analyzing a 20% random sample of Medicare Part B claims, Aaron Baum, PhD, with the Icahn School of Medicine at Mount Sinai, New York, and colleagues found that the services primary care physicians performed or ordered made up on average 8.3% of the low-value care their patients received (interquartile range, 3.9%-15.1%; 95th percentile, 35.6%) and their referrals made up 15.4% (IQR, 6.3%-26.4%; 95th percentile, 44.6%).

By specialty, cardiology had the worst record with 27% of all spending on low-value services ($1.8 billion) attributed to that specialty. Yet, of the 25 highest-spending specialties in the report, 12 of them were associated with 1% or less than 1% each of all low-value spending, indicating the waste was widely distributed.

Dr. Baum said in an interview that though there are some PCPs guilty of high spending on low-value services, overall, most primary care physicians’ low-value services add up to only 0.3% of Part B spending. He noted that Part B spending is about one-third of all Medicare spending.

Primary care is often thought to be at the core of care management and spending and PCPs are often seen as the gatekeepers, but this analysis suggests that efforts to make big differences in curtailing low-value spending might be more effective elsewhere.

“There’s only so much spending you can reduce by changing primary care physicians’ services that they directly perform,” Dr. Baum said.
 

Low-value care is costly, can be harmful

Mark Fendrick, MD, director of the University of Michigan’s Center for Value-Based Insurance Design in Ann Arbor, said in an interview that the report adds confirmation to previous research that has consistently shown low-value care is “extremely common, very costly, and provided by primary care providers and specialists alike.” He noted that it can also be harmful.

“The math is simple,” he said. “If we want to improve coverage and lower patient costs for essential services like visits, diagnostic tests, and drugs, we have to reduce spending on those services that do not make Americans any healthier.”

The study ranked 31 clinical services judged to be low value by physician societies, Medicare and clinical guidelines, and their use among beneficiaries enrolled between 2007 and 2014. Here’s how the top six low-value services compare.

Dr. Fendrick said a weakness of the paper is the years of the data (2007-2014). Some of the criteria around low-value care have changed since then. The age that a prostate-specific antigen test becomes low-value is now 70 years, for instance, instead of 75. He added that some of the figures attributed to non-PCP providers appear out of date.

Dr. Fendrick said, “I understand that there are Medicare patients who end up at a gastroenterologist or surgeon’s office to get colorectal cancer screening, but it would be very hard for me to believe that half of stress tests and over half of colon cancer screening over [age] 85 [years] and half of PSA for people over 75 did not have some type of referring clinicians involved. I certainly don’t think that would be the case in 2020-2021.”

Dr. Baum said those years were the latest years available for the data points needed for this analysis, but he and his colleagues were working to update the data for future publication.

Dr. Fendrick said not much has changed in recent years in terms of waste on low-value care, even with campaigns such as Choosing Wisely dedicated to identifying low-value services or procedures in each specialty.

“I believe there’s not a particular group of clinicians one way or the other who are actually doing any better now than they were 7 years ago,” he said. He would rather focus less on which specialties are associated with the most low-value care and more on the underlying policies that encourage low-value care.

“If you’re going to get paid for doing a stress test and get paid nothing or significantly less if you don’t, the incentives are in the wrong direction,” he said.

Dr. Fendrick said the pandemic era provides an opportunity to eliminate low-value care because use of those services has dropped drastically as resources have been diverted to COVID-19 patients and many services have been delayed or canceled.

He said he has been pushing an approach that providers should be paid more after the pandemic “to do the things we want them to do.”

As an example, he said, instead of paying $886 million on colonoscopies for people over the age of 85, “why don’t we put a policy in place that would make it better for patients by lowering cost sharing and better for providers by paying them more to do the service on the people who need it as opposed to the people who don’t?”

The research was funded by the American Board of Family Medicine Foundation. Dr. Baum and a coauthor reported receiving personal fees from American Board of Family Medicine Foundation during the conduct of the study. Another coauthor reported receiving personal fees from Collective Health, HealthRight 360, PLOS Medicine, and the New England Journal of Medicine, outside the submitted work. Dr. Fendrick disclosed no relevant financial relationships.

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

Primary care physicians (PCPs) generate only a small part of the $75 billion to $100 billion wasted every year on low-value care, according to a brief report published online Jan. 18 in Annals of Internal Medicine.

However, one expert said there are better ways to curb low-value care than focusing on which specialties are guilty of the practice.

Analyzing a 20% random sample of Medicare Part B claims, Aaron Baum, PhD, with the Icahn School of Medicine at Mount Sinai, New York, and colleagues found that the services primary care physicians performed or ordered made up on average 8.3% of the low-value care their patients received (interquartile range, 3.9%-15.1%; 95th percentile, 35.6%) and their referrals made up 15.4% (IQR, 6.3%-26.4%; 95th percentile, 44.6%).

By specialty, cardiology had the worst record with 27% of all spending on low-value services ($1.8 billion) attributed to that specialty. Yet, of the 25 highest-spending specialties in the report, 12 of them were associated with 1% or less than 1% each of all low-value spending, indicating the waste was widely distributed.

Dr. Baum said in an interview that though there are some PCPs guilty of high spending on low-value services, overall, most primary care physicians’ low-value services add up to only 0.3% of Part B spending. He noted that Part B spending is about one-third of all Medicare spending.

Primary care is often thought to be at the core of care management and spending and PCPs are often seen as the gatekeepers, but this analysis suggests that efforts to make big differences in curtailing low-value spending might be more effective elsewhere.

“There’s only so much spending you can reduce by changing primary care physicians’ services that they directly perform,” Dr. Baum said.
 

Low-value care is costly, can be harmful

Mark Fendrick, MD, director of the University of Michigan’s Center for Value-Based Insurance Design in Ann Arbor, said in an interview that the report adds confirmation to previous research that has consistently shown low-value care is “extremely common, very costly, and provided by primary care providers and specialists alike.” He noted that it can also be harmful.

“The math is simple,” he said. “If we want to improve coverage and lower patient costs for essential services like visits, diagnostic tests, and drugs, we have to reduce spending on those services that do not make Americans any healthier.”

The study ranked 31 clinical services judged to be low value by physician societies, Medicare and clinical guidelines, and their use among beneficiaries enrolled between 2007 and 2014. Here’s how the top six low-value services compare.

Dr. Fendrick said a weakness of the paper is the years of the data (2007-2014). Some of the criteria around low-value care have changed since then. The age that a prostate-specific antigen test becomes low-value is now 70 years, for instance, instead of 75. He added that some of the figures attributed to non-PCP providers appear out of date.

Dr. Fendrick said, “I understand that there are Medicare patients who end up at a gastroenterologist or surgeon’s office to get colorectal cancer screening, but it would be very hard for me to believe that half of stress tests and over half of colon cancer screening over [age] 85 [years] and half of PSA for people over 75 did not have some type of referring clinicians involved. I certainly don’t think that would be the case in 2020-2021.”

Dr. Baum said those years were the latest years available for the data points needed for this analysis, but he and his colleagues were working to update the data for future publication.

Dr. Fendrick said not much has changed in recent years in terms of waste on low-value care, even with campaigns such as Choosing Wisely dedicated to identifying low-value services or procedures in each specialty.

“I believe there’s not a particular group of clinicians one way or the other who are actually doing any better now than they were 7 years ago,” he said. He would rather focus less on which specialties are associated with the most low-value care and more on the underlying policies that encourage low-value care.

“If you’re going to get paid for doing a stress test and get paid nothing or significantly less if you don’t, the incentives are in the wrong direction,” he said.

Dr. Fendrick said the pandemic era provides an opportunity to eliminate low-value care because use of those services has dropped drastically as resources have been diverted to COVID-19 patients and many services have been delayed or canceled.

He said he has been pushing an approach that providers should be paid more after the pandemic “to do the things we want them to do.”

As an example, he said, instead of paying $886 million on colonoscopies for people over the age of 85, “why don’t we put a policy in place that would make it better for patients by lowering cost sharing and better for providers by paying them more to do the service on the people who need it as opposed to the people who don’t?”

The research was funded by the American Board of Family Medicine Foundation. Dr. Baum and a coauthor reported receiving personal fees from American Board of Family Medicine Foundation during the conduct of the study. Another coauthor reported receiving personal fees from Collective Health, HealthRight 360, PLOS Medicine, and the New England Journal of Medicine, outside the submitted work. Dr. Fendrick disclosed no relevant financial relationships.

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

President Joe Biden kicked off his new administration Jan. 20 with an immediate focus on attempts to stop the spread of COVID-19, including closer coordination with other nations.

Mr. Biden signed 17 executive orders, memoranda, and directives addressing not only the pandemic but also economic concerns, climate change, and racial inequity.

At the top of the list of actions was what his transition team called a “100 Days Masking Challenge.” Mr. Biden issued an executive order requiring masks and physical distancing in all federal buildings, on all federal lands, and by federal employees and contractors.

The president also halted the Trump administration’s process of withdrawing from the World Health Organization. Instead, Mr. Biden named Anthony Fauci, MD, the director of the National Institute for Allergy and Infectious Diseases, as the head of a delegation to participate in the WHO executive board meeting that is being held this week.

Mr. Biden also signed an executive order creating the position of COVID-19 response coordinator, which will report directly to the president and be responsible for coordinating all elements of the COVID-19 response across government, including the production and distribution of vaccines and medical supplies.

The newly inaugurated president also intends to restore the National Security Council’s Directorate for Global Health Security and Biodefense, which will aid in the response to the pandemic, his transition team said.

The American Medical Association was among the first to commend the first-day actions.

“Defeating COVID-19 requires bold, coordinated federal leadership and strong adherence to the public health steps we know stop the spread of this virus – wearing masks, practicing physical distancing, and washing hands,” said AMA President Susan R. Bailey, MD in a news release. “We are pleased by the Biden administration’s steps today, including universal mask wearing within federal jurisdictions, providing federal leadership for COVID-19 response, and reengaging with the World Health Organization. Taking these actions on day 1 of the administration sends the right message – that our nation is laser focused on stopping the ravages of COVID-19.”

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

President Joe Biden kicked off his new administration Jan. 20 with an immediate focus on attempts to stop the spread of COVID-19, including closer coordination with other nations.

Mr. Biden signed 17 executive orders, memoranda, and directives addressing not only the pandemic but also economic concerns, climate change, and racial inequity.

At the top of the list of actions was what his transition team called a “100 Days Masking Challenge.” Mr. Biden issued an executive order requiring masks and physical distancing in all federal buildings, on all federal lands, and by federal employees and contractors.

The president also halted the Trump administration’s process of withdrawing from the World Health Organization. Instead, Mr. Biden named Anthony Fauci, MD, the director of the National Institute for Allergy and Infectious Diseases, as the head of a delegation to participate in the WHO executive board meeting that is being held this week.

Mr. Biden also signed an executive order creating the position of COVID-19 response coordinator, which will report directly to the president and be responsible for coordinating all elements of the COVID-19 response across government, including the production and distribution of vaccines and medical supplies.

The newly inaugurated president also intends to restore the National Security Council’s Directorate for Global Health Security and Biodefense, which will aid in the response to the pandemic, his transition team said.

The American Medical Association was among the first to commend the first-day actions.

“Defeating COVID-19 requires bold, coordinated federal leadership and strong adherence to the public health steps we know stop the spread of this virus – wearing masks, practicing physical distancing, and washing hands,” said AMA President Susan R. Bailey, MD in a news release. “We are pleased by the Biden administration’s steps today, including universal mask wearing within federal jurisdictions, providing federal leadership for COVID-19 response, and reengaging with the World Health Organization. Taking these actions on day 1 of the administration sends the right message – that our nation is laser focused on stopping the ravages of COVID-19.”

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

President Joe Biden kicked off his new administration Jan. 20 with an immediate focus on attempts to stop the spread of COVID-19, including closer coordination with other nations.

Mr. Biden signed 17 executive orders, memoranda, and directives addressing not only the pandemic but also economic concerns, climate change, and racial inequity.

At the top of the list of actions was what his transition team called a “100 Days Masking Challenge.” Mr. Biden issued an executive order requiring masks and physical distancing in all federal buildings, on all federal lands, and by federal employees and contractors.

The president also halted the Trump administration’s process of withdrawing from the World Health Organization. Instead, Mr. Biden named Anthony Fauci, MD, the director of the National Institute for Allergy and Infectious Diseases, as the head of a delegation to participate in the WHO executive board meeting that is being held this week.

