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How Much Does Long COVID Cost Society? New Data Shed Light
Long COVID, a major public health crisis, is also becoming a significant economic crisis. A new study in Nature reports that the global annual economic impact of long COVID has hit $1 trillion — or about 1% of the global economy.
Long COVID is estimated to affect 6%-7% of adults. Those afflicted are often unable to work for extended periods, and some simply stop working altogether.
Besides damaging individual lives, long COVID is having wide-ranging impacts on health systems and economies worldwide, as those who suffer from it have large absences from work, leading to lower productivity. Even those who return to work after weeks, months, or even up to a year out of work may come back with worse productivity and some functional impairment — as a few of the condition’s common symptoms include fatigue and brain fog.
Experts say more is needed not only in terms of scientific research into new treatments for long COVID but also from a public policy perspective.
Long COVID’s impact on the labor force is already having ripple effects throughout the economy of the United States and other countries. Earlier this year, the US Government Accountability Office stated long COVID potentially affects up to 23 million Americans, with as many as a million people out of work. The healthcare industry is particularly hard hit.
The latest survey from the National Center for Health Statistics estimated 17.3%-18.6% of adults have experienced long COVID. This isn’t the same as those who have it now, only a broad indicator of people who’ve ever experienced symptoms.
Public health experts, economists, researchers, and physicians say they are only beginning to focus on ways to reduce long COVID’s impact.
They suggest a range of potential solutions to address the public health crisis and the economic impacts — including implementing a more thorough surveillance system to track long COVID cases, building better ventilation systems in hospitals and buildings to reduce the spread of the virus, increasing vaccination efforts as new viral strains continuously emerge, and more funding for long COVID research to better quantify and qualify the disease’s impact.
Shaky Statistics, Inconsistent Surveillance
David Smith, MD, an infectious disease specialist at the University of California, San Diego, said more needs to be done to survey, quantify, and qualify the impacts of long COVID on the economy before practical solutions can be identified.
“Our surveillance system sucks,” Smith said. “I can see how many people test positive for COVID, but how many of those people have long COVID?”
Long COVID also doesn’t have a true definition or standard diagnosis, which complicates surveillance efforts. It includes a spectrum of symptoms such as shortness of breath, chronic fatigue, and brain fog that linger for 2-3 months after an acute infection. But there’s no “concrete case definition,” Smith said. “And not everybody’s long COVID is exactly the same as everybody else’s.”
As a result, epidemiologists can’t effectively characterize the disease, and health economists can’t measure its exact economic impact.
Few countries have established comprehensive surveillance systems to estimate the burden of long COVID at the population level.
The United States currently tracks new cases by measuring wastewater levels, which isn’t as comprehensive as the tracking that was done during the pandemic. But positive wastewater samples can’t tell us who is infected in an area, nor can it distinguish whether a visitor/tourist or resident is mostly contributing to the wastewater analysis — an important distinction in public health studies.
Wastewater surveillance is an excellent complement to traditional disease surveillance with advantages and disadvantages, but it shouldn’t be the sole way to measure disease.
What Research Best Informs the Debate?
A study by Economist Impact — a think tank that partners with corporations, foundations, NGOs, and governments to help drive policy — estimated between a 0.5% and 2.3% gross domestic product (GDP) loss across eight separate countries in 2024. The study included the United Kingdom and United States.
Meanwhile, Australian researchers recently detailed how long COVID-related reductions in labor supply affected its productivity and GDP from 2022 to 2024. The study found that long COVID could be costing the Australian economy about 0.5% of its GDP, which researchers deemed a conservative estimate.
Public health researchers in New Zealand used the estimate of GDP loss in Australia to measure their own potential losses and advocated for strengthening occupational support across all sectors to protect health.
But these studies can’t quite compare with what would have to be done for the United States economy.
“New Zealand is small ... and has an excellent public health system with good delivery of vaccines and treatments…so how do we compare that to us?” Smith said. “They do better in all of their public health metrics than we do.”
Measuring the Economic Impact
Gopi Shah Goda, PhD, a health economist and senior fellow in economic studies at the Brookings Institution, co-authored a 2023 study that found COVID-19 reduced the US labor force by about 500,000 people.
Plus, workers who missed a full week due to COVID-19 absences became 7% less likely to return to the labor force a year later compared with workers who didn’t miss work for health reasons. That amounts to 0.2% of the labor force, a significant number.
“Even a small percent of the labor force is a big number…it’s like an extra year of populating aging,” Goda said.
“Some people who get long COVID might have dropped out of the labor force anyway,” Goda added.
The study concluded that average individual earnings lost from long COVID were $9000, and the total lost labor supply amounted to $62 billion annually — about half the estimated productivity losses from cancer or diabetes.
But research into long COVID research continues to be underfunded compared with other health conditions, experts noted.
Cancer and diabetes both receive billions of research dollars annually from the National Institutes of Health. Long COVID research gets only a few million, according to Goda.
Informing Public Health Policy
When it comes to caring for patients with long COVID, the big issue facing every nation’s public policy leaders is how best to allocate limited health resources.
“Public health never has enough money ... Do they buy more vaccines? Do they do educational programs? Who do they target the most?” Smith said.
Though Smith thinks the best preventative measure is increased vaccination, vaccination rates remain low in the United States.
“Unfortunately, as last fall demonstrated, there’s a lot of vaccine indifference and skepticism,” said William Schaffner, MD, an infectious disease specialist at Vanderbilt University School of Medicine, Nashville, Tennessee.
Over the past year, only 14% of eligible children and 22% of adults received the 2023-2024 COVID vaccine boosters.
Schaffner said public health experts wrestle with ways to assure the public vaccines are safe and effective.
“They’re trying to provide a level of comfort that [getting vaccinated] is the socially appropriate thing to do,” which remains a significant challenge, Schaffner said.
Some people don’t have access to vaccines and comprehensive medical services because they lack insurance, Medicaid, and Medicare. And the United States still doesn’t distribute vaccines as well as other countries, Schaffner added.
“In other countries, every doctor’s office gets vaccines for free ... here, we have a large commercial enterprise that basically runs it…there are still populations who aren’t reached,” he said.
Long COVID clinics that have opened around the country have offered help to some patients with long COVID. A year and a half ago, Yale University, New Haven, Connecticut, established its Long COVID Care Center. Stanford University, Stanford, California, opened its Long COVID Clinic back in 2021. Vanderbilt University now has its own, as well — the Adult Post-COVID Clinic.
But these clinics have faced declining federal resources, forcing some to close and others to face questions about whether they will be able to continue to operate without more aggressive federal direction and policy planning.
“With some central direction, we could provide better supportive care for the many patients with long COVID out there,” Schaffner said.
For countries with universal healthcare systems, services such as occupational health, extended sick leave, extended time for disability, and workers’ compensation benefits are readily available.
But in the United States, it’s often left to the physicians and their patients to figure out a plan.
“I think we could make physicians more aware of options for their patients…for example, regularly check eligibility for workers compensation,” Schaffner said.
A version of this article first appeared on Medscape.com.
Long COVID, a major public health crisis, is also becoming a significant economic crisis. A new study in Nature reports that the global annual economic impact of long COVID has hit $1 trillion — or about 1% of the global economy.
Long COVID is estimated to affect 6%-7% of adults. Those afflicted are often unable to work for extended periods, and some simply stop working altogether.
Besides damaging individual lives, long COVID is having wide-ranging impacts on health systems and economies worldwide, as those who suffer from it have large absences from work, leading to lower productivity. Even those who return to work after weeks, months, or even up to a year out of work may come back with worse productivity and some functional impairment — as a few of the condition’s common symptoms include fatigue and brain fog.
Experts say more is needed not only in terms of scientific research into new treatments for long COVID but also from a public policy perspective.
Long COVID’s impact on the labor force is already having ripple effects throughout the economy of the United States and other countries. Earlier this year, the US Government Accountability Office stated long COVID potentially affects up to 23 million Americans, with as many as a million people out of work. The healthcare industry is particularly hard hit.
The latest survey from the National Center for Health Statistics estimated 17.3%-18.6% of adults have experienced long COVID. This isn’t the same as those who have it now, only a broad indicator of people who’ve ever experienced symptoms.
Public health experts, economists, researchers, and physicians say they are only beginning to focus on ways to reduce long COVID’s impact.
They suggest a range of potential solutions to address the public health crisis and the economic impacts — including implementing a more thorough surveillance system to track long COVID cases, building better ventilation systems in hospitals and buildings to reduce the spread of the virus, increasing vaccination efforts as new viral strains continuously emerge, and more funding for long COVID research to better quantify and qualify the disease’s impact.
Shaky Statistics, Inconsistent Surveillance
David Smith, MD, an infectious disease specialist at the University of California, San Diego, said more needs to be done to survey, quantify, and qualify the impacts of long COVID on the economy before practical solutions can be identified.
“Our surveillance system sucks,” Smith said. “I can see how many people test positive for COVID, but how many of those people have long COVID?”
Long COVID also doesn’t have a true definition or standard diagnosis, which complicates surveillance efforts. It includes a spectrum of symptoms such as shortness of breath, chronic fatigue, and brain fog that linger for 2-3 months after an acute infection. But there’s no “concrete case definition,” Smith said. “And not everybody’s long COVID is exactly the same as everybody else’s.”
As a result, epidemiologists can’t effectively characterize the disease, and health economists can’t measure its exact economic impact.
Few countries have established comprehensive surveillance systems to estimate the burden of long COVID at the population level.
The United States currently tracks new cases by measuring wastewater levels, which isn’t as comprehensive as the tracking that was done during the pandemic. But positive wastewater samples can’t tell us who is infected in an area, nor can it distinguish whether a visitor/tourist or resident is mostly contributing to the wastewater analysis — an important distinction in public health studies.
Wastewater surveillance is an excellent complement to traditional disease surveillance with advantages and disadvantages, but it shouldn’t be the sole way to measure disease.
What Research Best Informs the Debate?
A study by Economist Impact — a think tank that partners with corporations, foundations, NGOs, and governments to help drive policy — estimated between a 0.5% and 2.3% gross domestic product (GDP) loss across eight separate countries in 2024. The study included the United Kingdom and United States.
Meanwhile, Australian researchers recently detailed how long COVID-related reductions in labor supply affected its productivity and GDP from 2022 to 2024. The study found that long COVID could be costing the Australian economy about 0.5% of its GDP, which researchers deemed a conservative estimate.
Public health researchers in New Zealand used the estimate of GDP loss in Australia to measure their own potential losses and advocated for strengthening occupational support across all sectors to protect health.
But these studies can’t quite compare with what would have to be done for the United States economy.
“New Zealand is small ... and has an excellent public health system with good delivery of vaccines and treatments…so how do we compare that to us?” Smith said. “They do better in all of their public health metrics than we do.”
Measuring the Economic Impact
Gopi Shah Goda, PhD, a health economist and senior fellow in economic studies at the Brookings Institution, co-authored a 2023 study that found COVID-19 reduced the US labor force by about 500,000 people.
Plus, workers who missed a full week due to COVID-19 absences became 7% less likely to return to the labor force a year later compared with workers who didn’t miss work for health reasons. That amounts to 0.2% of the labor force, a significant number.
“Even a small percent of the labor force is a big number…it’s like an extra year of populating aging,” Goda said.
“Some people who get long COVID might have dropped out of the labor force anyway,” Goda added.
The study concluded that average individual earnings lost from long COVID were $9000, and the total lost labor supply amounted to $62 billion annually — about half the estimated productivity losses from cancer or diabetes.
But research into long COVID research continues to be underfunded compared with other health conditions, experts noted.
Cancer and diabetes both receive billions of research dollars annually from the National Institutes of Health. Long COVID research gets only a few million, according to Goda.
Informing Public Health Policy
When it comes to caring for patients with long COVID, the big issue facing every nation’s public policy leaders is how best to allocate limited health resources.
“Public health never has enough money ... Do they buy more vaccines? Do they do educational programs? Who do they target the most?” Smith said.
Though Smith thinks the best preventative measure is increased vaccination, vaccination rates remain low in the United States.
“Unfortunately, as last fall demonstrated, there’s a lot of vaccine indifference and skepticism,” said William Schaffner, MD, an infectious disease specialist at Vanderbilt University School of Medicine, Nashville, Tennessee.
