Long COVID

After catching COVID-19 for the second time in July 2022, Daniel Lewis suffered persistent headaches, chest pain, and a dangerously high heart rate. He recalls that he was also so exhausted packing for a family wedding that he had to take a break to rest each time he put something into his suitcase.

Instead of attending the wedding, the 30-year-old Washington data analyst visited his doctor, who diagnosed “some postviral thing” and prescribed rest. Mr. Lewis found a new doctor, went to a long COVID clinic, and saw multiple specialists, but a year later, he’s still sick – and disabled. He meets the federal criteria for long COVID (symptoms that last more than 4 weeks).

He now uses an electric wheelchair whenever he leaves his apartment, a far cry from his pre-COVID life, when he was training for a half marathon.

“Some doctors have genuinely tried to help,” he said. “Most don’t really know what long COVID is, and ... since there’s no official guidance on what to do with long COVID patients, they just throw up their hands and say there’s nothing to do.”

That could be changing – at least the part about official guidance. New findings published in JAMA indicate we’re getting closer to unraveling what long COVID is all about and may help refine how it is defined and diagnosed. The study identified the 37 most common symptoms of long COVID, an important step toward better understanding and treatment of the condition, which affects an estimated 65 million people worldwide.

Although the study provides a way to systematically identify the condition, the authors were clear that this is significant but that it is only a first step. Naming symptoms is very different from understanding what causes them, and understanding them is critical for developing effective treatments, said pulmonologist Bruce Levy, MD, a study coauthor who is interim chair of medicine at Brigham and Women’s Hospital and a professor of medicine at Harvard Medical School, both in Boston.

Researchers relied on self-reported symptoms from the 9,764 participants, all adults who are part of the ongoing Researching COVID to Enhance Recovery (RECOVER) Initiative, a longitudinal study run by the National Institutes of Health. Some patients had long COVID when they signed up for the study, some developed it afterward, and some had never had it, or if they had, they were unaware.

Other studies, most of them involving smaller groups of patients, have examined long COVID biomarkers, risk factors, and specific symptoms. Dr. Levy said it’s important to have a symptom-based definition of long COVID that draws from a large cohort of patients who reported on their experiences with symptoms during the aftermath of infection. However, he pointed out that because participants volunteered for the study and were not chosen on the basis of specific criteria, they may not be representative of the more general population of patients with long COVID.

“We need this kind of evidence – it’s important to have self-reported symptoms, because clearly, the patients know what they’re feeling,” Dr. Levy said. “But it’s only part of the picture.”

Dr. Levy said the definition of long COVID needs to be further refined by ongoing research, including objective assessments of clinical findings, laboratory testing, imaging, and biomarkers.

One of the notable findings in the JAMA study is that certain symptoms tend to occur in clusters. The biostatisticians and analysts who processed the data identified four subgroups of very common symptoms that appeared together in more than 80% of the long COVID patients: loss of or change in smell and taste; postexertional malaise and fatigue; brain fog, postexertional malaise, and fatigue; and fatigue, postexertional malaise, dizziness, brain fog, gastrointestinal issues, and palpitations.

Many of those symptoms are also associated with underlying conditions not related to long COVID, which makes an accurate diagnosis a challenge.

“Just the fact that they would cluster into four groups suggests that underlying all this is not just one unifying pathobiology,” Dr. Levy said. He stressed that clinicians need to understand what’s causing the symptoms before they can properly treat patients.

He pointed out that two of the possible disease-driving mechanisms are persistence of the virus and prolonged inflammation that is slow to resolve. For patients experiencing inflammation after the virus is gone, an anti-inflammatory therapy would be most appropriate.

But if they have persistent virus, “you would want to treat with an antiviral antibiotic and not quiet down the body’s antiviral inflammatory response,” he said. “How you treat the two potential underlying causes of long COVID could thus be almost diametrically opposed, so that’s part of the importance of figuring out what is the underlying cause of those symptoms, not just identifying the symptoms themselves.”

More studies are needed to determine whether long COVID is a syndrome or is related to a singular pathobiology, experts said.

That’s consistent with the impression of long COVID researcher Harlan Krumholz, MD, the Harold H. Hines Jr. professor of medicine (cardiology) at Yale University, New Haven, Conn.

Dr. Krumholz worries that some clinicians might use the JAMA findings to dismiss patients whose symptoms meet the criteria in the scoring system developed for the study.

“It’s important for people who read this paper to know that this is preliminary,” said Dr. Krumholz, a principal investigator of another patient-focused study designed to understand long COVID – the Yale Listen to Immune, Symptom, and Treatment Experiences Now (LISTEN) Study. “It’s a condition we don’t understand yet.”

Dr. Krumholz said he has lost track of the number of patients he knows who, like Daniel Lewis, are ill and are unable to get answers. “There is an intense sense of inadequacy on the clinical side and the research side,” he said. “Every day people ask me, ‘Are there any evidence-based strategies?’ And so far I have to say, every day, ‘No.’ I hate to say it, but it’s kind of like every patient is on their own. They’re trying different things because they can’t wait. There is an imperative to help them.”

At the end of July, the National Institutes of Health launched phase 2 clinical trials to evaluate at least four new treatments for long COVID, all part of the RECOVER initiative. By then, Mr. Lewis, who believes his myalgic encephalomyelitis/chronic fatigue syndrome was triggered by the virus, had made plans to try an alternative, experimental therapy.

“My hope is that it will fix me,” he said. “I’m excited about those kinds of hard-hitting infusion, immunological treatment.”

As for the JAMA study, he didn’t allow himself to get excited when it was released, a function of his experience as a data analyst and long COVID patient.

“I don’t think it moves the needle much yet,” he said. “It’s the first study, and we shouldn’t expect much from the first pieces of data to come out of that. If they keep following that cohort and go deeper and deeper, they’re going to find some interesting stuff that will lead to treatments.”

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

After catching COVID-19 for the second time in July 2022, Daniel Lewis suffered persistent headaches, chest pain, and a dangerously high heart rate. He recalls that he was also so exhausted packing for a family wedding that he had to take a break to rest each time he put something into his suitcase.

Instead of attending the wedding, the 30-year-old Washington data analyst visited his doctor, who diagnosed “some postviral thing” and prescribed rest. Mr. Lewis found a new doctor, went to a long COVID clinic, and saw multiple specialists, but a year later, he’s still sick – and disabled. He meets the federal criteria for long COVID (symptoms that last more than 4 weeks).

He now uses an electric wheelchair whenever he leaves his apartment, a far cry from his pre-COVID life, when he was training for a half marathon.

“Some doctors have genuinely tried to help,” he said. “Most don’t really know what long COVID is, and ... since there’s no official guidance on what to do with long COVID patients, they just throw up their hands and say there’s nothing to do.”

That could be changing – at least the part about official guidance. New findings published in JAMA indicate we’re getting closer to unraveling what long COVID is all about and may help refine how it is defined and diagnosed. The study identified the 37 most common symptoms of long COVID, an important step toward better understanding and treatment of the condition, which affects an estimated 65 million people worldwide.

Although the study provides a way to systematically identify the condition, the authors were clear that this is significant but that it is only a first step. Naming symptoms is very different from understanding what causes them, and understanding them is critical for developing effective treatments, said pulmonologist Bruce Levy, MD, a study coauthor who is interim chair of medicine at Brigham and Women’s Hospital and a professor of medicine at Harvard Medical School, both in Boston.

Researchers relied on self-reported symptoms from the 9,764 participants, all adults who are part of the ongoing Researching COVID to Enhance Recovery (RECOVER) Initiative, a longitudinal study run by the National Institutes of Health. Some patients had long COVID when they signed up for the study, some developed it afterward, and some had never had it, or if they had, they were unaware.

Other studies, most of them involving smaller groups of patients, have examined long COVID biomarkers, risk factors, and specific symptoms. Dr. Levy said it’s important to have a symptom-based definition of long COVID that draws from a large cohort of patients who reported on their experiences with symptoms during the aftermath of infection. However, he pointed out that because participants volunteered for the study and were not chosen on the basis of specific criteria, they may not be representative of the more general population of patients with long COVID.

“We need this kind of evidence – it’s important to have self-reported symptoms, because clearly, the patients know what they’re feeling,” Dr. Levy said. “But it’s only part of the picture.”

Dr. Levy said the definition of long COVID needs to be further refined by ongoing research, including objective assessments of clinical findings, laboratory testing, imaging, and biomarkers.

One of the notable findings in the JAMA study is that certain symptoms tend to occur in clusters. The biostatisticians and analysts who processed the data identified four subgroups of very common symptoms that appeared together in more than 80% of the long COVID patients: loss of or change in smell and taste; postexertional malaise and fatigue; brain fog, postexertional malaise, and fatigue; and fatigue, postexertional malaise, dizziness, brain fog, gastrointestinal issues, and palpitations.

Many of those symptoms are also associated with underlying conditions not related to long COVID, which makes an accurate diagnosis a challenge.

“Just the fact that they would cluster into four groups suggests that underlying all this is not just one unifying pathobiology,” Dr. Levy said. He stressed that clinicians need to understand what’s causing the symptoms before they can properly treat patients.

He pointed out that two of the possible disease-driving mechanisms are persistence of the virus and prolonged inflammation that is slow to resolve. For patients experiencing inflammation after the virus is gone, an anti-inflammatory therapy would be most appropriate.

But if they have persistent virus, “you would want to treat with an antiviral antibiotic and not quiet down the body’s antiviral inflammatory response,” he said. “How you treat the two potential underlying causes of long COVID could thus be almost diametrically opposed, so that’s part of the importance of figuring out what is the underlying cause of those symptoms, not just identifying the symptoms themselves.”

More studies are needed to determine whether long COVID is a syndrome or is related to a singular pathobiology, experts said.

That’s consistent with the impression of long COVID researcher Harlan Krumholz, MD, the Harold H. Hines Jr. professor of medicine (cardiology) at Yale University, New Haven, Conn.

Dr. Krumholz worries that some clinicians might use the JAMA findings to dismiss patients whose symptoms meet the criteria in the scoring system developed for the study.

“It’s important for people who read this paper to know that this is preliminary,” said Dr. Krumholz, a principal investigator of another patient-focused study designed to understand long COVID – the Yale Listen to Immune, Symptom, and Treatment Experiences Now (LISTEN) Study. “It’s a condition we don’t understand yet.”

Dr. Krumholz said he has lost track of the number of patients he knows who, like Daniel Lewis, are ill and are unable to get answers. “There is an intense sense of inadequacy on the clinical side and the research side,” he said. “Every day people ask me, ‘Are there any evidence-based strategies?’ And so far I have to say, every day, ‘No.’ I hate to say it, but it’s kind of like every patient is on their own. They’re trying different things because they can’t wait. There is an imperative to help them.”

At the end of July, the National Institutes of Health launched phase 2 clinical trials to evaluate at least four new treatments for long COVID, all part of the RECOVER initiative. By then, Mr. Lewis, who believes his myalgic encephalomyelitis/chronic fatigue syndrome was triggered by the virus, had made plans to try an alternative, experimental therapy.

“My hope is that it will fix me,” he said. “I’m excited about those kinds of hard-hitting infusion, immunological treatment.”

As for the JAMA study, he didn’t allow himself to get excited when it was released, a function of his experience as a data analyst and long COVID patient.

“I don’t think it moves the needle much yet,” he said. “It’s the first study, and we shouldn’t expect much from the first pieces of data to come out of that. If they keep following that cohort and go deeper and deeper, they’re going to find some interesting stuff that will lead to treatments.”

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

After catching COVID-19 for the second time in July 2022, Daniel Lewis suffered persistent headaches, chest pain, and a dangerously high heart rate. He recalls that he was also so exhausted packing for a family wedding that he had to take a break to rest each time he put something into his suitcase.

Instead of attending the wedding, the 30-year-old Washington data analyst visited his doctor, who diagnosed “some postviral thing” and prescribed rest. Mr. Lewis found a new doctor, went to a long COVID clinic, and saw multiple specialists, but a year later, he’s still sick – and disabled. He meets the federal criteria for long COVID (symptoms that last more than 4 weeks).

He now uses an electric wheelchair whenever he leaves his apartment, a far cry from his pre-COVID life, when he was training for a half marathon.

“Some doctors have genuinely tried to help,” he said. “Most don’t really know what long COVID is, and ... since there’s no official guidance on what to do with long COVID patients, they just throw up their hands and say there’s nothing to do.”

That could be changing – at least the part about official guidance. New findings published in JAMA indicate we’re getting closer to unraveling what long COVID is all about and may help refine how it is defined and diagnosed. The study identified the 37 most common symptoms of long COVID, an important step toward better understanding and treatment of the condition, which affects an estimated 65 million people worldwide.

Although the study provides a way to systematically identify the condition, the authors were clear that this is significant but that it is only a first step. Naming symptoms is very different from understanding what causes them, and understanding them is critical for developing effective treatments, said pulmonologist Bruce Levy, MD, a study coauthor who is interim chair of medicine at Brigham and Women’s Hospital and a professor of medicine at Harvard Medical School, both in Boston.

Researchers relied on self-reported symptoms from the 9,764 participants, all adults who are part of the ongoing Researching COVID to Enhance Recovery (RECOVER) Initiative, a longitudinal study run by the National Institutes of Health. Some patients had long COVID when they signed up for the study, some developed it afterward, and some had never had it, or if they had, they were unaware.

Other studies, most of them involving smaller groups of patients, have examined long COVID biomarkers, risk factors, and specific symptoms. Dr. Levy said it’s important to have a symptom-based definition of long COVID that draws from a large cohort of patients who reported on their experiences with symptoms during the aftermath of infection. However, he pointed out that because participants volunteered for the study and were not chosen on the basis of specific criteria, they may not be representative of the more general population of patients with long COVID.

“We need this kind of evidence – it’s important to have self-reported symptoms, because clearly, the patients know what they’re feeling,” Dr. Levy said. “But it’s only part of the picture.”

Dr. Levy said the definition of long COVID needs to be further refined by ongoing research, including objective assessments of clinical findings, laboratory testing, imaging, and biomarkers.

One of the notable findings in the JAMA study is that certain symptoms tend to occur in clusters. The biostatisticians and analysts who processed the data identified four subgroups of very common symptoms that appeared together in more than 80% of the long COVID patients: loss of or change in smell and taste; postexertional malaise and fatigue; brain fog, postexertional malaise, and fatigue; and fatigue, postexertional malaise, dizziness, brain fog, gastrointestinal issues, and palpitations.

Many of those symptoms are also associated with underlying conditions not related to long COVID, which makes an accurate diagnosis a challenge.

“Just the fact that they would cluster into four groups suggests that underlying all this is not just one unifying pathobiology,” Dr. Levy said. He stressed that clinicians need to understand what’s causing the symptoms before they can properly treat patients.

He pointed out that two of the possible disease-driving mechanisms are persistence of the virus and prolonged inflammation that is slow to resolve. For patients experiencing inflammation after the virus is gone, an anti-inflammatory therapy would be most appropriate.

But if they have persistent virus, “you would want to treat with an antiviral antibiotic and not quiet down the body’s antiviral inflammatory response,” he said. “How you treat the two potential underlying causes of long COVID could thus be almost diametrically opposed, so that’s part of the importance of figuring out what is the underlying cause of those symptoms, not just identifying the symptoms themselves.”

More studies are needed to determine whether long COVID is a syndrome or is related to a singular pathobiology, experts said.

That’s consistent with the impression of long COVID researcher Harlan Krumholz, MD, the Harold H. Hines Jr. professor of medicine (cardiology) at Yale University, New Haven, Conn.

Dr. Krumholz worries that some clinicians might use the JAMA findings to dismiss patients whose symptoms meet the criteria in the scoring system developed for the study.

“It’s important for people who read this paper to know that this is preliminary,” said Dr. Krumholz, a principal investigator of another patient-focused study designed to understand long COVID – the Yale Listen to Immune, Symptom, and Treatment Experiences Now (LISTEN) Study. “It’s a condition we don’t understand yet.”

Dr. Krumholz said he has lost track of the number of patients he knows who, like Daniel Lewis, are ill and are unable to get answers. “There is an intense sense of inadequacy on the clinical side and the research side,” he said. “Every day people ask me, ‘Are there any evidence-based strategies?’ And so far I have to say, every day, ‘No.’ I hate to say it, but it’s kind of like every patient is on their own. They’re trying different things because they can’t wait. There is an imperative to help them.”

At the end of July, the National Institutes of Health launched phase 2 clinical trials to evaluate at least four new treatments for long COVID, all part of the RECOVER initiative. By then, Mr. Lewis, who believes his myalgic encephalomyelitis/chronic fatigue syndrome was triggered by the virus, had made plans to try an alternative, experimental therapy.

“My hope is that it will fix me,” he said. “I’m excited about those kinds of hard-hitting infusion, immunological treatment.”

As for the JAMA study, he didn’t allow himself to get excited when it was released, a function of his experience as a data analyst and long COVID patient.

“I don’t think it moves the needle much yet,” he said. “It’s the first study, and we shouldn’t expect much from the first pieces of data to come out of that. If they keep following that cohort and go deeper and deeper, they’re going to find some interesting stuff that will lead to treatments.”

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

A growing number of long COVID patients, denied disability benefits despite being unable to work, are turning to the courts for legal relief.

At least 30 lawsuits have been filed seeking legal resolution of disability insurance claims, according to searches of court records. In addition, the Social Security Administration said it has received about 52,000 disability claims tied to SARS-CoV-2 infections, which represents 1% of all applications.

But legal experts say those cases may not reflect the total number of cases that have gone to court. They note many claims are initially dismissed and are not appealed by claimants.

“With this system, they deny two-thirds of initial applications, then people who appeal get denied almost 90% of the time, and then they can appeal before a judge,” said Kevin LaPorte, a Social Security disability attorney at LaPorte Law Firm in Oakland, Calif. “What happens next doesn’t have a lot of precedent because long COVID is a mass disabling event, and we haven’t seen that many of these cases get all the way through the legal system yet.”

As a result, the exact number of long COVID disability claims and the number of these cases going to court isn’t clear, he said.

“It can take a year or more for cases to get to court, and even longer to reach resolution,” Mr. LaPorte added. “I suspect the few cases we’ve heard about at this point are going to be the tip of the iceberg.”

The process is convoluted and can drag on for months with multiple denials and appeals along the way. Many disabled workers find their only recourse is to take insurers to court.

Long COVID patients typically apply for disability benefits through private insurance or Social Security. But the process can drag on for months, so many find their only recourse is to take insurers to court, according to legal experts.

But even in the courts, many encounter delays and hurdles to resolution.

In one of the first federal lawsuits involving long COVID disability benefits, William Abrams, a trial and appellate attorney and active marathon runner, sued Unum Life Insurance seeking long-term disability income. Symptoms included extreme fatigue, brain fog, decreased attention and concentration, and nearly daily fevers, causing him to stop working in April 2020.