Mr. Biden also signed an executive order creating the position of COVID-19 response coordinator, which will report directly to the president and be responsible for coordinating all elements of the COVID-19 response across government, including the production and distribution of vaccines and medical supplies.

The newly inaugurated president also intends to restore the National Security Council’s Directorate for Global Health Security and Biodefense, which will aid in the response to the pandemic, his transition team said.

The American Medical Association was among the first to commend the first-day actions.

“Defeating COVID-19 requires bold, coordinated federal leadership and strong adherence to the public health steps we know stop the spread of this virus – wearing masks, practicing physical distancing, and washing hands,” said AMA President Susan R. Bailey, MD in a news release. “We are pleased by the Biden administration’s steps today, including universal mask wearing within federal jurisdictions, providing federal leadership for COVID-19 response, and reengaging with the World Health Organization. Taking these actions on day 1 of the administration sends the right message – that our nation is laser focused on stopping the ravages of COVID-19.”

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

While some guidelines support serotonin norepinephrine reuptake inhibitors (SNRIs) as treatments for back pain, a new systematic review and meta-analysis of existing research found no firm evidence of a benefit. Adverse effects, however, are common.

“Our review shows that, although these medicines are effective, the effect is small and unlikely to be considered clinically important by most patients,” wrote the authors of the review, which appeared Jan. 20 in the BMJ. “Our review also showed that about two-thirds of patients using SNRIs experience adverse events.”

However, the report hinted that certain classes of antidepressants may provide significant relief in knee OA and sciatica.

According to a 2018 review, 10 of 15 clinical guidelines from around the world – including those of the American College of Physicians – recommended antidepressants as treatments for low back pain, and 2 advised against them. “Evidence supporting the use of antidepressants is, however, uncertain,” wrote the authors of the new review, led by Giovanni E. Ferreira, PhD, of the University of Sydney. “Systematic reviews of antidepressants for back pain and osteoarthritis have either not included several published trials, considered only one type of antidepressant (e.g., duloxetine), or failed to assess the certainty of evidence.”

For the new review, the authors analyzed 33 randomized, controlled trials with a total of 5,318 subjects. Both published data and unpublished data from clinical trial registries were included.
 

Back pain trials

A total of 19 trials examined back pain, mostly lower back pain (16 trials), and none lasted more than 1 year. Fifteen examined SNRIs while others looked at other kinds of antidepressants.

The researchers found that “the effect of SNRIs was small [on back pain] and below this review’s predetermined threshold of clinical importance. ... Evidence ranging from low to very low certainty showed no benefit of a range of antidepressant classes, including SSRIs [selective serotonin reuptake inhibitors], tetracyclic antidepressants, SARIs [serotonin antagonist and reuptake inhibitors], and NDRIs [norepinephrine and dopamine reuptake inhibitors] for pain and disability across follow-ups of 2 weeks or less, 3-13 weeks, and 3-12 months.”
 

Sciatica trials

Six trials examined antidepressants as treatments for sciatica. Very-low-certainty evidence suggested that SNRIs reduced pain at up to 2 weeks (1 trial, n = 50) but not at 3-13 weeks (3 trials, n = 96). The results of trials of tricyclic antidepressants (TCAs) were the opposite: low- to very-low-certainty evidence suggested the drugs didn’t reduce pain at up to 2 weeks (2 trials, n = 94) but did at 3-13 weeks (2 trials, n = 114) and 3-12 months (1 trial, n = 60).

“All sciatica trials were small, had imprecise estimates, and were at high risk of bias, which reduced the certainty of evidence to low and very low,” the authors cautioned. “This level of uncertainty indicates that the true estimate of effect of TCAs and SNRIs for sciatica is likely to be substantially different from what we estimated in our review.”
 

Knee OA trials

Eight trials examined SNRIs in knee OA. Moderate-certainty evidence linked the drugs to less pain at up to 2 weeks (four trials, n = 1,328) and low-certainty evidence linked them to less pain at 3-13 weeks (eight trials, n = 1,941). Low-certainty evidence also linked the drugs to less disability at 2 weeks or less (one trial, n = 353) and 3-13 weeks (seven trials, n = 1,810).

In knee OA, “the effect of SNRIs was small and below this review’s predetermined threshold of clinical importance,” the researchers wrote. “However, the lower limit of the confidence interval did contain clinically important effects for pain, but not for disability.”
 

Antidepressant side effects in trials

A total of 21 trials (n = 4,107) looked at side effects when antidepressants were studied as treatments for back pain and OA. Low-certainty evidence in 13 SNRI trials (n = 3,447) suggested a higher risk of any adverse events in antidepressant versus placebo (62.5% vs. 49.7%; relative risk, 1.23, 95% confidence interval, 1.16-1.30), but there was no significantly higher risk of serious adverse events in 10 SNRI trials with 3,309 subjects (1.6% vs. 1.3%; RR, 1.12, 95% CI, 0.61-2.07).

As for adverse effects of non-SNRIs, “the number of studies evaluating the safety of other antidepressant classes was small, trials were underpowered to detect harm, and the certainty of evidence ranged from low to very low,” the researchers wrote.

Going forward, the authors said that “large, definitive randomized trials that are free of industry ties are urgently needed to resolve uncertainties about the efficacy of antidepressants for sciatica and osteoarthritis highlighted by this review.”
 

‘Largely ineffective’ drug treatments

In an accompanying commentary, Martin Underwood, of the University of Warwick in Coventry, England, and Colin Tysall, of the University Hospitals of Coventry and Warwickshire, also in Coventry, noted that “drug treatments are largely ineffective for back pain and osteoarthritis and have the potential for serious harm. We need to work harder to help people with these disorders to live better with their pain without recourse to the prescription pad.”

However, they noted that SNRIs may still be helpful for patients with back pain or OA. “Absolute effect sizes for physical treatments for low-back pain are of similar magnitudes to those reported here and translate into numbers needed to treat of between five and nine. If the same were true for SNRIs, some people might choose to a try that option for a 1 in 10 chance of a worthwhile reduction in pain after 3 months. They can easily stop if treatment is ineffective or does not suit them.”

The research received no specific funding. The review authors disclosed relationships with GlaxoSmithKline (postgraduate scholarship), Pfizer (investigational product for two trials), and Flexeze (provision of heat wraps for a trial). Mr. Underwood reported being a director and shareholder of Clinvivo. Mr. Tysall reported no disclosures.

While some guidelines support serotonin norepinephrine reuptake inhibitors (SNRIs) as treatments for back pain, a new systematic review and meta-analysis of existing research found no firm evidence of a benefit. Adverse effects, however, are common.

“Our review shows that, although these medicines are effective, the effect is small and unlikely to be considered clinically important by most patients,” wrote the authors of the review, which appeared Jan. 20 in the BMJ. “Our review also showed that about two-thirds of patients using SNRIs experience adverse events.”

However, the report hinted that certain classes of antidepressants may provide significant relief in knee OA and sciatica.

According to a 2018 review, 10 of 15 clinical guidelines from around the world – including those of the American College of Physicians – recommended antidepressants as treatments for low back pain, and 2 advised against them. “Evidence supporting the use of antidepressants is, however, uncertain,” wrote the authors of the new review, led by Giovanni E. Ferreira, PhD, of the University of Sydney. “Systematic reviews of antidepressants for back pain and osteoarthritis have either not included several published trials, considered only one type of antidepressant (e.g., duloxetine), or failed to assess the certainty of evidence.”

For the new review, the authors analyzed 33 randomized, controlled trials with a total of 5,318 subjects. Both published data and unpublished data from clinical trial registries were included.
 

Back pain trials

A total of 19 trials examined back pain, mostly lower back pain (16 trials), and none lasted more than 1 year. Fifteen examined SNRIs while others looked at other kinds of antidepressants.

The researchers found that “the effect of SNRIs was small [on back pain] and below this review’s predetermined threshold of clinical importance. ... Evidence ranging from low to very low certainty showed no benefit of a range of antidepressant classes, including SSRIs [selective serotonin reuptake inhibitors], tetracyclic antidepressants, SARIs [serotonin antagonist and reuptake inhibitors], and NDRIs [norepinephrine and dopamine reuptake inhibitors] for pain and disability across follow-ups of 2 weeks or less, 3-13 weeks, and 3-12 months.”
 

Sciatica trials

Six trials examined antidepressants as treatments for sciatica. Very-low-certainty evidence suggested that SNRIs reduced pain at up to 2 weeks (1 trial, n = 50) but not at 3-13 weeks (3 trials, n = 96). The results of trials of tricyclic antidepressants (TCAs) were the opposite: low- to very-low-certainty evidence suggested the drugs didn’t reduce pain at up to 2 weeks (2 trials, n = 94) but did at 3-13 weeks (2 trials, n = 114) and 3-12 months (1 trial, n = 60).

“All sciatica trials were small, had imprecise estimates, and were at high risk of bias, which reduced the certainty of evidence to low and very low,” the authors cautioned. “This level of uncertainty indicates that the true estimate of effect of TCAs and SNRIs for sciatica is likely to be substantially different from what we estimated in our review.”
 

Knee OA trials

Eight trials examined SNRIs in knee OA. Moderate-certainty evidence linked the drugs to less pain at up to 2 weeks (four trials, n = 1,328) and low-certainty evidence linked them to less pain at 3-13 weeks (eight trials, n = 1,941). Low-certainty evidence also linked the drugs to less disability at 2 weeks or less (one trial, n = 353) and 3-13 weeks (seven trials, n = 1,810).

In knee OA, “the effect of SNRIs was small and below this review’s predetermined threshold of clinical importance,” the researchers wrote. “However, the lower limit of the confidence interval did contain clinically important effects for pain, but not for disability.”
 

Antidepressant side effects in trials

A total of 21 trials (n = 4,107) looked at side effects when antidepressants were studied as treatments for back pain and OA. Low-certainty evidence in 13 SNRI trials (n = 3,447) suggested a higher risk of any adverse events in antidepressant versus placebo (62.5% vs. 49.7%; relative risk, 1.23, 95% confidence interval, 1.16-1.30), but there was no significantly higher risk of serious adverse events in 10 SNRI trials with 3,309 subjects (1.6% vs. 1.3%; RR, 1.12, 95% CI, 0.61-2.07).

As for adverse effects of non-SNRIs, “the number of studies evaluating the safety of other antidepressant classes was small, trials were underpowered to detect harm, and the certainty of evidence ranged from low to very low,” the researchers wrote.

Going forward, the authors said that “large, definitive randomized trials that are free of industry ties are urgently needed to resolve uncertainties about the efficacy of antidepressants for sciatica and osteoarthritis highlighted by this review.”
 

‘Largely ineffective’ drug treatments

In an accompanying commentary, Martin Underwood, of the University of Warwick in Coventry, England, and Colin Tysall, of the University Hospitals of Coventry and Warwickshire, also in Coventry, noted that “drug treatments are largely ineffective for back pain and osteoarthritis and have the potential for serious harm. We need to work harder to help people with these disorders to live better with their pain without recourse to the prescription pad.”

However, they noted that SNRIs may still be helpful for patients with back pain or OA. “Absolute effect sizes for physical treatments for low-back pain are of similar magnitudes to those reported here and translate into numbers needed to treat of between five and nine. If the same were true for SNRIs, some people might choose to a try that option for a 1 in 10 chance of a worthwhile reduction in pain after 3 months. They can easily stop if treatment is ineffective or does not suit them.”

The research received no specific funding. The review authors disclosed relationships with GlaxoSmithKline (postgraduate scholarship), Pfizer (investigational product for two trials), and Flexeze (provision of heat wraps for a trial). Mr. Underwood reported being a director and shareholder of Clinvivo. Mr. Tysall reported no disclosures.

While some guidelines support serotonin norepinephrine reuptake inhibitors (SNRIs) as treatments for back pain, a new systematic review and meta-analysis of existing research found no firm evidence of a benefit. Adverse effects, however, are common.

“Our review shows that, although these medicines are effective, the effect is small and unlikely to be considered clinically important by most patients,” wrote the authors of the review, which appeared Jan. 20 in the BMJ. “Our review also showed that about two-thirds of patients using SNRIs experience adverse events.”

However, the report hinted that certain classes of antidepressants may provide significant relief in knee OA and sciatica.