Over the past year, only 14% of eligible children and 22% of adults received the 2023-2024 COVID vaccine boosters.
Schaffner said public health experts wrestle with ways to assure the public vaccines are safe and effective.
“They’re trying to provide a level of comfort that [getting vaccinated] is the socially appropriate thing to do,” which remains a significant challenge, Schaffner said.
Some people don’t have access to vaccines and comprehensive medical services because they lack insurance, Medicaid, and Medicare. And the United States still doesn’t distribute vaccines as well as other countries, Schaffner added.
“In other countries, every doctor’s office gets vaccines for free ... here, we have a large commercial enterprise that basically runs it…there are still populations who aren’t reached,” he said.
Long COVID clinics that have opened around the country have offered help to some patients with long COVID. A year and a half ago, Yale University, New Haven, Connecticut, established its Long COVID Care Center. Stanford University, Stanford, California, opened its Long COVID Clinic back in 2021. Vanderbilt University now has its own, as well — the Adult Post-COVID Clinic.
But these clinics have faced declining federal resources, forcing some to close and others to face questions about whether they will be able to continue to operate without more aggressive federal direction and policy planning.
“With some central direction, we could provide better supportive care for the many patients with long COVID out there,” Schaffner said.
For countries with universal healthcare systems, services such as occupational health, extended sick leave, extended time for disability, and workers’ compensation benefits are readily available.
But in the United States, it’s often left to the physicians and their patients to figure out a plan.
“I think we could make physicians more aware of options for their patients…for example, regularly check eligibility for workers compensation,” Schaffner said.
A version of this article first appeared on Medscape.com.
Long COVID, a major public health crisis, is also becoming a significant economic crisis. A new study in Nature reports that the global annual economic impact of long COVID has hit $1 trillion — or about 1% of the global economy.
Long COVID is estimated to affect 6%-7% of adults. Those afflicted are often unable to work for extended periods, and some simply stop working altogether.
Besides damaging individual lives, long COVID is having wide-ranging impacts on health systems and economies worldwide, as those who suffer from it have large absences from work, leading to lower productivity. Even those who return to work after weeks, months, or even up to a year out of work may come back with worse productivity and some functional impairment — as a few of the condition’s common symptoms include fatigue and brain fog.
Experts say more is needed not only in terms of scientific research into new treatments for long COVID but also from a public policy perspective.
Long COVID’s impact on the labor force is already having ripple effects throughout the economy of the United States and other countries. Earlier this year, the US Government Accountability Office stated long COVID potentially affects up to 23 million Americans, with as many as a million people out of work. The healthcare industry is particularly hard hit.
The latest survey from the National Center for Health Statistics estimated 17.3%-18.6% of adults have experienced long COVID. This isn’t the same as those who have it now, only a broad indicator of people who’ve ever experienced symptoms.
Public health experts, economists, researchers, and physicians say they are only beginning to focus on ways to reduce long COVID’s impact.
They suggest a range of potential solutions to address the public health crisis and the economic impacts — including implementing a more thorough surveillance system to track long COVID cases, building better ventilation systems in hospitals and buildings to reduce the spread of the virus, increasing vaccination efforts as new viral strains continuously emerge, and more funding for long COVID research to better quantify and qualify the disease’s impact.
Shaky Statistics, Inconsistent Surveillance
David Smith, MD, an infectious disease specialist at the University of California, San Diego, said more needs to be done to survey, quantify, and qualify the impacts of long COVID on the economy before practical solutions can be identified.
“Our surveillance system sucks,” Smith said. “I can see how many people test positive for COVID, but how many of those people have long COVID?”
Long COVID also doesn’t have a true definition or standard diagnosis, which complicates surveillance efforts. It includes a spectrum of symptoms such as shortness of breath, chronic fatigue, and brain fog that linger for 2-3 months after an acute infection. But there’s no “concrete case definition,” Smith said. “And not everybody’s long COVID is exactly the same as everybody else’s.”
As a result, epidemiologists can’t effectively characterize the disease, and health economists can’t measure its exact economic impact.
Few countries have established comprehensive surveillance systems to estimate the burden of long COVID at the population level.
The United States currently tracks new cases by measuring wastewater levels, which isn’t as comprehensive as the tracking that was done during the pandemic. But positive wastewater samples can’t tell us who is infected in an area, nor can it distinguish whether a visitor/tourist or resident is mostly contributing to the wastewater analysis — an important distinction in public health studies.
Wastewater surveillance is an excellent complement to traditional disease surveillance with advantages and disadvantages, but it shouldn’t be the sole way to measure disease.
What Research Best Informs the Debate?
A study by Economist Impact — a think tank that partners with corporations, foundations, NGOs, and governments to help drive policy — estimated between a 0.5% and 2.3% gross domestic product (GDP) loss across eight separate countries in 2024. The study included the United Kingdom and United States.
Meanwhile, Australian researchers recently detailed how long COVID-related reductions in labor supply affected its productivity and GDP from 2022 to 2024. The study found that long COVID could be costing the Australian economy about 0.5% of its GDP, which researchers deemed a conservative estimate.
Public health researchers in New Zealand used the estimate of GDP loss in Australia to measure their own potential losses and advocated for strengthening occupational support across all sectors to protect health.
But these studies can’t quite compare with what would have to be done for the United States economy.
“New Zealand is small ... and has an excellent public health system with good delivery of vaccines and treatments…so how do we compare that to us?” Smith said. “They do better in all of their public health metrics than we do.”
Measuring the Economic Impact
Gopi Shah Goda, PhD, a health economist and senior fellow in economic studies at the Brookings Institution, co-authored a 2023 study that found COVID-19 reduced the US labor force by about 500,000 people.
Plus, workers who missed a full week due to COVID-19 absences became 7% less likely to return to the labor force a year later compared with workers who didn’t miss work for health reasons. That amounts to 0.2% of the labor force, a significant number.
“Even a small percent of the labor force is a big number…it’s like an extra year of populating aging,” Goda said.
“Some people who get long COVID might have dropped out of the labor force anyway,” Goda added.
The study concluded that average individual earnings lost from long COVID were $9000, and the total lost labor supply amounted to $62 billion annually — about half the estimated productivity losses from cancer or diabetes.
But research into long COVID research continues to be underfunded compared with other health conditions, experts noted.
Cancer and diabetes both receive billions of research dollars annually from the National Institutes of Health. Long COVID research gets only a few million, according to Goda.
Informing Public Health Policy
When it comes to caring for patients with long COVID, the big issue facing every nation’s public policy leaders is how best to allocate limited health resources.
“Public health never has enough money ... Do they buy more vaccines? Do they do educational programs? Who do they target the most?” Smith said.
Though Smith thinks the best preventative measure is increased vaccination, vaccination rates remain low in the United States.
“Unfortunately, as last fall demonstrated, there’s a lot of vaccine indifference and skepticism,” said William Schaffner, MD, an infectious disease specialist at Vanderbilt University School of Medicine, Nashville, Tennessee.
Over the past year, only 14% of eligible children and 22% of adults received the 2023-2024 COVID vaccine boosters.
Schaffner said public health experts wrestle with ways to assure the public vaccines are safe and effective.
“They’re trying to provide a level of comfort that [getting vaccinated] is the socially appropriate thing to do,” which remains a significant challenge, Schaffner said.
Some people don’t have access to vaccines and comprehensive medical services because they lack insurance, Medicaid, and Medicare. And the United States still doesn’t distribute vaccines as well as other countries, Schaffner added.
“In other countries, every doctor’s office gets vaccines for free ... here, we have a large commercial enterprise that basically runs it…there are still populations who aren’t reached,” he said.
Long COVID clinics that have opened around the country have offered help to some patients with long COVID. A year and a half ago, Yale University, New Haven, Connecticut, established its Long COVID Care Center. Stanford University, Stanford, California, opened its Long COVID Clinic back in 2021. Vanderbilt University now has its own, as well — the Adult Post-COVID Clinic.
But these clinics have faced declining federal resources, forcing some to close and others to face questions about whether they will be able to continue to operate without more aggressive federal direction and policy planning.
“With some central direction, we could provide better supportive care for the many patients with long COVID out there,” Schaffner said.
For countries with universal healthcare systems, services such as occupational health, extended sick leave, extended time for disability, and workers’ compensation benefits are readily available.
But in the United States, it’s often left to the physicians and their patients to figure out a plan.
“I think we could make physicians more aware of options for their patients…for example, regularly check eligibility for workers compensation,” Schaffner said.
A version of this article first appeared on Medscape.com.
FROM NATURE
Paxlovid, Supplements May Improve Long COVID Symptoms
Paxlovid, an antiviral approved in 2023 to treat acute infections of COVID-19, is showing great potential as a new treatment for long COVID and may be the most promising experimental therapy now being studied for treating the condition.
New research offers strong evidence that Paxlovid provides significant benefits for COVID-19 patients who are at high risk for severe or prolonged disease, particularly older adults and those who are immunocompromised, said Lisa Sanders, MD, medical director of Yale’s Long COVID Multidisciplinary Care Center, New Haven, Connecticut.
“We all know that long COVID is a disease smorgasbord of illnesses that have been somehow triggered by COVID. So, the question is, are there some types of these disorders that can respond to Paxlovid?” Dr. Sanders said.
Some patients have also benefited from supplements such as N-acetyl cysteine (NAC), as well as vitamins B, C, D and alpha lipoic acid, in which the risks are low and there are potential benefits, Dr. Sanders said.
A study published in 2023 by JAMA Internal Medicine reviewed the charts of nearly 300,000 veterans with severe acute COVID infections. The study found that Paxlovid treatment reduced the likelihood of developing long COVID. But a more recent study at Stanford University, Palo Alto, California — the STOP-PASC trial— did not find Paxlovid improved symptoms when given to 155 patients who had already recovered from acute infection. Participants with long COVID symptoms — and who had on average recovered from acute infection around 16 months earlier — were given a 15-day course of Paxlovid. Common symptoms like fog, fatigue, and cardiovascular or gastrointestinal symptoms did not improve.
However, long COVID likely has multiple drivers. Viral persistence may still be at play for a subset of patients. This means that, despite the fact that patients recover from acute infection, hidden reservoirs of SARS-CoV-2 are still present in the body, possibly bringing on long COVID symptoms. Which means Paxlovid may help some long COVID patients but not others, Dr. Sanders explained. That’s why research needs to continue to identify the best cases for Paxlovid’s use and to identify other treatments for those who do not benefit from Paxlovid.
The PAX LC trial at Yale suggests there may not be a one-size-fits-all treatment for the condition, but a range of factors that may determine the best therapy for individual patients. Led by Yale School of Medicine’s Harlan Krumholz, MD, and Akiko Iwasaki, PhD, the study tested the effects of Paxlovid overall and was designed to determine who is most likely to benefit from antiviral treatment and gain further understanding of the immune response in long COVID. Results should be reported soon.
“This acknowledges one line of thinking that long COVID is caused by viral persistence,” Dr. Sanders said. “Do these people have hidden reservoirs of the virus? The question is, are there people who seem to respond [to Paxlovid]? And if so, what characterizes these people?”
Low-Risk, High-Reward Supplements
Some of Dr. Sanders’ colleagues at Yale are focusing on long COVID’s neurological symptoms and neuropathogenesis. There’s evidence showing these symptoms — notably brain fog — can be treated with supplements.
In 2022, a Yale study by Arman Fesharaki-Zadeh, MD, PhD, found promise in treating brain fog through a combination supplement of NAC and guanfacine — the latter developed by Yale neuroscientist, Amy Arnsten, PhD.
The two published their study in Neuroimmunology Reports in November 2023. NAC is available over the counter and patients can get a prescription for guanfacine off label from their physician. Guanfacine is approved to treat high blood pressure by decreasing heart rate and relaxing blood vessels. But it’s also been shown to treat attention-deficit/hyperactivity disorder (ADHD) and other cognitive issues.
Though NAC can treat respiratory problems, it’s also commonly used to treat postconcussion symptoms. Dr. Fesharaki-Zadeh found that it helps treat brain fog, increases energy, and improves memory. When paired with guanfacine, substantial benefits were reported, such as better multitasking abilities and markedly improved organizational skills.
Dr. Sanders is now using NAC and guanfacine for patients in her clinic.
