Robin Macnofsky’s first symptoms, in April 2020, were so mild she didn’t take a test for COVID-19, preferring to save it for someone who really needed it.
A few weeks later her chest tightened and her temperature spiked. These ebbed, but an even stronger wave hit: a high fever and exhaustion that left her bedbound in a days-long “zombie sleep.” Macnofsky tested positive for COVID-19 (likely from remaining viral genetic material). Her symptoms endured.
Previously a champion multi-tasker who could split her concentration in four directions, the then-59-year-old could no longer follow the plot of a TV episode or walk her dog. Her temperature waxed and waned.
A realization dawned: The end was nowhere in sight, and no one could tell her why.
Scientists studying the unfamiliar and unfurling COVID-19 pandemic also began to realize that for Macnofsky and many other COVID-19 patients, a long hospital stay or a short, mild illness were not the only outcomes. For some people, mild symptoms, quickly resolved, were just the beginning.
Researchers worldwide, including many at Fred Hutchinson Cancer Research Center and the University of Washington, are working to understand long COVID-19, the long-lasting effects of COVID-19 infection that can affect adults, teens and children. Hutch and UW investigators are building on deep expertise in immunology and infectious diseases like HIV to figure out what causes long COVID-19, who is at risk, and how to treat it. To do so, they’re tackling challenges that range from basic questions about how best to measure symptoms to uncovering the complex immunological interplay that may drive symptoms.
In March 2020, Julie Czartoski, a nurse practitioner working with Fred Hutch virology expert and Joel D. Meyers Endowed Chair holder Dr. Julie McElrath, helped McElrath quickly put together a study, the Seattle COVID Cohort Study, to look at COVID-19 in first responders and those infected with SARS-CoV-2, the virus that causes COVID-19. They wanted to know who was getting it, and how badly. Soon they opened the study to others in the community. Luckily, few participants who contracted the coronavirus had symptoms that warranted hospitalization. Most had relatively mild infections that cleared up quickly.
But that wasn’t the end. For many, symptoms persisted, even worsened. Participants reported lingering fevers, new joint pain, exhaustion and brain fog, among a grab bag of other symptoms. When an unexpected number of young, healthy firefighters reported atrial fibrillation — a rapid, abnormal heart rhythm — Czartoski knew something was up.
“It’s not unheard of in young adults, but to have so many was weird,” she said. “I remember texting Julie McElrath and saying, ‘Something is different, because these people are still sick.’”
Because of their fast action and prompt study enrollment, Czartoski and McElrath were early to recognize a truth that would eventually become clear to other scientists: COVID-19 can cast a long shadow.
Many of the people in McElrath’s study who reported lasting problems had experienced mild, almost cold-like infections with SARS-CoV-2. Very few had been hospitalized.
It takes time to know for sure that a patient is suffering from long COVID-19. A week or two is not long enough to be sure their symptoms won’t clear up soon. Eventually, McElrath and her team found that about 30% of the coronavirus-positive participants in their study had lasting symptoms, or new symptoms attributed to COVID-19, that extended at least 60 days past their initial infection, Czartoski said.
Long COVID-19 dogs some patients, like Macnofsky, much longer, and their symptoms can be severe. After two different week-long hospital stays, in which she underwent terrifying procedures to remove nearly a liter of fluid pressing on her heart and then her lungs, Macnofsky took a leave of absence from her career as a community organizer. By early 2022, she still rations her energy and has yet to regain her prior multi-tasking abilities.
Time defines the syndrome and time challenges those suffering from it and the scientists working to untangle it. Also known as PASC, for post-acute sequelae of SARS-CoV-2 infection, long COVID-19 refers to symptoms that endure long after someone has recovered from their initial coronavirus infection. (The term “sequelae” refers to a disease’s aftereffects.) Symptoms can include fatigue, shortness of breath, brain fog, fever, anxiety and depression. COVID-19 patients who were sick enough to need ICU care may also be dealing with post-ICU syndrome, and it's not yet clear how their experience will unfold differently from patients who were treated in the ICU for other causes.
For a health problem as mysterious and as complex as long COVID-19, progress requires scientific teamwork.
That’s why, in summer 2021, Dr. Rachel Bender Ignacio reached out to investigators across Fred Hutch and the University of Washington, inviting them to join a long COVID-19 working group to share challenges and solutions, and find collaborators to help investigate specific questions.
As medical director of the Hutch’s COVID-19 Clinical Research Center, or CCRC, Bender Ignacio had a good sense of who at both institutions were treating or studying the syndrome. She was also hearing from CCRC trial participants who had transitioned from acute to long COVID-19 and wanted to know how scientists were addressing it. “I have my ear to the ground,” she said.
Bender Ignacio felt that progress required stronger connections between clinicians and laboratory and translational scientists. Physicians needed a better understanding of the biological mechanisms driving long COVID-19 before they could move proposed treatments into clinical trials, and basic scientists could reveal those mechanisms but needed tissue samples and clinical insights from the people providing patient care.
“Bringing everyone together was the least I could do,” Bender Ignacio said.
The working group she put together is an example of international and multidisciplinary efforts to tackle the challenges that vex investigators studying long COVID-19, including how to best classify and diagnose the syndrome, what’s causing it, and how to treat it. The recently launched National Institutes of Health RECOVER initiative, aimed at understanding PASC, is giving the investigators in the field hope that standards may be forthcoming, said Dr. Eric Chow, a working group member and UW infectious diseases fellow who studies the damage that respiratory viruses can do outside the lungs.