According to a 2018 review, 10 of 15 clinical guidelines from around the world – including those of the American College of Physicians – recommended antidepressants as treatments for low back pain, and 2 advised against them. “Evidence supporting the use of antidepressants is, however, uncertain,” wrote the authors of the new review, led by Giovanni E. Ferreira, PhD, of the University of Sydney. “Systematic reviews of antidepressants for back pain and osteoarthritis have either not included several published trials, considered only one type of antidepressant (e.g., duloxetine), or failed to assess the certainty of evidence.”

For the new review, the authors analyzed 33 randomized, controlled trials with a total of 5,318 subjects. Both published data and unpublished data from clinical trial registries were included.
 

Back pain trials

A total of 19 trials examined back pain, mostly lower back pain (16 trials), and none lasted more than 1 year. Fifteen examined SNRIs while others looked at other kinds of antidepressants.

The researchers found that “the effect of SNRIs was small [on back pain] and below this review’s predetermined threshold of clinical importance. ... Evidence ranging from low to very low certainty showed no benefit of a range of antidepressant classes, including SSRIs [selective serotonin reuptake inhibitors], tetracyclic antidepressants, SARIs [serotonin antagonist and reuptake inhibitors], and NDRIs [norepinephrine and dopamine reuptake inhibitors] for pain and disability across follow-ups of 2 weeks or less, 3-13 weeks, and 3-12 months.”
 

Sciatica trials

Six trials examined antidepressants as treatments for sciatica. Very-low-certainty evidence suggested that SNRIs reduced pain at up to 2 weeks (1 trial, n = 50) but not at 3-13 weeks (3 trials, n = 96). The results of trials of tricyclic antidepressants (TCAs) were the opposite: low- to very-low-certainty evidence suggested the drugs didn’t reduce pain at up to 2 weeks (2 trials, n = 94) but did at 3-13 weeks (2 trials, n = 114) and 3-12 months (1 trial, n = 60).

“All sciatica trials were small, had imprecise estimates, and were at high risk of bias, which reduced the certainty of evidence to low and very low,” the authors cautioned. “This level of uncertainty indicates that the true estimate of effect of TCAs and SNRIs for sciatica is likely to be substantially different from what we estimated in our review.”
 

Knee OA trials

Eight trials examined SNRIs in knee OA. Moderate-certainty evidence linked the drugs to less pain at up to 2 weeks (four trials, n = 1,328) and low-certainty evidence linked them to less pain at 3-13 weeks (eight trials, n = 1,941). Low-certainty evidence also linked the drugs to less disability at 2 weeks or less (one trial, n = 353) and 3-13 weeks (seven trials, n = 1,810).

In knee OA, “the effect of SNRIs was small and below this review’s predetermined threshold of clinical importance,” the researchers wrote. “However, the lower limit of the confidence interval did contain clinically important effects for pain, but not for disability.”
 

Antidepressant side effects in trials

A total of 21 trials (n = 4,107) looked at side effects when antidepressants were studied as treatments for back pain and OA. Low-certainty evidence in 13 SNRI trials (n = 3,447) suggested a higher risk of any adverse events in antidepressant versus placebo (62.5% vs. 49.7%; relative risk, 1.23, 95% confidence interval, 1.16-1.30), but there was no significantly higher risk of serious adverse events in 10 SNRI trials with 3,309 subjects (1.6% vs. 1.3%; RR, 1.12, 95% CI, 0.61-2.07).

As for adverse effects of non-SNRIs, “the number of studies evaluating the safety of other antidepressant classes was small, trials were underpowered to detect harm, and the certainty of evidence ranged from low to very low,” the researchers wrote.

Going forward, the authors said that “large, definitive randomized trials that are free of industry ties are urgently needed to resolve uncertainties about the efficacy of antidepressants for sciatica and osteoarthritis highlighted by this review.”
 

‘Largely ineffective’ drug treatments

In an accompanying commentary, Martin Underwood, of the University of Warwick in Coventry, England, and Colin Tysall, of the University Hospitals of Coventry and Warwickshire, also in Coventry, noted that “drug treatments are largely ineffective for back pain and osteoarthritis and have the potential for serious harm. We need to work harder to help people with these disorders to live better with their pain without recourse to the prescription pad.”

However, they noted that SNRIs may still be helpful for patients with back pain or OA. “Absolute effect sizes for physical treatments for low-back pain are of similar magnitudes to those reported here and translate into numbers needed to treat of between five and nine. If the same were true for SNRIs, some people might choose to a try that option for a 1 in 10 chance of a worthwhile reduction in pain after 3 months. They can easily stop if treatment is ineffective or does not suit them.”

The research received no specific funding. The review authors disclosed relationships with GlaxoSmithKline (postgraduate scholarship), Pfizer (investigational product for two trials), and Flexeze (provision of heat wraps for a trial). Mr. Underwood reported being a director and shareholder of Clinvivo. Mr. Tysall reported no disclosures.

Until now, the neurological manifestations of COVID-19 have been believed to be a result of direct damage to nerve cells. However, a new study suggests that the virus might actually damage the brain’s small blood vessels rather than nerve cells themselves.

A postmortem analysis found abnormalities in the brains of a small sample of patients with COVID-19, suggesting inflammation and vascular damage to the brain stem and olfactory bulb. The findings add further weight to previous research into neurological complications from COVID-19, according to Anna Cervantes, MD. Dr. Cervantes is assistant professor of neurology at the Boston University and has been studying the neurological effects of COVID-19, though she was not involved in this study. “I can tell from my personal experience, and things we’ve published on and the literature that’s out there – there are patients that are having complications like stroke that aren’t even critically ill from COVID. We’re seeing that not in just the acute setting, but also in a delayed fashion. Even though most of the coagulopathy is largely venous and probably microvascular, this does affect the brain through a myriad of ways,” Dr. Cervantes said.

The research was published online Jan. 12 in the New England Journal of Medicine. Myoung‑Hwa Lee, PhD, was the lead author.

The study included high resolution magnetic resonance imaging and histopathological examination of 13 individuals with a median age of 50 years. Among 10 patients with brain alterations, the researchers conducted further studies in 5 individuals using multiplex fluorescence imaging and chromogenic immunostaining in all 10.

The team conducted conventional histopathology on the brains of 18 individuals. Fourteen had a history of chronic illness, including diabetes, and hypertension, and 11 had died unexpectedly or been found dead. Magnetic resonance microscopy revealed punctuate hypo-intensities in nine subjects, indicating microvascular injury and fibrinogen leakage. Histopathology using fluorescence imaging showed the same features. Collagen IV immunostaining showed thinning of the basal lamina of the endothelial cells in five patients. Ten patients had congested blood vessels and surrounding fibrinogen leakage, but comparatively intact vasculature. The researchers interpreted linear hypo-intensities as micro-hemorrhages.

The researchers found little perivascular inflammation, and no vascular occlusion. Thirteen subjects had perivascular-activated microglia, macrophage infiltrates, and hypertrophic astrocytes. Eight had CD3+ and CD8+ T cells in the perivascular spaces and in lumens next to endothelial cells, which could help explain vascular injury.

The researchers found no evidence of the SARS-CoV-2 virus itself, despite efforts using polymerase chain reaction with multiple primer sets, RNA sequencing within the brain, or RNA in situ hybridization and immunostaining. Subjects may have cleared the virus by the time they died, or viral copy numbers could have been below the detection limit of the assays.

The researchers also obtained a convenience sample of subjects who had died from COVID-19. Magnetic resonance microscopy, histopathology, and immunohistochemical analysis of sections revealed microvascular injury in the brain and olfactory bulb, despite no evidence of viral infection. The authors stressed that they could not draw conclusions about the neurological features of COVID-19 because of a lack of clinical information.

Dr. Cervantes noted that limitation: “We’re seeing a lot of patients with encephalopathy or alterations in their mental status. A lot of things can cause that, and some are common in patients who are critically ill, like medications and metabolic derangement.”

Still, the findings could help to inform future medical management. “There’s going to be a large number of patients who don’t have really bad pulmonary disease but still may have encephalopathy. So if there is small vessel involvement because of inflammation that we might not necessarily catch in a lumbar puncture or routine imaging, there’s still somebody we can make better (using) steroids. Having more information on what’s happening on a pathophysiologic level and on pathology is really helpful.”

The study was supported by internal funds from the National Institute of Neurological Disorders and Stroke. Dr. Cervantes has no relevant financial disclosures.

Until now, the neurological manifestations of COVID-19 have been believed to be a result of direct damage to nerve cells. However, a new study suggests that the virus might actually damage the brain’s small blood vessels rather than nerve cells themselves.

A postmortem analysis found abnormalities in the brains of a small sample of patients with COVID-19, suggesting inflammation and vascular damage to the brain stem and olfactory bulb. The findings add further weight to previous research into neurological complications from COVID-19, according to Anna Cervantes, MD. Dr. Cervantes is assistant professor of neurology at the Boston University and has been studying the neurological effects of COVID-19, though she was not involved in this study. “I can tell from my personal experience, and things we’ve published on and the literature that’s out there – there are patients that are having complications like stroke that aren’t even critically ill from COVID. We’re seeing that not in just the acute setting, but also in a delayed fashion. Even though most of the coagulopathy is largely venous and probably microvascular, this does affect the brain through a myriad of ways,” Dr. Cervantes said.

The research was published online Jan. 12 in the New England Journal of Medicine. Myoung‑Hwa Lee, PhD, was the lead author.

The study included high resolution magnetic resonance imaging and histopathological examination of 13 individuals with a median age of 50 years. Among 10 patients with brain alterations, the researchers conducted further studies in 5 individuals using multiplex fluorescence imaging and chromogenic immunostaining in all 10.

The team conducted conventional histopathology on the brains of 18 individuals. Fourteen had a history of chronic illness, including diabetes, and hypertension, and 11 had died unexpectedly or been found dead. Magnetic resonance microscopy revealed punctuate hypo-intensities in nine subjects, indicating microvascular injury and fibrinogen leakage. Histopathology using fluorescence imaging showed the same features. Collagen IV immunostaining showed thinning of the basal lamina of the endothelial cells in five patients. Ten patients had congested blood vessels and surrounding fibrinogen leakage, but comparatively intact vasculature. The researchers interpreted linear hypo-intensities as micro-hemorrhages.

The researchers found little perivascular inflammation, and no vascular occlusion. Thirteen subjects had perivascular-activated microglia, macrophage infiltrates, and hypertrophic astrocytes. Eight had CD3+ and CD8+ T cells in the perivascular spaces and in lumens next to endothelial cells, which could help explain vascular injury.

The researchers found no evidence of the SARS-CoV-2 virus itself, despite efforts using polymerase chain reaction with multiple primer sets, RNA sequencing within the brain, or RNA in situ hybridization and immunostaining. Subjects may have cleared the virus by the time they died, or viral copy numbers could have been below the detection limit of the assays.

The researchers also obtained a convenience sample of subjects who had died from COVID-19. Magnetic resonance microscopy, histopathology, and immunohistochemical analysis of sections revealed microvascular injury in the brain and olfactory bulb, despite no evidence of viral infection. The authors stressed that they could not draw conclusions about the neurological features of COVID-19 because of a lack of clinical information.

Dr. Cervantes noted that limitation: “We’re seeing a lot of patients with encephalopathy or alterations in their mental status. A lot of things can cause that, and some are common in patients who are critically ill, like medications and metabolic derangement.”

Still, the findings could help to inform future medical management. “There’s going to be a large number of patients who don’t have really bad pulmonary disease but still may have encephalopathy. So if there is small vessel involvement because of inflammation that we might not necessarily catch in a lumbar puncture or routine imaging, there’s still somebody we can make better (using) steroids. Having more information on what’s happening on a pathophysiologic level and on pathology is really helpful.”

The study was supported by internal funds from the National Institute of Neurological Disorders and Stroke. Dr. Cervantes has no relevant financial disclosures.

Until now, the neurological manifestations of COVID-19 have been believed to be a result of direct damage to nerve cells. However, a new study suggests that the virus might actually damage the brain’s small blood vessels rather than nerve cells themselves.