His diagnosis wasn’t definitive. Three doctors said he had long COVID, and four said he had chronic fatigue syndrome. Unum cited this inconsistency as a rationale for rejecting his claim. But the court sided with Mr. Abrams, granting him disability income. The court concluded: “Unum may be correct that [the plaintiff] has not been correctly diagnosed. But that does not mean he is not sick. If [the plaintiff’s] complaints, and [the doctor’s] assessments, are to be believed, [the plaintiff] cannot focus for more than a few minutes at a time, making it impossible for [the plaintiff] to perform the varied and complex tasks his job requires.”

Unum said in an emailed statement that the company doesn’t comment on specific claims as a matter of policy, adding that its total payouts for disability claims from March 2020 to February 2022 were 35% higher than prepandemic levels. “In general, disability and leave claims connected to COVID-19 have been primarily short-term events with the majority of claimants recovering prior to completing the normal qualification period for long-term disability insurance,” Unum said.

Mr. Abrams prevailed in part because he had detailed documentation of the numerous impairments that eventually required him to stop work, said Michelle Roberts of Roberts Disability Law in Oakland, Calif.

He submitted videos of himself taking his temperature to prove he had almost daily fevers, according to court records. He underwent neuropsychological testing, which found learning deficiencies and memory deficits.

Mr. Abrams also submitted statements from a colleague who worked with him on a complex technology patent case involving radiofrequency identification. Before he got COVID, Mr. Abrams “had the analytical ability, legal acumen, and mental energy to attack that learning curve and get up to speed very rapidly,” according to court records.

“The court focused on credulity.” Ms. Roberts said. “There was all this work to be done to show this person was high functioning and ran marathons and worked in an intense, high-pressure occupation but then couldn’t do anything after long COVID.”

Documentation was also crucial in another early federal long COVID disability lawsuit that was filed in 2022 on behalf of Wendy Haut, an educational software sales representative in California who turned to the courts seeking disability income through her company’s employee benefits plan.

Several of Ms. Haut’s doctors documented a detailed list of long COVID symptoms, including “profound fatigue and extreme cognitive difficulties,” that they said prevented her from working as a sales representative or doing any other type of job. A settlement agreement in June 2022 required Reliance Standard Life Insurance to pay Ms. Haut long-term disability benefits, including previously unpaid benefits, according to a report by the advocacy group Pandemic Patients.

Representatives of Reliance Standard didn’t respond to a request for comment.

The growing number of workers being sidelined by long COVID makes more claims and more court cases likely. Right now, an estimated 16 million working-age Americans aged 18-65 years have long COVID, and as many as 4 million of them can’t work, according to a July 2023 Census Bureau report.

Uncertainty about the volume of claims in the pipeline is part of what’s driving some insurers to fight long COVID claims, Ms. Roberts said. Another factor is the lack of clarity around how many years people with long COVID may be out of work, particularly if they’re in their 30s or 40s and might be seeking disability income until they reach retirement age.

“Doctors are not always saying that this person will be permanently disabled,” Ms. Roberts said. “If this person doesn’t get better and they’re disabled until retirement age, this could be a payout in the high six or seven figures if a person is very young and was a very high earner.”

Insurance companies routinely deny claims that can’t be backed up with objective measures, such as specific lab test results or clear findings from a physical exam. But there are steps that can increase the odds of a successful claim for long COVID disability benefits, according to New York–based law firm Hiller.

For starters, patients can document COVID test results, and if testing wasn’t conducted, patients can detail the specific symptoms that led to this diagnosis, Hiller advises. Then patients can keep a daily symptom log at home that run lists all of the specific symptoms that occur at different times during the day and night to help establish a pattern of disability. These logs should provide specific details about every job duty patients have and exactly how specific symptoms of long COVID interfere with these duties.

Even though objective testing is hard to come by for long COVID, people should undergo all the tests they can that may help document the frequency or severity of specific symptoms that make it impossible to carry on with business as usual at work, Hiller advises. This may include neuropsychological testing to document brain fog, a cardiopulmonary exercise test to demonstrate chronic fatigue and the inability to exercise, or a tilt table test to measure dizziness.

Seeking a doctor’s diagnosis can be key to collecting disability payments, in or out of court.

All of this puts a lot of pressure on doctors and patients to build strong cases, said Jonathan Whiteson, MD, codirector of the NYU Langone Health post-COVID care program in New York. “Many physicians are not familiar with the disability benefit paperwork, and so this is a challenge for the doctors to know how to complete and to build the time into their highly scheduled days to take the time needed to complete.

“It’s also challenging because most of the disability benefit forms are ‘generic’ and do not ask specific questions about COVID disability,” Dr. Whiteson added. “It can be like trying to drive a square peg into a round hole.”

Still, when it comes to long COVID, completing disability paperwork is increasingly becoming part of standard care, along with managing medication, rehabilitation therapies, and lifestyle changes to navigate daily life with this illness, Dr. Whiteson noted.

Monica Verduzco-Gutierrez, MD, chair of rehabilitation medicine and director of the Post-COVID-19 Recovery Clinic at the University of Texas Health Science Center, San Antonio, agreed with this assessment.

“I have done letter upon letter of appeal to disability insurance companies,” she said.

Some doctors, however, are reluctant to step up in such cases, in part because no standard diagnostic guidelines exist for long COVID and because it can be frustrating.

“This is the work that is not paid and causes burnout in physicians,” Dr. Verduzco-Gutierrez said. “The paperwork, the fighting with insurance companies, the resubmission of forms for disability all to get what your patient needs – and then it gets denied.

“We will keep doing this because our patients need this disability income in order to live their lives and to afford what they need for recovery,” said Dr. Verduzco-Gutierrez. “But at some point something has to change because this isn’t sustainable.”

A version of this article appeared on Medscape.com.

A growing number of long COVID patients, denied disability benefits despite being unable to work, are turning to the courts for legal relief.

At least 30 lawsuits have been filed seeking legal resolution of disability insurance claims, according to searches of court records. In addition, the Social Security Administration said it has received about 52,000 disability claims tied to SARS-CoV-2 infections, which represents 1% of all applications.

But legal experts say those cases may not reflect the total number of cases that have gone to court. They note many claims are initially dismissed and are not appealed by claimants.

“With this system, they deny two-thirds of initial applications, then people who appeal get denied almost 90% of the time, and then they can appeal before a judge,” said Kevin LaPorte, a Social Security disability attorney at LaPorte Law Firm in Oakland, Calif. “What happens next doesn’t have a lot of precedent because long COVID is a mass disabling event, and we haven’t seen that many of these cases get all the way through the legal system yet.”

As a result, the exact number of long COVID disability claims and the number of these cases going to court isn’t clear, he said.

“It can take a year or more for cases to get to court, and even longer to reach resolution,” Mr. LaPorte added. “I suspect the few cases we’ve heard about at this point are going to be the tip of the iceberg.”

The process is convoluted and can drag on for months with multiple denials and appeals along the way. Many disabled workers find their only recourse is to take insurers to court.

Long COVID patients typically apply for disability benefits through private insurance or Social Security. But the process can drag on for months, so many find their only recourse is to take insurers to court, according to legal experts.

But even in the courts, many encounter delays and hurdles to resolution.

In one of the first federal lawsuits involving long COVID disability benefits, William Abrams, a trial and appellate attorney and active marathon runner, sued Unum Life Insurance seeking long-term disability income. Symptoms included extreme fatigue, brain fog, decreased attention and concentration, and nearly daily fevers, causing him to stop working in April 2020.

His diagnosis wasn’t definitive. Three doctors said he had long COVID, and four said he had chronic fatigue syndrome. Unum cited this inconsistency as a rationale for rejecting his claim. But the court sided with Mr. Abrams, granting him disability income. The court concluded: “Unum may be correct that [the plaintiff] has not been correctly diagnosed. But that does not mean he is not sick. If [the plaintiff’s] complaints, and [the doctor’s] assessments, are to be believed, [the plaintiff] cannot focus for more than a few minutes at a time, making it impossible for [the plaintiff] to perform the varied and complex tasks his job requires.”

Unum said in an emailed statement that the company doesn’t comment on specific claims as a matter of policy, adding that its total payouts for disability claims from March 2020 to February 2022 were 35% higher than prepandemic levels. “In general, disability and leave claims connected to COVID-19 have been primarily short-term events with the majority of claimants recovering prior to completing the normal qualification period for long-term disability insurance,” Unum said.

Mr. Abrams prevailed in part because he had detailed documentation of the numerous impairments that eventually required him to stop work, said Michelle Roberts of Roberts Disability Law in Oakland, Calif.

He submitted videos of himself taking his temperature to prove he had almost daily fevers, according to court records. He underwent neuropsychological testing, which found learning deficiencies and memory deficits.

Mr. Abrams also submitted statements from a colleague who worked with him on a complex technology patent case involving radiofrequency identification. Before he got COVID, Mr. Abrams “had the analytical ability, legal acumen, and mental energy to attack that learning curve and get up to speed very rapidly,” according to court records.

“The court focused on credulity.” Ms. Roberts said. “There was all this work to be done to show this person was high functioning and ran marathons and worked in an intense, high-pressure occupation but then couldn’t do anything after long COVID.”

Documentation was also crucial in another early federal long COVID disability lawsuit that was filed in 2022 on behalf of Wendy Haut, an educational software sales representative in California who turned to the courts seeking disability income through her company’s employee benefits plan.

Several of Ms. Haut’s doctors documented a detailed list of long COVID symptoms, including “profound fatigue and extreme cognitive difficulties,” that they said prevented her from working as a sales representative or doing any other type of job. A settlement agreement in June 2022 required Reliance Standard Life Insurance to pay Ms. Haut long-term disability benefits, including previously unpaid benefits, according to a report by the advocacy group Pandemic Patients.

Representatives of Reliance Standard didn’t respond to a request for comment.

The growing number of workers being sidelined by long COVID makes more claims and more court cases likely. Right now, an estimated 16 million working-age Americans aged 18-65 years have long COVID, and as many as 4 million of them can’t work, according to a July 2023 Census Bureau report.

Uncertainty about the volume of claims in the pipeline is part of what’s driving some insurers to fight long COVID claims, Ms. Roberts said. Another factor is the lack of clarity around how many years people with long COVID may be out of work, particularly if they’re in their 30s or 40s and might be seeking disability income until they reach retirement age.

“Doctors are not always saying that this person will be permanently disabled,” Ms. Roberts said. “If this person doesn’t get better and they’re disabled until retirement age, this could be a payout in the high six or seven figures if a person is very young and was a very high earner.”

Insurance companies routinely deny claims that can’t be backed up with objective measures, such as specific lab test results or clear findings from a physical exam. But there are steps that can increase the odds of a successful claim for long COVID disability benefits, according to New York–based law firm Hiller.

For starters, patients can document COVID test results, and if testing wasn’t conducted, patients can detail the specific symptoms that led to this diagnosis, Hiller advises. Then patients can keep a daily symptom log at home that run lists all of the specific symptoms that occur at different times during the day and night to help establish a pattern of disability. These logs should provide specific details about every job duty patients have and exactly how specific symptoms of long COVID interfere with these duties.

Even though objective testing is hard to come by for long COVID, people should undergo all the tests they can that may help document the frequency or severity of specific symptoms that make it impossible to carry on with business as usual at work, Hiller advises. This may include neuropsychological testing to document brain fog, a cardiopulmonary exercise test to demonstrate chronic fatigue and the inability to exercise, or a tilt table test to measure dizziness.

Seeking a doctor’s diagnosis can be key to collecting disability payments, in or out of court.

All of this puts a lot of pressure on doctors and patients to build strong cases, said Jonathan Whiteson, MD, codirector of the NYU Langone Health post-COVID care program in New York. “Many physicians are not familiar with the disability benefit paperwork, and so this is a challenge for the doctors to know how to complete and to build the time into their highly scheduled days to take the time needed to complete.

“It’s also challenging because most of the disability benefit forms are ‘generic’ and do not ask specific questions about COVID disability,” Dr. Whiteson added. “It can be like trying to drive a square peg into a round hole.”

Still, when it comes to long COVID, completing disability paperwork is increasingly becoming part of standard care, along with managing medication, rehabilitation therapies, and lifestyle changes to navigate daily life with this illness, Dr. Whiteson noted.

Monica Verduzco-Gutierrez, MD, chair of rehabilitation medicine and director of the Post-COVID-19 Recovery Clinic at the University of Texas Health Science Center, San Antonio, agreed with this assessment.

“I have done letter upon letter of appeal to disability insurance companies,” she said.

Some doctors, however, are reluctant to step up in such cases, in part because no standard diagnostic guidelines exist for long COVID and because it can be frustrating.

“This is the work that is not paid and causes burnout in physicians,” Dr. Verduzco-Gutierrez said. “The paperwork, the fighting with insurance companies, the resubmission of forms for disability all to get what your patient needs – and then it gets denied.

“We will keep doing this because our patients need this disability income in order to live their lives and to afford what they need for recovery,” said Dr. Verduzco-Gutierrez. “But at some point something has to change because this isn’t sustainable.”

A version of this article appeared on Medscape.com.

A growing number of long COVID patients, denied disability benefits despite being unable to work, are turning to the courts for legal relief.

At least 30 lawsuits have been filed seeking legal resolution of disability insurance claims, according to searches of court records. In addition, the Social Security Administration said it has received about 52,000 disability claims tied to SARS-CoV-2 infections, which represents 1% of all applications.

But legal experts say those cases may not reflect the total number of cases that have gone to court. They note many claims are initially dismissed and are not appealed by claimants.

“With this system, they deny two-thirds of initial applications, then people who appeal get denied almost 90% of the time, and then they can appeal before a judge,” said Kevin LaPorte, a Social Security disability attorney at LaPorte Law Firm in Oakland, Calif. “What happens next doesn’t have a lot of precedent because long COVID is a mass disabling event, and we haven’t seen that many of these cases get all the way through the legal system yet.”

As a result, the exact number of long COVID disability claims and the number of these cases going to court isn’t clear, he said.

“It can take a year or more for cases to get to court, and even longer to reach resolution,” Mr. LaPorte added. “I suspect the few cases we’ve heard about at this point are going to be the tip of the iceberg.”

The process is convoluted and can drag on for months with multiple denials and appeals along the way. Many disabled workers find their only recourse is to take insurers to court.

Long COVID patients typically apply for disability benefits through private insurance or Social Security. But the process can drag on for months, so many find their only recourse is to take insurers to court, according to legal experts.

But even in the courts, many encounter delays and hurdles to resolution.

In one of the first federal lawsuits involving long COVID disability benefits, William Abrams, a trial and appellate attorney and active marathon runner, sued Unum Life Insurance seeking long-term disability income. Symptoms included extreme fatigue, brain fog, decreased attention and concentration, and nearly daily fevers, causing him to stop working in April 2020.

His diagnosis wasn’t definitive. Three doctors said he had long COVID, and four said he had chronic fatigue syndrome. Unum cited this inconsistency as a rationale for rejecting his claim. But the court sided with Mr. Abrams, granting him disability income. The court concluded: “Unum may be correct that [the plaintiff] has not been correctly diagnosed. But that does not mean he is not sick. If [the plaintiff’s] complaints, and [the doctor’s] assessments, are to be believed, [the plaintiff] cannot focus for more than a few minutes at a time, making it impossible for [the plaintiff] to perform the varied and complex tasks his job requires.”

Unum said in an emailed statement that the company doesn’t comment on specific claims as a matter of policy, adding that its total payouts for disability claims from March 2020 to February 2022 were 35% higher than prepandemic levels. “In general, disability and leave claims connected to COVID-19 have been primarily short-term events with the majority of claimants recovering prior to completing the normal qualification period for long-term disability insurance,” Unum said.

Mr. Abrams prevailed in part because he had detailed documentation of the numerous impairments that eventually required him to stop work, said Michelle Roberts of Roberts Disability Law in Oakland, Calif.

He submitted videos of himself taking his temperature to prove he had almost daily fevers, according to court records. He underwent neuropsychological testing, which found learning deficiencies and memory deficits.

Mr. Abrams also submitted statements from a colleague who worked with him on a complex technology patent case involving radiofrequency identification. Before he got COVID, Mr. Abrams “had the analytical ability, legal acumen, and mental energy to attack that learning curve and get up to speed very rapidly,” according to court records.

“The court focused on credulity.” Ms. Roberts said. “There was all this work to be done to show this person was high functioning and ran marathons and worked in an intense, high-pressure occupation but then couldn’t do anything after long COVID.”

Documentation was also crucial in another early federal long COVID disability lawsuit that was filed in 2022 on behalf of Wendy Haut, an educational software sales representative in California who turned to the courts seeking disability income through her company’s employee benefits plan.

Several of Ms. Haut’s doctors documented a detailed list of long COVID symptoms, including “profound fatigue and extreme cognitive difficulties,” that they said prevented her from working as a sales representative or doing any other type of job. A settlement agreement in June 2022 required Reliance Standard Life Insurance to pay Ms. Haut long-term disability benefits, including previously unpaid benefits, according to a report by the advocacy group Pandemic Patients.

Representatives of Reliance Standard didn’t respond to a request for comment.

The growing number of workers being sidelined by long COVID makes more claims and more court cases likely. Right now, an estimated 16 million working-age Americans aged 18-65 years have long COVID, and as many as 4 million of them can’t work, according to a July 2023 Census Bureau report.

Uncertainty about the volume of claims in the pipeline is part of what’s driving some insurers to fight long COVID claims, Ms. Roberts said. Another factor is the lack of clarity around how many years people with long COVID may be out of work, particularly if they’re in their 30s or 40s and might be seeking disability income until they reach retirement age.

“Doctors are not always saying that this person will be permanently disabled,” Ms. Roberts said. “If this person doesn’t get better and they’re disabled until retirement age, this could be a payout in the high six or seven figures if a person is very young and was a very high earner.”

Insurance companies routinely deny claims that can’t be backed up with objective measures, such as specific lab test results or clear findings from a physical exam. But there are steps that can increase the odds of a successful claim for long COVID disability benefits, according to New York–based law firm Hiller.

For starters, patients can document COVID test results, and if testing wasn’t conducted, patients can detail the specific symptoms that led to this diagnosis, Hiller advises. Then patients can keep a daily symptom log at home that run lists all of the specific symptoms that occur at different times during the day and night to help establish a pattern of disability. These logs should provide specific details about every job duty patients have and exactly how specific symptoms of long COVID interfere with these duties.

Even though objective testing is hard to come by for long COVID, people should undergo all the tests they can that may help document the frequency or severity of specific symptoms that make it impossible to carry on with business as usual at work, Hiller advises. This may include neuropsychological testing to document brain fog, a cardiopulmonary exercise test to demonstrate chronic fatigue and the inability to exercise, or a tilt table test to measure dizziness.

Seeking a doctor’s diagnosis can be key to collecting disability payments, in or out of court.

All of this puts a lot of pressure on doctors and patients to build strong cases, said Jonathan Whiteson, MD, codirector of the NYU Langone Health post-COVID care program in New York. “Many physicians are not familiar with the disability benefit paperwork, and so this is a challenge for the doctors to know how to complete and to build the time into their highly scheduled days to take the time needed to complete.

