Carrie Arnold

Even before their baby is born, parents face some tough questions: Home birth or hospital? Cloth or disposable diapers? Breast, bottle, or both? But advances in genetic sequencing technology mean that parents will soon face yet another choice: whether to sequence their newborn’s DNA for an overview of the baby’s entire genome.

Genetic testing has been used for decades to diagnose conditions even before birth. But DNA sequencing technologies, once expensive and tough to access, are now rapid and cheap enough that doctors could order genomic screening for any infant, regardless of health status.

The possibility has raised many questions about the ethical, legal, and social repercussions of doing so. One of the biggest sticking points of sequencing newborns is the potential psychosocial fallout for families of such wide-scale use of genetic screening.

“There’s a narrative of catastrophic distress,” says Robert Green, MD, a geneticist at Harvard Medical School and lead investigator on the BabySeq study, which is evaluating the medical, social, and economic consequences of newborn genetic screening. The concern is that parents learning that their child carries a gene variant related to cancer or heart disease will become “incredibly anxious and distressed,” he says. “And it’s not an unreasonable speculation.”

But Dr. Green’s team found no evidence of such anxiety in the results from a randomized trial it conducted, published in JAMA Pediatrics. In the meantime, Genomics England announced it would begin a pilot study involving whole-genome sequencing of up to 200,000 babies. The first goal is to identify severe disease that starts in childhood, but the information would also be stored and used to detect drug sensitivities and conditions that come up later in life.

The large U.K. project is a bold move, according to David Amor, PhD, a pediatric geneticist at Murdoch Children’s Research Institute in Australia, who says its time has come. Geneticists have been accused of thinking their field involves unique pitfalls, compared with the rest of medicine, he points out, and that doctors need to protect patients and families from the potential harm genetic testing poses.

“But it is becoming apparent that that’s not really the case,” he says, and “maybe there’s not a whole lot special about genetics – it’s just medicine.”

When a first-draft copy of the human genome was published in 2001, scientists and doctors hailed the start of a new era of precision medicine. Knowing our genome sequence was expected to lead to a better grasp on our individual disease risks. Yet even as technologies advanced, clinical genetics remained focused on diagnosis rather than screening, according to Lilian Downie, a clinical genetics PhD candidate at the University of Melbourne. She calls the difference subtle but important.

Diagnostic genetic testing confirms whether a person has a specific condition, whereas genetic screening tests evaluate someone’s risk of getting an illness. Both approaches use sequencing, but they answer different questions, explains Ms. Downie.
 

Diagnosing disease versus predicting future illness

Genetic testing is on the upswing for both purposes, whether clinically for diagnosis or through direct-to-consumer screening-oriented services like 23andMe. Scientists began to note that many people carried disease-related genetic variants without having signs of disease. In some cases, a variant that is mathematically linked to a disease simply doesn’t cause it. In other cases, though, even if the gene variant contributes to a disease, not everyone who carries the genetic change will get the condition.

This potential disconnect between having a variant and developing the condition is a big problem, says Katie Stoll, a genetic counselor and executive director of the Genetic Support Foundation in Olympia, WA.

“It’s more complicated than just looking at one gene variant and one outcome,” she says. Without a sure link between the two, this information could unnecessarily entail “some pretty big emotional and financial costs.”

Ms. Stoll and others in the genetics field who share similar concerns are one reason the BabySeq project was first funded back in 2015. Although the overall aim of the initiative is to answer questions about the value of genomic sequencing in newborn screening, the media and scientific attention has focused on the psychosocial impact of healthy newborn sequencing, says Dr. Green. In the study published in JAMA Pediatrics, his group focused on these issues, too.

For that randomized trial, they enrolled 325 families, 257 with healthy babies and 68 whose babies had spent time in neonatal intensive care. Enrolled infants were randomly given standard care alone or standard care with genomic sequencing added on. The genomic sequencing report contained information about the presence of genetic variants associated with disease that start in childhood. Parents also could choose whether to learn about genetic risks for conditions that start in adulthood, such as cancer.

Boston-based Tina Moniz was one of those parents. When her first daughter was born in Jan. 2016, someone from the BabySeq study asked her and her husband if they would like to take part. The decision was simple for the couple.

“I didn’t hesitate,” she says. “To me, knowledge is power.”

Using screening tools for parental and marital distress and parent-child bonding, the research evaluated BabySeq families at 3 and 10 months after parents received the sequencing results. The investigators found no significant differences in any of these measures between screened and unscreened families. Ms. Moniz learned that her daughter’s only concerning result was being a carrier for cystic fibrosis. Rather than finding this information anxiety-provoking, Ms. Moniz considered it to be reassuring.

“My mom brain worries about so many things, but at least I know I don’t have to add genetic disease to the list,” she says.

But Ms. Stoll, who wasn’t involved in the BabySeq study, isn’t as convinced. She says that less than 10% of the families approached about the trial ultimately agreed to take part, suggesting potential bias in the selection process. Most participants were white, well-educated, and well-off, making it hard to generalize the study’s results.

What’s more, the standard care involved meeting with a genetic counselor and giving a detailed family history, neither of which is routinely offered to new parents, Ms. Stoll says. These study features leave her unconvinced that healthy newborn genetic screening is beneficial.

“We can’t assume these psychosocial consequences will be true for everyone,” she says.
 

Follow-up and treatment needed

Traditional newborn screening relies on blood biochemical tests to detect and diagnose metabolic diseases. This approach still outperforms DNA sequencing in trials, says Cynthia Powell, MD, a pediatric geneticist at the University of North Carolina at Chapel Hill, who wasn’t involved with the BabySeq study. Despite the enthusiasm for genomics, this kind of screening won’t replace newborn biochemical screening anytime soon, she says.

“There are some states that have only one geneticist available, so should we really be doing this if we can’t provide the necessary follow-up and treatment for these babies?” she asks.

Still, Dr. Powell says, the BabySeq study helps advance understanding of what the infrastructure needs are for widespread use of DNA sequencing in newborns. She says those needs include appropriate consent processes, access to genetic counselors to discuss testing, and referrals for further testing and treatment in those babies with concerning results.

The BabySeq program will also guide new initiatives, like the pilot program that Genomics England launched in Sept. 2021. As part of that project, the U.K. group intends to look into how practical whole-genome sequencing for newborn screening would be and look at the risks, benefits, and limits of its widespread use.

“For the first time, we’re putting real data into these questions that people have basically just speculated and hypothesized and created narratives about,” Dr. Green says.

But for now, the findings on the psychosocial effects of general newborn genomic screening show that “we should consider genetics to be just one more arrow in our medical quiver.”

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

Even before their baby is born, parents face some tough questions: Home birth or hospital? Cloth or disposable diapers? Breast, bottle, or both? But advances in genetic sequencing technology mean that parents will soon face yet another choice: whether to sequence their newborn’s DNA for an overview of the baby’s entire genome.

Genetic testing has been used for decades to diagnose conditions even before birth. But DNA sequencing technologies, once expensive and tough to access, are now rapid and cheap enough that doctors could order genomic screening for any infant, regardless of health status.

The possibility has raised many questions about the ethical, legal, and social repercussions of doing so. One of the biggest sticking points of sequencing newborns is the potential psychosocial fallout for families of such wide-scale use of genetic screening.