A postmortem analysis found abnormalities in the brains of a small sample of patients with COVID-19, suggesting inflammation and vascular damage to the brain stem and olfactory bulb. The findings add further weight to previous research into neurological complications from COVID-19, according to Anna Cervantes, MD. Dr. Cervantes is assistant professor of neurology at the Boston University and has been studying the neurological effects of COVID-19, though she was not involved in this study. “I can tell from my personal experience, and things we’ve published on and the literature that’s out there – there are patients that are having complications like stroke that aren’t even critically ill from COVID. We’re seeing that not in just the acute setting, but also in a delayed fashion. Even though most of the coagulopathy is largely venous and probably microvascular, this does affect the brain through a myriad of ways,” Dr. Cervantes said.

The research was published online Jan. 12 in the New England Journal of Medicine. Myoung‑Hwa Lee, PhD, was the lead author.

The study included high resolution magnetic resonance imaging and histopathological examination of 13 individuals with a median age of 50 years. Among 10 patients with brain alterations, the researchers conducted further studies in 5 individuals using multiplex fluorescence imaging and chromogenic immunostaining in all 10.

The team conducted conventional histopathology on the brains of 18 individuals. Fourteen had a history of chronic illness, including diabetes, and hypertension, and 11 had died unexpectedly or been found dead. Magnetic resonance microscopy revealed punctuate hypo-intensities in nine subjects, indicating microvascular injury and fibrinogen leakage. Histopathology using fluorescence imaging showed the same features. Collagen IV immunostaining showed thinning of the basal lamina of the endothelial cells in five patients. Ten patients had congested blood vessels and surrounding fibrinogen leakage, but comparatively intact vasculature. The researchers interpreted linear hypo-intensities as micro-hemorrhages.

The researchers found little perivascular inflammation, and no vascular occlusion. Thirteen subjects had perivascular-activated microglia, macrophage infiltrates, and hypertrophic astrocytes. Eight had CD3+ and CD8+ T cells in the perivascular spaces and in lumens next to endothelial cells, which could help explain vascular injury.

The researchers found no evidence of the SARS-CoV-2 virus itself, despite efforts using polymerase chain reaction with multiple primer sets, RNA sequencing within the brain, or RNA in situ hybridization and immunostaining. Subjects may have cleared the virus by the time they died, or viral copy numbers could have been below the detection limit of the assays.

The researchers also obtained a convenience sample of subjects who had died from COVID-19. Magnetic resonance microscopy, histopathology, and immunohistochemical analysis of sections revealed microvascular injury in the brain and olfactory bulb, despite no evidence of viral infection. The authors stressed that they could not draw conclusions about the neurological features of COVID-19 because of a lack of clinical information.

Dr. Cervantes noted that limitation: “We’re seeing a lot of patients with encephalopathy or alterations in their mental status. A lot of things can cause that, and some are common in patients who are critically ill, like medications and metabolic derangement.”

Still, the findings could help to inform future medical management. “There’s going to be a large number of patients who don’t have really bad pulmonary disease but still may have encephalopathy. So if there is small vessel involvement because of inflammation that we might not necessarily catch in a lumbar puncture or routine imaging, there’s still somebody we can make better (using) steroids. Having more information on what’s happening on a pathophysiologic level and on pathology is really helpful.”

The study was supported by internal funds from the National Institute of Neurological Disorders and Stroke. Dr. Cervantes has no relevant financial disclosures.

How much do I make compared with other doctors?

I see questions like that on surveys I get, asking me to fill something out on the Internet, then I’ll get back a list of how well other docs in my field/city/state/blood type are doing.

Nah. I’ll pass.

Realistically, why? So I can feel I’m superior or inferior to others? Isn’t keeping up with the Joneses the purpose of the doctors’ parking lot at the hospital? (Actually, the number of pricey cars there has dropped off over time).

I really don’t want to know how much others make. It’s probably more than what I make, but that’s the trade-off I accepted when I went with a small solo practice instead of a large group 20 years ago.

We become so obsessed with the question of “how much money should I be making?” and comparing it with the salaries of others that we lose track of the real question: “How much money do I need?”

That should be the real number to look at. How much money do I really need to pay for a comfortable home, support my family, pay for my kids’ education, fund my retirement?

Enough should be as good as a feast.

Yet, even when content we get caught in the trap of comparing ourselves with others. This is human nature. We’re programmed to be competitive to survive. Whether that means anything when we don’t have to be hunters and gatherers is irrelevant. It is who we are.

But we’re also intelligent enough to realize that. I for one, don’t want to know, or care, how much money the neurologist down the street is earning. All that matters to me is how much I am earning, and if it supports what I need it to.

To quote Sheryl Crow, “it’s not having what you want, it’s wanting what you’ve got.”

So I’ll skip the comparisons and focus on the only people that really matter to me.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

How much do I make compared with other doctors?

I see questions like that on surveys I get, asking me to fill something out on the Internet, then I’ll get back a list of how well other docs in my field/city/state/blood type are doing.

Nah. I’ll pass.

Realistically, why? So I can feel I’m superior or inferior to others? Isn’t keeping up with the Joneses the purpose of the doctors’ parking lot at the hospital? (Actually, the number of pricey cars there has dropped off over time).

I really don’t want to know how much others make. It’s probably more than what I make, but that’s the trade-off I accepted when I went with a small solo practice instead of a large group 20 years ago.

We become so obsessed with the question of “how much money should I be making?” and comparing it with the salaries of others that we lose track of the real question: “How much money do I need?”

That should be the real number to look at. How much money do I really need to pay for a comfortable home, support my family, pay for my kids’ education, fund my retirement?

Enough should be as good as a feast.

Yet, even when content we get caught in the trap of comparing ourselves with others. This is human nature. We’re programmed to be competitive to survive. Whether that means anything when we don’t have to be hunters and gatherers is irrelevant. It is who we are.

But we’re also intelligent enough to realize that. I for one, don’t want to know, or care, how much money the neurologist down the street is earning. All that matters to me is how much I am earning, and if it supports what I need it to.

To quote Sheryl Crow, “it’s not having what you want, it’s wanting what you’ve got.”

So I’ll skip the comparisons and focus on the only people that really matter to me.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

How much do I make compared with other doctors?

I see questions like that on surveys I get, asking me to fill something out on the Internet, then I’ll get back a list of how well other docs in my field/city/state/blood type are doing.

Nah. I’ll pass.

Realistically, why? So I can feel I’m superior or inferior to others? Isn’t keeping up with the Joneses the purpose of the doctors’ parking lot at the hospital? (Actually, the number of pricey cars there has dropped off over time).

I really don’t want to know how much others make. It’s probably more than what I make, but that’s the trade-off I accepted when I went with a small solo practice instead of a large group 20 years ago.

We become so obsessed with the question of “how much money should I be making?” and comparing it with the salaries of others that we lose track of the real question: “How much money do I need?”

That should be the real number to look at. How much money do I really need to pay for a comfortable home, support my family, pay for my kids’ education, fund my retirement?

Enough should be as good as a feast.

Yet, even when content we get caught in the trap of comparing ourselves with others. This is human nature. We’re programmed to be competitive to survive. Whether that means anything when we don’t have to be hunters and gatherers is irrelevant. It is who we are.

But we’re also intelligent enough to realize that. I for one, don’t want to know, or care, how much money the neurologist down the street is earning. All that matters to me is how much I am earning, and if it supports what I need it to.

To quote Sheryl Crow, “it’s not having what you want, it’s wanting what you’ve got.”

So I’ll skip the comparisons and focus on the only people that really matter to me.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

In contrast to what has been seen in other tumor types, recurrent glioblastoma (rGBM) may respond better to immunotherapy when tumor mutational burden (TMB) is low, new research suggests.

There’s an “unexpected correlation between TMB, tumor-intrinsic inflammation, and survival after immunotherapy” in this patient population, researchers noted in a Nature Communications report.

Cases of rGBM in which TMB is low are more likely to respond to immunotherapy than cases in which TMB is higher, the investigators concluded from an analysis of tumor tissue from more than 100 patients.

“We need to do a prospective study and establish a threshold in a particular assay format,” senior author David Ashley, MBBS, PhD, a neurosurgery professor at Duke University, Durham, N.C., said in an interview.

Andrew Sloan, MD, a neurosurgery professor at the Seidman Cancer Center, Cleveland, said in a comment that “many have given up on immunotherapy for GBM because these tumors tend to have lower TMB than tumors that typically respond to immunotherapy, including checkpoint inhibitors.” (Examples include melanoma and lung cancer.)

“If the findings are confirmed, it would be very useful clinically to select” patients for immunotherapy, Dr. Sloan commented.
 

Correlation seen with rGBM, not primary tumor

Recurrence of GBM is almost inevitable, even when aggressive standard-of-care therapy is given initially, according to Dr. Ashley and colleagues. Studies have indicated that, in 10%-20% of patients with rGBM, disease responds to subsequent immunotherapy, and patients live beyond the predicted median survival of about 12 months. It’s been unclear, however, what distinguishes these survivors from the other patients.

Dr. Ashley and colleagues looked for common genetic factors that distinguish survivors.

The tumor tissue the team analyzed came from three studies. The first was a trial of an intratumoral infusion of a recombinant nonpathogenic poliorhinovirus chimera (PVSRIPO), developed at Duke University, that induces innate inflammation and T-cell attack. Among 61 patients, 21% were alive at 3 years versus 4% of historical control patients.

The second study was a review of 66 patients with GBM who underwent treatment with pembrolizumab or nivolumab. The median survival was 14.3 months among those who experienced a response versus10.1 months for those who did not.

The third study involved more than 1,000 patients with advanced cancer who underwent treatment with checkpoint inhibitors. There was no survival benefit among the 117 patients with glioma who were treated with checkpoint inhibitors.

In the PVSRIPO trial, rGBM tumors from patients who survived longer than 20 months harbored very low TMB, less than 0.6 mutations/Mb. In the two checkpoint inhibitor trials, among 110 patients with rGBM, survival was longer for those whose TMB was at or below the median level.

The differences in survival were not driven by differences in steroid dosing, unfavorable responses among patients with hypermutations, or the presence or absence of IDH1 or PTEN mutations or MGMT promoter methylation, according to Dr. Ashley and colleagues.

“Increased survival of immunotherapy-treated rGBM patients with very low TMB is due to immunotherapy response,” the investigators concluded.

As for the explanation, the team found that rGBM tumors with lower TMB levels had enriched inflammatory gene signatures, compared with tumors with higher TMB levels.

The correlation – and longer survival with low TMB – was not observed in primary GBM tumors, “indicating that a relationship between tumor-intrinsic inflammation and TMB develops upon recurrence. ... We postulate that the baseline inflammatory status of rGBM tumors determines their susceptibility to immunotherapy,” the authors wrote.

Because the correlation between tumor inflammation and TMB was robust in rGBM but not in primary tumors, it might well have been caused by standard-of-care therapy, which affects mutation levels.

“Chemotherapy, which is the standard of care for newly diagnosed glioblastoma, might be altering the inflammatory response in these tumors” and priming an inflammatory process that increases vulnerability to immunotherapy in recurrent tumors, Dr. Ashley said in a press release.

Shorter time to recurrence also correlated with lower TMB and favorable response to PVSRIPO, so shorter duration of standard therapy or shorter time from initial surgery might improve immunotherapy response, he speculated.

The study was funded by the National Institutes of Health and other organizations. Dr. Ashley and other investigators own intellectual property related to PVSRIPO, which has been licensed to Istari Oncology. Several investigators hold equity in and/or are paid consultants for Istari. Dr. Sloan is the Ohio principal investigator for an rGBM PVSRIPO and pembrolizumab study funded by the company.

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

In contrast to what has been seen in other tumor types, recurrent glioblastoma (rGBM) may respond better to immunotherapy when tumor mutational burden (TMB) is low, new research suggests.

There’s an “unexpected correlation between TMB, tumor-intrinsic inflammation, and survival after immunotherapy” in this patient population, researchers noted in a Nature Communications report.

Cases of rGBM in which TMB is low are more likely to respond to immunotherapy than cases in which TMB is higher, the investigators concluded from an analysis of tumor tissue from more than 100 patients.

“We need to do a prospective study and establish a threshold in a particular assay format,” senior author David Ashley, MBBS, PhD, a neurosurgery professor at Duke University, Durham, N.C., said in an interview.

Andrew Sloan, MD, a neurosurgery professor at the Seidman Cancer Center, Cleveland, said in a comment that “many have given up on immunotherapy for GBM because these tumors tend to have lower TMB than tumors that typically respond to immunotherapy, including checkpoint inhibitors.” (Examples include melanoma and lung cancer.)