“It’s also challenging because most of the disability benefit forms are ‘generic’ and do not ask specific questions about COVID disability,” Dr. Whiteson added. “It can be like trying to drive a square peg into a round hole.”

Still, when it comes to long COVID, completing disability paperwork is increasingly becoming part of standard care, along with managing medication, rehabilitation therapies, and lifestyle changes to navigate daily life with this illness, Dr. Whiteson noted.

Monica Verduzco-Gutierrez, MD, chair of rehabilitation medicine and director of the Post-COVID-19 Recovery Clinic at the University of Texas Health Science Center, San Antonio, agreed with this assessment.

“I have done letter upon letter of appeal to disability insurance companies,” she said.

Some doctors, however, are reluctant to step up in such cases, in part because no standard diagnostic guidelines exist for long COVID and because it can be frustrating.

“This is the work that is not paid and causes burnout in physicians,” Dr. Verduzco-Gutierrez said. “The paperwork, the fighting with insurance companies, the resubmission of forms for disability all to get what your patient needs – and then it gets denied.

“We will keep doing this because our patients need this disability income in order to live their lives and to afford what they need for recovery,” said Dr. Verduzco-Gutierrez. “But at some point something has to change because this isn’t sustainable.”

A version of this article appeared on Medscape.com.

Enrollment is opening for four clinical trials that will evaluate new treatments for long COVID, the National Institutes of Health announced at a media briefing today. Additional clinical trials to test at least seven more treatments are expected to launch in the coming months, officials said.

The trials are part of the NIH’s research effort known as the Researching COVID to Enhance Recovery (RECOVER) Initiative. In December 2020, Congress approved $1.15 billion for the NIH to research and test treatments for long COVID. The new clinical trials are in phase 2 and will test safety and effectiveness.

“The condition affects nearly all body systems and presents with more than 200 symptoms,” said Walter J. Koroshetz, MD, director of the NIH National Institute of Neurological Disorders and Stroke and colead of the RECOVER Initiative. How many people have long COVID is uncertain, he told attendees at the briefing. “The answer kind of depends on how you define the problem and also what variant caused it. The incidence was higher in Delta.” Some estimates suggest that 5%-10% of those infected develop long COVID. “I don’t think we have solid numbers, as it’s a moving target,” Dr. Koroshetz said.

Patients with long COVID have grown increasingly frustrated at the lack of effective treatments. Some doctors have turned to off-label use of some drugs to treat them.

The four trials include the following:

• RECOVER-VITAL will focus on a treatment for viral persistence, which can occur if the virus lingers and causes the immune system to not work properly. One treatment will test a longer dose regimen of the antiviral Paxlovid (nirmatrelvir and ritonavir), which is currently used to treat mild to moderate COVID to halt progression to severe COVID.
• RECOVER-NEURO will target treatments for symptoms such as brain fog, memory problems, and attention challenges. Among the potential treatments are a program called BrainHQ, which provides Web-based training, and PASC-Cognitive Recovery (post-acute sequelae of COVID), a Web-based program developed by Mount Sinai Health System in New York. Also being tested is a direct current stimulation program to improve brain activity.
• RECOVER-SLEEP will evaluate treatments for sleep problems, which can include daytime sleepiness and other problems. According to Dr. Koroshetz, melatonin, light therapy, and an educational coaching system are among the treatments that will be studied.
• RECOVER-AUTONOMIC will evaluate treatments to address symptoms linked with problems of the autonomic nervous system. The first trial will target postural orthostatic tachycardia syndrome (POTS), which can include irregular heartbeat, fatigue, and dizziness. A treatment for immune disease and a drug currently used to treat chronic heart failure will be tested.

Timelines

The first trial, on viral persistence, has launched, said Kanecia Zimmerman, MD, a principal investigator at the Duke Clinical Research Institute, the clinical trials data coordinating center for the trials. “We are actively working to launch the second on cognitive dysfunction.” The sleep and autonomic trials will launch in the coming months, she said. Also planned is a trial to study exercise intolerance, which is reported by many with long COVID.

Information on how to join long COVID trials is available here.

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

Enrollment is opening for four clinical trials that will evaluate new treatments for long COVID, the National Institutes of Health announced at a media briefing today. Additional clinical trials to test at least seven more treatments are expected to launch in the coming months, officials said.

The trials are part of the NIH’s research effort known as the Researching COVID to Enhance Recovery (RECOVER) Initiative. In December 2020, Congress approved $1.15 billion for the NIH to research and test treatments for long COVID. The new clinical trials are in phase 2 and will test safety and effectiveness.

“The condition affects nearly all body systems and presents with more than 200 symptoms,” said Walter J. Koroshetz, MD, director of the NIH National Institute of Neurological Disorders and Stroke and colead of the RECOVER Initiative. How many people have long COVID is uncertain, he told attendees at the briefing. “The answer kind of depends on how you define the problem and also what variant caused it. The incidence was higher in Delta.” Some estimates suggest that 5%-10% of those infected develop long COVID. “I don’t think we have solid numbers, as it’s a moving target,” Dr. Koroshetz said.

Patients with long COVID have grown increasingly frustrated at the lack of effective treatments. Some doctors have turned to off-label use of some drugs to treat them.

The four trials include the following:

• RECOVER-VITAL will focus on a treatment for viral persistence, which can occur if the virus lingers and causes the immune system to not work properly. One treatment will test a longer dose regimen of the antiviral Paxlovid (nirmatrelvir and ritonavir), which is currently used to treat mild to moderate COVID to halt progression to severe COVID.
• RECOVER-NEURO will target treatments for symptoms such as brain fog, memory problems, and attention challenges. Among the potential treatments are a program called BrainHQ, which provides Web-based training, and PASC-Cognitive Recovery (post-acute sequelae of COVID), a Web-based program developed by Mount Sinai Health System in New York. Also being tested is a direct current stimulation program to improve brain activity.
• RECOVER-SLEEP will evaluate treatments for sleep problems, which can include daytime sleepiness and other problems. According to Dr. Koroshetz, melatonin, light therapy, and an educational coaching system are among the treatments that will be studied.
• RECOVER-AUTONOMIC will evaluate treatments to address symptoms linked with problems of the autonomic nervous system. The first trial will target postural orthostatic tachycardia syndrome (POTS), which can include irregular heartbeat, fatigue, and dizziness. A treatment for immune disease and a drug currently used to treat chronic heart failure will be tested.

Timelines

The first trial, on viral persistence, has launched, said Kanecia Zimmerman, MD, a principal investigator at the Duke Clinical Research Institute, the clinical trials data coordinating center for the trials. “We are actively working to launch the second on cognitive dysfunction.” The sleep and autonomic trials will launch in the coming months, she said. Also planned is a trial to study exercise intolerance, which is reported by many with long COVID.

Information on how to join long COVID trials is available here.

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

Enrollment is opening for four clinical trials that will evaluate new treatments for long COVID, the National Institutes of Health announced at a media briefing today. Additional clinical trials to test at least seven more treatments are expected to launch in the coming months, officials said.

The trials are part of the NIH’s research effort known as the Researching COVID to Enhance Recovery (RECOVER) Initiative. In December 2020, Congress approved $1.15 billion for the NIH to research and test treatments for long COVID. The new clinical trials are in phase 2 and will test safety and effectiveness.

“The condition affects nearly all body systems and presents with more than 200 symptoms,” said Walter J. Koroshetz, MD, director of the NIH National Institute of Neurological Disorders and Stroke and colead of the RECOVER Initiative. How many people have long COVID is uncertain, he told attendees at the briefing. “The answer kind of depends on how you define the problem and also what variant caused it. The incidence was higher in Delta.” Some estimates suggest that 5%-10% of those infected develop long COVID. “I don’t think we have solid numbers, as it’s a moving target,” Dr. Koroshetz said.

Patients with long COVID have grown increasingly frustrated at the lack of effective treatments. Some doctors have turned to off-label use of some drugs to treat them.

The four trials include the following:

• RECOVER-VITAL will focus on a treatment for viral persistence, which can occur if the virus lingers and causes the immune system to not work properly. One treatment will test a longer dose regimen of the antiviral Paxlovid (nirmatrelvir and ritonavir), which is currently used to treat mild to moderate COVID to halt progression to severe COVID.
• RECOVER-NEURO will target treatments for symptoms such as brain fog, memory problems, and attention challenges. Among the potential treatments are a program called BrainHQ, which provides Web-based training, and PASC-Cognitive Recovery (post-acute sequelae of COVID), a Web-based program developed by Mount Sinai Health System in New York. Also being tested is a direct current stimulation program to improve brain activity.
• RECOVER-SLEEP will evaluate treatments for sleep problems, which can include daytime sleepiness and other problems. According to Dr. Koroshetz, melatonin, light therapy, and an educational coaching system are among the treatments that will be studied.
• RECOVER-AUTONOMIC will evaluate treatments to address symptoms linked with problems of the autonomic nervous system. The first trial will target postural orthostatic tachycardia syndrome (POTS), which can include irregular heartbeat, fatigue, and dizziness. A treatment for immune disease and a drug currently used to treat chronic heart failure will be tested.

Timelines

The first trial, on viral persistence, has launched, said Kanecia Zimmerman, MD, a principal investigator at the Duke Clinical Research Institute, the clinical trials data coordinating center for the trials. “We are actively working to launch the second on cognitive dysfunction.” The sleep and autonomic trials will launch in the coming months, she said. Also planned is a trial to study exercise intolerance, which is reported by many with long COVID.

Information on how to join long COVID trials is available here.

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

Doctors who treat patients with long COVID, hampered by a lack of federally approved treatments, are turning to off-label use of drugs designed for addiction, diabetes, and other conditions.

Those with long COVID for years now are engaging in robust online conversations about a range of treatments not formally approved by the Food and Drug Administration for the condition, reporting good and bad results.

High on the current list: low-dose naltrexone (LDN). A version of drug developed to help addicts has been shown to help some long COVID patients.

But evidence is building for other treatments, many of them targeted to treat brain fog or one of the other long-term symptoms in individuals 3 months or more after acute COVID infection.

Some patients are taking metformin, which studies have found to be effective at lowering long COVID risk. Paxlovid is being tested for long COVID.  Antivirals are also on the list.

Alba Azola, MD, said she has treated long COVID patients with brain fog and dizziness who have postural orthostatic tachycardia syndrome (POTS).

Dr. Azola said she asked the staff at Johns Hopkins Medicine in Baltimore, where she is a rehabilitation specialist, to teach her how to treat the condition. Since there is no approved treatment for POTS, that meant using off-label drugs, she said. 

“It was super scary as a provider to start doing that, but my patients were suffering so much,” she  said, noting the wait for patients to get into the POTS clinic at Hopkins was 2 years.

Dr. Azola was the lead author on guidelines published by the American Academy of Physical Medicine and Rehabilitation (AAPM&R) last September on how to treat autonomic dysfunction, a common symptom of long COVID. 

The guidelines she helped write include drugs designed for blood pressure – such as midodrine – and steroids.

Dr. Azola noted the medications are prescribed on a case-by-case basis because the same drug that works for one patient may have awful side effects for another patient, she said. At the same time, some of these drugs have helped her patients go back to living relatively normal lives.

The first time JD Davids of Brooklyn, N.Y., took LDN, it was for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and he couldn’t tolerate it. He had nightmares. But when he took it for long COVID, he started out at a low dose and worked his way up, at his doctor’s advice. 

“It’s been a game-changer,” said Mr. Davids, cofounder of Long COVID Justice, an activist group. He has ME/CFS and several other chronic conditions, including long COVID. But, since he started taking LDN for long COVID, Mr. Davids said he has more energy and less pain. 

Technically, evidence is required to show off-label drug use could be effective in treating conditions for which the drug is not formally approved. Research suggests that 20%-30% of drugs are prescribed off-label.

No formal data exist on how widespread the use of off-label drugs for long COVID may be. But LDN is a major topic of discussion on public patient groups on Facebook. 

A recent study in The Lancet Infectious Diseases suggested that the diabetes drug metformin could be helpful. (The same study found no benefit from ivermectin, a drug since dismissed as a possible COVID treatment.)

Patients who testified at a virtual FDA hearing on drug development in April reported using vitamins, herbal supplements, over-the-counter medications and off-label drugs such as gabapentin and beta-blockers. Both of those drugs were on a list of potential treatments published in a January Nature Review article, along with LDN and Paxlovid.

Currently, Paxlovid is approved for acute COVID, and is in clinical trials as a treatment for long COVID as part of the federal government’s RECOVER Initiative. While only small studies of LDN have been conducted for long COVID, doctors are already prescribing the treatment. Mr. Davids said his primary care doctor recommended it.

Some doctors, such as Michael Peluso, MD, are comparing the trend to the early days of the AIDS epidemic, when the federal government was slow to recognize the viral disease. Patients banded together to protest and gain access to experimental treatments. 

Dr. Peluso, who treats long COVID patients at the University of California, San Francisco, said that without any approved treatment, patients are turning to one another to find out what works.

“A lot of people experiencing long COVID are looking for ways to feel better now, rather than waiting for the science or the guidelines to catch up,” he said in an interview.

In some cases, the drugs are backed by small studies, he said. 

“While we still need clinical trials to prove what will work, the drugs tested in these trials are also being informed by anecdotes shared by patients,” Dr. Peluso said.

Gail Van Norman, MD, of the University of Washington, Seattle, also said the long COVID situation today is reminiscent of the AIDS movement, which was “one of the times in history where we saw a real response to patient advocacy groups in terms of access to drugs.” Since then, the FDA has set up multiple programs to expand access to experimental drugs, added Dr. Van Norman, author of a recent study on off-label drug use.

But off-label use needs to be supervised by a physician, she and others said. Many patients get their information from social media, which Dr. Van Norman sees as a double-edged sword. Patients can share information, do their own research online, and alert practitioners to new findings, she said. But social media also promotes misinformation.

“People with no expertise have the same level of voice, and they are magnified,” Dr. Van Norman said.

The FDA requires doctors to have some evidence to support off-label use, she said. Doctors should talk to patients who want to try-off label drugs about what has been studied and what has not been studied.

“If I had [long COVID], I would be asking questions about all these drugs,” Dr. Van Norman said.

Mr. Davids has been asking questions like this for years. Diagnosed in 2019 with ME/CFS, he developed long COVID during the pandemic. Once he began started taking LDN, he started feeling better.

As someone with multiple chronic illnesses, Mr. Davids has tried a lot of treatments – he’s currently on two intravenous drugs and two compounded drugs, including LDN. But when his doctor first suggested it, he was wary. 

“I’ve worked with her to help increase the dosage slowly over time,” he said. “It’s very important for many people to start low and slow and work their way up.”

He hears stories of people who can’t get it from their physicians. Some, he said, think it may be because of the association of the drug with opioid abuse. 

Mr. Davids said long COVID patients have no other choice but to turn to alternative treatments. 
 

“I think we’ve been ill-served by our research establishment,” he said. “It is not set up for complex chronic conditions.”

Mr. Davids said he doesn’t know if LDN helps with underlying conditions or treats the symptoms – such as pain and fatigue – that keep him from doing things such as typing. 

“My understanding is that it may be doing both,” he said. “I sure am happy that it allows me to do things like keep my job.”

Dr. Azola and others said patients need to be monitored closely if they are taking an off-label drug. She recommends primary care doctors become familiar with them so they can offer patients some relief.

“It’s about the relationship between the patient and the provider and the provider being comfortable,” she said. “l was very transparent with my patients.”
 

A version of this article appeared on Medscape.com.

Doctors who treat patients with long COVID, hampered by a lack of federally approved treatments, are turning to off-label use of drugs designed for addiction, diabetes, and other conditions.

Those with long COVID for years now are engaging in robust online conversations about a range of treatments not formally approved by the Food and Drug Administration for the condition, reporting good and bad results.

High on the current list: low-dose naltrexone (LDN). A version of drug developed to help addicts has been shown to help some long COVID patients.

But evidence is building for other treatments, many of them targeted to treat brain fog or one of the other long-term symptoms in individuals 3 months or more after acute COVID infection.

Some patients are taking metformin, which studies have found to be effective at lowering long COVID risk. Paxlovid is being tested for long COVID.  Antivirals are also on the list.

Alba Azola, MD, said she has treated long COVID patients with brain fog and dizziness who have postural orthostatic tachycardia syndrome (POTS).

Dr. Azola said she asked the staff at Johns Hopkins Medicine in Baltimore, where she is a rehabilitation specialist, to teach her how to treat the condition. Since there is no approved treatment for POTS, that meant using off-label drugs, she said. 

“It was super scary as a provider to start doing that, but my patients were suffering so much,” she  said, noting the wait for patients to get into the POTS clinic at Hopkins was 2 years.

Dr. Azola was the lead author on guidelines published by the American Academy of Physical Medicine and Rehabilitation (AAPM&R) last September on how to treat autonomic dysfunction, a common symptom of long COVID. 

The guidelines she helped write include drugs designed for blood pressure – such as midodrine – and steroids.

Dr. Azola noted the medications are prescribed on a case-by-case basis because the same drug that works for one patient may have awful side effects for another patient, she said. At the same time, some of these drugs have helped her patients go back to living relatively normal lives.

The first time JD Davids of Brooklyn, N.Y., took LDN, it was for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and he couldn’t tolerate it. He had nightmares. But when he took it for long COVID, he started out at a low dose and worked his way up, at his doctor’s advice. 

“It’s been a game-changer,” said Mr. Davids, cofounder of Long COVID Justice, an activist group. He has ME/CFS and several other chronic conditions, including long COVID. But, since he started taking LDN for long COVID, Mr. Davids said he has more energy and less pain. 

Technically, evidence is required to show off-label drug use could be effective in treating conditions for which the drug is not formally approved. Research suggests that 20%-30% of drugs are prescribed off-label.

No formal data exist on how widespread the use of off-label drugs for long COVID may be. But LDN is a major topic of discussion on public patient groups on Facebook. 

A recent study in The Lancet Infectious Diseases suggested that the diabetes drug metformin could be helpful. (The same study found no benefit from ivermectin, a drug since dismissed as a possible COVID treatment.)

Patients who testified at a virtual FDA hearing on drug development in April reported using vitamins, herbal supplements, over-the-counter medications and off-label drugs such as gabapentin and beta-blockers. Both of those drugs were on a list of potential treatments published in a January Nature Review article, along with LDN and Paxlovid.

Currently, Paxlovid is approved for acute COVID, and is in clinical trials as a treatment for long COVID as part of the federal government’s RECOVER Initiative. While only small studies of LDN have been conducted for long COVID, doctors are already prescribing the treatment. Mr. Davids said his primary care doctor recommended it.

Some doctors, such as Michael Peluso, MD, are comparing the trend to the early days of the AIDS epidemic, when the federal government was slow to recognize the viral disease. Patients banded together to protest and gain access to experimental treatments. 