“There’s a narrative of catastrophic distress,” says Robert Green, MD, a geneticist at Harvard Medical School and lead investigator on the BabySeq study, which is evaluating the medical, social, and economic consequences of newborn genetic screening. The concern is that parents learning that their child carries a gene variant related to cancer or heart disease will become “incredibly anxious and distressed,” he says. “And it’s not an unreasonable speculation.”

But Dr. Green’s team found no evidence of such anxiety in the results from a randomized trial it conducted, published in JAMA Pediatrics. In the meantime, Genomics England announced it would begin a pilot study involving whole-genome sequencing of up to 200,000 babies. The first goal is to identify severe disease that starts in childhood, but the information would also be stored and used to detect drug sensitivities and conditions that come up later in life.

The large U.K. project is a bold move, according to David Amor, PhD, a pediatric geneticist at Murdoch Children’s Research Institute in Australia, who says its time has come. Geneticists have been accused of thinking their field involves unique pitfalls, compared with the rest of medicine, he points out, and that doctors need to protect patients and families from the potential harm genetic testing poses.

“But it is becoming apparent that that’s not really the case,” he says, and “maybe there’s not a whole lot special about genetics – it’s just medicine.”

When a first-draft copy of the human genome was published in 2001, scientists and doctors hailed the start of a new era of precision medicine. Knowing our genome sequence was expected to lead to a better grasp on our individual disease risks. Yet even as technologies advanced, clinical genetics remained focused on diagnosis rather than screening, according to Lilian Downie, a clinical genetics PhD candidate at the University of Melbourne. She calls the difference subtle but important.

Diagnostic genetic testing confirms whether a person has a specific condition, whereas genetic screening tests evaluate someone’s risk of getting an illness. Both approaches use sequencing, but they answer different questions, explains Ms. Downie.
 

Diagnosing disease versus predicting future illness

Genetic testing is on the upswing for both purposes, whether clinically for diagnosis or through direct-to-consumer screening-oriented services like 23andMe. Scientists began to note that many people carried disease-related genetic variants without having signs of disease. In some cases, a variant that is mathematically linked to a disease simply doesn’t cause it. In other cases, though, even if the gene variant contributes to a disease, not everyone who carries the genetic change will get the condition.

This potential disconnect between having a variant and developing the condition is a big problem, says Katie Stoll, a genetic counselor and executive director of the Genetic Support Foundation in Olympia, WA.

“It’s more complicated than just looking at one gene variant and one outcome,” she says. Without a sure link between the two, this information could unnecessarily entail “some pretty big emotional and financial costs.”

Ms. Stoll and others in the genetics field who share similar concerns are one reason the BabySeq project was first funded back in 2015. Although the overall aim of the initiative is to answer questions about the value of genomic sequencing in newborn screening, the media and scientific attention has focused on the psychosocial impact of healthy newborn sequencing, says Dr. Green. In the study published in JAMA Pediatrics, his group focused on these issues, too.

For that randomized trial, they enrolled 325 families, 257 with healthy babies and 68 whose babies had spent time in neonatal intensive care. Enrolled infants were randomly given standard care alone or standard care with genomic sequencing added on. The genomic sequencing report contained information about the presence of genetic variants associated with disease that start in childhood. Parents also could choose whether to learn about genetic risks for conditions that start in adulthood, such as cancer.

Boston-based Tina Moniz was one of those parents. When her first daughter was born in Jan. 2016, someone from the BabySeq study asked her and her husband if they would like to take part. The decision was simple for the couple.

“I didn’t hesitate,” she says. “To me, knowledge is power.”

Using screening tools for parental and marital distress and parent-child bonding, the research evaluated BabySeq families at 3 and 10 months after parents received the sequencing results. The investigators found no significant differences in any of these measures between screened and unscreened families. Ms. Moniz learned that her daughter’s only concerning result was being a carrier for cystic fibrosis. Rather than finding this information anxiety-provoking, Ms. Moniz considered it to be reassuring.

“My mom brain worries about so many things, but at least I know I don’t have to add genetic disease to the list,” she says.

But Ms. Stoll, who wasn’t involved in the BabySeq study, isn’t as convinced. She says that less than 10% of the families approached about the trial ultimately agreed to take part, suggesting potential bias in the selection process. Most participants were white, well-educated, and well-off, making it hard to generalize the study’s results.

What’s more, the standard care involved meeting with a genetic counselor and giving a detailed family history, neither of which is routinely offered to new parents, Ms. Stoll says. These study features leave her unconvinced that healthy newborn genetic screening is beneficial.

“We can’t assume these psychosocial consequences will be true for everyone,” she says.
 

Follow-up and treatment needed

Traditional newborn screening relies on blood biochemical tests to detect and diagnose metabolic diseases. This approach still outperforms DNA sequencing in trials, says Cynthia Powell, MD, a pediatric geneticist at the University of North Carolina at Chapel Hill, who wasn’t involved with the BabySeq study. Despite the enthusiasm for genomics, this kind of screening won’t replace newborn biochemical screening anytime soon, she says.

“There are some states that have only one geneticist available, so should we really be doing this if we can’t provide the necessary follow-up and treatment for these babies?” she asks.

Still, Dr. Powell says, the BabySeq study helps advance understanding of what the infrastructure needs are for widespread use of DNA sequencing in newborns. She says those needs include appropriate consent processes, access to genetic counselors to discuss testing, and referrals for further testing and treatment in those babies with concerning results.

The BabySeq program will also guide new initiatives, like the pilot program that Genomics England launched in Sept. 2021. As part of that project, the U.K. group intends to look into how practical whole-genome sequencing for newborn screening would be and look at the risks, benefits, and limits of its widespread use.

“For the first time, we’re putting real data into these questions that people have basically just speculated and hypothesized and created narratives about,” Dr. Green says.

But for now, the findings on the psychosocial effects of general newborn genomic screening show that “we should consider genetics to be just one more arrow in our medical quiver.”

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

Even before their baby is born, parents face some tough questions: Home birth or hospital? Cloth or disposable diapers? Breast, bottle, or both? But advances in genetic sequencing technology mean that parents will soon face yet another choice: whether to sequence their newborn’s DNA for an overview of the baby’s entire genome.

Genetic testing has been used for decades to diagnose conditions even before birth. But DNA sequencing technologies, once expensive and tough to access, are now rapid and cheap enough that doctors could order genomic screening for any infant, regardless of health status.

The possibility has raised many questions about the ethical, legal, and social repercussions of doing so. One of the biggest sticking points of sequencing newborns is the potential psychosocial fallout for families of such wide-scale use of genetic screening.

“There’s a narrative of catastrophic distress,” says Robert Green, MD, a geneticist at Harvard Medical School and lead investigator on the BabySeq study, which is evaluating the medical, social, and economic consequences of newborn genetic screening. The concern is that parents learning that their child carries a gene variant related to cancer or heart disease will become “incredibly anxious and distressed,” he says. “And it’s not an unreasonable speculation.”

But Dr. Green’s team found no evidence of such anxiety in the results from a randomized trial it conducted, published in JAMA Pediatrics. In the meantime, Genomics England announced it would begin a pilot study involving whole-genome sequencing of up to 200,000 babies. The first goal is to identify severe disease that starts in childhood, but the information would also be stored and used to detect drug sensitivities and conditions that come up later in life.