“If the findings are confirmed, it would be very useful clinically to select” patients for immunotherapy, Dr. Sloan commented.
 

Correlation seen with rGBM, not primary tumor

Recurrence of GBM is almost inevitable, even when aggressive standard-of-care therapy is given initially, according to Dr. Ashley and colleagues. Studies have indicated that, in 10%-20% of patients with rGBM, disease responds to subsequent immunotherapy, and patients live beyond the predicted median survival of about 12 months. It’s been unclear, however, what distinguishes these survivors from the other patients.

Dr. Ashley and colleagues looked for common genetic factors that distinguish survivors.

The tumor tissue the team analyzed came from three studies. The first was a trial of an intratumoral infusion of a recombinant nonpathogenic poliorhinovirus chimera (PVSRIPO), developed at Duke University, that induces innate inflammation and T-cell attack. Among 61 patients, 21% were alive at 3 years versus 4% of historical control patients.

The second study was a review of 66 patients with GBM who underwent treatment with pembrolizumab or nivolumab. The median survival was 14.3 months among those who experienced a response versus10.1 months for those who did not.

The third study involved more than 1,000 patients with advanced cancer who underwent treatment with checkpoint inhibitors. There was no survival benefit among the 117 patients with glioma who were treated with checkpoint inhibitors.

In the PVSRIPO trial, rGBM tumors from patients who survived longer than 20 months harbored very low TMB, less than 0.6 mutations/Mb. In the two checkpoint inhibitor trials, among 110 patients with rGBM, survival was longer for those whose TMB was at or below the median level.

The differences in survival were not driven by differences in steroid dosing, unfavorable responses among patients with hypermutations, or the presence or absence of IDH1 or PTEN mutations or MGMT promoter methylation, according to Dr. Ashley and colleagues.

“Increased survival of immunotherapy-treated rGBM patients with very low TMB is due to immunotherapy response,” the investigators concluded.

As for the explanation, the team found that rGBM tumors with lower TMB levels had enriched inflammatory gene signatures, compared with tumors with higher TMB levels.

The correlation – and longer survival with low TMB – was not observed in primary GBM tumors, “indicating that a relationship between tumor-intrinsic inflammation and TMB develops upon recurrence. ... We postulate that the baseline inflammatory status of rGBM tumors determines their susceptibility to immunotherapy,” the authors wrote.

Because the correlation between tumor inflammation and TMB was robust in rGBM but not in primary tumors, it might well have been caused by standard-of-care therapy, which affects mutation levels.

“Chemotherapy, which is the standard of care for newly diagnosed glioblastoma, might be altering the inflammatory response in these tumors” and priming an inflammatory process that increases vulnerability to immunotherapy in recurrent tumors, Dr. Ashley said in a press release.

Shorter time to recurrence also correlated with lower TMB and favorable response to PVSRIPO, so shorter duration of standard therapy or shorter time from initial surgery might improve immunotherapy response, he speculated.

The study was funded by the National Institutes of Health and other organizations. Dr. Ashley and other investigators own intellectual property related to PVSRIPO, which has been licensed to Istari Oncology. Several investigators hold equity in and/or are paid consultants for Istari. Dr. Sloan is the Ohio principal investigator for an rGBM PVSRIPO and pembrolizumab study funded by the company.

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

In contrast to what has been seen in other tumor types, recurrent glioblastoma (rGBM) may respond better to immunotherapy when tumor mutational burden (TMB) is low, new research suggests.

There’s an “unexpected correlation between TMB, tumor-intrinsic inflammation, and survival after immunotherapy” in this patient population, researchers noted in a Nature Communications report.

Cases of rGBM in which TMB is low are more likely to respond to immunotherapy than cases in which TMB is higher, the investigators concluded from an analysis of tumor tissue from more than 100 patients.

“We need to do a prospective study and establish a threshold in a particular assay format,” senior author David Ashley, MBBS, PhD, a neurosurgery professor at Duke University, Durham, N.C., said in an interview.

Andrew Sloan, MD, a neurosurgery professor at the Seidman Cancer Center, Cleveland, said in a comment that “many have given up on immunotherapy for GBM because these tumors tend to have lower TMB than tumors that typically respond to immunotherapy, including checkpoint inhibitors.” (Examples include melanoma and lung cancer.)

“If the findings are confirmed, it would be very useful clinically to select” patients for immunotherapy, Dr. Sloan commented.
 

Correlation seen with rGBM, not primary tumor

Recurrence of GBM is almost inevitable, even when aggressive standard-of-care therapy is given initially, according to Dr. Ashley and colleagues. Studies have indicated that, in 10%-20% of patients with rGBM, disease responds to subsequent immunotherapy, and patients live beyond the predicted median survival of about 12 months. It’s been unclear, however, what distinguishes these survivors from the other patients.

Dr. Ashley and colleagues looked for common genetic factors that distinguish survivors.

The tumor tissue the team analyzed came from three studies. The first was a trial of an intratumoral infusion of a recombinant nonpathogenic poliorhinovirus chimera (PVSRIPO), developed at Duke University, that induces innate inflammation and T-cell attack. Among 61 patients, 21% were alive at 3 years versus 4% of historical control patients.

The second study was a review of 66 patients with GBM who underwent treatment with pembrolizumab or nivolumab. The median survival was 14.3 months among those who experienced a response versus10.1 months for those who did not.

The third study involved more than 1,000 patients with advanced cancer who underwent treatment with checkpoint inhibitors. There was no survival benefit among the 117 patients with glioma who were treated with checkpoint inhibitors.

In the PVSRIPO trial, rGBM tumors from patients who survived longer than 20 months harbored very low TMB, less than 0.6 mutations/Mb. In the two checkpoint inhibitor trials, among 110 patients with rGBM, survival was longer for those whose TMB was at or below the median level.

The differences in survival were not driven by differences in steroid dosing, unfavorable responses among patients with hypermutations, or the presence or absence of IDH1 or PTEN mutations or MGMT promoter methylation, according to Dr. Ashley and colleagues.

“Increased survival of immunotherapy-treated rGBM patients with very low TMB is due to immunotherapy response,” the investigators concluded.

As for the explanation, the team found that rGBM tumors with lower TMB levels had enriched inflammatory gene signatures, compared with tumors with higher TMB levels.

The correlation – and longer survival with low TMB – was not observed in primary GBM tumors, “indicating that a relationship between tumor-intrinsic inflammation and TMB develops upon recurrence. ... We postulate that the baseline inflammatory status of rGBM tumors determines their susceptibility to immunotherapy,” the authors wrote.

Because the correlation between tumor inflammation and TMB was robust in rGBM but not in primary tumors, it might well have been caused by standard-of-care therapy, which affects mutation levels.

“Chemotherapy, which is the standard of care for newly diagnosed glioblastoma, might be altering the inflammatory response in these tumors” and priming an inflammatory process that increases vulnerability to immunotherapy in recurrent tumors, Dr. Ashley said in a press release.

Shorter time to recurrence also correlated with lower TMB and favorable response to PVSRIPO, so shorter duration of standard therapy or shorter time from initial surgery might improve immunotherapy response, he speculated.

The study was funded by the National Institutes of Health and other organizations. Dr. Ashley and other investigators own intellectual property related to PVSRIPO, which has been licensed to Istari Oncology. Several investigators hold equity in and/or are paid consultants for Istari. Dr. Sloan is the Ohio principal investigator for an rGBM PVSRIPO and pembrolizumab study funded by the company.

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

When Margot Gage-Witvliet began feeling run down after her family returned from a trip to the Netherlands in late February 2020, she initially chalked up her symptoms to jet lag. Three days later, however, her situation went from concerning to alarming as she struggled to breathe. “It felt like there was an elephant sitting on my chest,” she said.

Her husband and daughters also became ill with COVID-19, but Ms. Gage-Witvliet was the only one in her family who didn’t get better. After an early improvement, a rare coronavirus-induced tonic-clonic seizure in early April sent her spiraling back down. Ms. Gage-Witvliet spent the next several weeks in bed with the curtains drawn, unable to tolerate light or sound.

Today, Ms. Gage-Witvliet’s life looks nothing like it did 6 months ago when she first got sick. As one of COVID-19’s so called long-haulers, she continues to struggle with crushing fatigue, brain fog, and headaches – symptoms that worsen when she pushes herself to do more. Across the country, as many as 1 in 10 COVID-19 patients are reporting illnesses that continue for weeks and months after their initial diagnosis. Nearly all report neurologic issues like Ms. Gage-Witvliet, as well as shortness of breath and psychiatric concerns.

For Avindra Nath, MD, a neurologist at the National Institutes of Health, the experience of these long-haul COVID-19 patients feels familiar and reminds him of myalgic encephalomyelitis, also known as chronic fatigue syndrome.

Dr. Nath has long been interested in the lingering neurologic issues connected to chronic fatigue. An estimated three-quarters of all patients with chronic fatigue syndrome report that their symptoms started after a viral infection, and they suffer unrelenting exhaustion, difficulties regulating pulse and blood pressure, aches and pains, and brain fog. When Dr. Nath first read about the novel coronavirus, he began to worry that the virus would trigger symptoms in a subset of those infected. Hearing about the experiences of long-haulers like Ms. Gage-Witvliet raised his suspicions even more.

Unlike COVID-19 long-haulers, however, many patients with chronic fatigue syndrome go at least a year with these symptoms before receiving a diagnosis, according to a British survey. That means researchers have had few opportunities to study the early stages of the syndrome. “When we see patients with myalgic encephalomyelitis, whatever infection they might have had occurred in the remote past, so there’s no way for us to know how they got infected with it, what the infection was, or what the effects of it were in that early phase. We’re seeing them 2 years afterward,” Dr. Nath said.

Dr. Nath quickly realized that studying patients like Ms. Gage-Witvliet would give physicians and scientists a unique opportunity to understand not only long-term outcomes of COVID-19 infections, but also other postviral syndromes, including chronic fatigue syndrome at their earliest stages. It’s why Dr. Nath has spent the past several months scrambling to launch two NIH studies to examine the phenomenon.

Although Dr. Nath said that the parallels between COVID-19 long-haulers and those with chronic fatigue syndrome are obvious, he cautions against assuming that they are the same phenomenon. Some long-haulers might simply be taking a much slower path to recovery, or they might have a condition that looks similar on the surface but differs from chronic fatigue syndrome on a molecular level. But even if Dr. Nath fails to see links to chronic fatigue syndrome, with more than 92.5 million documented cases of COVID-19 around the world, the work will be relevant to the substantial number of infected individuals who don’t recover quickly.

“With so many people having exposure to the same virus over a similar time period, we really have the opportunity to look at these manifestations and at the very least to understand postviral syndromes,” said Mady Hornig, MD, a psychiatrist at Columbia University, New York.

The origins of chronic fatigue syndrome date back to 1985, when the Centers for Disease Control and Prevention received a request from two physicians – Paul Cheney, MD, and Daniel Peterson, MD – to investigate a mysterious disease outbreak in Nevada. In November 1984, residents in and around the idyllic vacation spot of Incline Village, a small town tucked into the north shore of Lake Tahoe, had begun reporting flu-like symptoms that persisted for weeks, even months. The doctors had searched high and low for a cause, but they couldn’t figure out what was making their patients sick.

They reported a range of symptoms – including muscle aches and pains, low-grade fevers, sore throats, and headaches – but everyone said that crippling fatigue was the most debilitating issue. This wasn’t the kind of fatigue that could be cured by a nap or even a long holiday. No matter how much their patients slept – and some were almost completely bedbound – their fatigue didn’t abate. What’s more, the fatigue got worse whenever they tried to push themselves to do more. Puzzled, the CDC sent two epidemic intelligence service (EIS) officers to try to get to the bottom of what might be happening.


 

Muscle aches and pains with crippling fatigue

After their visit to Incline Village, however, the CDC was just as perplexed as Dr. Cheney and Dr. Peterson. Many of the people with the condition reported flu-like symptoms right around the time they first got sick, and the physicians’ leading hypothesis was that the outbreak and its lasting symptoms were caused by chronic Epstein-Barr virus infection. But neither the CDC nor anyone else could identify the infection or any other microbial cause. The two EIS officers duly wrote up a report for the CDC’s flagship publication, Morbidity and Mortality Weekly ReportI, titled “Chronic Fatigue Possibly Related to Epstein-Barr Virus – Nevada”.