Dr. Peluso, who treats long COVID patients at the University of California, San Francisco, said that without any approved treatment, patients are turning to one another to find out what works.

“A lot of people experiencing long COVID are looking for ways to feel better now, rather than waiting for the science or the guidelines to catch up,” he said in an interview.

In some cases, the drugs are backed by small studies, he said. 

“While we still need clinical trials to prove what will work, the drugs tested in these trials are also being informed by anecdotes shared by patients,” Dr. Peluso said.

Gail Van Norman, MD, of the University of Washington, Seattle, also said the long COVID situation today is reminiscent of the AIDS movement, which was “one of the times in history where we saw a real response to patient advocacy groups in terms of access to drugs.” Since then, the FDA has set up multiple programs to expand access to experimental drugs, added Dr. Van Norman, author of a recent study on off-label drug use.

But off-label use needs to be supervised by a physician, she and others said. Many patients get their information from social media, which Dr. Van Norman sees as a double-edged sword. Patients can share information, do their own research online, and alert practitioners to new findings, she said. But social media also promotes misinformation.

“People with no expertise have the same level of voice, and they are magnified,” Dr. Van Norman said.

The FDA requires doctors to have some evidence to support off-label use, she said. Doctors should talk to patients who want to try-off label drugs about what has been studied and what has not been studied.

“If I had [long COVID], I would be asking questions about all these drugs,” Dr. Van Norman said.

Mr. Davids has been asking questions like this for years. Diagnosed in 2019 with ME/CFS, he developed long COVID during the pandemic. Once he began started taking LDN, he started feeling better.

As someone with multiple chronic illnesses, Mr. Davids has tried a lot of treatments – he’s currently on two intravenous drugs and two compounded drugs, including LDN. But when his doctor first suggested it, he was wary. 

“I’ve worked with her to help increase the dosage slowly over time,” he said. “It’s very important for many people to start low and slow and work their way up.”

He hears stories of people who can’t get it from their physicians. Some, he said, think it may be because of the association of the drug with opioid abuse. 

Mr. Davids said long COVID patients have no other choice but to turn to alternative treatments. 
 

“I think we’ve been ill-served by our research establishment,” he said. “It is not set up for complex chronic conditions.”

Mr. Davids said he doesn’t know if LDN helps with underlying conditions or treats the symptoms – such as pain and fatigue – that keep him from doing things such as typing. 

“My understanding is that it may be doing both,” he said. “I sure am happy that it allows me to do things like keep my job.”

Dr. Azola and others said patients need to be monitored closely if they are taking an off-label drug. She recommends primary care doctors become familiar with them so they can offer patients some relief.

“It’s about the relationship between the patient and the provider and the provider being comfortable,” she said. “l was very transparent with my patients.”
 

A version of this article appeared on Medscape.com.

Doctors who treat patients with long COVID, hampered by a lack of federally approved treatments, are turning to off-label use of drugs designed for addiction, diabetes, and other conditions.

Those with long COVID for years now are engaging in robust online conversations about a range of treatments not formally approved by the Food and Drug Administration for the condition, reporting good and bad results.

High on the current list: low-dose naltrexone (LDN). A version of drug developed to help addicts has been shown to help some long COVID patients.

But evidence is building for other treatments, many of them targeted to treat brain fog or one of the other long-term symptoms in individuals 3 months or more after acute COVID infection.

Some patients are taking metformin, which studies have found to be effective at lowering long COVID risk. Paxlovid is being tested for long COVID.  Antivirals are also on the list.

Alba Azola, MD, said she has treated long COVID patients with brain fog and dizziness who have postural orthostatic tachycardia syndrome (POTS).

Dr. Azola said she asked the staff at Johns Hopkins Medicine in Baltimore, where she is a rehabilitation specialist, to teach her how to treat the condition. Since there is no approved treatment for POTS, that meant using off-label drugs, she said. 

“It was super scary as a provider to start doing that, but my patients were suffering so much,” she  said, noting the wait for patients to get into the POTS clinic at Hopkins was 2 years.

Dr. Azola was the lead author on guidelines published by the American Academy of Physical Medicine and Rehabilitation (AAPM&R) last September on how to treat autonomic dysfunction, a common symptom of long COVID. 

The guidelines she helped write include drugs designed for blood pressure – such as midodrine – and steroids.

Dr. Azola noted the medications are prescribed on a case-by-case basis because the same drug that works for one patient may have awful side effects for another patient, she said. At the same time, some of these drugs have helped her patients go back to living relatively normal lives.

The first time JD Davids of Brooklyn, N.Y., took LDN, it was for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and he couldn’t tolerate it. He had nightmares. But when he took it for long COVID, he started out at a low dose and worked his way up, at his doctor’s advice. 

“It’s been a game-changer,” said Mr. Davids, cofounder of Long COVID Justice, an activist group. He has ME/CFS and several other chronic conditions, including long COVID. But, since he started taking LDN for long COVID, Mr. Davids said he has more energy and less pain. 

Technically, evidence is required to show off-label drug use could be effective in treating conditions for which the drug is not formally approved. Research suggests that 20%-30% of drugs are prescribed off-label.

No formal data exist on how widespread the use of off-label drugs for long COVID may be. But LDN is a major topic of discussion on public patient groups on Facebook. 

A recent study in The Lancet Infectious Diseases suggested that the diabetes drug metformin could be helpful. (The same study found no benefit from ivermectin, a drug since dismissed as a possible COVID treatment.)

Patients who testified at a virtual FDA hearing on drug development in April reported using vitamins, herbal supplements, over-the-counter medications and off-label drugs such as gabapentin and beta-blockers. Both of those drugs were on a list of potential treatments published in a January Nature Review article, along with LDN and Paxlovid.

Currently, Paxlovid is approved for acute COVID, and is in clinical trials as a treatment for long COVID as part of the federal government’s RECOVER Initiative. While only small studies of LDN have been conducted for long COVID, doctors are already prescribing the treatment. Mr. Davids said his primary care doctor recommended it.

Some doctors, such as Michael Peluso, MD, are comparing the trend to the early days of the AIDS epidemic, when the federal government was slow to recognize the viral disease. Patients banded together to protest and gain access to experimental treatments. 

Dr. Peluso, who treats long COVID patients at the University of California, San Francisco, said that without any approved treatment, patients are turning to one another to find out what works.

“A lot of people experiencing long COVID are looking for ways to feel better now, rather than waiting for the science or the guidelines to catch up,” he said in an interview.

In some cases, the drugs are backed by small studies, he said. 

“While we still need clinical trials to prove what will work, the drugs tested in these trials are also being informed by anecdotes shared by patients,” Dr. Peluso said.

Gail Van Norman, MD, of the University of Washington, Seattle, also said the long COVID situation today is reminiscent of the AIDS movement, which was “one of the times in history where we saw a real response to patient advocacy groups in terms of access to drugs.” Since then, the FDA has set up multiple programs to expand access to experimental drugs, added Dr. Van Norman, author of a recent study on off-label drug use.

But off-label use needs to be supervised by a physician, she and others said. Many patients get their information from social media, which Dr. Van Norman sees as a double-edged sword. Patients can share information, do their own research online, and alert practitioners to new findings, she said. But social media also promotes misinformation.

“People with no expertise have the same level of voice, and they are magnified,” Dr. Van Norman said.

The FDA requires doctors to have some evidence to support off-label use, she said. Doctors should talk to patients who want to try-off label drugs about what has been studied and what has not been studied.

“If I had [long COVID], I would be asking questions about all these drugs,” Dr. Van Norman said.

Mr. Davids has been asking questions like this for years. Diagnosed in 2019 with ME/CFS, he developed long COVID during the pandemic. Once he began started taking LDN, he started feeling better.

As someone with multiple chronic illnesses, Mr. Davids has tried a lot of treatments – he’s currently on two intravenous drugs and two compounded drugs, including LDN. But when his doctor first suggested it, he was wary. 

“I’ve worked with her to help increase the dosage slowly over time,” he said. “It’s very important for many people to start low and slow and work their way up.”

He hears stories of people who can’t get it from their physicians. Some, he said, think it may be because of the association of the drug with opioid abuse. 

Mr. Davids said long COVID patients have no other choice but to turn to alternative treatments. 
 

“I think we’ve been ill-served by our research establishment,” he said. “It is not set up for complex chronic conditions.”

Mr. Davids said he doesn’t know if LDN helps with underlying conditions or treats the symptoms – such as pain and fatigue – that keep him from doing things such as typing. 

“My understanding is that it may be doing both,” he said. “I sure am happy that it allows me to do things like keep my job.”

Dr. Azola and others said patients need to be monitored closely if they are taking an off-label drug. She recommends primary care doctors become familiar with them so they can offer patients some relief.

“It’s about the relationship between the patient and the provider and the provider being comfortable,” she said. “l was very transparent with my patients.”
 

A version of this article appeared on Medscape.com.

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

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

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

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

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

Dr. Nath

Persistent infection, viral reactivation

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

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

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

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

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

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

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

Research needs, treatment trials

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

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

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

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

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

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

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

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

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

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

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

Columbia University Irving Medical Center

Calls for a new NIH center and patient involvement

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

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

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

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

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

Real-world treatment needs

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

Claudia Paul

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

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

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

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

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

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

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

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

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

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

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

Dr. Nath

Persistent infection, viral reactivation

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

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

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

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

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

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

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

Research needs, treatment trials

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

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

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

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

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

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

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

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

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

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

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

Columbia University Irving Medical Center

Calls for a new NIH center and patient involvement

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

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

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

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

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

Real-world treatment needs

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

Claudia Paul

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

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

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

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

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

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

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

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

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

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

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

Dr. Nath

Persistent infection, viral reactivation

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

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

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

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

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

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

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

Research needs, treatment trials

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

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

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

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

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

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

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

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

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

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

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

Columbia University Irving Medical Center

Calls for a new NIH center and patient involvement

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

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

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

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

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

Real-world treatment needs

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

Claudia Paul

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

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

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

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

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

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

The COVID-19 vaccines have been a game changer for millions of people worldwide in preventing death or disability from the virus. Research suggests that they offer significant protection against long COVID.

Studies have consistently found that these vaccines prevent the new onset of long COVID as well as flare-ups for people who already have the condition.

False and unfounded claims made by some antivaccine groups that the vaccines themselves may cause long COVID persist and serve as barriers to vaccination.

To help separate the facts from falsehoods, here’s a checklist for doctors on what scientific studies have determined about vaccination and long COVID.
 

What the research shows

Doctors who work in long COVID clinics have for years suspected that vaccination may help protect against the development of long COVID, noted Lawrence Purpura, MD, MPH, an infectious disease specialist at New York–Presbyterian/Columbia University Irving Medical Center, who treats patients with long COVID in his clinic.

Over the past year, several large, well-conducted studies have borne out that theory, including the following studies:

• In the RECOVER study, published in May in the journal Nature Communications, researchers examined the electronic health records of more than 5 million people who had been diagnosed with COVID and found that vaccination reduced the risk that they would develop long COVID. Although the researchers didn’t compare the effects of having boosters to being fully vaccinated without them, experts have suggested that having a full round of recommended shots may offer the most protection. “My thoughts are that more shots are better, and other work has shown compelling evidence that the protective effect of vaccination on COVID-19 wanes over time,” said study coauthor Daniel Brannock, MS, a research scientist at RTI International in Research Triangle Park, N.C. “It stands to reason that the same is true for long COVID.”
• A review published in February in BMJ Medicine concluded that 10 studies showed a significant reduction in the incidence of long COVID among vaccinated patients. Even one dose of a vaccine was protective.
• A meta-analysis of six studies published last December in Antimicrobial Stewardship and Healthcare Epidemiology found that one or more doses of a COVID-19 vaccine were 29% effective in preventing symptoms of long COVID.
• In a June meta-analysis published in JAMA Internal Medicine, researchers analyzed more than 40 studies that included 860,000 patients and found that two doses of a COVID-19 vaccine reduced the risk of long COVID by almost half.

The message? COVID vaccination is very effective in reducing the risk of long COVID.

“It’s important to emphasize that many of the risk factors [for long COVID] cannot be changed, or at least cannot be changed easily, but vaccination is a decision that can be taken by everyone,” said Vassilios Vassiliou, MBBS, PhD, clinical professor of cardiac medicine at Norwich Medical School in England, who coauthored the article in JAMA Internal Medicine.
 

Why vaccines may be protective

The COVID-19 vaccines work well to prevent serious illness from the virus, noted Aaron Friedberg, MD, clinical coleader of the Post COVID Recovery Program at the Ohio State University Wexner Medical Center. That may be a clue to why the vaccines help prevent long COVID symptoms.

“When you get COVID and you’ve been vaccinated, the virus may still attach in your nose and respiratory tract, but it’s less likely to spread throughout your body,” he explained. “It’s like a forest fire – if the ground is wet or it starts to rain, it’s less likely to create a great blaze. As a result, your body is less likely to experience inflammation and damage that makes it more likely that you’ll develop long COVID.”

Dr. Friedberg stressed that even for patients who have had COVID, it’s important to get vaccinated – a message he consistently delivers to his own patients.

“There is some protection that comes from having COVID before, but for some people, that’s not enough,” he said. “It’s true that after infection, your body creates antibodies that help protect you against the virus. But I explain to patients that these may be like old Velcro: They barely grab on enough to stay on for the moment, but they don’t last long term. You’re much more likely to get a reliable immune response from the vaccine.”

In addition, a second or third bout of COVID could be the one that gives patients long COVID, Dr. Friedberg adds.

“I have a number of patients in my clinic who were fine after their first bout of COVID but experienced debilitating long COVID symptoms after they developed COVID again,” he said. “Why leave it to chance?”
 

Vaccines and ‘long vax’

The COVID vaccines are considered very safe but have been linked to very rare side effects, such as blood clots and heart inflammation. There have also been anecdotal reports of symptoms that resemble long COVID – a syndrome that has come to be known as “long Vax” – an extremely rare condition that may or may not be tied to vaccination.

“I have seen people in my clinic who developed symptoms suggestive of long COVID that linger for months – brain fog, fatigue, heart palpitations – soon after they got the COVID-19 vaccine,” said Dr. Purpura. But no published studies have suggested a link, he cautions.

A study called LISTEN is being organized at Yale in an effort to better understand postvaccine adverse events and a potential link to long COVID.
 

Talking to patients

Discussions of vaccination with patients, including those with COVID or long COVID, are often fraught and challenging, said Dr. Purpura.

“There’s a lot of fear that they will have a worsening of their symptoms,” he explained. The conversation he has with his patients mirrors the conversation all physicians should have with their patients about COVID-19 vaccination, even if they don’t have long COVID. He stresses the importance of highlighting the following components:

• Show compassion and empathy. “A lot of people have strongly held opinions – it’s worth it to try to find out why they feel the way that they do,” said Dr. Friedberg.
• Walk them through side effects. “Many people are afraid of the side effects of the vaccine, especially if they already have long COVID,” explained Dr. Purpura. Such patients can be asked how they felt after their last vaccination, such a shingles or flu shot. Then explain that the COVID-19 vaccine is not much different and that they may experience temporary side effects such as fatigue, headache, or a mild fever for 24-48 hours.
• Explain the benefits. Eighty-five percent of people say their health care provider is a trusted source of information on COVID-19 vaccines, according to the Kaiser Family Foundation. That trust is conducive to talks about the vaccine’s benefits, including its ability to protect against long COVID.

Other ways to reduce risk of long COVID

Vaccines can lower the chances of a patient’s developing long COVID. So can the antiviral medication nirmatrelvir (Paxlovid). A March 2023 study published in JAMA Internal Medicine included more than 280,000 people with COVID. The researchers found that vaccination reduced the risk for developing the condition by about 25%.

“I mention that study to all of my long COVID patients who become reinfected with the virus,” said Dr. Purpura. “It not only appears protective against long COVID, but since it lowers levels of virus circulating in their body, it seems to help prevent a flare-up of symptoms.”

Another treatment that may help is the diabetes drug metformin, he added.

A June 2023 study published in The Lancet Infectious Diseases found that when metformin was given within 3 days of symptom onset, the incidence of long COVID was reduced by about 41%.

“We’re still trying to wrap our brains around this one, but the thought is it may help to lower inflammation, which plays a role in long COVID,” Dr. Purpura explained. More studies need to be conducted, though, before recommending its use.

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

The COVID-19 vaccines have been a game changer for millions of people worldwide in preventing death or disability from the virus. Research suggests that they offer significant protection against long COVID.

Studies have consistently found that these vaccines prevent the new onset of long COVID as well as flare-ups for people who already have the condition.

False and unfounded claims made by some antivaccine groups that the vaccines themselves may cause long COVID persist and serve as barriers to vaccination.

To help separate the facts from falsehoods, here’s a checklist for doctors on what scientific studies have determined about vaccination and long COVID.
 

What the research shows

Doctors who work in long COVID clinics have for years suspected that vaccination may help protect against the development of long COVID, noted Lawrence Purpura, MD, MPH, an infectious disease specialist at New York–Presbyterian/Columbia University Irving Medical Center, who treats patients with long COVID in his clinic.

Over the past year, several large, well-conducted studies have borne out that theory, including the following studies:

• In the RECOVER study, published in May in the journal Nature Communications, researchers examined the electronic health records of more than 5 million people who had been diagnosed with COVID and found that vaccination reduced the risk that they would develop long COVID. Although the researchers didn’t compare the effects of having boosters to being fully vaccinated without them, experts have suggested that having a full round of recommended shots may offer the most protection. “My thoughts are that more shots are better, and other work has shown compelling evidence that the protective effect of vaccination on COVID-19 wanes over time,” said study coauthor Daniel Brannock, MS, a research scientist at RTI International in Research Triangle Park, N.C. “It stands to reason that the same is true for long COVID.”
• A review published in February in BMJ Medicine concluded that 10 studies showed a significant reduction in the incidence of long COVID among vaccinated patients. Even one dose of a vaccine was protective.
• A meta-analysis of six studies published last December in Antimicrobial Stewardship and Healthcare Epidemiology found that one or more doses of a COVID-19 vaccine were 29% effective in preventing symptoms of long COVID.
• In a June meta-analysis published in JAMA Internal Medicine, researchers analyzed more than 40 studies that included 860,000 patients and found that two doses of a COVID-19 vaccine reduced the risk of long COVID by almost half.

The message? COVID vaccination is very effective in reducing the risk of long COVID.

“It’s important to emphasize that many of the risk factors [for long COVID] cannot be changed, or at least cannot be changed easily, but vaccination is a decision that can be taken by everyone,” said Vassilios Vassiliou, MBBS, PhD, clinical professor of cardiac medicine at Norwich Medical School in England, who coauthored the article in JAMA Internal Medicine.
 

Why vaccines may be protective

The COVID-19 vaccines work well to prevent serious illness from the virus, noted Aaron Friedberg, MD, clinical coleader of the Post COVID Recovery Program at the Ohio State University Wexner Medical Center. That may be a clue to why the vaccines help prevent long COVID symptoms.