‘Mitochondrial Enhancement’ Through Vitamins
Dr. Sanders has also used a combination of alpha lipoic acid and vitamin C, and a combo of B vitamins that make up what’s called a “mitochondrial enhancement regimen.”
To treat a very common symptom like fatigue, Dr. Sanders prefers supplement combinations over other drugs like Modafinil or Adderall.
Modafinil is a central nervous system stimulant used to reduce extreme sleepiness caused by narcolepsy or other sleep disorders. Adderall is an amphetamine also used to treat narcolepsy as well as ADHD. Both work on your sleep and alertness, but long COVID affects the whole body, causing a physical fatigue similar to postexertional malaise (PEM) that isn’t remedied by those kinds of drugs, as studies suggest what’s involved in PEM is mitochondria, Dr. Sanders said.
PEM is a worsening of symptoms that occurs after minimal physical or mental exertion. These are activities that should be well tolerated, but PEM causes extreme fatigue and flu-like symptoms. It’s become a hallmark symptom of long COVID after having already been a key diagnostic factor in myalgic encephalomyelitis/chronic fatigue syndrome.
As Dr. Sanders noted in her long COVID blog, which tracks the latest research and treatment options for doctors who treat long COVID patients, previous studies have shown low vitamin D levels may not only increase the risk for severe COVID-19 but delay recovery from long COVID. Those without long COVID had higher levels of vitamin D, compared with long COVID patients. Vitamin D is known to boost the immune system.
Dr. Sanders found that those with vitamin D deficiencies are most likely to benefit from this approach. For people who don’t have sufficient sun exposure, which prompts the production of vitamin D, she says supplementation with 1000 IUs of vitamin D3 daily is enough for most adults.
Research is also currently being underway on the use of the diabetes drug metformin in people with acute COVID infections to determine if it may reduce the likelihood of developing long COVID. In a recent long COVID clinical trial, early outpatient COVID-19 treatment with metformin decreased the subsequent risk for long COVID by 41.3% during 10-month follow-up.
Other New Treatments Under Study
Dr. Sanders believes the foundation for many of long COVID’s symptoms could be neurological.
“I think that long COVID is probably a neurologic disorder,” Dr. Sanders said.
Lindsey McAlpine, MD, director of the Yale Medicine NeuroCovid Clinic, is focusing on neuropsychiatric long COVID and the causes of neurologic post-acute sequelae of SARS-CoV-2 infection (neuro-PASC). Symptoms of neuro-PASC include cognitive impairment, headaches, and dizziness.
“Lindsey is trying to see which parts of the brain are involved and see if there are phenotypes of brain abnormalities that match up with clinical abnormalities,” Dr. Sanders said.
The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”
Utilizing advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, Dr. McAlpine hopes to unearth and better understand the pathophysiology behind neurological issues post COVID.
Many of Dr. McAlpine’s patients with cognitive symptoms have responded well to NAC and guanfacine.
Still, the hope is that her brain-imaging studies will bear fruit that leads to a better understanding of long COVID and new treatment methods.
A version of this article first appeared on Medscape.com.
Paxlovid, an antiviral approved in 2023 to treat acute infections of COVID-19, is showing great potential as a new treatment for long COVID and may be the most promising experimental therapy now being studied for treating the condition.
New research offers strong evidence that Paxlovid provides significant benefits for COVID-19 patients who are at high risk for severe or prolonged disease, particularly older adults and those who are immunocompromised, said Lisa Sanders, MD, medical director of Yale’s Long COVID Multidisciplinary Care Center, New Haven, Connecticut.
“We all know that long COVID is a disease smorgasbord of illnesses that have been somehow triggered by COVID. So, the question is, are there some types of these disorders that can respond to Paxlovid?” Dr. Sanders said.
Some patients have also benefited from supplements such as N-acetyl cysteine (NAC), as well as vitamins B, C, D and alpha lipoic acid, in which the risks are low and there are potential benefits, Dr. Sanders said.
A study published in 2023 by JAMA Internal Medicine reviewed the charts of nearly 300,000 veterans with severe acute COVID infections. The study found that Paxlovid treatment reduced the likelihood of developing long COVID. But a more recent study at Stanford University, Palo Alto, California — the STOP-PASC trial— did not find Paxlovid improved symptoms when given to 155 patients who had already recovered from acute infection. Participants with long COVID symptoms — and who had on average recovered from acute infection around 16 months earlier — were given a 15-day course of Paxlovid. Common symptoms like fog, fatigue, and cardiovascular or gastrointestinal symptoms did not improve.
However, long COVID likely has multiple drivers. Viral persistence may still be at play for a subset of patients. This means that, despite the fact that patients recover from acute infection, hidden reservoirs of SARS-CoV-2 are still present in the body, possibly bringing on long COVID symptoms. Which means Paxlovid may help some long COVID patients but not others, Dr. Sanders explained. That’s why research needs to continue to identify the best cases for Paxlovid’s use and to identify other treatments for those who do not benefit from Paxlovid.
The PAX LC trial at Yale suggests there may not be a one-size-fits-all treatment for the condition, but a range of factors that may determine the best therapy for individual patients. Led by Yale School of Medicine’s Harlan Krumholz, MD, and Akiko Iwasaki, PhD, the study tested the effects of Paxlovid overall and was designed to determine who is most likely to benefit from antiviral treatment and gain further understanding of the immune response in long COVID. Results should be reported soon.
“This acknowledges one line of thinking that long COVID is caused by viral persistence,” Dr. Sanders said. “Do these people have hidden reservoirs of the virus? The question is, are there people who seem to respond [to Paxlovid]? And if so, what characterizes these people?”
Low-Risk, High-Reward Supplements
Some of Dr. Sanders’ colleagues at Yale are focusing on long COVID’s neurological symptoms and neuropathogenesis. There’s evidence showing these symptoms — notably brain fog — can be treated with supplements.
In 2022, a Yale study by Arman Fesharaki-Zadeh, MD, PhD, found promise in treating brain fog through a combination supplement of NAC and guanfacine — the latter developed by Yale neuroscientist, Amy Arnsten, PhD.
The two published their study in Neuroimmunology Reports in November 2023. NAC is available over the counter and patients can get a prescription for guanfacine off label from their physician. Guanfacine is approved to treat high blood pressure by decreasing heart rate and relaxing blood vessels. But it’s also been shown to treat attention-deficit/hyperactivity disorder (ADHD) and other cognitive issues.
Though NAC can treat respiratory problems, it’s also commonly used to treat postconcussion symptoms. Dr. Fesharaki-Zadeh found that it helps treat brain fog, increases energy, and improves memory. When paired with guanfacine, substantial benefits were reported, such as better multitasking abilities and markedly improved organizational skills.
Dr. Sanders is now using NAC and guanfacine for patients in her clinic.
‘Mitochondrial Enhancement’ Through Vitamins
Dr. Sanders has also used a combination of alpha lipoic acid and vitamin C, and a combo of B vitamins that make up what’s called a “mitochondrial enhancement regimen.”
To treat a very common symptom like fatigue, Dr. Sanders prefers supplement combinations over other drugs like Modafinil or Adderall.
Modafinil is a central nervous system stimulant used to reduce extreme sleepiness caused by narcolepsy or other sleep disorders. Adderall is an amphetamine also used to treat narcolepsy as well as ADHD. Both work on your sleep and alertness, but long COVID affects the whole body, causing a physical fatigue similar to postexertional malaise (PEM) that isn’t remedied by those kinds of drugs, as studies suggest what’s involved in PEM is mitochondria, Dr. Sanders said.
PEM is a worsening of symptoms that occurs after minimal physical or mental exertion. These are activities that should be well tolerated, but PEM causes extreme fatigue and flu-like symptoms. It’s become a hallmark symptom of long COVID after having already been a key diagnostic factor in myalgic encephalomyelitis/chronic fatigue syndrome.
As Dr. Sanders noted in her long COVID blog, which tracks the latest research and treatment options for doctors who treat long COVID patients, previous studies have shown low vitamin D levels may not only increase the risk for severe COVID-19 but delay recovery from long COVID. Those without long COVID had higher levels of vitamin D, compared with long COVID patients. Vitamin D is known to boost the immune system.
Dr. Sanders found that those with vitamin D deficiencies are most likely to benefit from this approach. For people who don’t have sufficient sun exposure, which prompts the production of vitamin D, she says supplementation with 1000 IUs of vitamin D3 daily is enough for most adults.
Research is also currently being underway on the use of the diabetes drug metformin in people with acute COVID infections to determine if it may reduce the likelihood of developing long COVID. In a recent long COVID clinical trial, early outpatient COVID-19 treatment with metformin decreased the subsequent risk for long COVID by 41.3% during 10-month follow-up.
Other New Treatments Under Study
Dr. Sanders believes the foundation for many of long COVID’s symptoms could be neurological.
“I think that long COVID is probably a neurologic disorder,” Dr. Sanders said.
Lindsey McAlpine, MD, director of the Yale Medicine NeuroCovid Clinic, is focusing on neuropsychiatric long COVID and the causes of neurologic post-acute sequelae of SARS-CoV-2 infection (neuro-PASC). Symptoms of neuro-PASC include cognitive impairment, headaches, and dizziness.
“Lindsey is trying to see which parts of the brain are involved and see if there are phenotypes of brain abnormalities that match up with clinical abnormalities,” Dr. Sanders said.
The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”
Utilizing advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, Dr. McAlpine hopes to unearth and better understand the pathophysiology behind neurological issues post COVID.
Many of Dr. McAlpine’s patients with cognitive symptoms have responded well to NAC and guanfacine.
Still, the hope is that her brain-imaging studies will bear fruit that leads to a better understanding of long COVID and new treatment methods.
A version of this article first appeared on Medscape.com.
Paxlovid, an antiviral approved in 2023 to treat acute infections of COVID-19, is showing great potential as a new treatment for long COVID and may be the most promising experimental therapy now being studied for treating the condition.
New research offers strong evidence that Paxlovid provides significant benefits for COVID-19 patients who are at high risk for severe or prolonged disease, particularly older adults and those who are immunocompromised, said Lisa Sanders, MD, medical director of Yale’s Long COVID Multidisciplinary Care Center, New Haven, Connecticut.
“We all know that long COVID is a disease smorgasbord of illnesses that have been somehow triggered by COVID. So, the question is, are there some types of these disorders that can respond to Paxlovid?” Dr. Sanders said.
Some patients have also benefited from supplements such as N-acetyl cysteine (NAC), as well as vitamins B, C, D and alpha lipoic acid, in which the risks are low and there are potential benefits, Dr. Sanders said.
A study published in 2023 by JAMA Internal Medicine reviewed the charts of nearly 300,000 veterans with severe acute COVID infections. The study found that Paxlovid treatment reduced the likelihood of developing long COVID. But a more recent study at Stanford University, Palo Alto, California — the STOP-PASC trial— did not find Paxlovid improved symptoms when given to 155 patients who had already recovered from acute infection. Participants with long COVID symptoms — and who had on average recovered from acute infection around 16 months earlier — were given a 15-day course of Paxlovid. Common symptoms like fog, fatigue, and cardiovascular or gastrointestinal symptoms did not improve.
However, long COVID likely has multiple drivers. Viral persistence may still be at play for a subset of patients. This means that, despite the fact that patients recover from acute infection, hidden reservoirs of SARS-CoV-2 are still present in the body, possibly bringing on long COVID symptoms. Which means Paxlovid may help some long COVID patients but not others, Dr. Sanders explained. That’s why research needs to continue to identify the best cases for Paxlovid’s use and to identify other treatments for those who do not benefit from Paxlovid.
The PAX LC trial at Yale suggests there may not be a one-size-fits-all treatment for the condition, but a range of factors that may determine the best therapy for individual patients. Led by Yale School of Medicine’s Harlan Krumholz, MD, and Akiko Iwasaki, PhD, the study tested the effects of Paxlovid overall and was designed to determine who is most likely to benefit from antiviral treatment and gain further understanding of the immune response in long COVID. Results should be reported soon.
“This acknowledges one line of thinking that long COVID is caused by viral persistence,” Dr. Sanders said. “Do these people have hidden reservoirs of the virus? The question is, are there people who seem to respond [to Paxlovid]? And if so, what characterizes these people?”