That investigators focused on the fatigue aspect made sense, says Leonard A. Jason, PhD, professor of psychology at DePaul University and director of the Center for Community Research, both in Chicago, because it was one of the few symptoms shared by all the individuals studied and it was also the most debilitating. But that focus – and the name “chronic fatigue syndrome” – led to broad public dismissal of the condition’s severity, as did an editorial note in MMWR urging physicians to look for “more definable, and possibly treatable, conditions.” Subsequent research failed to confirm a specific link to the Epstein-Barr virus, which only added to the condition’s phony reputation. Rather than being considered a potentially disabling illness, it was disregarded as a “yuppie flu” or a fancy name for malingering.

“It’s not a surprise that patients are being dismissed because there’s already this sort of grandfathered-in sense that fatigue is not real,” said Jennifer Frankovich, MD, a pediatric rheumatologist at Stanford (Calif.) University’s Lucile Packard Children’s Hospital in Palo Alto. “I’m sure that’s frustrating for them to be tired and then to have the clinician not believe them or dismiss them or think they’re making it up. It would be more helpful to the families to say: ‘You know what, we don’t know, we do not have the answer, and we believe you.’ ”
 

A syndrome’s shame

As time passed, patient advocacy groups began pushing back against the negative way the condition was being perceived. This criticism came as organizations like the CDC worked to develop a set of diagnostic criteria that researchers and clinicians dealing with chronic fatigue syndrome could use. With such a heterogeneous group of patients and symptoms, the task was no small challenge. The discussions, which took place over nearly 2 decades, played a key role in helping scientists home in on the single factor that was central to chronic fatigue: postexertional malaise.

“This is quite unique for chronic fatigue syndrome. With other diseases, yes, you may have fatigue as one of the components of the disease, but postexertional fatigue is very specific,” said Alain Moreau, PhD, a molecular biologist at the University of Montreal.

Of course, plenty of people have pushed themselves too hard physically and paid the price the next day. But those with chronic fatigue syndrome weren’t running marathons. To them, exertion could be anything from getting the mail to reading a book. Nor could the resulting exhaustion be resolved by an afternoon on the couch or a long vacation.

“If they do these activities, they can crash for weeks, even months,” Dr. Moreau said. It was deep, persistent, and – for 40% of those with chronic fatigue syndrome – disabling. In 2015, a study group from the Institute of Medicine proposed renaming chronic fatigue to “systemic exercise intolerance disease” because of the centrality of this symptom. Although that effort mostly stalled, their report did bring the condition out of its historic place as a scientific backwater. What resulted was an uptick in research on chronic fatigue syndrome, which helped define some of the physiological issues that either contribute to or result from the condition.

Researchers had long known about the link between infection and fatigue, said Dr. Frankovich. Work included mysterious outbreaks like the one in Lake Tahoe and well-documented issues like the wave of encephalitis lethargica (a condition that leaves patients in an almost vegetative state) that followed the 1918 H1N1 influenza pandemic.

“As a clinician, when you see someone who comes in with a chronic infection, they’re tired. I think that’s why, in the chronic-fatigue world, people are desperately looking for the infection so we can treat it, and maybe these poor suffering people will feel better,” Dr. Frankovich added. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.
 

Immunologic symptoms

Given the close link between a nonspecific viral illness and the onset of symptoms in chronic fatigue syndrome, scientists like Dr. Hornig opted to focus on immunologic symptoms. In a 2015 analysis published in Science, Dr. Hornig and colleagues showed that immune problems can be found in the earliest stages of chronic fatigue syndrome, and that they change as the illness progresses. Patients who had been sick for less than 3 years showed significant increases in levels of both pro- and anti-inflammatory cytokines, and the factor most strongly correlated to this inability to regulate cytokine levels was the duration of symptoms, not their severity. A series of other studies also revealed problems with regulation of the immune system, although no one could show what might have set these problems in motion.

Other researchers found signs of mitochondrial dysfunction in those with chronic fatigue syndrome. Because mitochondria make energy for cells, it wasn’t an intellectual stretch to believe that glitches in this process could contribute to fatigue. As early as 1991, scientists had discovered signs of mitochondrial degeneration in muscle biopsies from people with chronic fatigue syndrome. Subsequent studies showed that those affected by chronic fatigue were missing segments of mitochondrial DNA and had significantly reduced levels of mitochondrial activity. Although exercise normally improves mitochondrial functioning, the opposite appears to happen in chronic fatigue.

To Dr. Nath, these dual hypotheses aren’t necessarily mutually exclusive. Some studies have hinted that infection with the common human herpesvirus–6 (HHV-6) can lead to an autoimmune condition in which the body makes antibodies against the mitochondria. Mitochondria also play a key role in the ability of the innate immune system to produce interferon and other proinflammatory cytokines. It might also be that the link between immune and mitochondrial problems is more convoluted than originally thought, or that the two systems are affected independent of one another, Dr. Nath said.

Finding answers, especially those that could lead to potential treatments, wouldn’t be easy, however. In 2016, the NIH launched an in-depth study of a small number of individuals with chronic fatigue, hoping to find clues about what the condition was and how it might be treated.

For scientists like Dr. Nath, the NIH study provided a way to get at the underlying biology of chronic fatigue syndrome. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.
 

Chronic post-SARS syndrome

In March 2020, retired physician Harvey Moldofsky, MD, began receiving inquiries about a 2011 study he and his colleague, John Patcai, MD, had published in BMC Neurology about something they dubbed “chronic post-SARS syndrome.” The small case-control study, which involved mainly health care workers in Toronto, received little attention when it was first published, but with COVID-19, it was suddenly relevant.

Early clusters of similar cases in Miami made local physicians desperate for Dr. Moldofsky’s expertise. Luckily, he was nearby; he had fled the frigid Canadian winter for the warmth of Sarasota, Fla.

“I had people from various countries around the world writing to me and asking what they should do. And of course I don’t have any answers,” he said. But the study contained one of the world’s only references to the syndrome.

In 2003, a woman arrived in Toronto from Hong Kong. She didn’t know it at the time, but her preairport stay at the Hotel Metropole had infected her with the first SARS (severe acute respiratory syndrome) coronavirus. Her subsequent hospitalization in Toronto sparked a city-wide outbreak of SARS in which 273 people became ill and 44 died. Many of those affected were health care workers, including nurses and respiratory therapists. Although most eventually returned to work, a subset couldn’t. They complained of energy-sapping fatigue, poor sleep, brain fog, and assorted body aches and pains that persisted for more than 18 months. The aches and pains brought them to the attention of Dr. Moldofsky, then director of the Centre for the Study of Pain at the University of Toronto.

His primary interest at the time was fibromyalgia, which caused symptoms similar to those reported by the original SARS long-haulers. Intrigued, Dr. Moldofsky agreed to take a look. Their chest x-rays were clear and the nurses showed no signs of lingering viral infection. Dr. Moldofsky could see that the nurses were ill and suffering, but no lab tests or anything else could identify what was causing their symptoms.

In 2011, Dr. Moldofsky and Dr. Patcai found a strong overlap between chronic SARS, fibromyalgia, and chronic fatigue syndrome when they compared 22 patients with long-term SARS issues with 21 who had fibromyalgia. “Their problems are exactly the same. They have strange symptoms and nobody can figure out what they’re about. And these symptoms are aches and pains, and they have trouble thinking and concentrating,” Dr. Moldofsky said. Reports of COVID-19 long-haulers didn’t surprise Dr. Moldofsky, and he immediately recognized that Nath’s intention to follow these patients could provide insights into both fibromyalgia and chronic fatigue syndrome.

That’s exactly what Dr. Nath is proposing with the two NIH studies. One will focus solely on the neurologic impacts of COVID-19, including stroke, loss of taste and smell, and brain fog. The other will bring patients who have had COVID-19 symptoms for at least 6 months to the NIH Clinical Center for an inpatient stay during which they will undergo detailed physiologic tests.

Scientists around the world are launching their own post–COVID-19 studies. Dr. Moreau’s group in Montreal has laid the groundwork for such an endeavor, and the CoroNerve group in the United Kingdom is monitoring neurologic complications from the coronavirus. Many of them have the same goals as the NIH studies: Leverage the large number of COVID-19 long-haulers to better understand the earliest stages of postviral syndrome.

“At this juncture, after all the reports that we’ve seen so far, I think it’s very unlikely that there will be no relationship whatsoever between COVID-19 and chronic fatigue syndrome,” Dr. Hornig said. “I think there certainly will be some, but again, what’s the scope, what’s the size? And then, of course, even more importantly, if it is happening, what is the mechanism and how is it happening?”

For people like Ms. Gage-Witvliet, the answers can’t come soon enough. For the first time in more than a decade, the full-time professor of epidemiology didn’t prepare to teach this year because she simply can’t. It’s too taxing for her brain to deal with impromptu student questions. Ms. Gage-Witvliet hopes that, by sharing her own experiences with post COVID-19, she can help others.

“In my work, I use data to give a voice to people who don’t have a voice,” she said. “Now, I am one of those people.”

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

When Margot Gage-Witvliet began feeling run down after her family returned from a trip to the Netherlands in late February 2020, she initially chalked up her symptoms to jet lag. Three days later, however, her situation went from concerning to alarming as she struggled to breathe. “It felt like there was an elephant sitting on my chest,” she said.

Her husband and daughters also became ill with COVID-19, but Ms. Gage-Witvliet was the only one in her family who didn’t get better. After an early improvement, a rare coronavirus-induced tonic-clonic seizure in early April sent her spiraling back down. Ms. Gage-Witvliet spent the next several weeks in bed with the curtains drawn, unable to tolerate light or sound.

Today, Ms. Gage-Witvliet’s life looks nothing like it did 6 months ago when she first got sick. As one of COVID-19’s so called long-haulers, she continues to struggle with crushing fatigue, brain fog, and headaches – symptoms that worsen when she pushes herself to do more. Across the country, as many as 1 in 10 COVID-19 patients are reporting illnesses that continue for weeks and months after their initial diagnosis. Nearly all report neurologic issues like Ms. Gage-Witvliet, as well as shortness of breath and psychiatric concerns.

For Avindra Nath, MD, a neurologist at the National Institutes of Health, the experience of these long-haul COVID-19 patients feels familiar and reminds him of myalgic encephalomyelitis, also known as chronic fatigue syndrome.

Dr. Nath has long been interested in the lingering neurologic issues connected to chronic fatigue. An estimated three-quarters of all patients with chronic fatigue syndrome report that their symptoms started after a viral infection, and they suffer unrelenting exhaustion, difficulties regulating pulse and blood pressure, aches and pains, and brain fog. When Dr. Nath first read about the novel coronavirus, he began to worry that the virus would trigger symptoms in a subset of those infected. Hearing about the experiences of long-haulers like Ms. Gage-Witvliet raised his suspicions even more.

Unlike COVID-19 long-haulers, however, many patients with chronic fatigue syndrome go at least a year with these symptoms before receiving a diagnosis, according to a British survey. That means researchers have had few opportunities to study the early stages of the syndrome. “When we see patients with myalgic encephalomyelitis, whatever infection they might have had occurred in the remote past, so there’s no way for us to know how they got infected with it, what the infection was, or what the effects of it were in that early phase. We’re seeing them 2 years afterward,” Dr. Nath said.

Dr. Nath quickly realized that studying patients like Ms. Gage-Witvliet would give physicians and scientists a unique opportunity to understand not only long-term outcomes of COVID-19 infections, but also other postviral syndromes, including chronic fatigue syndrome at their earliest stages. It’s why Dr. Nath has spent the past several months scrambling to launch two NIH studies to examine the phenomenon.

Although Dr. Nath said that the parallels between COVID-19 long-haulers and those with chronic fatigue syndrome are obvious, he cautions against assuming that they are the same phenomenon. Some long-haulers might simply be taking a much slower path to recovery, or they might have a condition that looks similar on the surface but differs from chronic fatigue syndrome on a molecular level. But even if Dr. Nath fails to see links to chronic fatigue syndrome, with more than 92.5 million documented cases of COVID-19 around the world, the work will be relevant to the substantial number of infected individuals who don’t recover quickly.

“With so many people having exposure to the same virus over a similar time period, we really have the opportunity to look at these manifestations and at the very least to understand postviral syndromes,” said Mady Hornig, MD, a psychiatrist at Columbia University, New York.