The large U.K. project is a bold move, according to David Amor, PhD, a pediatric geneticist at Murdoch Children’s Research Institute in Australia, who says its time has come. Geneticists have been accused of thinking their field involves unique pitfalls, compared with the rest of medicine, he points out, and that doctors need to protect patients and families from the potential harm genetic testing poses.

“But it is becoming apparent that that’s not really the case,” he says, and “maybe there’s not a whole lot special about genetics – it’s just medicine.”

When a first-draft copy of the human genome was published in 2001, scientists and doctors hailed the start of a new era of precision medicine. Knowing our genome sequence was expected to lead to a better grasp on our individual disease risks. Yet even as technologies advanced, clinical genetics remained focused on diagnosis rather than screening, according to Lilian Downie, a clinical genetics PhD candidate at the University of Melbourne. She calls the difference subtle but important.

Diagnostic genetic testing confirms whether a person has a specific condition, whereas genetic screening tests evaluate someone’s risk of getting an illness. Both approaches use sequencing, but they answer different questions, explains Ms. Downie.
 

Diagnosing disease versus predicting future illness

Genetic testing is on the upswing for both purposes, whether clinically for diagnosis or through direct-to-consumer screening-oriented services like 23andMe. Scientists began to note that many people carried disease-related genetic variants without having signs of disease. In some cases, a variant that is mathematically linked to a disease simply doesn’t cause it. In other cases, though, even if the gene variant contributes to a disease, not everyone who carries the genetic change will get the condition.

This potential disconnect between having a variant and developing the condition is a big problem, says Katie Stoll, a genetic counselor and executive director of the Genetic Support Foundation in Olympia, WA.

“It’s more complicated than just looking at one gene variant and one outcome,” she says. Without a sure link between the two, this information could unnecessarily entail “some pretty big emotional and financial costs.”

Ms. Stoll and others in the genetics field who share similar concerns are one reason the BabySeq project was first funded back in 2015. Although the overall aim of the initiative is to answer questions about the value of genomic sequencing in newborn screening, the media and scientific attention has focused on the psychosocial impact of healthy newborn sequencing, says Dr. Green. In the study published in JAMA Pediatrics, his group focused on these issues, too.

For that randomized trial, they enrolled 325 families, 257 with healthy babies and 68 whose babies had spent time in neonatal intensive care. Enrolled infants were randomly given standard care alone or standard care with genomic sequencing added on. The genomic sequencing report contained information about the presence of genetic variants associated with disease that start in childhood. Parents also could choose whether to learn about genetic risks for conditions that start in adulthood, such as cancer.

Boston-based Tina Moniz was one of those parents. When her first daughter was born in Jan. 2016, someone from the BabySeq study asked her and her husband if they would like to take part. The decision was simple for the couple.

“I didn’t hesitate,” she says. “To me, knowledge is power.”

Using screening tools for parental and marital distress and parent-child bonding, the research evaluated BabySeq families at 3 and 10 months after parents received the sequencing results. The investigators found no significant differences in any of these measures between screened and unscreened families. Ms. Moniz learned that her daughter’s only concerning result was being a carrier for cystic fibrosis. Rather than finding this information anxiety-provoking, Ms. Moniz considered it to be reassuring.

“My mom brain worries about so many things, but at least I know I don’t have to add genetic disease to the list,” she says.

But Ms. Stoll, who wasn’t involved in the BabySeq study, isn’t as convinced. She says that less than 10% of the families approached about the trial ultimately agreed to take part, suggesting potential bias in the selection process. Most participants were white, well-educated, and well-off, making it hard to generalize the study’s results.

What’s more, the standard care involved meeting with a genetic counselor and giving a detailed family history, neither of which is routinely offered to new parents, Ms. Stoll says. These study features leave her unconvinced that healthy newborn genetic screening is beneficial.

“We can’t assume these psychosocial consequences will be true for everyone,” she says.
 

Follow-up and treatment needed

Traditional newborn screening relies on blood biochemical tests to detect and diagnose metabolic diseases. This approach still outperforms DNA sequencing in trials, says Cynthia Powell, MD, a pediatric geneticist at the University of North Carolina at Chapel Hill, who wasn’t involved with the BabySeq study. Despite the enthusiasm for genomics, this kind of screening won’t replace newborn biochemical screening anytime soon, she says.

“There are some states that have only one geneticist available, so should we really be doing this if we can’t provide the necessary follow-up and treatment for these babies?” she asks.

Still, Dr. Powell says, the BabySeq study helps advance understanding of what the infrastructure needs are for widespread use of DNA sequencing in newborns. She says those needs include appropriate consent processes, access to genetic counselors to discuss testing, and referrals for further testing and treatment in those babies with concerning results.

The BabySeq program will also guide new initiatives, like the pilot program that Genomics England launched in Sept. 2021. As part of that project, the U.K. group intends to look into how practical whole-genome sequencing for newborn screening would be and look at the risks, benefits, and limits of its widespread use.

“For the first time, we’re putting real data into these questions that people have basically just speculated and hypothesized and created narratives about,” Dr. Green says.

But for now, the findings on the psychosocial effects of general newborn genomic screening show that “we should consider genetics to be just one more arrow in our medical quiver.”

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

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

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

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

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

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

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

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

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

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

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

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


 

Muscle aches and pains with crippling fatigue

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

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

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

A syndrome’s shame

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

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

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

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

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

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

Immunologic symptoms

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

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

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

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

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

Chronic post-SARS syndrome

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


 

Muscle aches and pains with crippling fatigue

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

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

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

A syndrome’s shame

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

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

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

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

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

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

Immunologic symptoms

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

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

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

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

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

Chronic post-SARS syndrome

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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


 

Muscle aches and pains with crippling fatigue

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

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

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

A syndrome’s shame

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

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

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

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

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

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

Immunologic symptoms

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

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

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

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

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

Chronic post-SARS syndrome

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

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

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

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

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

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

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

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

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

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

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

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

By the time she was discharged from a suburban New Jersey hospital on April 10, Kathleen Ronan thought the worst was behind her. For a week before her husband rushed her to the emergency department (ED), incoherent and struggling to breathe, the novel coronavirus had ravaged her body. She tried to treat her fevers with acetaminophen and ice packs. Despite taking enough Tylenol to risk liver damage and packing herself on ice like the catch of the day, Ronan’s fever continued to rise. By the time her temperature reached 104.5° F, Ronan knew the time had come for more drastic measures.

A team of masked and gowned nurses greeted her at a triage tent outside the ED, and from there, everything becomes hazy for Ronan. She was immediately rushed to the hospital’s special COVID-19 intensive care unit (ICU), where she spent 5 days. But she has few distinct memories from this time. What she does remember is the exhaustion, the pain, the loneliness, and the fear. Her family couldn’t visit, and though Ronan works as a home health nurse, her brain was so addled with fever that she couldn’t make sense of what was happening. After a week in the hospital, 5 days of which were spent in the ICU, 51-year-old Ronan was discharged.

Her years of working as a home health nurse told her that the return home wouldn’t be easy, but nothing prepared her for just how much she would struggle. The once-active Ronan, who had supplemented long days on her feet caring for others as a nurse with regular trips to the gym, now needed a walker to traverse the few steps from her bed to the toilet, an effort that left her gasping for air. Her brain couldn’t even focus on an audiobook, let alone a short magazine article.