Low-Risk, High-Reward Supplements
Some of Dr. Sanders’ colleagues at Yale are focusing on long COVID’s neurological symptoms and neuropathogenesis. There’s evidence showing these symptoms — notably brain fog — can be treated with supplements.
In 2022, a Yale study by Arman Fesharaki-Zadeh, MD, PhD, found promise in treating brain fog through a combination supplement of NAC and guanfacine — the latter developed by Yale neuroscientist, Amy Arnsten, PhD.
The two published their study in Neuroimmunology Reports in November 2023. NAC is available over the counter and patients can get a prescription for guanfacine off label from their physician. Guanfacine is approved to treat high blood pressure by decreasing heart rate and relaxing blood vessels. But it’s also been shown to treat attention-deficit/hyperactivity disorder (ADHD) and other cognitive issues.
Though NAC can treat respiratory problems, it’s also commonly used to treat postconcussion symptoms. Dr. Fesharaki-Zadeh found that it helps treat brain fog, increases energy, and improves memory. When paired with guanfacine, substantial benefits were reported, such as better multitasking abilities and markedly improved organizational skills.
Dr. Sanders is now using NAC and guanfacine for patients in her clinic.
‘Mitochondrial Enhancement’ Through Vitamins
Dr. Sanders has also used a combination of alpha lipoic acid and vitamin C, and a combo of B vitamins that make up what’s called a “mitochondrial enhancement regimen.”
To treat a very common symptom like fatigue, Dr. Sanders prefers supplement combinations over other drugs like Modafinil or Adderall.
Modafinil is a central nervous system stimulant used to reduce extreme sleepiness caused by narcolepsy or other sleep disorders. Adderall is an amphetamine also used to treat narcolepsy as well as ADHD. Both work on your sleep and alertness, but long COVID affects the whole body, causing a physical fatigue similar to postexertional malaise (PEM) that isn’t remedied by those kinds of drugs, as studies suggest what’s involved in PEM is mitochondria, Dr. Sanders said.
PEM is a worsening of symptoms that occurs after minimal physical or mental exertion. These are activities that should be well tolerated, but PEM causes extreme fatigue and flu-like symptoms. It’s become a hallmark symptom of long COVID after having already been a key diagnostic factor in myalgic encephalomyelitis/chronic fatigue syndrome.
As Dr. Sanders noted in her long COVID blog, which tracks the latest research and treatment options for doctors who treat long COVID patients, previous studies have shown low vitamin D levels may not only increase the risk for severe COVID-19 but delay recovery from long COVID. Those without long COVID had higher levels of vitamin D, compared with long COVID patients. Vitamin D is known to boost the immune system.
Dr. Sanders found that those with vitamin D deficiencies are most likely to benefit from this approach. For people who don’t have sufficient sun exposure, which prompts the production of vitamin D, she says supplementation with 1000 IUs of vitamin D3 daily is enough for most adults.
Research is also currently being underway on the use of the diabetes drug metformin in people with acute COVID infections to determine if it may reduce the likelihood of developing long COVID. In a recent long COVID clinical trial, early outpatient COVID-19 treatment with metformin decreased the subsequent risk for long COVID by 41.3% during 10-month follow-up.
Other New Treatments Under Study
Dr. Sanders believes the foundation for many of long COVID’s symptoms could be neurological.
“I think that long COVID is probably a neurologic disorder,” Dr. Sanders said.
Lindsey McAlpine, MD, director of the Yale Medicine NeuroCovid Clinic, is focusing on neuropsychiatric long COVID and the causes of neurologic post-acute sequelae of SARS-CoV-2 infection (neuro-PASC). Symptoms of neuro-PASC include cognitive impairment, headaches, and dizziness.
“Lindsey is trying to see which parts of the brain are involved and see if there are phenotypes of brain abnormalities that match up with clinical abnormalities,” Dr. Sanders said.
The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”
Utilizing advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, Dr. McAlpine hopes to unearth and better understand the pathophysiology behind neurological issues post COVID.
Many of Dr. McAlpine’s patients with cognitive symptoms have responded well to NAC and guanfacine.
Still, the hope is that her brain-imaging studies will bear fruit that leads to a better understanding of long COVID and new treatment methods.
A version of this article first appeared on Medscape.com.
Scientist Aims to Unravel Long COVID’s Neurologic Impacts
Neurologic symptoms of long COVID are vast, common, hard to treat, disabling, and can mimic dozens of other syndromes, with some symptoms as serious as those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).
Now, recent evidence has suggested long COVID is primarily an autonomic nervous system disorder.
Their lives may never be the same.
Lindsay S. McAlpine, MD, a specialist in the neurologic sequelae of COVID-19 at the Yale School of Medicine and director of the Yale NeuroCOVID Clinic, New Haven, Connecticut, treats patients who struggle with neurologic symptoms even after disease recovery.
“Some people have the brain fog and the shortness of breath; some have the palpitations and the headaches ... it’s kind of a mix and match,” she said.
Dr. McAlpine’s research has been slowly building up into what could bring about a significant breakthrough in treating some of the most misunderstood and difficult-to-treat symptoms of long COVID.
The Effect of Vascular Inflammation on Long COVID
The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”
Using advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, McAlpine hopes to unearth and better understand the pathophysiology behind neurologic issues post-COVID.
Dr. McAlpine said, “What we’re seeing is that there’s a unique signature of vascular inflammation in long COVID that is distinct from acute COVID. And it has to do with endothelial apathy and platelet dysfunction.”
She’s also looking into whether microvascular dysfunction could increase one’s risk for small vessel disease. Her research is quantitatively building an overall pathophysiology piece by piece.
“We’re quantifying cognitive dysfunction and using objective testing ... a very rigorous 3-hour protocol to really identify the patterns of weakness until we find deficits in memory working and declarative memory, deficits in executive functioning, and others. Those are the three pieces that I’m trying to piece together: The MRI, the blood work, and the cognitive testing,” she said.
Ultimately, Dr. McAlpine believes long COVID will eventually be classified as a peripheral autonomic disorder. The damage being wrought to the whole body also damages the brain’s vasculature, and Dr. McAlpine’s MRI techniques probe at this connection.
“Some of my MRI techniques are dependent on the very subtle changes in blood flow to different regions in response to demand. Brain fog has been a key symptom of POTS and ME/CFS. And it’s now a key symptom of long COVID ... what I’m looking at in some of my studies is how and in which parts of the brain are affected by this,” she said.
Dr. McAlpine’s interest in COVID’s effect on our nervous system goes back all the way to the first wave of patients with COVID, where she noticed an unusually high incidence of ischemic stroke.
“We recognized that COVID really has a huge impact on the vessels ... there’s quite a bit of vascular inflammation. In terms of neurology, we were seeing quite a bit of ischemic stroke, which is unusual,” she said.
Patients don’t normally present with stroke while infected with a virus. Seeking answers, she conducted a stroke study in patients with acute COVID and found profound endotheliopathy — damage to key cells in the lining of blood vessels — leading to a cascade of dysfunction and clotting.
A Constellation of Neuropsychiatric Symptoms
In early June, Dr. McAlpine gave a presentation of her research at the Demystifying Long COVID North American Conference 2024 in Boston. She’s been hard at work in extrapolating the causes of neuropsychiatric long COVID, a tangled web of symptoms seen in patients with long COVID that range from cognitive dysfunction to headaches, neuropathy, mental health, and the aforementioned dysautonomia.
Amid the sea of neurologic long COVID symptoms, she said “symptoms that are mixing and matching are very similar. So, I wanted to specifically look at a symptom that I could definitely isolate to the brain, and that is brain fog and cognitive dysfunction and impairment.”
In September 2021, the journal Translational Psychiatry published a study titled “Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions.”
Going back all the way to the first cases of COVID in March 2020, the initial symptoms most patients complained of during an acute viral infection were around the respiratory system. Yet delirium, confusion, and neurocognitive disorders were also reported, puzzling experts and inciting a well-founded fear among many.
Even worse, after recovery, these neuropsychiatric symptoms persisted. The study found that coronavirus was able to invade the central nervous system through blood vessels and neuronal retrograde pathways, leading to brain injury and dysfunction of the cardiorespiratory center in the brainstem.
The study concluded by reporting that neuroimaging and neurochemical evidence indicated neuroimmune dysfunction and brain injury in severe patients with COVID-19. Suggested treatments included immunosuppressive therapies, vaccines to target the coronavirus’ spike protein, and pharmacological agents to improve endothelial integrity.
But there was still much that was unknown, and the study’s authors stressed the need for multidisciplinary research going forward.
How Immune Dysfunction Plays a Role
Similarly, Dr. McAlpine and her research team are still trying to sift their way through this opaque web to see why long COVID can cause autoimmune flare-ups.
In a study published in April, Dr. McAlpine and others found that small fiber neuropathy (SFN) after COVID is autoimmune-mediated and a dysfunction of the immune system.
Notably, they found that SFN could be a key pathologic finding in long COVID. SFN before the pandemic had been linked to ME/CFS and POTS, and the basic hypothesis revolved around an inflammatory immune response during a viral illness that may lead to immune dysregulation (dysimmunity) and damage to small fiber nerves.
But much still remains to be answered.
“We’ve seen quite a bit of that, but we still haven’t figured it out,” Dr. McAlpine said. “My big question is, how is this autonomic dysfunction related to the immune dysfunction, and how is that related to the vascular inflammation? There’s quite a bit of overlap in individuals with autoimmune disease and those who go on to develop this long COVID,” she added.
Still, a large portion of patients with long COVID don’t show autoimmune dysfunction, and those patients lack common biomarkers for an autoimmune condition.
“When we look at the spinal fluid in those individuals [with multiple sclerosis or a neuroinfectious disease], there’s inflammation going on ... the white blood cell count is elevated, the protein is elevated, the antibodies, the bands are elevated. I’ve been seeing long COVID patients now for 4 years, and their presentation is so distinctly different compared to my individuals that I see my patients with MS, or a neuroinfectious disease,” she said.
The mechanisms behind how all of this is interlaced remain unclear, and there may not be a one-size-fits-all treatment or definite pathogenesis for everyone.
“It’s that intersection of the immune system and the vessel wall ... Next is to figure out what do we treat, what are the targets, all of that, but there’s so many different presentations, and everybody has kind of a unique case,” she said.
How Physician Can Treat Common Symptoms Now
Though a cure for symptoms still eludes the scientific community, recent evidence has suggested that a combination of N-acetyl cysteine (NAC) and guanfacine has been successful in easing neurologic symptoms.
In November 2023, Arman Fesharaki-Zadeh, MD, PhD, a Yale Medicine behavioral neurologist and neuropsychiatrist, published a small study in Neuroimmunology Reports with his colleague, Yale neuroscientist Amy Arnsten, PhD. The two researchers showed how among 12 patients given 600 mg NAC daily, along with 1 mg guanfacine (increased to 2 mg after a month if well-tolerated), eight demonstrated improved cognitive abilities.
In patients who stayed on guanfacine + NAC, improved working memory, concentration, and executive functions were seen.
Also, they resumed their normal work schedule. Interruption and inability to work has been a significant factor in the lower quality-of-life long COVID patients experience.
Placebo-controlled trials will be needed going forward, but their small study has established safety and could open up a larger study in the future. For the moment, NAC can be gotten over the counter, and patients could get a prescription off-label from their doctor.
Dr. McAlpine has seen this combination work well for her own patients at Yale’s NeuroCOVID clinic.
Additionally, lifestyle practices such as quitting tobacco, increased exercise, exercising the mind, lowering alcohol intake, and even vitamin D supplementation (1000-2000 IU daily) could prove beneficial in tamping down persistent brain fog.
Vitamin D supports brain and nerve function through its reduction of brain aging biomarkers, regulating genes important for brain function, activating and deactivating enzymes important for neurotransmitter synthesis, and supporting neuronal growth and survival.
A version of this article first appeared on Medscape.com.
Neurologic symptoms of long COVID are vast, common, hard to treat, disabling, and can mimic dozens of other syndromes, with some symptoms as serious as those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).
Now, recent evidence has suggested long COVID is primarily an autonomic nervous system disorder.
Their lives may never be the same.
Lindsay S. McAlpine, MD, a specialist in the neurologic sequelae of COVID-19 at the Yale School of Medicine and director of the Yale NeuroCOVID Clinic, New Haven, Connecticut, treats patients who struggle with neurologic symptoms even after disease recovery.