“When you get COVID and you’ve been vaccinated, the virus may still attach in your nose and respiratory tract, but it’s less likely to spread throughout your body,” he explained. “It’s like a forest fire – if the ground is wet or it starts to rain, it’s less likely to create a great blaze. As a result, your body is less likely to experience inflammation and damage that makes it more likely that you’ll develop long COVID.”

Dr. Friedberg stressed that even for patients who have had COVID, it’s important to get vaccinated – a message he consistently delivers to his own patients.

“There is some protection that comes from having COVID before, but for some people, that’s not enough,” he said. “It’s true that after infection, your body creates antibodies that help protect you against the virus. But I explain to patients that these may be like old Velcro: They barely grab on enough to stay on for the moment, but they don’t last long term. You’re much more likely to get a reliable immune response from the vaccine.”

In addition, a second or third bout of COVID could be the one that gives patients long COVID, Dr. Friedberg adds.

“I have a number of patients in my clinic who were fine after their first bout of COVID but experienced debilitating long COVID symptoms after they developed COVID again,” he said. “Why leave it to chance?”
 

Vaccines and ‘long vax’

The COVID vaccines are considered very safe but have been linked to very rare side effects, such as blood clots and heart inflammation. There have also been anecdotal reports of symptoms that resemble long COVID – a syndrome that has come to be known as “long Vax” – an extremely rare condition that may or may not be tied to vaccination.

“I have seen people in my clinic who developed symptoms suggestive of long COVID that linger for months – brain fog, fatigue, heart palpitations – soon after they got the COVID-19 vaccine,” said Dr. Purpura. But no published studies have suggested a link, he cautions.

A study called LISTEN is being organized at Yale in an effort to better understand postvaccine adverse events and a potential link to long COVID.
 

Talking to patients

Discussions of vaccination with patients, including those with COVID or long COVID, are often fraught and challenging, said Dr. Purpura.

“There’s a lot of fear that they will have a worsening of their symptoms,” he explained. The conversation he has with his patients mirrors the conversation all physicians should have with their patients about COVID-19 vaccination, even if they don’t have long COVID. He stresses the importance of highlighting the following components:

• Show compassion and empathy. “A lot of people have strongly held opinions – it’s worth it to try to find out why they feel the way that they do,” said Dr. Friedberg.
• Walk them through side effects. “Many people are afraid of the side effects of the vaccine, especially if they already have long COVID,” explained Dr. Purpura. Such patients can be asked how they felt after their last vaccination, such a shingles or flu shot. Then explain that the COVID-19 vaccine is not much different and that they may experience temporary side effects such as fatigue, headache, or a mild fever for 24-48 hours.
• Explain the benefits. Eighty-five percent of people say their health care provider is a trusted source of information on COVID-19 vaccines, according to the Kaiser Family Foundation. That trust is conducive to talks about the vaccine’s benefits, including its ability to protect against long COVID.

Other ways to reduce risk of long COVID

Vaccines can lower the chances of a patient’s developing long COVID. So can the antiviral medication nirmatrelvir (Paxlovid). A March 2023 study published in JAMA Internal Medicine included more than 280,000 people with COVID. The researchers found that vaccination reduced the risk for developing the condition by about 25%.

“I mention that study to all of my long COVID patients who become reinfected with the virus,” said Dr. Purpura. “It not only appears protective against long COVID, but since it lowers levels of virus circulating in their body, it seems to help prevent a flare-up of symptoms.”

Another treatment that may help is the diabetes drug metformin, he added.

A June 2023 study published in The Lancet Infectious Diseases found that when metformin was given within 3 days of symptom onset, the incidence of long COVID was reduced by about 41%.

“We’re still trying to wrap our brains around this one, but the thought is it may help to lower inflammation, which plays a role in long COVID,” Dr. Purpura explained. More studies need to be conducted, though, before recommending its use.

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

The COVID-19 vaccines have been a game changer for millions of people worldwide in preventing death or disability from the virus. Research suggests that they offer significant protection against long COVID.

Studies have consistently found that these vaccines prevent the new onset of long COVID as well as flare-ups for people who already have the condition.

False and unfounded claims made by some antivaccine groups that the vaccines themselves may cause long COVID persist and serve as barriers to vaccination.

To help separate the facts from falsehoods, here’s a checklist for doctors on what scientific studies have determined about vaccination and long COVID.
 

What the research shows

Doctors who work in long COVID clinics have for years suspected that vaccination may help protect against the development of long COVID, noted Lawrence Purpura, MD, MPH, an infectious disease specialist at New York–Presbyterian/Columbia University Irving Medical Center, who treats patients with long COVID in his clinic.

Over the past year, several large, well-conducted studies have borne out that theory, including the following studies:

• In the RECOVER study, published in May in the journal Nature Communications, researchers examined the electronic health records of more than 5 million people who had been diagnosed with COVID and found that vaccination reduced the risk that they would develop long COVID. Although the researchers didn’t compare the effects of having boosters to being fully vaccinated without them, experts have suggested that having a full round of recommended shots may offer the most protection. “My thoughts are that more shots are better, and other work has shown compelling evidence that the protective effect of vaccination on COVID-19 wanes over time,” said study coauthor Daniel Brannock, MS, a research scientist at RTI International in Research Triangle Park, N.C. “It stands to reason that the same is true for long COVID.”
• A review published in February in BMJ Medicine concluded that 10 studies showed a significant reduction in the incidence of long COVID among vaccinated patients. Even one dose of a vaccine was protective.
• A meta-analysis of six studies published last December in Antimicrobial Stewardship and Healthcare Epidemiology found that one or more doses of a COVID-19 vaccine were 29% effective in preventing symptoms of long COVID.
• In a June meta-analysis published in JAMA Internal Medicine, researchers analyzed more than 40 studies that included 860,000 patients and found that two doses of a COVID-19 vaccine reduced the risk of long COVID by almost half.

The message? COVID vaccination is very effective in reducing the risk of long COVID.

“It’s important to emphasize that many of the risk factors [for long COVID] cannot be changed, or at least cannot be changed easily, but vaccination is a decision that can be taken by everyone,” said Vassilios Vassiliou, MBBS, PhD, clinical professor of cardiac medicine at Norwich Medical School in England, who coauthored the article in JAMA Internal Medicine.
 

Why vaccines may be protective

The COVID-19 vaccines work well to prevent serious illness from the virus, noted Aaron Friedberg, MD, clinical coleader of the Post COVID Recovery Program at the Ohio State University Wexner Medical Center. That may be a clue to why the vaccines help prevent long COVID symptoms.

“When you get COVID and you’ve been vaccinated, the virus may still attach in your nose and respiratory tract, but it’s less likely to spread throughout your body,” he explained. “It’s like a forest fire – if the ground is wet or it starts to rain, it’s less likely to create a great blaze. As a result, your body is less likely to experience inflammation and damage that makes it more likely that you’ll develop long COVID.”

Dr. Friedberg stressed that even for patients who have had COVID, it’s important to get vaccinated – a message he consistently delivers to his own patients.

“There is some protection that comes from having COVID before, but for some people, that’s not enough,” he said. “It’s true that after infection, your body creates antibodies that help protect you against the virus. But I explain to patients that these may be like old Velcro: They barely grab on enough to stay on for the moment, but they don’t last long term. You’re much more likely to get a reliable immune response from the vaccine.”

In addition, a second or third bout of COVID could be the one that gives patients long COVID, Dr. Friedberg adds.

“I have a number of patients in my clinic who were fine after their first bout of COVID but experienced debilitating long COVID symptoms after they developed COVID again,” he said. “Why leave it to chance?”
 

Vaccines and ‘long vax’

The COVID vaccines are considered very safe but have been linked to very rare side effects, such as blood clots and heart inflammation. There have also been anecdotal reports of symptoms that resemble long COVID – a syndrome that has come to be known as “long Vax” – an extremely rare condition that may or may not be tied to vaccination.

“I have seen people in my clinic who developed symptoms suggestive of long COVID that linger for months – brain fog, fatigue, heart palpitations – soon after they got the COVID-19 vaccine,” said Dr. Purpura. But no published studies have suggested a link, he cautions.

A study called LISTEN is being organized at Yale in an effort to better understand postvaccine adverse events and a potential link to long COVID.
 

Talking to patients

Discussions of vaccination with patients, including those with COVID or long COVID, are often fraught and challenging, said Dr. Purpura.

“There’s a lot of fear that they will have a worsening of their symptoms,” he explained. The conversation he has with his patients mirrors the conversation all physicians should have with their patients about COVID-19 vaccination, even if they don’t have long COVID. He stresses the importance of highlighting the following components:

• Show compassion and empathy. “A lot of people have strongly held opinions – it’s worth it to try to find out why they feel the way that they do,” said Dr. Friedberg.
• Walk them through side effects. “Many people are afraid of the side effects of the vaccine, especially if they already have long COVID,” explained Dr. Purpura. Such patients can be asked how they felt after their last vaccination, such a shingles or flu shot. Then explain that the COVID-19 vaccine is not much different and that they may experience temporary side effects such as fatigue, headache, or a mild fever for 24-48 hours.
• Explain the benefits. Eighty-five percent of people say their health care provider is a trusted source of information on COVID-19 vaccines, according to the Kaiser Family Foundation. That trust is conducive to talks about the vaccine’s benefits, including its ability to protect against long COVID.

Other ways to reduce risk of long COVID

Vaccines can lower the chances of a patient’s developing long COVID. So can the antiviral medication nirmatrelvir (Paxlovid). A March 2023 study published in JAMA Internal Medicine included more than 280,000 people with COVID. The researchers found that vaccination reduced the risk for developing the condition by about 25%.

“I mention that study to all of my long COVID patients who become reinfected with the virus,” said Dr. Purpura. “It not only appears protective against long COVID, but since it lowers levels of virus circulating in their body, it seems to help prevent a flare-up of symptoms.”

Another treatment that may help is the diabetes drug metformin, he added.

A June 2023 study published in The Lancet Infectious Diseases found that when metformin was given within 3 days of symptom onset, the incidence of long COVID was reduced by about 41%.

“We’re still trying to wrap our brains around this one, but the thought is it may help to lower inflammation, which plays a role in long COVID,” Dr. Purpura explained. More studies need to be conducted, though, before recommending its use.

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

As millions of Americans face another year of long COVID, some are finding they are unable to return to work or cannot work as they did before they got sick and are turning to doctors for help with documenting their disability.

For those who can return to work, a doctor’s diagnosis of long COVID is key to gaining access to workplace accommodations, such as working flex hours or remotely. For those who cannot work, a note from the doctor is the first step to collecting disability payments.

With no definitive blood tests or scans for long COVID that could confirm a diagnosis, some say doctors may feel uncomfortable in this role, which puts them in a tough spot, said Wes Ely, MD, MPH, codirector of the critical illness, brain dysfunction and survivorship center at Vanderbilt University, Nashville, Tenn.

Doctors typically are not taught to deal with vagueness in diagnostics.

“Long COVID falls straight into the gray zone,” he said. There are no tests and a long list of common symptoms. “It makes a lot of doctors feel super insecure,” he said.

Now, patients and their advocates are calling for doctors to be more open-minded about how they assess those with long COVID and other chronic illnesses. Although their disability may not be visible, many with long COVID struggle to function. If they need help, they say, they need a doctor to confirm their limitations – test results or no test results.

Better documentation of patient-reported symptoms would go a long way, according to a perspective published in The New England Journal of Medicine.

“There’s a long history of people with disabilities being forced to ask doctors to legitimize their symptoms,” said study author Zackary Berger, MD, PhD, Johns Hopkins University, Baltimore, Md. Dr. Berger believes doctors should learn to listen more closely to patients, turn their narratives into patient notes, and use the new International Classification of Diseases 10 (ICD-10) code, a worldwide system for identifying and generating data on diseases, when they diagnose long COVID. He also thinks doctors should become advocates for their patients.

The Americans With Disabilities Act allows employers to request medical proof of disability, “and thereby assigns physicians the gate-keeping role of determining patients’ eligibility for reasonable accommodations,” according to the analysis. Those accommodations may mean a handicapped parking space or extra days working remotely.

Without a definitive diagnostic test, long COVID joins fibromyalgia and ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome), which lack biomarkers or imaging tests to support a diagnosis, they write.

“These diagnoses are therefore contentious, and government agencies, employers, and many physicians do not accept these conditions as real,” they write.

Physicians make a good faith effort in trying to understand long COVID, but both doctors and the courts like to see evidence, said Michael Ashley Stein, JD, PHD, director of the Harvard Law School Project on Disability. Dr. Stein and others say that doctors should listen closely to their patients’ descriptions of their symptoms.

“In the absence of agreed-upon biomarkers, doctors need to listen to their patients and look for other [indications] and other consistent evidence of conditions, and then work from there rather than dismiss the existence of these conditions,” he said.

Dr. Ely said he and others were taught in medical school that if it doesn’t come up on a diagnostic test, there’s no problem. “I am absolutely complicit,” he said. “I’m part of the community that did that for so many years.”

Dr. Ely agreed that the demand for clinical test results does not work for long COVID and chronic diseases such as ME/CFS. People come in with complaints and they get a typical medical workup with labs, he said, and the labs look normal on paper.

“And [the doctor is] thinking: ‘I don’t know what is wrong with this person and there’s nothing on paper I can treat. I don’t know if I even believe in long COVID.’ ”

At the same time, patients might need support from a doctor to get accommodations at work under the ADA, such as flexible hours. Or doctors’ notes may be required if a patient is trying to collect private disability insurance, workers compensation, or federal disability payments through Social Security.

The U.S. Centers for Disease Control and Prevention guidelines on diagnosing long COVID, updated last December, point out that normal laboratory or imaging findings do not rule out long COVID.

In addition, 12 key symptoms of long COVID were identified in May by scientists working with the RECOVER Initiative, the federal government’s long COVID research program. These symptoms include fatigue, brain fog, dizziness, gastrointestinal symptoms, loss of or change in smell or taste, chest pain, and abnormal movements.

Still, patients with long COVID seeking help also face the “disability con,” a term coined by the second author of the NEJM article, Doron Dorfman, a professor at Seton Hall Law School in Newark, N.J.

“Nowadays, when people think disability, they immediately think fraud,” he said.

Prof. Dorfman thinks the perception that many people are faking disabilities to gain an unfair advantage is the biggest barrier for anyone seeking help. The disability system is “preventing people who deserve legal rights from actually obtaining them,” he said.

He urged doctors to believe their patients. One way is to try to “translate the person’s narrative into medical language.”

His coauthor Dr. Berger did not agree with the argument that doctors cannot diagnose without tests.

“Any clinician knows that lab tests are not everything,” he said. “There are conditions that don’t have specific biomarkers that we diagnose all the time.” He cited acquired pneumonia and urinary tract infections as examples.

Benefits lawyers have taken note of the complexities for people with long COVID who seek help through the ADA and federal disability program.

One law firm noted: “The government safety net is not designed to help an emerging disease with no clear diagnosis or treatment plans. Insurance carriers are denying claims, and long-term disability benefits are being denied.”

About 16 million working-age Americans have long COVID, according to an update of a 2022 report by the Brookings Institute. Up to 4 million of these people are out of work because of the condition, the study found. The research is based on newly collected U.S. Census Bureau data that show 24% of those with long COVID report “significant activity limitations.”

Dr. Ely said he sees progress in this area. Many of these issues have come up at the committee convened by the National Academy of Science to look at the working definition of long COVID. NAS, a Washington research group, held a public meeting on their findings on June 22.
 

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

As millions of Americans face another year of long COVID, some are finding they are unable to return to work or cannot work as they did before they got sick and are turning to doctors for help with documenting their disability.

For those who can return to work, a doctor’s diagnosis of long COVID is key to gaining access to workplace accommodations, such as working flex hours or remotely. For those who cannot work, a note from the doctor is the first step to collecting disability payments.

With no definitive blood tests or scans for long COVID that could confirm a diagnosis, some say doctors may feel uncomfortable in this role, which puts them in a tough spot, said Wes Ely, MD, MPH, codirector of the critical illness, brain dysfunction and survivorship center at Vanderbilt University, Nashville, Tenn.

Doctors typically are not taught to deal with vagueness in diagnostics.

“Long COVID falls straight into the gray zone,” he said. There are no tests and a long list of common symptoms. “It makes a lot of doctors feel super insecure,” he said.

Now, patients and their advocates are calling for doctors to be more open-minded about how they assess those with long COVID and other chronic illnesses. Although their disability may not be visible, many with long COVID struggle to function. If they need help, they say, they need a doctor to confirm their limitations – test results or no test results.

Better documentation of patient-reported symptoms would go a long way, according to a perspective published in The New England Journal of Medicine.

“There’s a long history of people with disabilities being forced to ask doctors to legitimize their symptoms,” said study author Zackary Berger, MD, PhD, Johns Hopkins University, Baltimore, Md. Dr. Berger believes doctors should learn to listen more closely to patients, turn their narratives into patient notes, and use the new International Classification of Diseases 10 (ICD-10) code, a worldwide system for identifying and generating data on diseases, when they diagnose long COVID. He also thinks doctors should become advocates for their patients.

The Americans With Disabilities Act allows employers to request medical proof of disability, “and thereby assigns physicians the gate-keeping role of determining patients’ eligibility for reasonable accommodations,” according to the analysis. Those accommodations may mean a handicapped parking space or extra days working remotely.

Without a definitive diagnostic test, long COVID joins fibromyalgia and ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome), which lack biomarkers or imaging tests to support a diagnosis, they write.

“These diagnoses are therefore contentious, and government agencies, employers, and many physicians do not accept these conditions as real,” they write.

Physicians make a good faith effort in trying to understand long COVID, but both doctors and the courts like to see evidence, said Michael Ashley Stein, JD, PHD, director of the Harvard Law School Project on Disability. Dr. Stein and others say that doctors should listen closely to their patients’ descriptions of their symptoms.

“In the absence of agreed-upon biomarkers, doctors need to listen to their patients and look for other [indications] and other consistent evidence of conditions, and then work from there rather than dismiss the existence of these conditions,” he said.

Dr. Ely said he and others were taught in medical school that if it doesn’t come up on a diagnostic test, there’s no problem. “I am absolutely complicit,” he said. “I’m part of the community that did that for so many years.”

Dr. Ely agreed that the demand for clinical test results does not work for long COVID and chronic diseases such as ME/CFS. People come in with complaints and they get a typical medical workup with labs, he said, and the labs look normal on paper.

“And [the doctor is] thinking: ‘I don’t know what is wrong with this person and there’s nothing on paper I can treat. I don’t know if I even believe in long COVID.’ ”

At the same time, patients might need support from a doctor to get accommodations at work under the ADA, such as flexible hours. Or doctors’ notes may be required if a patient is trying to collect private disability insurance, workers compensation, or federal disability payments through Social Security.

The U.S. Centers for Disease Control and Prevention guidelines on diagnosing long COVID, updated last December, point out that normal laboratory or imaging findings do not rule out long COVID.