“It just completely knocked the stuffing out of me,” Ronan said.

Ronan’s lingering symptoms aren’t unique to COVID-19 patients. In as many as 80% of patients leaving the ICU, researchers have documented what they call post–intensive care syndrome (PICS) — a constellation of physical, cognitive, and psychiatric symptoms that result from an ICU stay. Although underlying illness plays a role in these symptoms, the amount of time spent in critical care is a major factor.

Nor is PICS simply a set of side effects that will go away on their own. It includes ongoing cognitive difficulties and physical weakness, both of which can lead to employment problems. Beyond that, depression and anxiety can exacerbate – and be exacerbated by – these challenges. Psychologist Jim Jackson, PsyD, assistant director of the ICU Recovery Center at Vanderbilt University Medical Center, Nashville, Tennessee, recently spoke with a former ICU patient who has struggled since her discharge 30 years ago.

“Her life essentially stopped with her critical care stay. She hasn’t been able to move forward,” he said. “She’s part of a whole fraternity of people who are struggling.”

The good news is that over the past decade, researchers have made important strides in understanding what makes PICS symptoms worse and how critical care physicians can tweak ICU protocols to reduce PICS severity. Practitioners will need to draw on this knowledge to help Ronan and the thousands of COVID-19 ICU patients like her.
 

Surviving the ICU

Although the new coronavirus has pushed the world’s critical care system to its limits, it was an outbreak in 1952 that inspired the creation of intensive care units. That summer, a wave of paralytic polio swept over Copenhagen, Denmark, and anesthesiologist Bjørn Ibsen, MD, PhD, used mechanical ventilation — physically operated by medical and dental students – to help 316 children breathe for weeks at a time while their small bodies worked to fight off the virus. The effort halved the mortality rate from polio that affected breathing, from 80% to 40%.

In these wards, dedicated to the very sickest, each patient was assigned his or her own nurse. Over the next decade, hospitals in the United Kingdom and the United States established their own ICUs to treat patients with a variety of conditions. Although it helped improve survival, mortality rates in critical care units remained stubbornly high, owing to the patients’ severe underlying illnesses.

“We thought we were doing a good job if the patient survived, but we had no idea what happened after discharge,” said Carla Sevin, MD, medical director of Vanderbilt’s ICU Recovery Center. Nor did their efforts to find out always bring answers. “We struggled to get people to come in for support — they were debilitated, physically burdened, and weak.”

Through further advances in life support, by the early 2000s, the average mortality rates in American ICUs had dropped to 8% to 19%. As the number of critical care survivors began to climb, clinical researchers noticed that the lives of these patients and their families were profoundly altered by their severe illness.

As Dale Needham, MD, PhD, began his pulmonology and critical care residency in Toronto, Canada, in 2005, a group of physicians there began a 5-year longitudinal study to assess long-term outcomes of patients who developed acute respiratory distress syndrome (ARDS). Although ARDS is an acute condition, the investigators found that patients felt effects for years. Younger patients recovered better than older ones, but none of the patients› physical functioning was equivalent to that of age-matched control persons. Even 5 years later, former ICU patients only reached 76% of expected physical functioning, according to results published in the New England Journal of Medicine. The study was a wake-up call.

At a meeting in Chicago in 2010, Needham, now an intensivist at Johns Hopkins Hospital in Baltimore, Maryland, gathered an interdisciplinary group of colleagues, including patients and caregivers, to clarify the phenomena they were seeing. What emerged from that meeting, published in 2012 in Critical Care Medicine, were the diagnostic criteria for PICS: According to the new definition, PICS is characterized by new or worsening physical and neuropsychiatric deficits that range from forgetfulness and loss of motivation to physical weakness and insomnia.

The issue, Needham says, is that although the trouble starts in the ICU, it only becomes clear once patients leave. “ICU doctors aren’t the ones dealing with this,” Needham said. “We need to build stronger bridges between critical care and other professions.” That’s where PICS comes in, a definition that exists explicitly to alert healthcare providers about the constellation of challenges many of these individuals face as they try to reenter “normal” life.
 

Defining the problem

As an ICU nurse at the Mayo Clinic in Rochester, Minnesota, Annie Johnson, ACNP-BC, knew lots about helping hospitalized patients, but she says she didn’t know anything about what to do after discharge – at least not until her own mother became a patient.

On the first day of retirement in October 2014, Johnson’s mother flatlined. Quick-thinking paramedics resuscitated her, and after several days in critical care, she was discharged. Since then, her heart has remained healthy. Johnson’s sister, who spent time worrying over her mother at the hospital, also had lingering effects. Both have since struggled, plagued by nightmares, flashbacks, and insomnia.

Johnson initially believed her mom’s and sister’s neuropsychiatric, post-ICU struggles were unique to her family. It was only a year later, at a seminar she was attending, that she first heard the words “post–intensive care syndrome.” Suddenly, Johnson had a name for her family’s experiences, and she began to create support groups and resources to help other families like hers.

“I thought of all the patients I had treated over the years who had been on ventilators for days and days and days. And if this happened to my mom after 48 hours, what must they be going through?” she asked.

Once physicians formally defined PICS, the Society for Critical Care Medicine helped create programs to educate ICU staff, patients, and families about potential post-discharge challenges. Researchers also began to investigate factors affecting post-ICU functioning. Follow-up studies of patients with delirium (ranging from general confusion about time and place to extreme agitation and violence) showed they had striking cognitive deficits. Problems with short-term memory, flexible thinking, and motivation plagued patients for years after their critical illness, similar to the physical deficiencies seen after ARDS. Delirium was one of the strongest risk factors for neuropsychiatric problems.

“Delirium is basically a stress test for the brain,” said Babar Khan, MD, a critical care specialist at Indiana University’s Regenstrief Institute, in Bloomington. But whether delirium accentuates preexisting cognitive difficulties or creates them afresh isn’t yet clear.

Sophia Wang, MD, a geriatric psychiatrist at Indiana University who works with many critical care patients, says patients who had experienced delirium in the ICU showed significant defects in memory and executive functioning long after their hospital stay. She points to a 2015 study that followed 47 ICU patients for a year post discharge. Among those who experienced delirium, brain volumes, as measured by MRI, were smaller at 3 months, something associated with cognitive problems at 1 year. Many struggled at work, and unemployment was common. Depression and posttraumatic stress compounded these difficulties. Among those with acute respiratory distress, ICU patients who are young, female, and unemployed are most likely to suffer from posttraumatic stress disorder after they are discharge.

Critical care medicine may have given these patients a second chance at life, Wang says, but the life they return to often looks nothing like the one they had before their illness.

Prolonged mechanical ventilation and the heavy sedation that often accompanies it are predictors of PICS severity. Some of these links could be explained by the gravity of the illness that landed someone in critical care, but others are more likely to be iatrogenic, says Gerald Weinhouse, MD, a pulmonology and critical care physician and co-director of the Critical Illness Recovery Program at the Brigham and Women’s Hospital in Boston. The involvement of loved ones at the patient’s bedside, however, improved the entire family’s outcome.