“Some people have the brain fog and the shortness of breath; some have the palpitations and the headaches ... it’s kind of a mix and match,” she said.
Dr. McAlpine’s research has been slowly building up into what could bring about a significant breakthrough in treating some of the most misunderstood and difficult-to-treat symptoms of long COVID.
The Effect of Vascular Inflammation on Long COVID
The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”
Using advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, McAlpine hopes to unearth and better understand the pathophysiology behind neurologic issues post-COVID.
Dr. McAlpine said, “What we’re seeing is that there’s a unique signature of vascular inflammation in long COVID that is distinct from acute COVID. And it has to do with endothelial apathy and platelet dysfunction.”
She’s also looking into whether microvascular dysfunction could increase one’s risk for small vessel disease. Her research is quantitatively building an overall pathophysiology piece by piece.
“We’re quantifying cognitive dysfunction and using objective testing ... a very rigorous 3-hour protocol to really identify the patterns of weakness until we find deficits in memory working and declarative memory, deficits in executive functioning, and others. Those are the three pieces that I’m trying to piece together: The MRI, the blood work, and the cognitive testing,” she said.
Ultimately, Dr. McAlpine believes long COVID will eventually be classified as a peripheral autonomic disorder. The damage being wrought to the whole body also damages the brain’s vasculature, and Dr. McAlpine’s MRI techniques probe at this connection.
“Some of my MRI techniques are dependent on the very subtle changes in blood flow to different regions in response to demand. Brain fog has been a key symptom of POTS and ME/CFS. And it’s now a key symptom of long COVID ... what I’m looking at in some of my studies is how and in which parts of the brain are affected by this,” she said.
Dr. McAlpine’s interest in COVID’s effect on our nervous system goes back all the way to the first wave of patients with COVID, where she noticed an unusually high incidence of ischemic stroke.
“We recognized that COVID really has a huge impact on the vessels ... there’s quite a bit of vascular inflammation. In terms of neurology, we were seeing quite a bit of ischemic stroke, which is unusual,” she said.
Patients don’t normally present with stroke while infected with a virus. Seeking answers, she conducted a stroke study in patients with acute COVID and found profound endotheliopathy — damage to key cells in the lining of blood vessels — leading to a cascade of dysfunction and clotting.
A Constellation of Neuropsychiatric Symptoms
In early June, Dr. McAlpine gave a presentation of her research at the Demystifying Long COVID North American Conference 2024 in Boston. She’s been hard at work in extrapolating the causes of neuropsychiatric long COVID, a tangled web of symptoms seen in patients with long COVID that range from cognitive dysfunction to headaches, neuropathy, mental health, and the aforementioned dysautonomia.
Amid the sea of neurologic long COVID symptoms, she said “symptoms that are mixing and matching are very similar. So, I wanted to specifically look at a symptom that I could definitely isolate to the brain, and that is brain fog and cognitive dysfunction and impairment.”
In September 2021, the journal Translational Psychiatry published a study titled “Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions.”
Going back all the way to the first cases of COVID in March 2020, the initial symptoms most patients complained of during an acute viral infection were around the respiratory system. Yet delirium, confusion, and neurocognitive disorders were also reported, puzzling experts and inciting a well-founded fear among many.
Even worse, after recovery, these neuropsychiatric symptoms persisted. The study found that coronavirus was able to invade the central nervous system through blood vessels and neuronal retrograde pathways, leading to brain injury and dysfunction of the cardiorespiratory center in the brainstem.
The study concluded by reporting that neuroimaging and neurochemical evidence indicated neuroimmune dysfunction and brain injury in severe patients with COVID-19. Suggested treatments included immunosuppressive therapies, vaccines to target the coronavirus’ spike protein, and pharmacological agents to improve endothelial integrity.
But there was still much that was unknown, and the study’s authors stressed the need for multidisciplinary research going forward.
How Immune Dysfunction Plays a Role
Similarly, Dr. McAlpine and her research team are still trying to sift their way through this opaque web to see why long COVID can cause autoimmune flare-ups.
In a study published in April, Dr. McAlpine and others found that small fiber neuropathy (SFN) after COVID is autoimmune-mediated and a dysfunction of the immune system.
Notably, they found that SFN could be a key pathologic finding in long COVID. SFN before the pandemic had been linked to ME/CFS and POTS, and the basic hypothesis revolved around an inflammatory immune response during a viral illness that may lead to immune dysregulation (dysimmunity) and damage to small fiber nerves.
But much still remains to be answered.
“We’ve seen quite a bit of that, but we still haven’t figured it out,” Dr. McAlpine said. “My big question is, how is this autonomic dysfunction related to the immune dysfunction, and how is that related to the vascular inflammation? There’s quite a bit of overlap in individuals with autoimmune disease and those who go on to develop this long COVID,” she added.
Still, a large portion of patients with long COVID don’t show autoimmune dysfunction, and those patients lack common biomarkers for an autoimmune condition.
“When we look at the spinal fluid in those individuals [with multiple sclerosis or a neuroinfectious disease], there’s inflammation going on ... the white blood cell count is elevated, the protein is elevated, the antibodies, the bands are elevated. I’ve been seeing long COVID patients now for 4 years, and their presentation is so distinctly different compared to my individuals that I see my patients with MS, or a neuroinfectious disease,” she said.
The mechanisms behind how all of this is interlaced remain unclear, and there may not be a one-size-fits-all treatment or definite pathogenesis for everyone.
“It’s that intersection of the immune system and the vessel wall ... Next is to figure out what do we treat, what are the targets, all of that, but there’s so many different presentations, and everybody has kind of a unique case,” she said.
How Physician Can Treat Common Symptoms Now
Though a cure for symptoms still eludes the scientific community, recent evidence has suggested that a combination of N-acetyl cysteine (NAC) and guanfacine has been successful in easing neurologic symptoms.
In November 2023, Arman Fesharaki-Zadeh, MD, PhD, a Yale Medicine behavioral neurologist and neuropsychiatrist, published a small study in Neuroimmunology Reports with his colleague, Yale neuroscientist Amy Arnsten, PhD. The two researchers showed how among 12 patients given 600 mg NAC daily, along with 1 mg guanfacine (increased to 2 mg after a month if well-tolerated), eight demonstrated improved cognitive abilities.
In patients who stayed on guanfacine + NAC, improved working memory, concentration, and executive functions were seen.
Also, they resumed their normal work schedule. Interruption and inability to work has been a significant factor in the lower quality-of-life long COVID patients experience.
Placebo-controlled trials will be needed going forward, but their small study has established safety and could open up a larger study in the future. For the moment, NAC can be gotten over the counter, and patients could get a prescription off-label from their doctor.
Dr. McAlpine has seen this combination work well for her own patients at Yale’s NeuroCOVID clinic.
Additionally, lifestyle practices such as quitting tobacco, increased exercise, exercising the mind, lowering alcohol intake, and even vitamin D supplementation (1000-2000 IU daily) could prove beneficial in tamping down persistent brain fog.
Vitamin D supports brain and nerve function through its reduction of brain aging biomarkers, regulating genes important for brain function, activating and deactivating enzymes important for neurotransmitter synthesis, and supporting neuronal growth and survival.
A version of this article first appeared on Medscape.com.
Neurologic symptoms of long COVID are vast, common, hard to treat, disabling, and can mimic dozens of other syndromes, with some symptoms as serious as those seen in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and postural orthostatic tachycardia syndrome (POTS).
Now, recent evidence has suggested long COVID is primarily an autonomic nervous system disorder.
Their lives may never be the same.
Lindsay S. McAlpine, MD, a specialist in the neurologic sequelae of COVID-19 at the Yale School of Medicine and director of the Yale NeuroCOVID Clinic, New Haven, Connecticut, treats patients who struggle with neurologic symptoms even after disease recovery.
“Some people have the brain fog and the shortness of breath; some have the palpitations and the headaches ... it’s kind of a mix and match,” she said.
Dr. McAlpine’s research has been slowly building up into what could bring about a significant breakthrough in treating some of the most misunderstood and difficult-to-treat symptoms of long COVID.
The Effect of Vascular Inflammation on Long COVID
The National Institute of Neurological Disorders and Stroke recently awarded her a 5-year K23 grant to support her ongoing study, “Magnetic Resonance Imaging Biomarkers of Post-COVID-19 Cerebral Microvascular Dysfunction.”
Using advanced MRI techniques to identify microvascular dysfunction biomarkers in the brain, McAlpine hopes to unearth and better understand the pathophysiology behind neurologic issues post-COVID.
Dr. McAlpine said, “What we’re seeing is that there’s a unique signature of vascular inflammation in long COVID that is distinct from acute COVID. And it has to do with endothelial apathy and platelet dysfunction.”
She’s also looking into whether microvascular dysfunction could increase one’s risk for small vessel disease. Her research is quantitatively building an overall pathophysiology piece by piece.
“We’re quantifying cognitive dysfunction and using objective testing ... a very rigorous 3-hour protocol to really identify the patterns of weakness until we find deficits in memory working and declarative memory, deficits in executive functioning, and others. Those are the three pieces that I’m trying to piece together: The MRI, the blood work, and the cognitive testing,” she said.
Ultimately, Dr. McAlpine believes long COVID will eventually be classified as a peripheral autonomic disorder. The damage being wrought to the whole body also damages the brain’s vasculature, and Dr. McAlpine’s MRI techniques probe at this connection.
“Some of my MRI techniques are dependent on the very subtle changes in blood flow to different regions in response to demand. Brain fog has been a key symptom of POTS and ME/CFS. And it’s now a key symptom of long COVID ... what I’m looking at in some of my studies is how and in which parts of the brain are affected by this,” she said.
Dr. McAlpine’s interest in COVID’s effect on our nervous system goes back all the way to the first wave of patients with COVID, where she noticed an unusually high incidence of ischemic stroke.
“We recognized that COVID really has a huge impact on the vessels ... there’s quite a bit of vascular inflammation. In terms of neurology, we were seeing quite a bit of ischemic stroke, which is unusual,” she said.
Patients don’t normally present with stroke while infected with a virus. Seeking answers, she conducted a stroke study in patients with acute COVID and found profound endotheliopathy — damage to key cells in the lining of blood vessels — leading to a cascade of dysfunction and clotting.
A Constellation of Neuropsychiatric Symptoms
In early June, Dr. McAlpine gave a presentation of her research at the Demystifying Long COVID North American Conference 2024 in Boston. She’s been hard at work in extrapolating the causes of neuropsychiatric long COVID, a tangled web of symptoms seen in patients with long COVID that range from cognitive dysfunction to headaches, neuropathy, mental health, and the aforementioned dysautonomia.
Amid the sea of neurologic long COVID symptoms, she said “symptoms that are mixing and matching are very similar. So, I wanted to specifically look at a symptom that I could definitely isolate to the brain, and that is brain fog and cognitive dysfunction and impairment.”
In September 2021, the journal Translational Psychiatry published a study titled “Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions.”
Going back all the way to the first cases of COVID in March 2020, the initial symptoms most patients complained of during an acute viral infection were around the respiratory system. Yet delirium, confusion, and neurocognitive disorders were also reported, puzzling experts and inciting a well-founded fear among many.
Even worse, after recovery, these neuropsychiatric symptoms persisted. The study found that coronavirus was able to invade the central nervous system through blood vessels and neuronal retrograde pathways, leading to brain injury and dysfunction of the cardiorespiratory center in the brainstem.
The study concluded by reporting that neuroimaging and neurochemical evidence indicated neuroimmune dysfunction and brain injury in severe patients with COVID-19. Suggested treatments included immunosuppressive therapies, vaccines to target the coronavirus’ spike protein, and pharmacological agents to improve endothelial integrity.
But there was still much that was unknown, and the study’s authors stressed the need for multidisciplinary research going forward.
How Immune Dysfunction Plays a Role
Similarly, Dr. McAlpine and her research team are still trying to sift their way through this opaque web to see why long COVID can cause autoimmune flare-ups.
In a study published in April, Dr. McAlpine and others found that small fiber neuropathy (SFN) after COVID is autoimmune-mediated and a dysfunction of the immune system.
Notably, they found that SFN could be a key pathologic finding in long COVID. SFN before the pandemic had been linked to ME/CFS and POTS, and the basic hypothesis revolved around an inflammatory immune response during a viral illness that may lead to immune dysregulation (dysimmunity) and damage to small fiber nerves.