In addition, 12 key symptoms of long COVID were identified in May by scientists working with the RECOVER Initiative, the federal government’s long COVID research program. These symptoms include fatigue, brain fog, dizziness, gastrointestinal symptoms, loss of or change in smell or taste, chest pain, and abnormal movements.

Still, patients with long COVID seeking help also face the “disability con,” a term coined by the second author of the NEJM article, Doron Dorfman, a professor at Seton Hall Law School in Newark, N.J.

“Nowadays, when people think disability, they immediately think fraud,” he said.

Prof. Dorfman thinks the perception that many people are faking disabilities to gain an unfair advantage is the biggest barrier for anyone seeking help. The disability system is “preventing people who deserve legal rights from actually obtaining them,” he said.

He urged doctors to believe their patients. One way is to try to “translate the person’s narrative into medical language.”

His coauthor Dr. Berger did not agree with the argument that doctors cannot diagnose without tests.

“Any clinician knows that lab tests are not everything,” he said. “There are conditions that don’t have specific biomarkers that we diagnose all the time.” He cited acquired pneumonia and urinary tract infections as examples.

Benefits lawyers have taken note of the complexities for people with long COVID who seek help through the ADA and federal disability program.

One law firm noted: “The government safety net is not designed to help an emerging disease with no clear diagnosis or treatment plans. Insurance carriers are denying claims, and long-term disability benefits are being denied.”

About 16 million working-age Americans have long COVID, according to an update of a 2022 report by the Brookings Institute. Up to 4 million of these people are out of work because of the condition, the study found. The research is based on newly collected U.S. Census Bureau data that show 24% of those with long COVID report “significant activity limitations.”

Dr. Ely said he sees progress in this area. Many of these issues have come up at the committee convened by the National Academy of Science to look at the working definition of long COVID. NAS, a Washington research group, held a public meeting on their findings on June 22.
 

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

As millions of Americans face another year of long COVID, some are finding they are unable to return to work or cannot work as they did before they got sick and are turning to doctors for help with documenting their disability.

For those who can return to work, a doctor’s diagnosis of long COVID is key to gaining access to workplace accommodations, such as working flex hours or remotely. For those who cannot work, a note from the doctor is the first step to collecting disability payments.

With no definitive blood tests or scans for long COVID that could confirm a diagnosis, some say doctors may feel uncomfortable in this role, which puts them in a tough spot, said Wes Ely, MD, MPH, codirector of the critical illness, brain dysfunction and survivorship center at Vanderbilt University, Nashville, Tenn.

Doctors typically are not taught to deal with vagueness in diagnostics.

“Long COVID falls straight into the gray zone,” he said. There are no tests and a long list of common symptoms. “It makes a lot of doctors feel super insecure,” he said.

Now, patients and their advocates are calling for doctors to be more open-minded about how they assess those with long COVID and other chronic illnesses. Although their disability may not be visible, many with long COVID struggle to function. If they need help, they say, they need a doctor to confirm their limitations – test results or no test results.

Better documentation of patient-reported symptoms would go a long way, according to a perspective published in The New England Journal of Medicine.

“There’s a long history of people with disabilities being forced to ask doctors to legitimize their symptoms,” said study author Zackary Berger, MD, PhD, Johns Hopkins University, Baltimore, Md. Dr. Berger believes doctors should learn to listen more closely to patients, turn their narratives into patient notes, and use the new International Classification of Diseases 10 (ICD-10) code, a worldwide system for identifying and generating data on diseases, when they diagnose long COVID. He also thinks doctors should become advocates for their patients.

The Americans With Disabilities Act allows employers to request medical proof of disability, “and thereby assigns physicians the gate-keeping role of determining patients’ eligibility for reasonable accommodations,” according to the analysis. Those accommodations may mean a handicapped parking space or extra days working remotely.

Without a definitive diagnostic test, long COVID joins fibromyalgia and ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome), which lack biomarkers or imaging tests to support a diagnosis, they write.

“These diagnoses are therefore contentious, and government agencies, employers, and many physicians do not accept these conditions as real,” they write.

Physicians make a good faith effort in trying to understand long COVID, but both doctors and the courts like to see evidence, said Michael Ashley Stein, JD, PHD, director of the Harvard Law School Project on Disability. Dr. Stein and others say that doctors should listen closely to their patients’ descriptions of their symptoms.

“In the absence of agreed-upon biomarkers, doctors need to listen to their patients and look for other [indications] and other consistent evidence of conditions, and then work from there rather than dismiss the existence of these conditions,” he said.

Dr. Ely said he and others were taught in medical school that if it doesn’t come up on a diagnostic test, there’s no problem. “I am absolutely complicit,” he said. “I’m part of the community that did that for so many years.”

Dr. Ely agreed that the demand for clinical test results does not work for long COVID and chronic diseases such as ME/CFS. People come in with complaints and they get a typical medical workup with labs, he said, and the labs look normal on paper.

“And [the doctor is] thinking: ‘I don’t know what is wrong with this person and there’s nothing on paper I can treat. I don’t know if I even believe in long COVID.’ ”

At the same time, patients might need support from a doctor to get accommodations at work under the ADA, such as flexible hours. Or doctors’ notes may be required if a patient is trying to collect private disability insurance, workers compensation, or federal disability payments through Social Security.

The U.S. Centers for Disease Control and Prevention guidelines on diagnosing long COVID, updated last December, point out that normal laboratory or imaging findings do not rule out long COVID.

In addition, 12 key symptoms of long COVID were identified in May by scientists working with the RECOVER Initiative, the federal government’s long COVID research program. These symptoms include fatigue, brain fog, dizziness, gastrointestinal symptoms, loss of or change in smell or taste, chest pain, and abnormal movements.

Still, patients with long COVID seeking help also face the “disability con,” a term coined by the second author of the NEJM article, Doron Dorfman, a professor at Seton Hall Law School in Newark, N.J.

“Nowadays, when people think disability, they immediately think fraud,” he said.

Prof. Dorfman thinks the perception that many people are faking disabilities to gain an unfair advantage is the biggest barrier for anyone seeking help. The disability system is “preventing people who deserve legal rights from actually obtaining them,” he said.

He urged doctors to believe their patients. One way is to try to “translate the person’s narrative into medical language.”

His coauthor Dr. Berger did not agree with the argument that doctors cannot diagnose without tests.

“Any clinician knows that lab tests are not everything,” he said. “There are conditions that don’t have specific biomarkers that we diagnose all the time.” He cited acquired pneumonia and urinary tract infections as examples.

Benefits lawyers have taken note of the complexities for people with long COVID who seek help through the ADA and federal disability program.

One law firm noted: “The government safety net is not designed to help an emerging disease with no clear diagnosis or treatment plans. Insurance carriers are denying claims, and long-term disability benefits are being denied.”

About 16 million working-age Americans have long COVID, according to an update of a 2022 report by the Brookings Institute. Up to 4 million of these people are out of work because of the condition, the study found. The research is based on newly collected U.S. Census Bureau data that show 24% of those with long COVID report “significant activity limitations.”

Dr. Ely said he sees progress in this area. Many of these issues have come up at the committee convened by the National Academy of Science to look at the working definition of long COVID. NAS, a Washington research group, held a public meeting on their findings on June 22.
 

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

Kate Whitley was petrified of COVID-19 from the beginning of the pandemic because she has Hashimoto disease, an autoimmune disorder that she knew put her at high risk for complications.

She was right to be worried. Two months after contracting the infection in September 2022, the 42-year-old Nashville resident was diagnosed with long COVID. For Ms. Whitley, the resulting brain fog has been the most challenging factor. She is the owner of a successful paper goods store, and she can’t remember basic aspects of her job. She can’t tolerate loud noises and gets so distracted that she has trouble remembering what she was doing.

Ms. Whitley doesn’t like the term “brain fog” because it doesn’t begin to describe the dramatic disruption to her life over the past 7 months.

“I just can’t think anymore,” she said. “It makes you realize that you’re nothing without your brain. Sometimes I feel like a shell of my former self.”

Brain fog is among the most common symptoms of long COVID, and also one of the most poorly understood. A reported 46% of those diagnosed with long COVID complain of brain fog or a loss of memory. Many clinicians agree that the term is vague and often doesn’t truly represent the condition. That, in turn, makes it harder for doctors to diagnose and treat it. There are no standard tests for it, nor are there guidelines for symptom management or treatment.

“There’s a lot of imprecision in the term because it might mean different things to different patients,” said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University, Nashville, Tenn., and author of a new book, “Clearing the Fog: From Surviving to Thriving With Long COVID – A Practical Guide.”

Dr. Jackson, who began treating Ms. Whitley in February 2023, said that it makes more sense to call brain fog a brain impairment or an acquired brain injury (ABI) because it doesn’t occur gradually. COVID damages the brain and causes injury. For those with long COVID who were previously in the intensive care unit and may have undergone ventilation, hypoxic brain injury may result from the lack of oxygen to the brain.

Even among those with milder cases of acute COVID, there’s some evidence that persistent neuroinflammation in the brain caused by an activated immune system may also cause damage.

In both cases, the results can be debilitating. Ms. Whitley also has dysautonomia – a disorder of the autonomic nervous system that can cause dizziness, sweating, and headaches along with fatigue and heart palpitations.

She said that she’s so forgetful that when she sees people socially, she’s nervous of what she’ll say. “I feel like I’m constantly sticking my foot in my mouth because I can’t remember details of other people’s lives,” she said.

Although brain disorders such as Alzheimer’s disease and other forms of dementia are marked by a slow decline, ABI occurs more suddenly and may include a loss of executive function and attention.

“With a brain injury, you’re doing fine, and then some event happens (in this case COVID), and immediately after that, your cognitive function is different,” said Dr. Jackson.

Additionally, ABI is an actual diagnosis, whereas brain fog is not.

“With a brain injury, there’s a treatment pathway for cognitive rehabilitation,” said Dr. Jackson.

Treatments may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for treatment of the mental and behavioral disorders that may result. Dr. Jackson said that while many patients aren’t functioning cognitively or physically at 100%, they can make enough strides that they don’t have to give up things such as driving and, in some cases, their jobs.

Other experts agree that long COVID may damage the brain. An April 2022 study published in the journal Nature found strong evidence that SARS-CoV-2 infection may cause brain-related abnormalities, for example, a reduction in gray matter in certain parts of the brain, including the prefrontal cortex, hypothalamus, and amygdala.

Additionally, white matter, which is found deeper in the brain and is responsible for the exchange of information between different parts of the brain, may also be at risk of damage as a result of the virus, according to a November 2022 study published in the journal SN Comprehensive Clinical Medicine.

Calling it a “fog” makes it easier for clinicians and the general public to dismiss its severity, said Tyler Reed Bell, PhD, a researcher who specializes in viruses that cause brain injury. He is a fellow in the department of psychiatry at the University of California, San Diego. Brain fog can make driving and returning to work especially dangerous. Because of difficulty focusing, patients are much more likely to make mistakes that cause accidents.

“The COVID virus is very invasive to the brain,” Dr. Bell said.

Others contend this may be a rush to judgment. Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina at Chapel Hill’s COVID Recovery Clinic, agrees that in more serious cases of COVID that cause a lack of oxygen to the brain, it’s reasonable to call it a brain injury. But brain fog can also be associated with other long COVID symptoms, not just damage to the brain.

Chronic fatigue and poor sleep are both commonly reported symptoms of long COVID that negatively affect brain function, she said. Sleep disturbances, cardiac problems, dysautonomia, and emotional distress could also affect the way the brain functions post COVID. Finding the right treatment requires identifying all the factors contributing to cognitive impairment.

Part of the problem in treating long COVID brain fog is that diagnostic technology is not sensitive enough to detect inflammation that could be causing damage.

Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, said her team is working on identifying biomarkers that could detect brain inflammation in a way similar to the manner researchers have identified biomarkers to help diagnose chronic fatigue syndrome. Additionally, a new study published last month in JAMA for the first time clearly defined 12 symptoms of long COVID, and brain fog was listed among them. All of this contributes to the development of clear diagnostic criteria.

“It will make a big difference once we have some consistency among clinicians in diagnosing the condition,” said Dr. McComsey.

Ms. Whitley is thankful for the treatment that she’s received thus far. She’s seeing a cognitive rehabilitation therapist, who assesses her memory, cognition, and attention span and gives her tools to break up simple tasks, such as driving, so that they don’t feel overwhelming. She’s back behind the wheel and back to work.

But perhaps most importantly, Ms. Whitley joined a support group, led by Dr. Jackson, that includes other people experiencing the same symptoms she is. When she was at her darkest, they understood.

“Talking to other survivors has been the only solace in all this,” Ms. Whitley said. “Together, we grieve all that’s been lost.”

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

Kate Whitley was petrified of COVID-19 from the beginning of the pandemic because she has Hashimoto disease, an autoimmune disorder that she knew put her at high risk for complications.

She was right to be worried. Two months after contracting the infection in September 2022, the 42-year-old Nashville resident was diagnosed with long COVID. For Ms. Whitley, the resulting brain fog has been the most challenging factor. She is the owner of a successful paper goods store, and she can’t remember basic aspects of her job. She can’t tolerate loud noises and gets so distracted that she has trouble remembering what she was doing.

Ms. Whitley doesn’t like the term “brain fog” because it doesn’t begin to describe the dramatic disruption to her life over the past 7 months.

“I just can’t think anymore,” she said. “It makes you realize that you’re nothing without your brain. Sometimes I feel like a shell of my former self.”

Brain fog is among the most common symptoms of long COVID, and also one of the most poorly understood. A reported 46% of those diagnosed with long COVID complain of brain fog or a loss of memory. Many clinicians agree that the term is vague and often doesn’t truly represent the condition. That, in turn, makes it harder for doctors to diagnose and treat it. There are no standard tests for it, nor are there guidelines for symptom management or treatment.

“There’s a lot of imprecision in the term because it might mean different things to different patients,” said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University, Nashville, Tenn., and author of a new book, “Clearing the Fog: From Surviving to Thriving With Long COVID – A Practical Guide.”

Dr. Jackson, who began treating Ms. Whitley in February 2023, said that it makes more sense to call brain fog a brain impairment or an acquired brain injury (ABI) because it doesn’t occur gradually. COVID damages the brain and causes injury. For those with long COVID who were previously in the intensive care unit and may have undergone ventilation, hypoxic brain injury may result from the lack of oxygen to the brain.

Even among those with milder cases of acute COVID, there’s some evidence that persistent neuroinflammation in the brain caused by an activated immune system may also cause damage.

In both cases, the results can be debilitating. Ms. Whitley also has dysautonomia – a disorder of the autonomic nervous system that can cause dizziness, sweating, and headaches along with fatigue and heart palpitations.

She said that she’s so forgetful that when she sees people socially, she’s nervous of what she’ll say. “I feel like I’m constantly sticking my foot in my mouth because I can’t remember details of other people’s lives,” she said.

Although brain disorders such as Alzheimer’s disease and other forms of dementia are marked by a slow decline, ABI occurs more suddenly and may include a loss of executive function and attention.

“With a brain injury, you’re doing fine, and then some event happens (in this case COVID), and immediately after that, your cognitive function is different,” said Dr. Jackson.

Additionally, ABI is an actual diagnosis, whereas brain fog is not.

“With a brain injury, there’s a treatment pathway for cognitive rehabilitation,” said Dr. Jackson.

Treatments may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for treatment of the mental and behavioral disorders that may result. Dr. Jackson said that while many patients aren’t functioning cognitively or physically at 100%, they can make enough strides that they don’t have to give up things such as driving and, in some cases, their jobs.

Other experts agree that long COVID may damage the brain. An April 2022 study published in the journal Nature found strong evidence that SARS-CoV-2 infection may cause brain-related abnormalities, for example, a reduction in gray matter in certain parts of the brain, including the prefrontal cortex, hypothalamus, and amygdala.

Additionally, white matter, which is found deeper in the brain and is responsible for the exchange of information between different parts of the brain, may also be at risk of damage as a result of the virus, according to a November 2022 study published in the journal SN Comprehensive Clinical Medicine.

Calling it a “fog” makes it easier for clinicians and the general public to dismiss its severity, said Tyler Reed Bell, PhD, a researcher who specializes in viruses that cause brain injury. He is a fellow in the department of psychiatry at the University of California, San Diego. Brain fog can make driving and returning to work especially dangerous. Because of difficulty focusing, patients are much more likely to make mistakes that cause accidents.

“The COVID virus is very invasive to the brain,” Dr. Bell said.

Others contend this may be a rush to judgment. Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina at Chapel Hill’s COVID Recovery Clinic, agrees that in more serious cases of COVID that cause a lack of oxygen to the brain, it’s reasonable to call it a brain injury. But brain fog can also be associated with other long COVID symptoms, not just damage to the brain.

Chronic fatigue and poor sleep are both commonly reported symptoms of long COVID that negatively affect brain function, she said. Sleep disturbances, cardiac problems, dysautonomia, and emotional distress could also affect the way the brain functions post COVID. Finding the right treatment requires identifying all the factors contributing to cognitive impairment.

Part of the problem in treating long COVID brain fog is that diagnostic technology is not sensitive enough to detect inflammation that could be causing damage.

Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, said her team is working on identifying biomarkers that could detect brain inflammation in a way similar to the manner researchers have identified biomarkers to help diagnose chronic fatigue syndrome. Additionally, a new study published last month in JAMA for the first time clearly defined 12 symptoms of long COVID, and brain fog was listed among them. All of this contributes to the development of clear diagnostic criteria.

“It will make a big difference once we have some consistency among clinicians in diagnosing the condition,” said Dr. McComsey.

Ms. Whitley is thankful for the treatment that she’s received thus far. She’s seeing a cognitive rehabilitation therapist, who assesses her memory, cognition, and attention span and gives her tools to break up simple tasks, such as driving, so that they don’t feel overwhelming. She’s back behind the wheel and back to work.

But perhaps most importantly, Ms. Whitley joined a support group, led by Dr. Jackson, that includes other people experiencing the same symptoms she is. When she was at her darkest, they understood.

“Talking to other survivors has been the only solace in all this,” Ms. Whitley said. “Together, we grieve all that’s been lost.”

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

Kate Whitley was petrified of COVID-19 from the beginning of the pandemic because she has Hashimoto disease, an autoimmune disorder that she knew put her at high risk for complications.

She was right to be worried. Two months after contracting the infection in September 2022, the 42-year-old Nashville resident was diagnosed with long COVID. For Ms. Whitley, the resulting brain fog has been the most challenging factor. She is the owner of a successful paper goods store, and she can’t remember basic aspects of her job. She can’t tolerate loud noises and gets so distracted that she has trouble remembering what she was doing.

Ms. Whitley doesn’t like the term “brain fog” because it doesn’t begin to describe the dramatic disruption to her life over the past 7 months.

“I just can’t think anymore,” she said. “It makes you realize that you’re nothing without your brain. Sometimes I feel like a shell of my former self.”