When Weinhouse saw those data, he and his colleagues founded a peer support program for ICU survivors. In a study published in 2019 in Critical Care Medicine, they identified six different models for peer support for those with PICS and their families, including both online and in-person approaches. An ongoing challenge for physicians, Weinhouse says, is getting patients to engage with these programs, given that their calendars are crowded with medical appointments and that they suffer from increased physical and mental disability.

Studies such as these led critical care physicians to form the ICU Liberation Collaborative to rethink critical care medicine. At Vanderbilt, Sevin and Jackson headed up one of the world’s first post-ICU clinics, which uses an interdisciplinary team to help patients maximize their functioning. They redesigned their critical care unit in a way that allows families to spend the night and that encourages patient mobility. Both Needham and Weinhouse continue tracking patient outcomes.

Even before the novel coronavirus struck, the United States — and the world — had begun to realize that graduating from the ICU was only the start of what was often an extensive recovery.
 

The long road back

When COVID-19 patients began flooding intensive care wards around the world, physicians scrambled to meet their complex and desperate acute medical needs. Over the past few months, physicians have focused on keeping these patients alive. “We’ve never seen anything like it ― not even during polio — with the sheer number of patients, all with respiratory distress,” Needham said.

But he and his colleagues know this is only the beginning.

“We’re aware that survivorship issues are coming. There’s going to be a wave of sick people who survived the coronavirus but are going to need more help,” Weinhouse said.

Intensivists have been drawing on PICS research in their fight to help COVID-19 patients. Work from the past few years has shown that although sedation is required during intubation itself, not everyone needs it while on a ventilator. Titrating down sedating medication helps reduce delirium, Wang says. Such medication has been shown to contribute to later cognitive problems. Needham’s studies showing that prolonged bedrest by ICU patients causes muscular atrophy has led him to encourage patients to move as much as possible. With the help of physical therapists, many patients on ventilators can be awake, alert, and moving around the ward.

One of the biggest challenges critical-care coronavirus patients face is prolonged isolation. The constant presence of a familiar face helps orient confused and delirious patients and provides emotional support during a frightening time. But because the immediate need for infection control outweighs these benefits, few hospitals allow visitors, especially for COVID-19 patients.

To address this, some units have been using video technology to allow loved ones to call in. At Johns Hopkins, physicians have also been relying on the expertise of occupational therapists (OTs). Needham says that one OT found that rubbing the hand and back of an agitated, delirious patient helped soothe and calm him better than many medications.

Ronan, who spent 5 days in intensive care, echoes that problem. She says she found the relative lack of human contact to be one of the most challenging parts of being in a bed on a COVID-19 ward. Separated from her husband and daughter, suffering from high fever and severe illness, she lost all track of time.

Her return home was difficult, too. Although her job as a home health nurse had prepared her on some level for the challenges she would face after discharge, Ronan says the hospital provided little practical help.

“Everything is so much harder at home, even little things like going to the bathroom,” she said. “I feel like I’m trying to bail out a sinking ship with a teacup.”

Khan and other physicians, aware of the challenges Ronan and others face once home, aim to create post-ICU clinics specifically for COVID-19 patients. They want to build what Khan calls a “one-stop shop” for all the support patients need to recover. Some of that can be provided via telehealth, which may also help ease the physical burden.

Because there’s so much physicians don’t know about the coronavirus, Johnson says, such clinics are not only a chance to help the sickest COVID-19 patients, they will also help researchers learn more about the virus and improve critical care for other illnesses.

Today, nearly 2 months after discharge, Ronan is back on the job but struggles with a persistent cough — likely due to the lung damage she sustained while ill. She has constant fatigue, as well as ongoing upset stomach from all the medications she took to reduce fever and body aches. When she dons a mask for work, the tangible reminder of her hospital stay sends her into a panic attack. Physically, she’s weaker than before.

Researchers are still trying to understand everything that Ronan and other COVID-19 patients need to move on with their lives after being in the ICU. Mysteries abound, but the ground laid by Sevin, Needham, Weinhouse, and others has provided a solid foundation on which to build.
 

This article first appeared on Medscape.com.

By the time she was discharged from a suburban New Jersey hospital on April 10, Kathleen Ronan thought the worst was behind her. For a week before her husband rushed her to the emergency department (ED), incoherent and struggling to breathe, the novel coronavirus had ravaged her body. She tried to treat her fevers with acetaminophen and ice packs. Despite taking enough Tylenol to risk liver damage and packing herself on ice like the catch of the day, Ronan’s fever continued to rise. By the time her temperature reached 104.5° F, Ronan knew the time had come for more drastic measures.

A team of masked and gowned nurses greeted her at a triage tent outside the ED, and from there, everything becomes hazy for Ronan. She was immediately rushed to the hospital’s special COVID-19 intensive care unit (ICU), where she spent 5 days. But she has few distinct memories from this time. What she does remember is the exhaustion, the pain, the loneliness, and the fear. Her family couldn’t visit, and though Ronan works as a home health nurse, her brain was so addled with fever that she couldn’t make sense of what was happening. After a week in the hospital, 5 days of which were spent in the ICU, 51-year-old Ronan was discharged.

Her years of working as a home health nurse told her that the return home wouldn’t be easy, but nothing prepared her for just how much she would struggle. The once-active Ronan, who had supplemented long days on her feet caring for others as a nurse with regular trips to the gym, now needed a walker to traverse the few steps from her bed to the toilet, an effort that left her gasping for air. Her brain couldn’t even focus on an audiobook, let alone a short magazine article.

“It just completely knocked the stuffing out of me,” Ronan said.

Ronan’s lingering symptoms aren’t unique to COVID-19 patients. In as many as 80% of patients leaving the ICU, researchers have documented what they call post–intensive care syndrome (PICS) — a constellation of physical, cognitive, and psychiatric symptoms that result from an ICU stay. Although underlying illness plays a role in these symptoms, the amount of time spent in critical care is a major factor.

Nor is PICS simply a set of side effects that will go away on their own. It includes ongoing cognitive difficulties and physical weakness, both of which can lead to employment problems. Beyond that, depression and anxiety can exacerbate – and be exacerbated by – these challenges. Psychologist Jim Jackson, PsyD, assistant director of the ICU Recovery Center at Vanderbilt University Medical Center, Nashville, Tennessee, recently spoke with a former ICU patient who has struggled since her discharge 30 years ago.

“Her life essentially stopped with her critical care stay. She hasn’t been able to move forward,” he said. “She’s part of a whole fraternity of people who are struggling.”

The good news is that over the past decade, researchers have made important strides in understanding what makes PICS symptoms worse and how critical care physicians can tweak ICU protocols to reduce PICS severity. Practitioners will need to draw on this knowledge to help Ronan and the thousands of COVID-19 ICU patients like her.
 

Surviving the ICU

Although the new coronavirus has pushed the world’s critical care system to its limits, it was an outbreak in 1952 that inspired the creation of intensive care units. That summer, a wave of paralytic polio swept over Copenhagen, Denmark, and anesthesiologist Bjørn Ibsen, MD, PhD, used mechanical ventilation — physically operated by medical and dental students – to help 316 children breathe for weeks at a time while their small bodies worked to fight off the virus. The effort halved the mortality rate from polio that affected breathing, from 80% to 40%.