But much still remains to be answered.
“We’ve seen quite a bit of that, but we still haven’t figured it out,” Dr. McAlpine said. “My big question is, how is this autonomic dysfunction related to the immune dysfunction, and how is that related to the vascular inflammation? There’s quite a bit of overlap in individuals with autoimmune disease and those who go on to develop this long COVID,” she added.
Still, a large portion of patients with long COVID don’t show autoimmune dysfunction, and those patients lack common biomarkers for an autoimmune condition.
“When we look at the spinal fluid in those individuals [with multiple sclerosis or a neuroinfectious disease], there’s inflammation going on ... the white blood cell count is elevated, the protein is elevated, the antibodies, the bands are elevated. I’ve been seeing long COVID patients now for 4 years, and their presentation is so distinctly different compared to my individuals that I see my patients with MS, or a neuroinfectious disease,” she said.
The mechanisms behind how all of this is interlaced remain unclear, and there may not be a one-size-fits-all treatment or definite pathogenesis for everyone.
“It’s that intersection of the immune system and the vessel wall ... Next is to figure out what do we treat, what are the targets, all of that, but there’s so many different presentations, and everybody has kind of a unique case,” she said.
How Physician Can Treat Common Symptoms Now
Though a cure for symptoms still eludes the scientific community, recent evidence has suggested that a combination of N-acetyl cysteine (NAC) and guanfacine has been successful in easing neurologic symptoms.
In November 2023, Arman Fesharaki-Zadeh, MD, PhD, a Yale Medicine behavioral neurologist and neuropsychiatrist, published a small study in Neuroimmunology Reports with his colleague, Yale neuroscientist Amy Arnsten, PhD. The two researchers showed how among 12 patients given 600 mg NAC daily, along with 1 mg guanfacine (increased to 2 mg after a month if well-tolerated), eight demonstrated improved cognitive abilities.
In patients who stayed on guanfacine + NAC, improved working memory, concentration, and executive functions were seen.
Also, they resumed their normal work schedule. Interruption and inability to work has been a significant factor in the lower quality-of-life long COVID patients experience.
Placebo-controlled trials will be needed going forward, but their small study has established safety and could open up a larger study in the future. For the moment, NAC can be gotten over the counter, and patients could get a prescription off-label from their doctor.
Dr. McAlpine has seen this combination work well for her own patients at Yale’s NeuroCOVID clinic.
Additionally, lifestyle practices such as quitting tobacco, increased exercise, exercising the mind, lowering alcohol intake, and even vitamin D supplementation (1000-2000 IU daily) could prove beneficial in tamping down persistent brain fog.
Vitamin D supports brain and nerve function through its reduction of brain aging biomarkers, regulating genes important for brain function, activating and deactivating enzymes important for neurotransmitter synthesis, and supporting neuronal growth and survival.
A version of this article first appeared on Medscape.com.
New Drug Offers Hope for CPAP-Free Nights for Sleep Apnea
Roughly 30 million to 40 million people in the United States, and nearly a billion people worldwide, have sleep apnea. Because they are cumbersome and often uncomfortable, many sleep apnea patients don’t use their continuous positive airway pressure (CPAP) machine.
“In my patients, I’d say a quarter of them don’t get compliant on the machine and require other treatments,” said David Kuhlmann, MD, medical director of sleep medicine at Bothwell Regional Health Center in Sedalia, MO. That’s often because they “just don’t want to wear a mask at night.”
For Dr. Kuhlmann, who’s also a spokesperson for the American Academy of Sleep Medicine, no other treatment can replace something that continually supplies air throughout the night.
But that may be changing.
New Pill Making Waves in Sleep Apnea
That’s what researchers at Apnimed hope. Apnimed is a company that’s developed a new oral drug for sleep apnea — currently called AD109. AD109 combines the drugs aroxybutynin and atomoxetine.
Aroxybutynin is used to treat symptoms of an overactive bladder, while atomoxetine is used to treat attention deficit hyperactivity disorder.
“The drug is unique in the sense that, currently, there’s no approved drug for the treatment of sleep apnea,” said Douglas Kirsch, MD, medical director of sleep medicine at Atrium Health in Charlotte, NC. “AD109 keeps the airway from collapsing during the night. And that function is through a combination of drugs, which, in theory, both help keep the airway a little bit more open, but also helps keep people asleep.”
AD109 is currently in phase 3 trials, but results are already out for phase 2.
The conclusion of those phase 2 studies?
“AD109 showed clinically meaningful improvement in [sleep apnea], suggesting that further development of the compound is warranted.” That’s taken straight from the study’s published data.
And onto phase 3 clinical trials the drug goes. But there’s something to consider when looking at these results.
Evaluating AD109’s Results
One promising result out of the phase 2 trials was the lack of major side effects in people who took the drug.
“What you are kind of hoping for from a phase 2 trial, both from a set safety perspective and an efficacy perspective, is that it did change the level of sleep apnea when compared to placebo,” said Dr. Kirsch, who’s also a former president of the American Academy of Sleep Medicine.
For phase 2 trials, patients were separated into groups after they were tested to see how severe their sleep apnea was, using the apnea-hypopnea index (AHI).
Dr. Kuhlmann said there are two big things they noticed: The apnea-hypopnea index dropped in patients given two different doses of the drug. Those in the group that took the lower dosage actually saw “clinically significant improvement in fatigue.”
For those with an index score of 10-15 (mild), 77% had their scores lowered to below 10.
But only 42% with a score of 15-30 (moderate) were able to get below 10. And only 7% of those with a score of over 30 were able to get all the way down to 10 or below.
Regarding some of the index score drops, Dr. Kuhlmann said, “If you drop from an AHI of 20-10, that’s still OSA [obstructive sleep apnea] if you have diabetes, high blood pressure, depression, daytime sleepiness, or insomnia.”
Phase 3 should include a broader range of people. “Phase 2 provides a proof of concept…phase 3 is a little bit broader…you can open the use of the drug to more people,” said Dr. Kirsch.
A Suspicious Omission
Significantly, the AD109 phase 2 trial also seemed not to include a crucial thing when sleep experts look at how well treatments work: Oxygen saturation.
“Often, when you review a sleep study with a patient, you’ll talk about both AHI and minimum oxygen saturation,” Dr. Kirsch said.
Dr. Kuhlmann was skeptical of this omission. Instead of reporting the minimum oxygen saturation, Apnimed used something called “hypoxic burden,” he said.
“They didn’t give us oxygen saturation information at all. But there’s a big difference between somebody who has a minimum oxygen saturation of 89% and went from an AHI of 20 to 12…which sounds great…but had minimum oxygen saturation stay the same after.”
In explaining the importance of hypoxic burden, Dr. Kirsch said, “If 99% of a sleep study was at 90% and above, but there was one dip at 80%, that’s not the same as spending 45 minutes below 88%. What you really want to talk about is how much or how long does that oxygen get low?”
What Therapies Must Consider for the Future
Until phase 3 data is out, it’s not possible to say for sure where AD109 can work alone for people across the spectrum of severity.
“Like any form of data, there are going to be targeted populations that may do better…with any drug, you’re unlikely to fix everything…Until we see that phase 3 data…you really can’t say for sure,” Dr. Kirsch said.
“It seems AD109 treats more of a milder spectrum than maybe the ones who would get the most benefit,” Dr. Kuhlmann said.
But he said AD109 may still work well for a number of people. It’s just important to understand that a pill can’t be compared to positive airway pressure.
Dr. Kuhlmann said he’d like to see a medication — including AD109 — that could measure up as well to oral appliances or anything that treats mild to moderate cases and “have some clinical scales associated with it that are positive.”
Besides AD109, Dr. Kirsch said, “I think we are potentially on the precipice of having some drugs that may help with sleep apnea in the coming years.”
Big Need for Progress
The American Academy of Sleep Medicine estimates up to 80% of people with obstructive sleep apnea — the most common form — remain undiagnosed.
Cigarette smoking, high alcohol intake, drugs, or neurological disorders are common risk factors. But most importantly, it’s anything that decreases muscle tone around the upper airway — like obesity — or changes in structural features that narrow the airway.
Dr. Kuhlmann stressed the importance of weight issues linked to sleep apnea. “It’s a very common condition, especially as people are getting older and heavier…you have loss of muscle tone to your entire body, including the upper airway muscles.”
SOURCES:
- David Kuhlmann, MD, spokesperson, American Academy of Sleep Medicine; medical director of sleep medicine, Bothwell Regional Health Center, Sedalia, MO.
- Apnimed: “Parallel Arm Trial of AD109 and Placebo With Patients With OSA (LunAIRo),” “Parallel-Arm Study to Compare AD109 to Placebo With Patients With OSA (SynAIRgy Study).”
- Douglas Kirsch, MD, former president, American Academy of Sleep Medicine; medical director of sleep medicine, Atrium Health, Charlotte, NC.
- American Academy of Sleep Medicine: “Rising Prevalence of Sleep Apnea in US Threatens Public Health.”
- National Council on Aging: “Sleep Apnea Statistics and Facts You Should Know.”
This article originally appeared on WebMD.
Roughly 30 million to 40 million people in the United States, and nearly a billion people worldwide, have sleep apnea. Because they are cumbersome and often uncomfortable, many sleep apnea patients don’t use their continuous positive airway pressure (CPAP) machine.
“In my patients, I’d say a quarter of them don’t get compliant on the machine and require other treatments,” said David Kuhlmann, MD, medical director of sleep medicine at Bothwell Regional Health Center in Sedalia, MO. That’s often because they “just don’t want to wear a mask at night.”
For Dr. Kuhlmann, who’s also a spokesperson for the American Academy of Sleep Medicine, no other treatment can replace something that continually supplies air throughout the night.
But that may be changing.
New Pill Making Waves in Sleep Apnea
That’s what researchers at Apnimed hope. Apnimed is a company that’s developed a new oral drug for sleep apnea — currently called AD109. AD109 combines the drugs aroxybutynin and atomoxetine.
Aroxybutynin is used to treat symptoms of an overactive bladder, while atomoxetine is used to treat attention deficit hyperactivity disorder.
“The drug is unique in the sense that, currently, there’s no approved drug for the treatment of sleep apnea,” said Douglas Kirsch, MD, medical director of sleep medicine at Atrium Health in Charlotte, NC. “AD109 keeps the airway from collapsing during the night. And that function is through a combination of drugs, which, in theory, both help keep the airway a little bit more open, but also helps keep people asleep.”
AD109 is currently in phase 3 trials, but results are already out for phase 2.
The conclusion of those phase 2 studies?
“AD109 showed clinically meaningful improvement in [sleep apnea], suggesting that further development of the compound is warranted.” That’s taken straight from the study’s published data.
And onto phase 3 clinical trials the drug goes. But there’s something to consider when looking at these results.
Evaluating AD109’s Results
One promising result out of the phase 2 trials was the lack of major side effects in people who took the drug.
“What you are kind of hoping for from a phase 2 trial, both from a set safety perspective and an efficacy perspective, is that it did change the level of sleep apnea when compared to placebo,” said Dr. Kirsch, who’s also a former president of the American Academy of Sleep Medicine.
For phase 2 trials, patients were separated into groups after they were tested to see how severe their sleep apnea was, using the apnea-hypopnea index (AHI).
Dr. Kuhlmann said there are two big things they noticed: The apnea-hypopnea index dropped in patients given two different doses of the drug. Those in the group that took the lower dosage actually saw “clinically significant improvement in fatigue.”
For those with an index score of 10-15 (mild), 77% had their scores lowered to below 10.
But only 42% with a score of 15-30 (moderate) were able to get below 10. And only 7% of those with a score of over 30 were able to get all the way down to 10 or below.
Regarding some of the index score drops, Dr. Kuhlmann said, “If you drop from an AHI of 20-10, that’s still OSA [obstructive sleep apnea] if you have diabetes, high blood pressure, depression, daytime sleepiness, or insomnia.”
Phase 3 should include a broader range of people. “Phase 2 provides a proof of concept…phase 3 is a little bit broader…you can open the use of the drug to more people,” said Dr. Kirsch.
A Suspicious Omission
Significantly, the AD109 phase 2 trial also seemed not to include a crucial thing when sleep experts look at how well treatments work: Oxygen saturation.