Brain fog is among the most common symptoms of long COVID, and also one of the most poorly understood. A reported 46% of those diagnosed with long COVID complain of brain fog or a loss of memory. Many clinicians agree that the term is vague and often doesn’t truly represent the condition. That, in turn, makes it harder for doctors to diagnose and treat it. There are no standard tests for it, nor are there guidelines for symptom management or treatment.

“There’s a lot of imprecision in the term because it might mean different things to different patients,” said James C. Jackson, PsyD, a neuropsychiatrist at Vanderbilt University, Nashville, Tenn., and author of a new book, “Clearing the Fog: From Surviving to Thriving With Long COVID – A Practical Guide.”

Dr. Jackson, who began treating Ms. Whitley in February 2023, said that it makes more sense to call brain fog a brain impairment or an acquired brain injury (ABI) because it doesn’t occur gradually. COVID damages the brain and causes injury. For those with long COVID who were previously in the intensive care unit and may have undergone ventilation, hypoxic brain injury may result from the lack of oxygen to the brain.

Even among those with milder cases of acute COVID, there’s some evidence that persistent neuroinflammation in the brain caused by an activated immune system may also cause damage.

In both cases, the results can be debilitating. Ms. Whitley also has dysautonomia – a disorder of the autonomic nervous system that can cause dizziness, sweating, and headaches along with fatigue and heart palpitations.

She said that she’s so forgetful that when she sees people socially, she’s nervous of what she’ll say. “I feel like I’m constantly sticking my foot in my mouth because I can’t remember details of other people’s lives,” she said.

Although brain disorders such as Alzheimer’s disease and other forms of dementia are marked by a slow decline, ABI occurs more suddenly and may include a loss of executive function and attention.

“With a brain injury, you’re doing fine, and then some event happens (in this case COVID), and immediately after that, your cognitive function is different,” said Dr. Jackson.

Additionally, ABI is an actual diagnosis, whereas brain fog is not.

“With a brain injury, there’s a treatment pathway for cognitive rehabilitation,” said Dr. Jackson.

Treatments may include speech, cognitive, and occupational therapy as well as meeting with a neuropsychiatrist for treatment of the mental and behavioral disorders that may result. Dr. Jackson said that while many patients aren’t functioning cognitively or physically at 100%, they can make enough strides that they don’t have to give up things such as driving and, in some cases, their jobs.

Other experts agree that long COVID may damage the brain. An April 2022 study published in the journal Nature found strong evidence that SARS-CoV-2 infection may cause brain-related abnormalities, for example, a reduction in gray matter in certain parts of the brain, including the prefrontal cortex, hypothalamus, and amygdala.

Additionally, white matter, which is found deeper in the brain and is responsible for the exchange of information between different parts of the brain, may also be at risk of damage as a result of the virus, according to a November 2022 study published in the journal SN Comprehensive Clinical Medicine.

Calling it a “fog” makes it easier for clinicians and the general public to dismiss its severity, said Tyler Reed Bell, PhD, a researcher who specializes in viruses that cause brain injury. He is a fellow in the department of psychiatry at the University of California, San Diego. Brain fog can make driving and returning to work especially dangerous. Because of difficulty focusing, patients are much more likely to make mistakes that cause accidents.

“The COVID virus is very invasive to the brain,” Dr. Bell said.

Others contend this may be a rush to judgment. Karla L. Thompson, PhD, lead neuropsychologist at the University of North Carolina at Chapel Hill’s COVID Recovery Clinic, agrees that in more serious cases of COVID that cause a lack of oxygen to the brain, it’s reasonable to call it a brain injury. But brain fog can also be associated with other long COVID symptoms, not just damage to the brain.

Chronic fatigue and poor sleep are both commonly reported symptoms of long COVID that negatively affect brain function, she said. Sleep disturbances, cardiac problems, dysautonomia, and emotional distress could also affect the way the brain functions post COVID. Finding the right treatment requires identifying all the factors contributing to cognitive impairment.

Part of the problem in treating long COVID brain fog is that diagnostic technology is not sensitive enough to detect inflammation that could be causing damage.

Grace McComsey, MD, who leads the long COVID RECOVER study at University Hospitals Health System in Cleveland, said her team is working on identifying biomarkers that could detect brain inflammation in a way similar to the manner researchers have identified biomarkers to help diagnose chronic fatigue syndrome. Additionally, a new study published last month in JAMA for the first time clearly defined 12 symptoms of long COVID, and brain fog was listed among them. All of this contributes to the development of clear diagnostic criteria.

“It will make a big difference once we have some consistency among clinicians in diagnosing the condition,” said Dr. McComsey.

Ms. Whitley is thankful for the treatment that she’s received thus far. She’s seeing a cognitive rehabilitation therapist, who assesses her memory, cognition, and attention span and gives her tools to break up simple tasks, such as driving, so that they don’t feel overwhelming. She’s back behind the wheel and back to work.

But perhaps most importantly, Ms. Whitley joined a support group, led by Dr. Jackson, that includes other people experiencing the same symptoms she is. When she was at her darkest, they understood.

“Talking to other survivors has been the only solace in all this,” Ms. Whitley said. “Together, we grieve all that’s been lost.”

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

Posthospitalization risks associated with COVID-19 are similar to those associated with other infectious diseases, new research finds.
 

A large observational study examined population-wide data for 13 postacute conditions in patients who had been hospitalized with a COVID-19 infection and found that all but one of these conditions, venous thromboembolism, occurred at comparable rates in those hospitalized for sepsis and influenza.

“For us, the main takeaway was that patients hospitalized for severe illness in general really require ongoing treatment and support after they’re discharged. That type of care is often very challenging to coordinate for people in a sometimes siloed and fragmented health care system,” study author Kieran Quinn, MD, PhD, a clinician at Sinai Health in Toronto, and assistant professor at the University of Toronto, said in an interview.

The study was published in JAMA Internal Medicine.
 

Postacute effects

The investigators compared clinical and health administrative data from 26,499 Ontarians hospitalized with COVID-19 with data from three additional cohorts who had been hospitalized with influenza (17,516 patients) and sepsis. The sepsis cohort was divided into two groups, those hospitalized during the COVID-19 pandemic (52,878 patients) and a historical control population (282,473 patients).

These comparators allowed the researchers to compare COVID-19 with other severe infectious illnesses and control for any changes in health care delivery that may have occurred during the pandemic. The addition of sepsis cohorts was needed for the latter purpose, since influenza rates dropped significantly after the onset of the pandemic.

The study outcomes (including cardiovascular, neurological, and mental health conditions and rheumatoid arthritis) were selected based on previous associations with COVID-19 infections, as well as their availability in the data, according to Dr. Quinn. The investigators used diagnostic codes recorded in Ontario’s Institute for Clinical Evaluative Sciences database. The investigators observed some of the studied conditions in their own patients. “Many of us on the research team are practicing clinicians who care for people living with long COVID,” said Dr. Quinn.

Compared with cohorts with other serious infections, those hospitalized with COVID-19 were not at increased risk for selected cardiovascular or neurological disorders, rheumatoid arthritis, or mental health conditions within 1 year following hospitalization. Incident venous thromboembolic disease, however, was more common after hospitalization for COVID-19 than after hospitalization for influenza (adjusted hazard ratio, 1.77).

The study results corroborate previous findings that influenza and sepsis can have serious long-term health effects, such as heart failure, dementia, and depression, and found that the same was true for COVID-19 infections. For all three infections, patients at high risk require additional support after their initial discharge.
 

Defining long COVID

Although there was no increased risk with COVID-19 for most conditions, these results do not mean that the postacute effects of the infection, often called “long COVID,” are not significant, Dr. Quinn emphasized. The researcher believes that it’s important to listen to the many patients reporting symptoms and validate their experiences.

There needs to be greater consensus among the global health community on what constitutes long COVID. While the research led by Dr. Quinn focuses on postacute health conditions, some definitions of long COVID, such as that of the World Health Organization, refer only to ongoing symptoms of the original infection.

While there is now a diagnostic code for treating long COVID in Ontario, the data available to the researchers did not include information on some common symptoms of post-COVID condition, like chronic fatigue. In the data used, there was not an accurate way to identify patients who had developed conditions like myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome, said Dr. Quinn.

In addition to creating clear definitions and determining the best treatments, prevention is essential, said Dr. Quinn. Prior studies have shown that vaccination helps prevent ICU admission for COVID-19.
 

‘Important questions remain’

Commenting on the finding, Aravind Ganesh, MD, DPhil, a neurologist at the University of Calgary (Alta.), said that by including control populations, the study addressed an important limitation of previous research. Dr. Ganesh, who was not involved in the study, said that the controls help to determine the cause of associations found in other studies, including his own research on long-term symptoms following outpatient care for COVID-19.

“I think what this tells us is that maybe a lot of the issues that we’ve been seeing as complications attributable to COVID are, in fact, complications attributable to serious illness,” said Dr. Ganesh. He also found the association with venous thromboembolism interesting because the condition is recognized as a key risk factor for COVID-19 outcomes.

Compared with smaller randomized control trials, the population-level data provided a much larger sample size for the study. However, this design comes with limitations as well, Dr. Ganesh noted. The study relies on the administrative data of diagnostic codes and misses symptoms that aren’t associated with a diagnosis. In addition, because the cohorts were not assigned randomly, it may not account for preexisting risk factors.

While the study demonstrates associations with physical and mental health conditions, the cause of postacute effects from COVID-19, influenza, and sepsis is still unclear. “Important questions remain,” said Dr. Ganesh. “Why is it that these patients are experiencing these symptoms?”

The study was supported by ICES and the Canadian Institutes of Health Research. Dr. Quinn reported part-time employment at Public Health Ontario and stock in Pfizer and BioNTech. Dr. Ganesh reported no relevant financial relationships.

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

Posthospitalization risks associated with COVID-19 are similar to those associated with other infectious diseases, new research finds.
 

A large observational study examined population-wide data for 13 postacute conditions in patients who had been hospitalized with a COVID-19 infection and found that all but one of these conditions, venous thromboembolism, occurred at comparable rates in those hospitalized for sepsis and influenza.

“For us, the main takeaway was that patients hospitalized for severe illness in general really require ongoing treatment and support after they’re discharged. That type of care is often very challenging to coordinate for people in a sometimes siloed and fragmented health care system,” study author Kieran Quinn, MD, PhD, a clinician at Sinai Health in Toronto, and assistant professor at the University of Toronto, said in an interview.

The study was published in JAMA Internal Medicine.
 

Postacute effects

The investigators compared clinical and health administrative data from 26,499 Ontarians hospitalized with COVID-19 with data from three additional cohorts who had been hospitalized with influenza (17,516 patients) and sepsis. The sepsis cohort was divided into two groups, those hospitalized during the COVID-19 pandemic (52,878 patients) and a historical control population (282,473 patients).

These comparators allowed the researchers to compare COVID-19 with other severe infectious illnesses and control for any changes in health care delivery that may have occurred during the pandemic. The addition of sepsis cohorts was needed for the latter purpose, since influenza rates dropped significantly after the onset of the pandemic.

The study outcomes (including cardiovascular, neurological, and mental health conditions and rheumatoid arthritis) were selected based on previous associations with COVID-19 infections, as well as their availability in the data, according to Dr. Quinn. The investigators used diagnostic codes recorded in Ontario’s Institute for Clinical Evaluative Sciences database. The investigators observed some of the studied conditions in their own patients. “Many of us on the research team are practicing clinicians who care for people living with long COVID,” said Dr. Quinn.

Compared with cohorts with other serious infections, those hospitalized with COVID-19 were not at increased risk for selected cardiovascular or neurological disorders, rheumatoid arthritis, or mental health conditions within 1 year following hospitalization. Incident venous thromboembolic disease, however, was more common after hospitalization for COVID-19 than after hospitalization for influenza (adjusted hazard ratio, 1.77).

The study results corroborate previous findings that influenza and sepsis can have serious long-term health effects, such as heart failure, dementia, and depression, and found that the same was true for COVID-19 infections. For all three infections, patients at high risk require additional support after their initial discharge.
 

Defining long COVID

Although there was no increased risk with COVID-19 for most conditions, these results do not mean that the postacute effects of the infection, often called “long COVID,” are not significant, Dr. Quinn emphasized. The researcher believes that it’s important to listen to the many patients reporting symptoms and validate their experiences.

There needs to be greater consensus among the global health community on what constitutes long COVID. While the research led by Dr. Quinn focuses on postacute health conditions, some definitions of long COVID, such as that of the World Health Organization, refer only to ongoing symptoms of the original infection.

While there is now a diagnostic code for treating long COVID in Ontario, the data available to the researchers did not include information on some common symptoms of post-COVID condition, like chronic fatigue. In the data used, there was not an accurate way to identify patients who had developed conditions like myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome, said Dr. Quinn.

In addition to creating clear definitions and determining the best treatments, prevention is essential, said Dr. Quinn. Prior studies have shown that vaccination helps prevent ICU admission for COVID-19.
 

‘Important questions remain’

Commenting on the finding, Aravind Ganesh, MD, DPhil, a neurologist at the University of Calgary (Alta.), said that by including control populations, the study addressed an important limitation of previous research. Dr. Ganesh, who was not involved in the study, said that the controls help to determine the cause of associations found in other studies, including his own research on long-term symptoms following outpatient care for COVID-19.

“I think what this tells us is that maybe a lot of the issues that we’ve been seeing as complications attributable to COVID are, in fact, complications attributable to serious illness,” said Dr. Ganesh. He also found the association with venous thromboembolism interesting because the condition is recognized as a key risk factor for COVID-19 outcomes.

Compared with smaller randomized control trials, the population-level data provided a much larger sample size for the study. However, this design comes with limitations as well, Dr. Ganesh noted. The study relies on the administrative data of diagnostic codes and misses symptoms that aren’t associated with a diagnosis. In addition, because the cohorts were not assigned randomly, it may not account for preexisting risk factors.

While the study demonstrates associations with physical and mental health conditions, the cause of postacute effects from COVID-19, influenza, and sepsis is still unclear. “Important questions remain,” said Dr. Ganesh. “Why is it that these patients are experiencing these symptoms?”

The study was supported by ICES and the Canadian Institutes of Health Research. Dr. Quinn reported part-time employment at Public Health Ontario and stock in Pfizer and BioNTech. Dr. Ganesh reported no relevant financial relationships.

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

Posthospitalization risks associated with COVID-19 are similar to those associated with other infectious diseases, new research finds.
 

A large observational study examined population-wide data for 13 postacute conditions in patients who had been hospitalized with a COVID-19 infection and found that all but one of these conditions, venous thromboembolism, occurred at comparable rates in those hospitalized for sepsis and influenza.

“For us, the main takeaway was that patients hospitalized for severe illness in general really require ongoing treatment and support after they’re discharged. That type of care is often very challenging to coordinate for people in a sometimes siloed and fragmented health care system,” study author Kieran Quinn, MD, PhD, a clinician at Sinai Health in Toronto, and assistant professor at the University of Toronto, said in an interview.

The study was published in JAMA Internal Medicine.
 

Postacute effects

The investigators compared clinical and health administrative data from 26,499 Ontarians hospitalized with COVID-19 with data from three additional cohorts who had been hospitalized with influenza (17,516 patients) and sepsis. The sepsis cohort was divided into two groups, those hospitalized during the COVID-19 pandemic (52,878 patients) and a historical control population (282,473 patients).

These comparators allowed the researchers to compare COVID-19 with other severe infectious illnesses and control for any changes in health care delivery that may have occurred during the pandemic. The addition of sepsis cohorts was needed for the latter purpose, since influenza rates dropped significantly after the onset of the pandemic.

The study outcomes (including cardiovascular, neurological, and mental health conditions and rheumatoid arthritis) were selected based on previous associations with COVID-19 infections, as well as their availability in the data, according to Dr. Quinn. The investigators used diagnostic codes recorded in Ontario’s Institute for Clinical Evaluative Sciences database. The investigators observed some of the studied conditions in their own patients. “Many of us on the research team are practicing clinicians who care for people living with long COVID,” said Dr. Quinn.

Compared with cohorts with other serious infections, those hospitalized with COVID-19 were not at increased risk for selected cardiovascular or neurological disorders, rheumatoid arthritis, or mental health conditions within 1 year following hospitalization. Incident venous thromboembolic disease, however, was more common after hospitalization for COVID-19 than after hospitalization for influenza (adjusted hazard ratio, 1.77).

The study results corroborate previous findings that influenza and sepsis can have serious long-term health effects, such as heart failure, dementia, and depression, and found that the same was true for COVID-19 infections. For all three infections, patients at high risk require additional support after their initial discharge.
 

Defining long COVID

Although there was no increased risk with COVID-19 for most conditions, these results do not mean that the postacute effects of the infection, often called “long COVID,” are not significant, Dr. Quinn emphasized. The researcher believes that it’s important to listen to the many patients reporting symptoms and validate their experiences.

There needs to be greater consensus among the global health community on what constitutes long COVID. While the research led by Dr. Quinn focuses on postacute health conditions, some definitions of long COVID, such as that of the World Health Organization, refer only to ongoing symptoms of the original infection.

While there is now a diagnostic code for treating long COVID in Ontario, the data available to the researchers did not include information on some common symptoms of post-COVID condition, like chronic fatigue. In the data used, there was not an accurate way to identify patients who had developed conditions like myalgic encephalomyelitis/chronic fatigue syndrome and postural orthostatic tachycardia syndrome, said Dr. Quinn.

In addition to creating clear definitions and determining the best treatments, prevention is essential, said Dr. Quinn. Prior studies have shown that vaccination helps prevent ICU admission for COVID-19.
 

‘Important questions remain’

Commenting on the finding, Aravind Ganesh, MD, DPhil, a neurologist at the University of Calgary (Alta.), said that by including control populations, the study addressed an important limitation of previous research. Dr. Ganesh, who was not involved in the study, said that the controls help to determine the cause of associations found in other studies, including his own research on long-term symptoms following outpatient care for COVID-19.

“I think what this tells us is that maybe a lot of the issues that we’ve been seeing as complications attributable to COVID are, in fact, complications attributable to serious illness,” said Dr. Ganesh. He also found the association with venous thromboembolism interesting because the condition is recognized as a key risk factor for COVID-19 outcomes.

Compared with smaller randomized control trials, the population-level data provided a much larger sample size for the study. However, this design comes with limitations as well, Dr. Ganesh noted. The study relies on the administrative data of diagnostic codes and misses symptoms that aren’t associated with a diagnosis. In addition, because the cohorts were not assigned randomly, it may not account for preexisting risk factors.

While the study demonstrates associations with physical and mental health conditions, the cause of postacute effects from COVID-19, influenza, and sepsis is still unclear. “Important questions remain,” said Dr. Ganesh. “Why is it that these patients are experiencing these symptoms?”

The study was supported by ICES and the Canadian Institutes of Health Research. Dr. Quinn reported part-time employment at Public Health Ontario and stock in Pfizer and BioNTech. Dr. Ganesh reported no relevant financial relationships.

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

As the pandemic wanes, the public is clamoring for a return to normal. But individuals with long COVID face a challenging journey to get back to their baseline. Here’s what clinicians need to know to help patients with long COVID. 