In these wards, dedicated to the very sickest, each patient was assigned his or her own nurse. Over the next decade, hospitals in the United Kingdom and the United States established their own ICUs to treat patients with a variety of conditions. Although it helped improve survival, mortality rates in critical care units remained stubbornly high, owing to the patients’ severe underlying illnesses.

“We thought we were doing a good job if the patient survived, but we had no idea what happened after discharge,” said Carla Sevin, MD, medical director of Vanderbilt’s ICU Recovery Center. Nor did their efforts to find out always bring answers. “We struggled to get people to come in for support — they were debilitated, physically burdened, and weak.”

Through further advances in life support, by the early 2000s, the average mortality rates in American ICUs had dropped to 8% to 19%. As the number of critical care survivors began to climb, clinical researchers noticed that the lives of these patients and their families were profoundly altered by their severe illness.

As Dale Needham, MD, PhD, began his pulmonology and critical care residency in Toronto, Canada, in 2005, a group of physicians there began a 5-year longitudinal study to assess long-term outcomes of patients who developed acute respiratory distress syndrome (ARDS). Although ARDS is an acute condition, the investigators found that patients felt effects for years. Younger patients recovered better than older ones, but none of the patients› physical functioning was equivalent to that of age-matched control persons. Even 5 years later, former ICU patients only reached 76% of expected physical functioning, according to results published in the New England Journal of Medicine. The study was a wake-up call.

At a meeting in Chicago in 2010, Needham, now an intensivist at Johns Hopkins Hospital in Baltimore, Maryland, gathered an interdisciplinary group of colleagues, including patients and caregivers, to clarify the phenomena they were seeing. What emerged from that meeting, published in 2012 in Critical Care Medicine, were the diagnostic criteria for PICS: According to the new definition, PICS is characterized by new or worsening physical and neuropsychiatric deficits that range from forgetfulness and loss of motivation to physical weakness and insomnia.

The issue, Needham says, is that although the trouble starts in the ICU, it only becomes clear once patients leave. “ICU doctors aren’t the ones dealing with this,” Needham said. “We need to build stronger bridges between critical care and other professions.” That’s where PICS comes in, a definition that exists explicitly to alert healthcare providers about the constellation of challenges many of these individuals face as they try to reenter “normal” life.
 

Defining the problem

As an ICU nurse at the Mayo Clinic in Rochester, Minnesota, Annie Johnson, ACNP-BC, knew lots about helping hospitalized patients, but she says she didn’t know anything about what to do after discharge – at least not until her own mother became a patient.

On the first day of retirement in October 2014, Johnson’s mother flatlined. Quick-thinking paramedics resuscitated her, and after several days in critical care, she was discharged. Since then, her heart has remained healthy. Johnson’s sister, who spent time worrying over her mother at the hospital, also had lingering effects. Both have since struggled, plagued by nightmares, flashbacks, and insomnia.

Johnson initially believed her mom’s and sister’s neuropsychiatric, post-ICU struggles were unique to her family. It was only a year later, at a seminar she was attending, that she first heard the words “post–intensive care syndrome.” Suddenly, Johnson had a name for her family’s experiences, and she began to create support groups and resources to help other families like hers.

“I thought of all the patients I had treated over the years who had been on ventilators for days and days and days. And if this happened to my mom after 48 hours, what must they be going through?” she asked.

Once physicians formally defined PICS, the Society for Critical Care Medicine helped create programs to educate ICU staff, patients, and families about potential post-discharge challenges. Researchers also began to investigate factors affecting post-ICU functioning. Follow-up studies of patients with delirium (ranging from general confusion about time and place to extreme agitation and violence) showed they had striking cognitive deficits. Problems with short-term memory, flexible thinking, and motivation plagued patients for years after their critical illness, similar to the physical deficiencies seen after ARDS. Delirium was one of the strongest risk factors for neuropsychiatric problems.

“Delirium is basically a stress test for the brain,” said Babar Khan, MD, a critical care specialist at Indiana University’s Regenstrief Institute, in Bloomington. But whether delirium accentuates preexisting cognitive difficulties or creates them afresh isn’t yet clear.

Sophia Wang, MD, a geriatric psychiatrist at Indiana University who works with many critical care patients, says patients who had experienced delirium in the ICU showed significant defects in memory and executive functioning long after their hospital stay. She points to a 2015 study that followed 47 ICU patients for a year post discharge. Among those who experienced delirium, brain volumes, as measured by MRI, were smaller at 3 months, something associated with cognitive problems at 1 year. Many struggled at work, and unemployment was common. Depression and posttraumatic stress compounded these difficulties. Among those with acute respiratory distress, ICU patients who are young, female, and unemployed are most likely to suffer from posttraumatic stress disorder after they are discharge.

Critical care medicine may have given these patients a second chance at life, Wang says, but the life they return to often looks nothing like the one they had before their illness.

Prolonged mechanical ventilation and the heavy sedation that often accompanies it are predictors of PICS severity. Some of these links could be explained by the gravity of the illness that landed someone in critical care, but others are more likely to be iatrogenic, says Gerald Weinhouse, MD, a pulmonology and critical care physician and co-director of the Critical Illness Recovery Program at the Brigham and Women’s Hospital in Boston. The involvement of loved ones at the patient’s bedside, however, improved the entire family’s outcome.

When Weinhouse saw those data, he and his colleagues founded a peer support program for ICU survivors. In a study published in 2019 in Critical Care Medicine, they identified six different models for peer support for those with PICS and their families, including both online and in-person approaches. An ongoing challenge for physicians, Weinhouse says, is getting patients to engage with these programs, given that their calendars are crowded with medical appointments and that they suffer from increased physical and mental disability.

Studies such as these led critical care physicians to form the ICU Liberation Collaborative to rethink critical care medicine. At Vanderbilt, Sevin and Jackson headed up one of the world’s first post-ICU clinics, which uses an interdisciplinary team to help patients maximize their functioning. They redesigned their critical care unit in a way that allows families to spend the night and that encourages patient mobility. Both Needham and Weinhouse continue tracking patient outcomes.

Even before the novel coronavirus struck, the United States — and the world — had begun to realize that graduating from the ICU was only the start of what was often an extensive recovery.
 

The long road back

When COVID-19 patients began flooding intensive care wards around the world, physicians scrambled to meet their complex and desperate acute medical needs. Over the past few months, physicians have focused on keeping these patients alive. “We’ve never seen anything like it ― not even during polio — with the sheer number of patients, all with respiratory distress,” Needham said.

But he and his colleagues know this is only the beginning.

“We’re aware that survivorship issues are coming. There’s going to be a wave of sick people who survived the coronavirus but are going to need more help,” Weinhouse said.

Intensivists have been drawing on PICS research in their fight to help COVID-19 patients. Work from the past few years has shown that although sedation is required during intubation itself, not everyone needs it while on a ventilator. Titrating down sedating medication helps reduce delirium, Wang says. Such medication has been shown to contribute to later cognitive problems. Needham’s studies showing that prolonged bedrest by ICU patients causes muscular atrophy has led him to encourage patients to move as much as possible. With the help of physical therapists, many patients on ventilators can be awake, alert, and moving around the ward.

One of the biggest challenges critical-care coronavirus patients face is prolonged isolation. The constant presence of a familiar face helps orient confused and delirious patients and provides emotional support during a frightening time. But because the immediate need for infection control outweighs these benefits, few hospitals allow visitors, especially for COVID-19 patients.