“Often, when you review a sleep study with a patient, you’ll talk about both AHI and minimum oxygen saturation,” Dr. Kirsch said.
Dr. Kuhlmann was skeptical of this omission. Instead of reporting the minimum oxygen saturation, Apnimed used something called “hypoxic burden,” he said.
“They didn’t give us oxygen saturation information at all. But there’s a big difference between somebody who has a minimum oxygen saturation of 89% and went from an AHI of 20 to 12…which sounds great…but had minimum oxygen saturation stay the same after.”
In explaining the importance of hypoxic burden, Dr. Kirsch said, “If 99% of a sleep study was at 90% and above, but there was one dip at 80%, that’s not the same as spending 45 minutes below 88%. What you really want to talk about is how much or how long does that oxygen get low?”
What Therapies Must Consider for the Future
Until phase 3 data is out, it’s not possible to say for sure where AD109 can work alone for people across the spectrum of severity.
“Like any form of data, there are going to be targeted populations that may do better…with any drug, you’re unlikely to fix everything…Until we see that phase 3 data…you really can’t say for sure,” Dr. Kirsch said.
“It seems AD109 treats more of a milder spectrum than maybe the ones who would get the most benefit,” Dr. Kuhlmann said.
But he said AD109 may still work well for a number of people. It’s just important to understand that a pill can’t be compared to positive airway pressure.
Dr. Kuhlmann said he’d like to see a medication — including AD109 — that could measure up as well to oral appliances or anything that treats mild to moderate cases and “have some clinical scales associated with it that are positive.”
Besides AD109, Dr. Kirsch said, “I think we are potentially on the precipice of having some drugs that may help with sleep apnea in the coming years.”
Big Need for Progress
The American Academy of Sleep Medicine estimates up to 80% of people with obstructive sleep apnea — the most common form — remain undiagnosed.
Cigarette smoking, high alcohol intake, drugs, or neurological disorders are common risk factors. But most importantly, it’s anything that decreases muscle tone around the upper airway — like obesity — or changes in structural features that narrow the airway.
Dr. Kuhlmann stressed the importance of weight issues linked to sleep apnea. “It’s a very common condition, especially as people are getting older and heavier…you have loss of muscle tone to your entire body, including the upper airway muscles.”
SOURCES:
- David Kuhlmann, MD, spokesperson, American Academy of Sleep Medicine; medical director of sleep medicine, Bothwell Regional Health Center, Sedalia, MO.
- Apnimed: “Parallel Arm Trial of AD109 and Placebo With Patients With OSA (LunAIRo),” “Parallel-Arm Study to Compare AD109 to Placebo With Patients With OSA (SynAIRgy Study).”
- Douglas Kirsch, MD, former president, American Academy of Sleep Medicine; medical director of sleep medicine, Atrium Health, Charlotte, NC.
- American Academy of Sleep Medicine: “Rising Prevalence of Sleep Apnea in US Threatens Public Health.”
- National Council on Aging: “Sleep Apnea Statistics and Facts You Should Know.”
This article originally appeared on WebMD.
Roughly 30 million to 40 million people in the United States, and nearly a billion people worldwide, have sleep apnea. Because they are cumbersome and often uncomfortable, many sleep apnea patients don’t use their continuous positive airway pressure (CPAP) machine.
“In my patients, I’d say a quarter of them don’t get compliant on the machine and require other treatments,” said David Kuhlmann, MD, medical director of sleep medicine at Bothwell Regional Health Center in Sedalia, MO. That’s often because they “just don’t want to wear a mask at night.”
For Dr. Kuhlmann, who’s also a spokesperson for the American Academy of Sleep Medicine, no other treatment can replace something that continually supplies air throughout the night.
But that may be changing.
New Pill Making Waves in Sleep Apnea
That’s what researchers at Apnimed hope. Apnimed is a company that’s developed a new oral drug for sleep apnea — currently called AD109. AD109 combines the drugs aroxybutynin and atomoxetine.
Aroxybutynin is used to treat symptoms of an overactive bladder, while atomoxetine is used to treat attention deficit hyperactivity disorder.
“The drug is unique in the sense that, currently, there’s no approved drug for the treatment of sleep apnea,” said Douglas Kirsch, MD, medical director of sleep medicine at Atrium Health in Charlotte, NC. “AD109 keeps the airway from collapsing during the night. And that function is through a combination of drugs, which, in theory, both help keep the airway a little bit more open, but also helps keep people asleep.”
AD109 is currently in phase 3 trials, but results are already out for phase 2.
The conclusion of those phase 2 studies?
“AD109 showed clinically meaningful improvement in [sleep apnea], suggesting that further development of the compound is warranted.” That’s taken straight from the study’s published data.
And onto phase 3 clinical trials the drug goes. But there’s something to consider when looking at these results.
Evaluating AD109’s Results
One promising result out of the phase 2 trials was the lack of major side effects in people who took the drug.
“What you are kind of hoping for from a phase 2 trial, both from a set safety perspective and an efficacy perspective, is that it did change the level of sleep apnea when compared to placebo,” said Dr. Kirsch, who’s also a former president of the American Academy of Sleep Medicine.
For phase 2 trials, patients were separated into groups after they were tested to see how severe their sleep apnea was, using the apnea-hypopnea index (AHI).
Dr. Kuhlmann said there are two big things they noticed: The apnea-hypopnea index dropped in patients given two different doses of the drug. Those in the group that took the lower dosage actually saw “clinically significant improvement in fatigue.”
For those with an index score of 10-15 (mild), 77% had their scores lowered to below 10.
But only 42% with a score of 15-30 (moderate) were able to get below 10. And only 7% of those with a score of over 30 were able to get all the way down to 10 or below.
Regarding some of the index score drops, Dr. Kuhlmann said, “If you drop from an AHI of 20-10, that’s still OSA [obstructive sleep apnea] if you have diabetes, high blood pressure, depression, daytime sleepiness, or insomnia.”
Phase 3 should include a broader range of people. “Phase 2 provides a proof of concept…phase 3 is a little bit broader…you can open the use of the drug to more people,” said Dr. Kirsch.
A Suspicious Omission
Significantly, the AD109 phase 2 trial also seemed not to include a crucial thing when sleep experts look at how well treatments work: Oxygen saturation.
“Often, when you review a sleep study with a patient, you’ll talk about both AHI and minimum oxygen saturation,” Dr. Kirsch said.
Dr. Kuhlmann was skeptical of this omission. Instead of reporting the minimum oxygen saturation, Apnimed used something called “hypoxic burden,” he said.
“They didn’t give us oxygen saturation information at all. But there’s a big difference between somebody who has a minimum oxygen saturation of 89% and went from an AHI of 20 to 12…which sounds great…but had minimum oxygen saturation stay the same after.”
In explaining the importance of hypoxic burden, Dr. Kirsch said, “If 99% of a sleep study was at 90% and above, but there was one dip at 80%, that’s not the same as spending 45 minutes below 88%. What you really want to talk about is how much or how long does that oxygen get low?”
What Therapies Must Consider for the Future
Until phase 3 data is out, it’s not possible to say for sure where AD109 can work alone for people across the spectrum of severity.
“Like any form of data, there are going to be targeted populations that may do better…with any drug, you’re unlikely to fix everything…Until we see that phase 3 data…you really can’t say for sure,” Dr. Kirsch said.
“It seems AD109 treats more of a milder spectrum than maybe the ones who would get the most benefit,” Dr. Kuhlmann said.
But he said AD109 may still work well for a number of people. It’s just important to understand that a pill can’t be compared to positive airway pressure.
Dr. Kuhlmann said he’d like to see a medication — including AD109 — that could measure up as well to oral appliances or anything that treats mild to moderate cases and “have some clinical scales associated with it that are positive.”
Besides AD109, Dr. Kirsch said, “I think we are potentially on the precipice of having some drugs that may help with sleep apnea in the coming years.”
Big Need for Progress
The American Academy of Sleep Medicine estimates up to 80% of people with obstructive sleep apnea — the most common form — remain undiagnosed.
Cigarette smoking, high alcohol intake, drugs, or neurological disorders are common risk factors. But most importantly, it’s anything that decreases muscle tone around the upper airway — like obesity — or changes in structural features that narrow the airway.
Dr. Kuhlmann stressed the importance of weight issues linked to sleep apnea. “It’s a very common condition, especially as people are getting older and heavier…you have loss of muscle tone to your entire body, including the upper airway muscles.”
SOURCES:
- David Kuhlmann, MD, spokesperson, American Academy of Sleep Medicine; medical director of sleep medicine, Bothwell Regional Health Center, Sedalia, MO.
- Apnimed: “Parallel Arm Trial of AD109 and Placebo With Patients With OSA (LunAIRo),” “Parallel-Arm Study to Compare AD109 to Placebo With Patients With OSA (SynAIRgy Study).”
- Douglas Kirsch, MD, former president, American Academy of Sleep Medicine; medical director of sleep medicine, Atrium Health, Charlotte, NC.
- American Academy of Sleep Medicine: “Rising Prevalence of Sleep Apnea in US Threatens Public Health.”
- National Council on Aging: “Sleep Apnea Statistics and Facts You Should Know.”
This article originally appeared on WebMD.
Getting Reluctant Patients to ‘Yes’ on COVID Vaccination
No matter how much we’d like to leave it in the dust, COVID-19 remains prevalent and potent. Tens of thousands of people still contract COVID per week in the United States. Hundreds die. And those who don’t may still develop long COVID.
Pleas from public health officials for people to get a COVID vaccine or booster shot have been ignored by many people. About 80% of eligible Americans haven’t taken any kind of COVID booster. Meantime, the virus continues to mutate, eroding the efficacy of the vaccine’s past versions.
How to get more people to get the jab? Vaccine hesitancy, said infectious disease specialist William Schaffner, MD, is likely rooted in a lack of trust in authority, whether it’s public health officials or politicians.
Dr. Schaffner, professor of infectious diseases at the Vanderbilt University School of Medicine, Nashville, Tennessee, and former medical director of the National Foundation for Infectious Diseases, recommended five strategies physicians can try when discussing the importance of staying up to date on COVID vaccines with patients.
#1: Be Patient With Your Patient
First and foremost, if doctors are feeling reluctance from their patients, they need to know “what they shouldn’t do,” Dr. Schaffner said.
When a patient initially doesn’t want the vaccine, doctors shouldn’t express surprise. “Do not scold or berate or belittle. Do not give the impression the patient is somehow wrong or has failed a test of some sort,” Dr. Schaffner said.
Step back and affirm that they understand what the patient is saying so they feel reassured, even if they don’t agree or it’s based on falsehoods about the vaccine.
He said patients need to feel “the doctor heard them; it’s okay to tell the doctor this.” When you affirm what the patient says, it puts them at ease and provides a smoother road to eventually getting them to say “yes.”
But if there’s still a roadblock, don’t bulldoze them. “You don’t want to punish the patient ... let them know you’ll continue to hear them,” Dr. Schaffner said.
#2: Always Acknowledge a Concern
Fear of side effects is great among some patients, even if the risks are low, Dr. Schaffner said. Patients may be hesitant because they’re afraid they’ll become one of the “two or three in a million” who suffer extremely rare side effects from the vaccine, Dr. Schaffner said.
In that case, doctors should acknowledge their concern is valid, he said. Never be dismissive. Ask the patients how they feel about the vaccine, listen to their responses, and let them know “I hear you. This is a new mRNA vaccine…you have concern about that,” Dr. Schaffner said.
Doctors can segue into how there’s little reason to wait for some elusive perfectly risk-free vaccine when they can help themselves right now.
“The adverse events that occur with vaccines occur within 2 months [and are typically mild]. I don’t know of a single vaccine that has genuinely long-term implications,” Dr. Schaffner said. “We should remember that old French philosopher Voltaire. He admonished us: Waiting for perfection is the great enemy of the current good.”
#3: Make a Strong Recommendation
Here’s something that may seem obvious: Don’t treat the vaccine as an afterthought. “Survey after survey tells us this ... it has everything to do with the strength of the recommendation,” Dr. Schaffner said.
Doctors typically make strong treatment recommendations such conditions as diabetes or high blood pressure, but “when it comes to vaccines, they’re often rather nonchalant,” he said.