The COVID-19 pandemic is waning. The official federal public health emergency ended on May 11, 2023. Moreover, the public is ready to move on 3 years after the beginning of a pandemic that resulted in over a million deaths in the United States.  

But not everyone can go back to normal. The Centers for Disease Control and Prevention (CDC) estimates that 1 in 13 US adults (7.5%) have long COVID symptoms. Many of these people feel as if they are the forgotten patients. While everyone else is moving on, a significant number of people have not returned to their baseline. 

A group from Yale School of Medicine, myself included, reviewed a number of studies to gain a better understanding of 1) how long COVID manifests and 2) potential treatment options. Highlights of our evaluation are presented here.

Long COVID: The Basics
What exactly is long COVID-19, and how is it thought to develop? 

The World Health Organization (WHO) defines long COVID as symptoms that persist 3 months postinfection, last for ≥ 2 months, and are not attributable to another cause. 

Hypotheses about the mechanisms of long COVID include the presence of a persistent viral reservoir, an imbalance in the viral and microbial ecosystems, reactivation of latent DNA viruses, and endothelial dysfunction. 

Who is most at risk?

• Females

• Older individuals

• Individuals with preexisting conditions, including hypertension, diabetes, obesity, and lung disease 

• Individuals who experienced > 5 symptoms within the first week of COVID-19 illness 

• Individuals with breakthrough infections after vaccination against COVID-19 appear to be at increased risk of at least 1 postacute condition

Additionally, as the risk of contracting COVID-19 is demonstrably higher in certain racial and ethnic populations, it stands to reason that more of these individuals will experience long COVID. 

Long COVID symptoms: how long is long?

Long COVID symptoms may persist for 2 years after initial infection. One analysis from China showed that nearly 7 in 10 patients experienced at least 1 ongoing symptom 6 months following infection, with more than half reporting symptoms at 24 months. Dyspnea, anxiety, and depression are especially persistent. 

In another analysis, 90% of individuals reported symptoms 35 weeks postinfection. Symptoms did not only occur in people who were hospitalized; they also occurred in people who had a “mild case.”

Clinical Manifestations of Long COVID

More than 50 symptoms have been identified as potentially associated with long COVID. The most common manifestations involve pulmonary, cardiac, and neuropsychiatric sequelae. There is no single test to determine if symptoms are due to long COVID.

Pulmonary

How it manifests

• Chronic cough 

• Shortness of breath 

• Interstitial lung disease

Treatment options

Treatment options are variable and depend on predominant symptoms. Chronic cough should be managed based on primary etiology. Treatment for interstitial lung disease depends on whether the process continues to evolve or stabilizes. The role of antifibrotics in these patients is being investigated. Lung transplantation has largely been reserved for unresolved acute injury. 

Cardiac

How it manifests

• Postacute sequelae cardiovascular disease, where cardiovascular disorders are uncovered during diagnostic testing

• Postacute sequelae cardiovascular syndrome, such as exercise intolerance, tachycardia and chest pain, and dyspnea

Other important considerations:

• Cardiac symptoms can occur independent of preexisting conditions, severity, course of acute illness, and time from original diagnosis

• Cardiac involvement can occur in any age group

• One analysis revealed increased risk of stroke, arrythmias, pericarditis, myocarditis, and ischemic heart disease 1 year after COVID-19 infection

• Postural orthostatic tachycardia syndrome (POTS) and neurogenic orthostatic hypotension have also been observed

Treatment options

Treatment options are dictated by clinical manifestations and course. Patients who have autonomic dysfunction can be advised to increase salt and water intake since hypovolemia can worsen symptoms. Consider fludrocortisone and midodrine along with recumbent and semirecumbent exercises as tolerated, as exercise can sometimes worsen symptoms.

Neuropsychiatric

How it manifests

Patients can present with fatigue, memory disorders, headache, vertigo, myalgia, neuropathy, and smell and taste disorders, and there have been reports of cognitive decline postinfection. 

Other important considerations:

• A retrospective cohort study revealed that 34% of individuals had a new neurological or psychiatric diagnosis in the first 6 months after infection, including intracranial hemorrhage, ischemic stroke, parkinsonism, and dementia. Many COVID survivors experienced critical illness requiring mechanical ventilation, sedation, and paralytics, increasing the odds of developing postintensive care syndrome

Treatment options

Use of standard of care treatments, as well as neurocognitive rehabilitation and psychosocial support, is recommended for specific neuropsychiatric conditions. Patients with headache may benefit from treatment with amitriptyline or similar medications. Olfactory training and intranasal treatments can benefit those with loss of smell. 

Future Directions

Two medications that may hold promise for treating individuals long COVID symptoms are currently undergoing early investigation.

Pyridostigmine may help improve peak exercise capacity

Pyridostigmine improved peak exercise oxygen uptake in patients with chronic fatigue syndrome in a randomized, double-blind, placebo-controlled trial involving 45 individuals. Participants were assigned to receive either pyridostigmine 60 mg orally or placebo, and the pyridostigmine group showed an improved peak exercise uptake via increased cardiac output and right ventricular filling pressures. 

An investigational compound may improve fatigue-based symptoms

A 4-week protocol using the compound AXA1125 improved fatigue-based symptoms in patients with long COVID in a double-blind, randomized, controlled phase 2a pilot study involving 41 individuals. Investigators looked at average change in postexertional skeletal muscle phosphocreatine (PCr) recovery rate from baseline to day 28 after moderate exercise as well as fatigue levels. Although PCr recovery rate did not differ significantly between groups, use of the compound was linked with significant reduction in fatigue-based symptoms.

Summary

It is important to exercise caution when interpreting data involving individuals with long COVID. Most studies to date are retrospective and observational, definitions and assessments are not yet standardized, and long-term follow-up is lacking, among other factors. 

Clinicians should remain vigilant, keeping the following in mind as they see patients who may be experiencing long COVID: 

• Those most at risk include females, older individuals, those with obesity, people with preexisting conditions, individuals who experienced multiple symptoms early in their COVID-19 illness, and those who had breakthrough infections after COVID-19 vaccination 

• Symptoms may persist up to 2 years after acute infection

• The most common manifestations of long COVID involve pulmonary, cardiac, and neuropsychiatric complications

• Two medications, pyridostigmine and the compound AXA1125, are under investigation and may hold promise in treating some symptoms

As the pandemic wanes, the public is clamoring for a return to normal. But individuals with long COVID face a challenging journey to get back to their baseline. Here’s what clinicians need to know to help patients with long COVID. 

The COVID-19 pandemic is waning. The official federal public health emergency ended on May 11, 2023. Moreover, the public is ready to move on 3 years after the beginning of a pandemic that resulted in over a million deaths in the United States.  

But not everyone can go back to normal. The Centers for Disease Control and Prevention (CDC) estimates that 1 in 13 US adults (7.5%) have long COVID symptoms. Many of these people feel as if they are the forgotten patients. While everyone else is moving on, a significant number of people have not returned to their baseline. 

A group from Yale School of Medicine, myself included, reviewed a number of studies to gain a better understanding of 1) how long COVID manifests and 2) potential treatment options. Highlights of our evaluation are presented here.

Long COVID: The Basics
What exactly is long COVID-19, and how is it thought to develop? 

The World Health Organization (WHO) defines long COVID as symptoms that persist 3 months postinfection, last for ≥ 2 months, and are not attributable to another cause. 

Hypotheses about the mechanisms of long COVID include the presence of a persistent viral reservoir, an imbalance in the viral and microbial ecosystems, reactivation of latent DNA viruses, and endothelial dysfunction. 

Who is most at risk?

• Females

• Older individuals

• Individuals with preexisting conditions, including hypertension, diabetes, obesity, and lung disease 

• Individuals who experienced > 5 symptoms within the first week of COVID-19 illness 

• Individuals with breakthrough infections after vaccination against COVID-19 appear to be at increased risk of at least 1 postacute condition

Additionally, as the risk of contracting COVID-19 is demonstrably higher in certain racial and ethnic populations, it stands to reason that more of these individuals will experience long COVID. 

Long COVID symptoms: how long is long?

Long COVID symptoms may persist for 2 years after initial infection. One analysis from China showed that nearly 7 in 10 patients experienced at least 1 ongoing symptom 6 months following infection, with more than half reporting symptoms at 24 months. Dyspnea, anxiety, and depression are especially persistent. 

In another analysis, 90% of individuals reported symptoms 35 weeks postinfection. Symptoms did not only occur in people who were hospitalized; they also occurred in people who had a “mild case.”

Clinical Manifestations of Long COVID

More than 50 symptoms have been identified as potentially associated with long COVID. The most common manifestations involve pulmonary, cardiac, and neuropsychiatric sequelae. There is no single test to determine if symptoms are due to long COVID.

Pulmonary

How it manifests

• Chronic cough 

• Shortness of breath 

• Interstitial lung disease

Treatment options

Treatment options are variable and depend on predominant symptoms. Chronic cough should be managed based on primary etiology. Treatment for interstitial lung disease depends on whether the process continues to evolve or stabilizes. The role of antifibrotics in these patients is being investigated. Lung transplantation has largely been reserved for unresolved acute injury. 

Cardiac

How it manifests

• Postacute sequelae cardiovascular disease, where cardiovascular disorders are uncovered during diagnostic testing

• Postacute sequelae cardiovascular syndrome, such as exercise intolerance, tachycardia and chest pain, and dyspnea

Other important considerations:

• Cardiac symptoms can occur independent of preexisting conditions, severity, course of acute illness, and time from original diagnosis

• Cardiac involvement can occur in any age group

• One analysis revealed increased risk of stroke, arrythmias, pericarditis, myocarditis, and ischemic heart disease 1 year after COVID-19 infection

• Postural orthostatic tachycardia syndrome (POTS) and neurogenic orthostatic hypotension have also been observed

Treatment options

Treatment options are dictated by clinical manifestations and course. Patients who have autonomic dysfunction can be advised to increase salt and water intake since hypovolemia can worsen symptoms. Consider fludrocortisone and midodrine along with recumbent and semirecumbent exercises as tolerated, as exercise can sometimes worsen symptoms.

Neuropsychiatric

How it manifests

Patients can present with fatigue, memory disorders, headache, vertigo, myalgia, neuropathy, and smell and taste disorders, and there have been reports of cognitive decline postinfection. 

Other important considerations:

• A retrospective cohort study revealed that 34% of individuals had a new neurological or psychiatric diagnosis in the first 6 months after infection, including intracranial hemorrhage, ischemic stroke, parkinsonism, and dementia. Many COVID survivors experienced critical illness requiring mechanical ventilation, sedation, and paralytics, increasing the odds of developing postintensive care syndrome

Treatment options

Use of standard of care treatments, as well as neurocognitive rehabilitation and psychosocial support, is recommended for specific neuropsychiatric conditions. Patients with headache may benefit from treatment with amitriptyline or similar medications. Olfactory training and intranasal treatments can benefit those with loss of smell. 

Future Directions

Two medications that may hold promise for treating individuals long COVID symptoms are currently undergoing early investigation.

Pyridostigmine may help improve peak exercise capacity

Pyridostigmine improved peak exercise oxygen uptake in patients with chronic fatigue syndrome in a randomized, double-blind, placebo-controlled trial involving 45 individuals. Participants were assigned to receive either pyridostigmine 60 mg orally or placebo, and the pyridostigmine group showed an improved peak exercise uptake via increased cardiac output and right ventricular filling pressures. 

An investigational compound may improve fatigue-based symptoms

A 4-week protocol using the compound AXA1125 improved fatigue-based symptoms in patients with long COVID in a double-blind, randomized, controlled phase 2a pilot study involving 41 individuals. Investigators looked at average change in postexertional skeletal muscle phosphocreatine (PCr) recovery rate from baseline to day 28 after moderate exercise as well as fatigue levels. Although PCr recovery rate did not differ significantly between groups, use of the compound was linked with significant reduction in fatigue-based symptoms.

Summary

It is important to exercise caution when interpreting data involving individuals with long COVID. Most studies to date are retrospective and observational, definitions and assessments are not yet standardized, and long-term follow-up is lacking, among other factors. 

Clinicians should remain vigilant, keeping the following in mind as they see patients who may be experiencing long COVID: 

• Those most at risk include females, older individuals, those with obesity, people with preexisting conditions, individuals who experienced multiple symptoms early in their COVID-19 illness, and those who had breakthrough infections after COVID-19 vaccination 

• Symptoms may persist up to 2 years after acute infection

• The most common manifestations of long COVID involve pulmonary, cardiac, and neuropsychiatric complications

• Two medications, pyridostigmine and the compound AXA1125, are under investigation and may hold promise in treating some symptoms

As the pandemic wanes, the public is clamoring for a return to normal. But individuals with long COVID face a challenging journey to get back to their baseline. Here’s what clinicians need to know to help patients with long COVID. 

The COVID-19 pandemic is waning. The official federal public health emergency ended on May 11, 2023. Moreover, the public is ready to move on 3 years after the beginning of a pandemic that resulted in over a million deaths in the United States.  

But not everyone can go back to normal. The Centers for Disease Control and Prevention (CDC) estimates that 1 in 13 US adults (7.5%) have long COVID symptoms. Many of these people feel as if they are the forgotten patients. While everyone else is moving on, a significant number of people have not returned to their baseline. 

A group from Yale School of Medicine, myself included, reviewed a number of studies to gain a better understanding of 1) how long COVID manifests and 2) potential treatment options. Highlights of our evaluation are presented here.

Long COVID: The Basics
What exactly is long COVID-19, and how is it thought to develop? 

The World Health Organization (WHO) defines long COVID as symptoms that persist 3 months postinfection, last for ≥ 2 months, and are not attributable to another cause. 

Hypotheses about the mechanisms of long COVID include the presence of a persistent viral reservoir, an imbalance in the viral and microbial ecosystems, reactivation of latent DNA viruses, and endothelial dysfunction. 

Who is most at risk?

• Females

• Older individuals

• Individuals with preexisting conditions, including hypertension, diabetes, obesity, and lung disease 

• Individuals who experienced > 5 symptoms within the first week of COVID-19 illness 

• Individuals with breakthrough infections after vaccination against COVID-19 appear to be at increased risk of at least 1 postacute condition

Additionally, as the risk of contracting COVID-19 is demonstrably higher in certain racial and ethnic populations, it stands to reason that more of these individuals will experience long COVID. 

Long COVID symptoms: how long is long?

Long COVID symptoms may persist for 2 years after initial infection. One analysis from China showed that nearly 7 in 10 patients experienced at least 1 ongoing symptom 6 months following infection, with more than half reporting symptoms at 24 months. Dyspnea, anxiety, and depression are especially persistent. 

In another analysis, 90% of individuals reported symptoms 35 weeks postinfection. Symptoms did not only occur in people who were hospitalized; they also occurred in people who had a “mild case.”

Clinical Manifestations of Long COVID

More than 50 symptoms have been identified as potentially associated with long COVID. The most common manifestations involve pulmonary, cardiac, and neuropsychiatric sequelae. There is no single test to determine if symptoms are due to long COVID.

Pulmonary

How it manifests

• Chronic cough 

• Shortness of breath 

• Interstitial lung disease

Treatment options

Treatment options are variable and depend on predominant symptoms. Chronic cough should be managed based on primary etiology. Treatment for interstitial lung disease depends on whether the process continues to evolve or stabilizes. The role of antifibrotics in these patients is being investigated. Lung transplantation has largely been reserved for unresolved acute injury. 

Cardiac

How it manifests

• Postacute sequelae cardiovascular disease, where cardiovascular disorders are uncovered during diagnostic testing

• Postacute sequelae cardiovascular syndrome, such as exercise intolerance, tachycardia and chest pain, and dyspnea

Other important considerations:

• Cardiac symptoms can occur independent of preexisting conditions, severity, course of acute illness, and time from original diagnosis

• Cardiac involvement can occur in any age group

• One analysis revealed increased risk of stroke, arrythmias, pericarditis, myocarditis, and ischemic heart disease 1 year after COVID-19 infection

• Postural orthostatic tachycardia syndrome (POTS) and neurogenic orthostatic hypotension have also been observed

Treatment options

Treatment options are dictated by clinical manifestations and course. Patients who have autonomic dysfunction can be advised to increase salt and water intake since hypovolemia can worsen symptoms. Consider fludrocortisone and midodrine along with recumbent and semirecumbent exercises as tolerated, as exercise can sometimes worsen symptoms.

Neuropsychiatric

How it manifests

Patients can present with fatigue, memory disorders, headache, vertigo, myalgia, neuropathy, and smell and taste disorders, and there have been reports of cognitive decline postinfection. 

Other important considerations:

• A retrospective cohort study revealed that 34% of individuals had a new neurological or psychiatric diagnosis in the first 6 months after infection, including intracranial hemorrhage, ischemic stroke, parkinsonism, and dementia. Many COVID survivors experienced critical illness requiring mechanical ventilation, sedation, and paralytics, increasing the odds of developing postintensive care syndrome

Treatment options

Use of standard of care treatments, as well as neurocognitive rehabilitation and psychosocial support, is recommended for specific neuropsychiatric conditions. Patients with headache may benefit from treatment with amitriptyline or similar medications. Olfactory training and intranasal treatments can benefit those with loss of smell. 

Future Directions

Two medications that may hold promise for treating individuals long COVID symptoms are currently undergoing early investigation.

Pyridostigmine may help improve peak exercise capacity

Pyridostigmine improved peak exercise oxygen uptake in patients with chronic fatigue syndrome in a randomized, double-blind, placebo-controlled trial involving 45 individuals. Participants were assigned to receive either pyridostigmine 60 mg orally or placebo, and the pyridostigmine group showed an improved peak exercise uptake via increased cardiac output and right ventricular filling pressures. 

An investigational compound may improve fatigue-based symptoms

A 4-week protocol using the compound AXA1125 improved fatigue-based symptoms in patients with long COVID in a double-blind, randomized, controlled phase 2a pilot study involving 41 individuals. Investigators looked at average change in postexertional skeletal muscle phosphocreatine (PCr) recovery rate from baseline to day 28 after moderate exercise as well as fatigue levels. Although PCr recovery rate did not differ significantly between groups, use of the compound was linked with significant reduction in fatigue-based symptoms.

Summary

It is important to exercise caution when interpreting data involving individuals with long COVID. Most studies to date are retrospective and observational, definitions and assessments are not yet standardized, and long-term follow-up is lacking, among other factors. 

Clinicians should remain vigilant, keeping the following in mind as they see patients who may be experiencing long COVID: 

• Those most at risk include females, older individuals, those with obesity, people with preexisting conditions, individuals who experienced multiple symptoms early in their COVID-19 illness, and those who had breakthrough infections after COVID-19 vaccination 

• Symptoms may persist up to 2 years after acute infection

• The most common manifestations of long COVID involve pulmonary, cardiac, and neuropsychiatric complications

• Two medications, pyridostigmine and the compound AXA1125, are under investigation and may hold promise in treating some symptoms