The origins of chronic fatigue syndrome date back to 1985, when the Centers for Disease Control and Prevention received a request from two physicians – Paul Cheney, MD, and Daniel Peterson, MD – to investigate a mysterious disease outbreak in Nevada. In November 1984, residents in and around the idyllic vacation spot of Incline Village, a small town tucked into the north shore of Lake Tahoe, had begun reporting flu-like symptoms that persisted for weeks, even months. The doctors had searched high and low for a cause, but they couldn’t figure out what was making their patients sick.

They reported a range of symptoms – including muscle aches and pains, low-grade fevers, sore throats, and headaches – but everyone said that crippling fatigue was the most debilitating issue. This wasn’t the kind of fatigue that could be cured by a nap or even a long holiday. No matter how much their patients slept – and some were almost completely bedbound – their fatigue didn’t abate. What’s more, the fatigue got worse whenever they tried to push themselves to do more. Puzzled, the CDC sent two epidemic intelligence service (EIS) officers to try to get to the bottom of what might be happening.


 

Muscle aches and pains with crippling fatigue

After their visit to Incline Village, however, the CDC was just as perplexed as Dr. Cheney and Dr. Peterson. Many of the people with the condition reported flu-like symptoms right around the time they first got sick, and the physicians’ leading hypothesis was that the outbreak and its lasting symptoms were caused by chronic Epstein-Barr virus infection. But neither the CDC nor anyone else could identify the infection or any other microbial cause. The two EIS officers duly wrote up a report for the CDC’s flagship publication, Morbidity and Mortality Weekly ReportI, titled “Chronic Fatigue Possibly Related to Epstein-Barr Virus – Nevada”.

That investigators focused on the fatigue aspect made sense, says Leonard A. Jason, PhD, professor of psychology at DePaul University and director of the Center for Community Research, both in Chicago, because it was one of the few symptoms shared by all the individuals studied and it was also the most debilitating. But that focus – and the name “chronic fatigue syndrome” – led to broad public dismissal of the condition’s severity, as did an editorial note in MMWR urging physicians to look for “more definable, and possibly treatable, conditions.” Subsequent research failed to confirm a specific link to the Epstein-Barr virus, which only added to the condition’s phony reputation. Rather than being considered a potentially disabling illness, it was disregarded as a “yuppie flu” or a fancy name for malingering.

“It’s not a surprise that patients are being dismissed because there’s already this sort of grandfathered-in sense that fatigue is not real,” said Jennifer Frankovich, MD, a pediatric rheumatologist at Stanford (Calif.) University’s Lucile Packard Children’s Hospital in Palo Alto. “I’m sure that’s frustrating for them to be tired and then to have the clinician not believe them or dismiss them or think they’re making it up. It would be more helpful to the families to say: ‘You know what, we don’t know, we do not have the answer, and we believe you.’ ”
 

A syndrome’s shame

As time passed, patient advocacy groups began pushing back against the negative way the condition was being perceived. This criticism came as organizations like the CDC worked to develop a set of diagnostic criteria that researchers and clinicians dealing with chronic fatigue syndrome could use. With such a heterogeneous group of patients and symptoms, the task was no small challenge. The discussions, which took place over nearly 2 decades, played a key role in helping scientists home in on the single factor that was central to chronic fatigue: postexertional malaise.

“This is quite unique for chronic fatigue syndrome. With other diseases, yes, you may have fatigue as one of the components of the disease, but postexertional fatigue is very specific,” said Alain Moreau, PhD, a molecular biologist at the University of Montreal.

Of course, plenty of people have pushed themselves too hard physically and paid the price the next day. But those with chronic fatigue syndrome weren’t running marathons. To them, exertion could be anything from getting the mail to reading a book. Nor could the resulting exhaustion be resolved by an afternoon on the couch or a long vacation.

“If they do these activities, they can crash for weeks, even months,” Dr. Moreau said. It was deep, persistent, and – for 40% of those with chronic fatigue syndrome – disabling. In 2015, a study group from the Institute of Medicine proposed renaming chronic fatigue to “systemic exercise intolerance disease” because of the centrality of this symptom. Although that effort mostly stalled, their report did bring the condition out of its historic place as a scientific backwater. What resulted was an uptick in research on chronic fatigue syndrome, which helped define some of the physiological issues that either contribute to or result from the condition.

Researchers had long known about the link between infection and fatigue, said Dr. Frankovich. Work included mysterious outbreaks like the one in Lake Tahoe and well-documented issues like the wave of encephalitis lethargica (a condition that leaves patients in an almost vegetative state) that followed the 1918 H1N1 influenza pandemic.

“As a clinician, when you see someone who comes in with a chronic infection, they’re tired. I think that’s why, in the chronic-fatigue world, people are desperately looking for the infection so we can treat it, and maybe these poor suffering people will feel better,” Dr. Frankovich added. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.
 

Immunologic symptoms

Given the close link between a nonspecific viral illness and the onset of symptoms in chronic fatigue syndrome, scientists like Dr. Hornig opted to focus on immunologic symptoms. In a 2015 analysis published in Science, Dr. Hornig and colleagues showed that immune problems can be found in the earliest stages of chronic fatigue syndrome, and that they change as the illness progresses. Patients who had been sick for less than 3 years showed significant increases in levels of both pro- and anti-inflammatory cytokines, and the factor most strongly correlated to this inability to regulate cytokine levels was the duration of symptoms, not their severity. A series of other studies also revealed problems with regulation of the immune system, although no one could show what might have set these problems in motion.

Other researchers found signs of mitochondrial dysfunction in those with chronic fatigue syndrome. Because mitochondria make energy for cells, it wasn’t an intellectual stretch to believe that glitches in this process could contribute to fatigue. As early as 1991, scientists had discovered signs of mitochondrial degeneration in muscle biopsies from people with chronic fatigue syndrome. Subsequent studies showed that those affected by chronic fatigue were missing segments of mitochondrial DNA and had significantly reduced levels of mitochondrial activity. Although exercise normally improves mitochondrial functioning, the opposite appears to happen in chronic fatigue.

To Dr. Nath, these dual hypotheses aren’t necessarily mutually exclusive. Some studies have hinted that infection with the common human herpesvirus–6 (HHV-6) can lead to an autoimmune condition in which the body makes antibodies against the mitochondria. Mitochondria also play a key role in the ability of the innate immune system to produce interferon and other proinflammatory cytokines. It might also be that the link between immune and mitochondrial problems is more convoluted than originally thought, or that the two systems are affected independent of one another, Dr. Nath said.

Finding answers, especially those that could lead to potential treatments, wouldn’t be easy, however. In 2016, the NIH launched an in-depth study of a small number of individuals with chronic fatigue, hoping to find clues about what the condition was and how it might be treated.

For scientists like Dr. Nath, the NIH study provided a way to get at the underlying biology of chronic fatigue syndrome. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.
 

Chronic post-SARS syndrome

In March 2020, retired physician Harvey Moldofsky, MD, began receiving inquiries about a 2011 study he and his colleague, John Patcai, MD, had published in BMC Neurology about something they dubbed “chronic post-SARS syndrome.” The small case-control study, which involved mainly health care workers in Toronto, received little attention when it was first published, but with COVID-19, it was suddenly relevant.

Early clusters of similar cases in Miami made local physicians desperate for Dr. Moldofsky’s expertise. Luckily, he was nearby; he had fled the frigid Canadian winter for the warmth of Sarasota, Fla.

“I had people from various countries around the world writing to me and asking what they should do. And of course I don’t have any answers,” he said. But the study contained one of the world’s only references to the syndrome.

In 2003, a woman arrived in Toronto from Hong Kong. She didn’t know it at the time, but her preairport stay at the Hotel Metropole had infected her with the first SARS (severe acute respiratory syndrome) coronavirus. Her subsequent hospitalization in Toronto sparked a city-wide outbreak of SARS in which 273 people became ill and 44 died. Many of those affected were health care workers, including nurses and respiratory therapists. Although most eventually returned to work, a subset couldn’t. They complained of energy-sapping fatigue, poor sleep, brain fog, and assorted body aches and pains that persisted for more than 18 months. The aches and pains brought them to the attention of Dr. Moldofsky, then director of the Centre for the Study of Pain at the University of Toronto.

His primary interest at the time was fibromyalgia, which caused symptoms similar to those reported by the original SARS long-haulers. Intrigued, Dr. Moldofsky agreed to take a look. Their chest x-rays were clear and the nurses showed no signs of lingering viral infection. Dr. Moldofsky could see that the nurses were ill and suffering, but no lab tests or anything else could identify what was causing their symptoms.

In 2011, Dr. Moldofsky and Dr. Patcai found a strong overlap between chronic SARS, fibromyalgia, and chronic fatigue syndrome when they compared 22 patients with long-term SARS issues with 21 who had fibromyalgia. “Their problems are exactly the same. They have strange symptoms and nobody can figure out what they’re about. And these symptoms are aches and pains, and they have trouble thinking and concentrating,” Dr. Moldofsky said. Reports of COVID-19 long-haulers didn’t surprise Dr. Moldofsky, and he immediately recognized that Nath’s intention to follow these patients could provide insights into both fibromyalgia and chronic fatigue syndrome.

That’s exactly what Dr. Nath is proposing with the two NIH studies. One will focus solely on the neurologic impacts of COVID-19, including stroke, loss of taste and smell, and brain fog. The other will bring patients who have had COVID-19 symptoms for at least 6 months to the NIH Clinical Center for an inpatient stay during which they will undergo detailed physiologic tests.

Scientists around the world are launching their own post–COVID-19 studies. Dr. Moreau’s group in Montreal has laid the groundwork for such an endeavor, and the CoroNerve group in the United Kingdom is monitoring neurologic complications from the coronavirus. Many of them have the same goals as the NIH studies: Leverage the large number of COVID-19 long-haulers to better understand the earliest stages of postviral syndrome.

“At this juncture, after all the reports that we’ve seen so far, I think it’s very unlikely that there will be no relationship whatsoever between COVID-19 and chronic fatigue syndrome,” Dr. Hornig said. “I think there certainly will be some, but again, what’s the scope, what’s the size? And then, of course, even more importantly, if it is happening, what is the mechanism and how is it happening?”

For people like Ms. Gage-Witvliet, the answers can’t come soon enough. For the first time in more than a decade, the full-time professor of epidemiology didn’t prepare to teach this year because she simply can’t. It’s too taxing for her brain to deal with impromptu student questions. Ms. Gage-Witvliet hopes that, by sharing her own experiences with post COVID-19, she can help others.

“In my work, I use data to give a voice to people who don’t have a voice,” she said. “Now, I am one of those people.”

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

When Margot Gage-Witvliet began feeling run down after her family returned from a trip to the Netherlands in late February 2020, she initially chalked up her symptoms to jet lag. Three days later, however, her situation went from concerning to alarming as she struggled to breathe. “It felt like there was an elephant sitting on my chest,” she said.

Her husband and daughters also became ill with COVID-19, but Ms. Gage-Witvliet was the only one in her family who didn’t get better. After an early improvement, a rare coronavirus-induced tonic-clonic seizure in early April sent her spiraling back down. Ms. Gage-Witvliet spent the next several weeks in bed with the curtains drawn, unable to tolerate light or sound.

Today, Ms. Gage-Witvliet’s life looks nothing like it did 6 months ago when she first got sick. As one of COVID-19’s so called long-haulers, she continues to struggle with crushing fatigue, brain fog, and headaches – symptoms that worsen when she pushes herself to do more. Across the country, as many as 1 in 10 COVID-19 patients are reporting illnesses that continue for weeks and months after their initial diagnosis. Nearly all report neurologic issues like Ms. Gage-Witvliet, as well as shortness of breath and psychiatric concerns.

For Avindra Nath, MD, a neurologist at the National Institutes of Health, the experience of these long-haul COVID-19 patients feels familiar and reminds him of myalgic encephalomyelitis, also known as chronic fatigue syndrome.

Dr. Nath has long been interested in the lingering neurologic issues connected to chronic fatigue. An estimated three-quarters of all patients with chronic fatigue syndrome report that their symptoms started after a viral infection, and they suffer unrelenting exhaustion, difficulties regulating pulse and blood pressure, aches and pains, and brain fog. When Dr. Nath first read about the novel coronavirus, he began to worry that the virus would trigger symptoms in a subset of those infected. Hearing about the experiences of long-haulers like Ms. Gage-Witvliet raised his suspicions even more.