If a patient is eligible for a vaccine, doctors should tell the patient they need to get it — not that you think they should get it. “Doctors have to make a firm recommendation: ‘You’re eligible for a vaccine ... and you need to get it ... you’ll receive it on your way out.’ It then becomes a distinct and strong recommendation,” he said.
#4: Appeal to Patients’ Hearts, Not Their Minds
In the opening of Charles Dickens’s novel “Hard Times,” the stern school superintendent, Mr. Gradgrind, scolds his students by beating their brow with the notion that, “Facts alone are wanted in life. Plant nothing else and root out everything else.”
The idea that facts alone can sway a vaccine-resistant patient is wrong. “It often doesn’t happen that way,” Dr. Schaffner said. “I don’t think facts do that. Psychologists tell us, yes, information is important, but it’s rarely sufficient to change behavior.”
Data and studies are foundational to medicine, but the key is to change how a patient feels about the data they’re presented with, not how they think about it. “Don’t attack their brain so much but their heart,” Dr. Schaffner said.
Dr. Schaffner has stressed with his patients that the COVID vaccine has become “the social norm,” suggesting virtually everyone he knows has received it and had no problem.
Once questions have been answered about whether the vaccine works and its various side effects, doctors could remind the patient, “You know, everyone in my office is getting the vaccine, and we’re trying to provide this protection to every patient,” he said.
You’re then delving deeper into their emotions and crossing a barrier that facts alone can’t breach.
#5: Make it Personal
Lead by example and personalize the fight against the virus. This allows doctors to act as if they’re building an alliance with their patients by framing the vaccine not as something that only affects them but can also confer benefits to a broader social circle.
Even after using these methods, patients may remain resistant, apprehensive, or even indifferent. In cases like these, Dr. Schaffner said it’s a good idea to let it go for the time being.
Let the patient know they “have access to you and can keep speaking with you about it” in the future, he said. “It takes more time, and you have to be cognizant of the nature of the conversation.”
Everybody is unique, but with trust, patience, and awareness of the patient’s feelings, doctors have a better shot at finding common ground with their patients and convincing them the vaccine is in their best interest, he said.
A version of this article first appeared on Medscape.com.
No matter how much we’d like to leave it in the dust, COVID-19 remains prevalent and potent. Tens of thousands of people still contract COVID per week in the United States. Hundreds die. And those who don’t may still develop long COVID.
Pleas from public health officials for people to get a COVID vaccine or booster shot have been ignored by many people. About 80% of eligible Americans haven’t taken any kind of COVID booster. Meantime, the virus continues to mutate, eroding the efficacy of the vaccine’s past versions.
How to get more people to get the jab? Vaccine hesitancy, said infectious disease specialist William Schaffner, MD, is likely rooted in a lack of trust in authority, whether it’s public health officials or politicians.
Dr. Schaffner, professor of infectious diseases at the Vanderbilt University School of Medicine, Nashville, Tennessee, and former medical director of the National Foundation for Infectious Diseases, recommended five strategies physicians can try when discussing the importance of staying up to date on COVID vaccines with patients.
#1: Be Patient With Your Patient
First and foremost, if doctors are feeling reluctance from their patients, they need to know “what they shouldn’t do,” Dr. Schaffner said.
When a patient initially doesn’t want the vaccine, doctors shouldn’t express surprise. “Do not scold or berate or belittle. Do not give the impression the patient is somehow wrong or has failed a test of some sort,” Dr. Schaffner said.
Step back and affirm that they understand what the patient is saying so they feel reassured, even if they don’t agree or it’s based on falsehoods about the vaccine.
He said patients need to feel “the doctor heard them; it’s okay to tell the doctor this.” When you affirm what the patient says, it puts them at ease and provides a smoother road to eventually getting them to say “yes.”
But if there’s still a roadblock, don’t bulldoze them. “You don’t want to punish the patient ... let them know you’ll continue to hear them,” Dr. Schaffner said.
#2: Always Acknowledge a Concern
Fear of side effects is great among some patients, even if the risks are low, Dr. Schaffner said. Patients may be hesitant because they’re afraid they’ll become one of the “two or three in a million” who suffer extremely rare side effects from the vaccine, Dr. Schaffner said.
In that case, doctors should acknowledge their concern is valid, he said. Never be dismissive. Ask the patients how they feel about the vaccine, listen to their responses, and let them know “I hear you. This is a new mRNA vaccine…you have concern about that,” Dr. Schaffner said.
Doctors can segue into how there’s little reason to wait for some elusive perfectly risk-free vaccine when they can help themselves right now.
“The adverse events that occur with vaccines occur within 2 months [and are typically mild]. I don’t know of a single vaccine that has genuinely long-term implications,” Dr. Schaffner said. “We should remember that old French philosopher Voltaire. He admonished us: Waiting for perfection is the great enemy of the current good.”
#3: Make a Strong Recommendation
Here’s something that may seem obvious: Don’t treat the vaccine as an afterthought. “Survey after survey tells us this ... it has everything to do with the strength of the recommendation,” Dr. Schaffner said.
Doctors typically make strong treatment recommendations such conditions as diabetes or high blood pressure, but “when it comes to vaccines, they’re often rather nonchalant,” he said.
If a patient is eligible for a vaccine, doctors should tell the patient they need to get it — not that you think they should get it. “Doctors have to make a firm recommendation: ‘You’re eligible for a vaccine ... and you need to get it ... you’ll receive it on your way out.’ It then becomes a distinct and strong recommendation,” he said.
#4: Appeal to Patients’ Hearts, Not Their Minds
In the opening of Charles Dickens’s novel “Hard Times,” the stern school superintendent, Mr. Gradgrind, scolds his students by beating their brow with the notion that, “Facts alone are wanted in life. Plant nothing else and root out everything else.”
The idea that facts alone can sway a vaccine-resistant patient is wrong. “It often doesn’t happen that way,” Dr. Schaffner said. “I don’t think facts do that. Psychologists tell us, yes, information is important, but it’s rarely sufficient to change behavior.”
Data and studies are foundational to medicine, but the key is to change how a patient feels about the data they’re presented with, not how they think about it. “Don’t attack their brain so much but their heart,” Dr. Schaffner said.
Dr. Schaffner has stressed with his patients that the COVID vaccine has become “the social norm,” suggesting virtually everyone he knows has received it and had no problem.
Once questions have been answered about whether the vaccine works and its various side effects, doctors could remind the patient, “You know, everyone in my office is getting the vaccine, and we’re trying to provide this protection to every patient,” he said.
You’re then delving deeper into their emotions and crossing a barrier that facts alone can’t breach.
#5: Make it Personal
Lead by example and personalize the fight against the virus. This allows doctors to act as if they’re building an alliance with their patients by framing the vaccine not as something that only affects them but can also confer benefits to a broader social circle.
Even after using these methods, patients may remain resistant, apprehensive, or even indifferent. In cases like these, Dr. Schaffner said it’s a good idea to let it go for the time being.
Let the patient know they “have access to you and can keep speaking with you about it” in the future, he said. “It takes more time, and you have to be cognizant of the nature of the conversation.”
Everybody is unique, but with trust, patience, and awareness of the patient’s feelings, doctors have a better shot at finding common ground with their patients and convincing them the vaccine is in their best interest, he said.
A version of this article first appeared on Medscape.com.
No matter how much we’d like to leave it in the dust, COVID-19 remains prevalent and potent. Tens of thousands of people still contract COVID per week in the United States. Hundreds die. And those who don’t may still develop long COVID.
Pleas from public health officials for people to get a COVID vaccine or booster shot have been ignored by many people. About 80% of eligible Americans haven’t taken any kind of COVID booster. Meantime, the virus continues to mutate, eroding the efficacy of the vaccine’s past versions.
How to get more people to get the jab? Vaccine hesitancy, said infectious disease specialist William Schaffner, MD, is likely rooted in a lack of trust in authority, whether it’s public health officials or politicians.
Dr. Schaffner, professor of infectious diseases at the Vanderbilt University School of Medicine, Nashville, Tennessee, and former medical director of the National Foundation for Infectious Diseases, recommended five strategies physicians can try when discussing the importance of staying up to date on COVID vaccines with patients.
#1: Be Patient With Your Patient
First and foremost, if doctors are feeling reluctance from their patients, they need to know “what they shouldn’t do,” Dr. Schaffner said.
When a patient initially doesn’t want the vaccine, doctors shouldn’t express surprise. “Do not scold or berate or belittle. Do not give the impression the patient is somehow wrong or has failed a test of some sort,” Dr. Schaffner said.
Step back and affirm that they understand what the patient is saying so they feel reassured, even if they don’t agree or it’s based on falsehoods about the vaccine.
He said patients need to feel “the doctor heard them; it’s okay to tell the doctor this.” When you affirm what the patient says, it puts them at ease and provides a smoother road to eventually getting them to say “yes.”
But if there’s still a roadblock, don’t bulldoze them. “You don’t want to punish the patient ... let them know you’ll continue to hear them,” Dr. Schaffner said.
#2: Always Acknowledge a Concern
Fear of side effects is great among some patients, even if the risks are low, Dr. Schaffner said. Patients may be hesitant because they’re afraid they’ll become one of the “two or three in a million” who suffer extremely rare side effects from the vaccine, Dr. Schaffner said.
In that case, doctors should acknowledge their concern is valid, he said. Never be dismissive. Ask the patients how they feel about the vaccine, listen to their responses, and let them know “I hear you. This is a new mRNA vaccine…you have concern about that,” Dr. Schaffner said.
Doctors can segue into how there’s little reason to wait for some elusive perfectly risk-free vaccine when they can help themselves right now.
“The adverse events that occur with vaccines occur within 2 months [and are typically mild]. I don’t know of a single vaccine that has genuinely long-term implications,” Dr. Schaffner said. “We should remember that old French philosopher Voltaire. He admonished us: Waiting for perfection is the great enemy of the current good.”
#3: Make a Strong Recommendation
Here’s something that may seem obvious: Don’t treat the vaccine as an afterthought. “Survey after survey tells us this ... it has everything to do with the strength of the recommendation,” Dr. Schaffner said.
Doctors typically make strong treatment recommendations such conditions as diabetes or high blood pressure, but “when it comes to vaccines, they’re often rather nonchalant,” he said.
If a patient is eligible for a vaccine, doctors should tell the patient they need to get it — not that you think they should get it. “Doctors have to make a firm recommendation: ‘You’re eligible for a vaccine ... and you need to get it ... you’ll receive it on your way out.’ It then becomes a distinct and strong recommendation,” he said.
#4: Appeal to Patients’ Hearts, Not Their Minds
In the opening of Charles Dickens’s novel “Hard Times,” the stern school superintendent, Mr. Gradgrind, scolds his students by beating their brow with the notion that, “Facts alone are wanted in life. Plant nothing else and root out everything else.”
The idea that facts alone can sway a vaccine-resistant patient is wrong. “It often doesn’t happen that way,” Dr. Schaffner said. “I don’t think facts do that. Psychologists tell us, yes, information is important, but it’s rarely sufficient to change behavior.”
Data and studies are foundational to medicine, but the key is to change how a patient feels about the data they’re presented with, not how they think about it. “Don’t attack their brain so much but their heart,” Dr. Schaffner said.
Dr. Schaffner has stressed with his patients that the COVID vaccine has become “the social norm,” suggesting virtually everyone he knows has received it and had no problem.
Once questions have been answered about whether the vaccine works and its various side effects, doctors could remind the patient, “You know, everyone in my office is getting the vaccine, and we’re trying to provide this protection to every patient,” he said.
You’re then delving deeper into their emotions and crossing a barrier that facts alone can’t breach.
#5: Make it Personal
Lead by example and personalize the fight against the virus. This allows doctors to act as if they’re building an alliance with their patients by framing the vaccine not as something that only affects them but can also confer benefits to a broader social circle.
Even after using these methods, patients may remain resistant, apprehensive, or even indifferent. In cases like these, Dr. Schaffner said it’s a good idea to let it go for the time being.
Let the patient know they “have access to you and can keep speaking with you about it” in the future, he said. “It takes more time, and you have to be cognizant of the nature of the conversation.”
Everybody is unique, but with trust, patience, and awareness of the patient’s feelings, doctors have a better shot at finding common ground with their patients and convincing them the vaccine is in their best interest, he said.
A version of this article first appeared on Medscape.com.