To address this, some units have been using video technology to allow loved ones to call in. At Johns Hopkins, physicians have also been relying on the expertise of occupational therapists (OTs). Needham says that one OT found that rubbing the hand and back of an agitated, delirious patient helped soothe and calm him better than many medications.

Ronan, who spent 5 days in intensive care, echoes that problem. She says she found the relative lack of human contact to be one of the most challenging parts of being in a bed on a COVID-19 ward. Separated from her husband and daughter, suffering from high fever and severe illness, she lost all track of time.

Her return home was difficult, too. Although her job as a home health nurse had prepared her on some level for the challenges she would face after discharge, Ronan says the hospital provided little practical help.

“Everything is so much harder at home, even little things like going to the bathroom,” she said. “I feel like I’m trying to bail out a sinking ship with a teacup.”

Khan and other physicians, aware of the challenges Ronan and others face once home, aim to create post-ICU clinics specifically for COVID-19 patients. They want to build what Khan calls a “one-stop shop” for all the support patients need to recover. Some of that can be provided via telehealth, which may also help ease the physical burden.

Because there’s so much physicians don’t know about the coronavirus, Johnson says, such clinics are not only a chance to help the sickest COVID-19 patients, they will also help researchers learn more about the virus and improve critical care for other illnesses.

Today, nearly 2 months after discharge, Ronan is back on the job but struggles with a persistent cough — likely due to the lung damage she sustained while ill. She has constant fatigue, as well as ongoing upset stomach from all the medications she took to reduce fever and body aches. When she dons a mask for work, the tangible reminder of her hospital stay sends her into a panic attack. Physically, she’s weaker than before.

Researchers are still trying to understand everything that Ronan and other COVID-19 patients need to move on with their lives after being in the ICU. Mysteries abound, but the ground laid by Sevin, Needham, Weinhouse, and others has provided a solid foundation on which to build.
 

This article first appeared on Medscape.com.

By the time she was discharged from a suburban New Jersey hospital on April 10, Kathleen Ronan thought the worst was behind her. For a week before her husband rushed her to the emergency department (ED), incoherent and struggling to breathe, the novel coronavirus had ravaged her body. She tried to treat her fevers with acetaminophen and ice packs. Despite taking enough Tylenol to risk liver damage and packing herself on ice like the catch of the day, Ronan’s fever continued to rise. By the time her temperature reached 104.5° F, Ronan knew the time had come for more drastic measures.

A team of masked and gowned nurses greeted her at a triage tent outside the ED, and from there, everything becomes hazy for Ronan. She was immediately rushed to the hospital’s special COVID-19 intensive care unit (ICU), where she spent 5 days. But she has few distinct memories from this time. What she does remember is the exhaustion, the pain, the loneliness, and the fear. Her family couldn’t visit, and though Ronan works as a home health nurse, her brain was so addled with fever that she couldn’t make sense of what was happening. After a week in the hospital, 5 days of which were spent in the ICU, 51-year-old Ronan was discharged.

Her years of working as a home health nurse told her that the return home wouldn’t be easy, but nothing prepared her for just how much she would struggle. The once-active Ronan, who had supplemented long days on her feet caring for others as a nurse with regular trips to the gym, now needed a walker to traverse the few steps from her bed to the toilet, an effort that left her gasping for air. Her brain couldn’t even focus on an audiobook, let alone a short magazine article.

“It just completely knocked the stuffing out of me,” Ronan said.

Ronan’s lingering symptoms aren’t unique to COVID-19 patients. In as many as 80% of patients leaving the ICU, researchers have documented what they call post–intensive care syndrome (PICS) — a constellation of physical, cognitive, and psychiatric symptoms that result from an ICU stay. Although underlying illness plays a role in these symptoms, the amount of time spent in critical care is a major factor.

Nor is PICS simply a set of side effects that will go away on their own. It includes ongoing cognitive difficulties and physical weakness, both of which can lead to employment problems. Beyond that, depression and anxiety can exacerbate – and be exacerbated by – these challenges. Psychologist Jim Jackson, PsyD, assistant director of the ICU Recovery Center at Vanderbilt University Medical Center, Nashville, Tennessee, recently spoke with a former ICU patient who has struggled since her discharge 30 years ago.

“Her life essentially stopped with her critical care stay. She hasn’t been able to move forward,” he said. “She’s part of a whole fraternity of people who are struggling.”

The good news is that over the past decade, researchers have made important strides in understanding what makes PICS symptoms worse and how critical care physicians can tweak ICU protocols to reduce PICS severity. Practitioners will need to draw on this knowledge to help Ronan and the thousands of COVID-19 ICU patients like her.
 

Surviving the ICU

Although the new coronavirus has pushed the world’s critical care system to its limits, it was an outbreak in 1952 that inspired the creation of intensive care units. That summer, a wave of paralytic polio swept over Copenhagen, Denmark, and anesthesiologist Bjørn Ibsen, MD, PhD, used mechanical ventilation — physically operated by medical and dental students – to help 316 children breathe for weeks at a time while their small bodies worked to fight off the virus. The effort halved the mortality rate from polio that affected breathing, from 80% to 40%.

In these wards, dedicated to the very sickest, each patient was assigned his or her own nurse. Over the next decade, hospitals in the United Kingdom and the United States established their own ICUs to treat patients with a variety of conditions. Although it helped improve survival, mortality rates in critical care units remained stubbornly high, owing to the patients’ severe underlying illnesses.

“We thought we were doing a good job if the patient survived, but we had no idea what happened after discharge,” said Carla Sevin, MD, medical director of Vanderbilt’s ICU Recovery Center. Nor did their efforts to find out always bring answers. “We struggled to get people to come in for support — they were debilitated, physically burdened, and weak.”

Through further advances in life support, by the early 2000s, the average mortality rates in American ICUs had dropped to 8% to 19%. As the number of critical care survivors began to climb, clinical researchers noticed that the lives of these patients and their families were profoundly altered by their severe illness.

As Dale Needham, MD, PhD, began his pulmonology and critical care residency in Toronto, Canada, in 2005, a group of physicians there began a 5-year longitudinal study to assess long-term outcomes of patients who developed acute respiratory distress syndrome (ARDS). Although ARDS is an acute condition, the investigators found that patients felt effects for years. Younger patients recovered better than older ones, but none of the patients› physical functioning was equivalent to that of age-matched control persons. Even 5 years later, former ICU patients only reached 76% of expected physical functioning, according to results published in the New England Journal of Medicine. The study was a wake-up call.

At a meeting in Chicago in 2010, Needham, now an intensivist at Johns Hopkins Hospital in Baltimore, Maryland, gathered an interdisciplinary group of colleagues, including patients and caregivers, to clarify the phenomena they were seeing. What emerged from that meeting, published in 2012 in Critical Care Medicine, were the diagnostic criteria for PICS: According to the new definition, PICS is characterized by new or worsening physical and neuropsychiatric deficits that range from forgetfulness and loss of motivation to physical weakness and insomnia.

The issue, Needham says, is that although the trouble starts in the ICU, it only becomes clear once patients leave. “ICU doctors aren’t the ones dealing with this,” Needham said. “We need to build stronger bridges between critical care and other professions.” That’s where PICS comes in, a definition that exists explicitly to alert healthcare providers about the constellation of challenges many of these individuals face as they try to reenter “normal” life.
 