Unlike COVID-19 long-haulers, however, many patients with chronic fatigue syndrome go at least a year with these symptoms before receiving a diagnosis, according to a British survey. That means researchers have had few opportunities to study the early stages of the syndrome. “When we see patients with myalgic encephalomyelitis, whatever infection they might have had occurred in the remote past, so there’s no way for us to know how they got infected with it, what the infection was, or what the effects of it were in that early phase. We’re seeing them 2 years afterward,” Dr. Nath said.

Dr. Nath quickly realized that studying patients like Ms. Gage-Witvliet would give physicians and scientists a unique opportunity to understand not only long-term outcomes of COVID-19 infections, but also other postviral syndromes, including chronic fatigue syndrome at their earliest stages. It’s why Dr. Nath has spent the past several months scrambling to launch two NIH studies to examine the phenomenon.

Although Dr. Nath said that the parallels between COVID-19 long-haulers and those with chronic fatigue syndrome are obvious, he cautions against assuming that they are the same phenomenon. Some long-haulers might simply be taking a much slower path to recovery, or they might have a condition that looks similar on the surface but differs from chronic fatigue syndrome on a molecular level. But even if Dr. Nath fails to see links to chronic fatigue syndrome, with more than 92.5 million documented cases of COVID-19 around the world, the work will be relevant to the substantial number of infected individuals who don’t recover quickly.

“With so many people having exposure to the same virus over a similar time period, we really have the opportunity to look at these manifestations and at the very least to understand postviral syndromes,” said Mady Hornig, MD, a psychiatrist at Columbia University, New York.

The origins of chronic fatigue syndrome date back to 1985, when the Centers for Disease Control and Prevention received a request from two physicians – Paul Cheney, MD, and Daniel Peterson, MD – to investigate a mysterious disease outbreak in Nevada. In November 1984, residents in and around the idyllic vacation spot of Incline Village, a small town tucked into the north shore of Lake Tahoe, had begun reporting flu-like symptoms that persisted for weeks, even months. The doctors had searched high and low for a cause, but they couldn’t figure out what was making their patients sick.

They reported a range of symptoms – including muscle aches and pains, low-grade fevers, sore throats, and headaches – but everyone said that crippling fatigue was the most debilitating issue. This wasn’t the kind of fatigue that could be cured by a nap or even a long holiday. No matter how much their patients slept – and some were almost completely bedbound – their fatigue didn’t abate. What’s more, the fatigue got worse whenever they tried to push themselves to do more. Puzzled, the CDC sent two epidemic intelligence service (EIS) officers to try to get to the bottom of what might be happening.


 

Muscle aches and pains with crippling fatigue

After their visit to Incline Village, however, the CDC was just as perplexed as Dr. Cheney and Dr. Peterson. Many of the people with the condition reported flu-like symptoms right around the time they first got sick, and the physicians’ leading hypothesis was that the outbreak and its lasting symptoms were caused by chronic Epstein-Barr virus infection. But neither the CDC nor anyone else could identify the infection or any other microbial cause. The two EIS officers duly wrote up a report for the CDC’s flagship publication, Morbidity and Mortality Weekly ReportI, titled “Chronic Fatigue Possibly Related to Epstein-Barr Virus – Nevada”.

That investigators focused on the fatigue aspect made sense, says Leonard A. Jason, PhD, professor of psychology at DePaul University and director of the Center for Community Research, both in Chicago, because it was one of the few symptoms shared by all the individuals studied and it was also the most debilitating. But that focus – and the name “chronic fatigue syndrome” – led to broad public dismissal of the condition’s severity, as did an editorial note in MMWR urging physicians to look for “more definable, and possibly treatable, conditions.” Subsequent research failed to confirm a specific link to the Epstein-Barr virus, which only added to the condition’s phony reputation. Rather than being considered a potentially disabling illness, it was disregarded as a “yuppie flu” or a fancy name for malingering.

“It’s not a surprise that patients are being dismissed because there’s already this sort of grandfathered-in sense that fatigue is not real,” said Jennifer Frankovich, MD, a pediatric rheumatologist at Stanford (Calif.) University’s Lucile Packard Children’s Hospital in Palo Alto. “I’m sure that’s frustrating for them to be tired and then to have the clinician not believe them or dismiss them or think they’re making it up. It would be more helpful to the families to say: ‘You know what, we don’t know, we do not have the answer, and we believe you.’ ”
 

A syndrome’s shame

As time passed, patient advocacy groups began pushing back against the negative way the condition was being perceived. This criticism came as organizations like the CDC worked to develop a set of diagnostic criteria that researchers and clinicians dealing with chronic fatigue syndrome could use. With such a heterogeneous group of patients and symptoms, the task was no small challenge. The discussions, which took place over nearly 2 decades, played a key role in helping scientists home in on the single factor that was central to chronic fatigue: postexertional malaise.

“This is quite unique for chronic fatigue syndrome. With other diseases, yes, you may have fatigue as one of the components of the disease, but postexertional fatigue is very specific,” said Alain Moreau, PhD, a molecular biologist at the University of Montreal.

Of course, plenty of people have pushed themselves too hard physically and paid the price the next day. But those with chronic fatigue syndrome weren’t running marathons. To them, exertion could be anything from getting the mail to reading a book. Nor could the resulting exhaustion be resolved by an afternoon on the couch or a long vacation.

“If they do these activities, they can crash for weeks, even months,” Dr. Moreau said. It was deep, persistent, and – for 40% of those with chronic fatigue syndrome – disabling. In 2015, a study group from the Institute of Medicine proposed renaming chronic fatigue to “systemic exercise intolerance disease” because of the centrality of this symptom. Although that effort mostly stalled, their report did bring the condition out of its historic place as a scientific backwater. What resulted was an uptick in research on chronic fatigue syndrome, which helped define some of the physiological issues that either contribute to or result from the condition.

Researchers had long known about the link between infection and fatigue, said Dr. Frankovich. Work included mysterious outbreaks like the one in Lake Tahoe and well-documented issues like the wave of encephalitis lethargica (a condition that leaves patients in an almost vegetative state) that followed the 1918 H1N1 influenza pandemic.

“As a clinician, when you see someone who comes in with a chronic infection, they’re tired. I think that’s why, in the chronic-fatigue world, people are desperately looking for the infection so we can treat it, and maybe these poor suffering people will feel better,” Dr. Frankovich added. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.
 

Immunologic symptoms

Given the close link between a nonspecific viral illness and the onset of symptoms in chronic fatigue syndrome, scientists like Dr. Hornig opted to focus on immunologic symptoms. In a 2015 analysis published in Science, Dr. Hornig and colleagues showed that immune problems can be found in the earliest stages of chronic fatigue syndrome, and that they change as the illness progresses. Patients who had been sick for less than 3 years showed significant increases in levels of both pro- and anti-inflammatory cytokines, and the factor most strongly correlated to this inability to regulate cytokine levels was the duration of symptoms, not their severity. A series of other studies also revealed problems with regulation of the immune system, although no one could show what might have set these problems in motion.

Other researchers found signs of mitochondrial dysfunction in those with chronic fatigue syndrome. Because mitochondria make energy for cells, it wasn’t an intellectual stretch to believe that glitches in this process could contribute to fatigue. As early as 1991, scientists had discovered signs of mitochondrial degeneration in muscle biopsies from people with chronic fatigue syndrome. Subsequent studies showed that those affected by chronic fatigue were missing segments of mitochondrial DNA and had significantly reduced levels of mitochondrial activity. Although exercise normally improves mitochondrial functioning, the opposite appears to happen in chronic fatigue.

To Dr. Nath, these dual hypotheses aren’t necessarily mutually exclusive. Some studies have hinted that infection with the common human herpesvirus–6 (HHV-6) can lead to an autoimmune condition in which the body makes antibodies against the mitochondria. Mitochondria also play a key role in the ability of the innate immune system to produce interferon and other proinflammatory cytokines. It might also be that the link between immune and mitochondrial problems is more convoluted than originally thought, or that the two systems are affected independent of one another, Dr. Nath said.

Finding answers, especially those that could lead to potential treatments, wouldn’t be easy, however. In 2016, the NIH launched an in-depth study of a small number of individuals with chronic fatigue, hoping to find clues about what the condition was and how it might be treated.

For scientists like Dr. Nath, the NIH study provided a way to get at the underlying biology of chronic fatigue syndrome. Then the pandemic struck, giving him yet another opportunity to study postviral syndromes.
 

Chronic post-SARS syndrome

In March 2020, retired physician Harvey Moldofsky, MD, began receiving inquiries about a 2011 study he and his colleague, John Patcai, MD, had published in BMC Neurology about something they dubbed “chronic post-SARS syndrome.” The small case-control study, which involved mainly health care workers in Toronto, received little attention when it was first published, but with COVID-19, it was suddenly relevant.

Early clusters of similar cases in Miami made local physicians desperate for Dr. Moldofsky’s expertise. Luckily, he was nearby; he had fled the frigid Canadian winter for the warmth of Sarasota, Fla.

“I had people from various countries around the world writing to me and asking what they should do. And of course I don’t have any answers,” he said. But the study contained one of the world’s only references to the syndrome.

In 2003, a woman arrived in Toronto from Hong Kong. She didn’t know it at the time, but her preairport stay at the Hotel Metropole had infected her with the first SARS (severe acute respiratory syndrome) coronavirus. Her subsequent hospitalization in Toronto sparked a city-wide outbreak of SARS in which 273 people became ill and 44 died. Many of those affected were health care workers, including nurses and respiratory therapists. Although most eventually returned to work, a subset couldn’t. They complained of energy-sapping fatigue, poor sleep, brain fog, and assorted body aches and pains that persisted for more than 18 months. The aches and pains brought them to the attention of Dr. Moldofsky, then director of the Centre for the Study of Pain at the University of Toronto.

His primary interest at the time was fibromyalgia, which caused symptoms similar to those reported by the original SARS long-haulers. Intrigued, Dr. Moldofsky agreed to take a look. Their chest x-rays were clear and the nurses showed no signs of lingering viral infection. Dr. Moldofsky could see that the nurses were ill and suffering, but no lab tests or anything else could identify what was causing their symptoms.

In 2011, Dr. Moldofsky and Dr. Patcai found a strong overlap between chronic SARS, fibromyalgia, and chronic fatigue syndrome when they compared 22 patients with long-term SARS issues with 21 who had fibromyalgia. “Their problems are exactly the same. They have strange symptoms and nobody can figure out what they’re about. And these symptoms are aches and pains, and they have trouble thinking and concentrating,” Dr. Moldofsky said. Reports of COVID-19 long-haulers didn’t surprise Dr. Moldofsky, and he immediately recognized that Nath’s intention to follow these patients could provide insights into both fibromyalgia and chronic fatigue syndrome.

That’s exactly what Dr. Nath is proposing with the two NIH studies. One will focus solely on the neurologic impacts of COVID-19, including stroke, loss of taste and smell, and brain fog. The other will bring patients who have had COVID-19 symptoms for at least 6 months to the NIH Clinical Center for an inpatient stay during which they will undergo detailed physiologic tests.

Scientists around the world are launching their own post–COVID-19 studies. Dr. Moreau’s group in Montreal has laid the groundwork for such an endeavor, and the CoroNerve group in the United Kingdom is monitoring neurologic complications from the coronavirus. Many of them have the same goals as the NIH studies: Leverage the large number of COVID-19 long-haulers to better understand the earliest stages of postviral syndrome.

“At this juncture, after all the reports that we’ve seen so far, I think it’s very unlikely that there will be no relationship whatsoever between COVID-19 and chronic fatigue syndrome,” Dr. Hornig said. “I think there certainly will be some, but again, what’s the scope, what’s the size? And then, of course, even more importantly, if it is happening, what is the mechanism and how is it happening?”

For people like Ms. Gage-Witvliet, the answers can’t come soon enough. For the first time in more than a decade, the full-time professor of epidemiology didn’t prepare to teach this year because she simply can’t. It’s too taxing for her brain to deal with impromptu student questions. Ms. Gage-Witvliet hopes that, by sharing her own experiences with post COVID-19, she can help others.

“In my work, I use data to give a voice to people who don’t have a voice,” she said. “Now, I am one of those people.”

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