Defining the problem

As an ICU nurse at the Mayo Clinic in Rochester, Minnesota, Annie Johnson, ACNP-BC, knew lots about helping hospitalized patients, but she says she didn’t know anything about what to do after discharge – at least not until her own mother became a patient.

On the first day of retirement in October 2014, Johnson’s mother flatlined. Quick-thinking paramedics resuscitated her, and after several days in critical care, she was discharged. Since then, her heart has remained healthy. Johnson’s sister, who spent time worrying over her mother at the hospital, also had lingering effects. Both have since struggled, plagued by nightmares, flashbacks, and insomnia.

Johnson initially believed her mom’s and sister’s neuropsychiatric, post-ICU struggles were unique to her family. It was only a year later, at a seminar she was attending, that she first heard the words “post–intensive care syndrome.” Suddenly, Johnson had a name for her family’s experiences, and she began to create support groups and resources to help other families like hers.

“I thought of all the patients I had treated over the years who had been on ventilators for days and days and days. And if this happened to my mom after 48 hours, what must they be going through?” she asked.

Once physicians formally defined PICS, the Society for Critical Care Medicine helped create programs to educate ICU staff, patients, and families about potential post-discharge challenges. Researchers also began to investigate factors affecting post-ICU functioning. Follow-up studies of patients with delirium (ranging from general confusion about time and place to extreme agitation and violence) showed they had striking cognitive deficits. Problems with short-term memory, flexible thinking, and motivation plagued patients for years after their critical illness, similar to the physical deficiencies seen after ARDS. Delirium was one of the strongest risk factors for neuropsychiatric problems.

“Delirium is basically a stress test for the brain,” said Babar Khan, MD, a critical care specialist at Indiana University’s Regenstrief Institute, in Bloomington. But whether delirium accentuates preexisting cognitive difficulties or creates them afresh isn’t yet clear.

Sophia Wang, MD, a geriatric psychiatrist at Indiana University who works with many critical care patients, says patients who had experienced delirium in the ICU showed significant defects in memory and executive functioning long after their hospital stay. She points to a 2015 study that followed 47 ICU patients for a year post discharge. Among those who experienced delirium, brain volumes, as measured by MRI, were smaller at 3 months, something associated with cognitive problems at 1 year. Many struggled at work, and unemployment was common. Depression and posttraumatic stress compounded these difficulties. Among those with acute respiratory distress, ICU patients who are young, female, and unemployed are most likely to suffer from posttraumatic stress disorder after they are discharge.

Critical care medicine may have given these patients a second chance at life, Wang says, but the life they return to often looks nothing like the one they had before their illness.

Prolonged mechanical ventilation and the heavy sedation that often accompanies it are predictors of PICS severity. Some of these links could be explained by the gravity of the illness that landed someone in critical care, but others are more likely to be iatrogenic, says Gerald Weinhouse, MD, a pulmonology and critical care physician and co-director of the Critical Illness Recovery Program at the Brigham and Women’s Hospital in Boston. The involvement of loved ones at the patient’s bedside, however, improved the entire family’s outcome.

When Weinhouse saw those data, he and his colleagues founded a peer support program for ICU survivors. In a study published in 2019 in Critical Care Medicine, they identified six different models for peer support for those with PICS and their families, including both online and in-person approaches. An ongoing challenge for physicians, Weinhouse says, is getting patients to engage with these programs, given that their calendars are crowded with medical appointments and that they suffer from increased physical and mental disability.

Studies such as these led critical care physicians to form the ICU Liberation Collaborative to rethink critical care medicine. At Vanderbilt, Sevin and Jackson headed up one of the world’s first post-ICU clinics, which uses an interdisciplinary team to help patients maximize their functioning. They redesigned their critical care unit in a way that allows families to spend the night and that encourages patient mobility. Both Needham and Weinhouse continue tracking patient outcomes.

Even before the novel coronavirus struck, the United States — and the world — had begun to realize that graduating from the ICU was only the start of what was often an extensive recovery.
 

The long road back

When COVID-19 patients began flooding intensive care wards around the world, physicians scrambled to meet their complex and desperate acute medical needs. Over the past few months, physicians have focused on keeping these patients alive. “We’ve never seen anything like it ― not even during polio — with the sheer number of patients, all with respiratory distress,” Needham said.

But he and his colleagues know this is only the beginning.

“We’re aware that survivorship issues are coming. There’s going to be a wave of sick people who survived the coronavirus but are going to need more help,” Weinhouse said.

Intensivists have been drawing on PICS research in their fight to help COVID-19 patients. Work from the past few years has shown that although sedation is required during intubation itself, not everyone needs it while on a ventilator. Titrating down sedating medication helps reduce delirium, Wang says. Such medication has been shown to contribute to later cognitive problems. Needham’s studies showing that prolonged bedrest by ICU patients causes muscular atrophy has led him to encourage patients to move as much as possible. With the help of physical therapists, many patients on ventilators can be awake, alert, and moving around the ward.

One of the biggest challenges critical-care coronavirus patients face is prolonged isolation. The constant presence of a familiar face helps orient confused and delirious patients and provides emotional support during a frightening time. But because the immediate need for infection control outweighs these benefits, few hospitals allow visitors, especially for COVID-19 patients.

To address this, some units have been using video technology to allow loved ones to call in. At Johns Hopkins, physicians have also been relying on the expertise of occupational therapists (OTs). Needham says that one OT found that rubbing the hand and back of an agitated, delirious patient helped soothe and calm him better than many medications.

Ronan, who spent 5 days in intensive care, echoes that problem. She says she found the relative lack of human contact to be one of the most challenging parts of being in a bed on a COVID-19 ward. Separated from her husband and daughter, suffering from high fever and severe illness, she lost all track of time.

Her return home was difficult, too. Although her job as a home health nurse had prepared her on some level for the challenges she would face after discharge, Ronan says the hospital provided little practical help.

“Everything is so much harder at home, even little things like going to the bathroom,” she said. “I feel like I’m trying to bail out a sinking ship with a teacup.”

Khan and other physicians, aware of the challenges Ronan and others face once home, aim to create post-ICU clinics specifically for COVID-19 patients. They want to build what Khan calls a “one-stop shop” for all the support patients need to recover. Some of that can be provided via telehealth, which may also help ease the physical burden.

Because there’s so much physicians don’t know about the coronavirus, Johnson says, such clinics are not only a chance to help the sickest COVID-19 patients, they will also help researchers learn more about the virus and improve critical care for other illnesses.

Today, nearly 2 months after discharge, Ronan is back on the job but struggles with a persistent cough — likely due to the lung damage she sustained while ill. She has constant fatigue, as well as ongoing upset stomach from all the medications she took to reduce fever and body aches. When she dons a mask for work, the tangible reminder of her hospital stay sends her into a panic attack. Physically, she’s weaker than before.

Researchers are still trying to understand everything that Ronan and other COVID-19 patients need to move on with their lives after being in the ICU. Mysteries abound, but the ground laid by Sevin, Needham, Weinhouse, and others has provided a solid foundation on which to build.
 

This article first appeared on Medscape.com.