The researchers who joined Bender Ignacio’s collective span disciplines and body systems, including the brain, heart and lungs. They include researchers and clinicians at UW and Harborview Medical Center, which opened one of the nation’s earliest clinics devoted to helping long COVID-19 patients. The working group members bring expertise in long-term complications from viral infections like HIV and influenza, and know how viruses or the immune reaction to them can damage the body. SARS-CoV-2 may be wreaking the most havoc right now, but it’s not the only virus that can upend sufferers’ lives: Many, including Bender Ignacio, have spent their careers studying the long-term effects of HIV.
Now the team is bringing their wide-ranging expertise to bear on the many questions of long-haul COVID-19, hoping to surmount its challenges and help patients.
Studying a little-understood problem in a rapidly shifting pandemic is incredibly challenging. At the beginning, scientists had no knowledge base to inform their data collection or study design. Every week or month brought new information that forced them to reassess the data they had already collected — and adjust their data-collection methods to incorporate new understanding.
“It’s like building a boat while you’re sailing it,” said working group and CCRC member Dr. James Andrews, a University of Washington rheumatologist who studies how sepsis, particularly severe cases requiring hospitalization, can lead to long-term disability.
The first challenge was realizing that a problem existed. Many of the long-haulers Czartoski interviewed for the Seattle COVID Cohort Study struggled to find help and even recognition of their symptoms, she said.
“In the beginning, a big part of my job was just listening,” Czartoski recalled.
Study participants wept as they described to her their crushing fatigue and debilitating symptoms, and the struggle to get health care providers to understand that their vague-seeming complaints posed a real problem. Macnofsky, too, found it difficult to get help for her constant fever, headaches, fatigue and brain fog.
In the beginning, no one knew what information would be important to understand why these patients were suffering and how to help.
A snapshot of data “is one piece of the whole puzzle,” said Hutch statistician Dr. Zoe Moodie, who helps design and analyze HIV vaccine trials and develops statistical methods to analyze immunological data. “Generally, the more pieces the better, and as time goes go on we learn which are the important pieces.”
Czartoski tackled the problem by collecting everything she could: “Sometimes [a symptom] didn’t seem important, then a week later I’d have five people reporting it.”
And sometimes the information that most impacts a patient’s life can seem negligible when committed to paper, she said. One person’s loss of smell or taste may seem like small potatoes compared to others’ chronic exhaustion and continual fevers. But such seemingly small symptoms can make life and some careers difficult: Firefighters smell phantom burning and parents who can no longer smell a dirty diaper. Once-favorite food now repells.
“And [those symptoms] are really tough on quality of life,” Czartoski noted. Depression can set in, straining a person’s long-term relationships, affecting quality of life and for some, the ability to hold down a job.
Initially, she had a limited systematized questionnaire, and took notes longhand while patients noted every symptom they could think of — whether they knew it related to their COVID-19 or not. As time passed, Czartoski and her colleagues were able to spot common symptoms that they added to an ever-expanding checklist. (Then, they had to get the checklist built into the study records system.)
The working group members brainstorm statistical and analytical strategies that could help, and which take into account the fact that not everyone’s data has been collected in the same way at the same time points during the course of their disease.
Even now, their efforts to untangle long COVID-19 are hampered by what they didn’t know six, 12, 18 months ago, Czartoski said.
“Researchers will ask about blood drawn a year and a half ago: Were they taking Tylenol?” she said. “It could change the immune response, but I don’t know!”
Another major challenge that long COVID-19 researchers face is classification. Many studies are producing data on the syndrome, but if symptoms aren’t collected and classified similarly, trying to compare different studies will be like comparing apples and oranges.
Decisions about how to classify symptoms also affect how patients are grouped together and how the data is analyzed. One big concern: Should patients be grouped by symptom, or should symptoms be grouped by the organs they affect?
It’s a bit of a chicken-and-egg issue, but it gets into the problem of what’s behind long COVID-19 to begin with, said Chow, who began treating Macnofsky after her hospital stay. (The two teamed up to tell Macnofsky’s story in a dual first-person essay published in the scientific journal Open Forum Infectious Diseases.)
“For example, what about fatigue? Do you group everyone with fatigue together? But what if one person’s fatigue is caused by damage to the nervous system, another’s by damage to their heart, and someone else’s by lung damage,” said Chow, who at the start of the pandemic was part of the Centers for Disease Control and Prevention team that went to New York state to confirm COVID-19-associated multisystem inflammatory syndrome in children.
Even in cases where it’s clear the immune system is at fault, fatigue may not have a single cause. Energy-sucking immune activation could explain one person’s fatigue, but post-infection autoimmunity, in which their own tissues are under attack, could be the reason behind another’s, Andrews said.
Trying to find the biological similarities in data taken from these patients would be like trying to compare pages of text written in different languages: more likely to result in gibberish than to identify a helpful pattern.
And sometimes, symptoms may not even be the result of a person’s coronavirus infection. Part of the problem is the often-vague, widely varying collection of symptoms, many of which long COVID-19 shares with other chronic health problems, such as autoimmune diseases or chronic fatigue syndrome. Autoimmune diseases often strike in young adulthood. For some people, SARS-CoV-2 infection and an autoimmune diagnosis are just two pieces of unrelated bad luck.
“In a longitudinal cohort like this, nothing is ever completely clean,” Czartoski said.
Working group members share questions and strategies. Should they classify symptoms by severity score, or follow the CDC’s recommendations to classify symptoms by outcome measures in different areas? Members often draw on their or other members’ expertise in different disciplines, such as adapting questionnaires used by neurologists to assess cognitive difficulties. Czartoski recommended a severity scale long used by HIV researchers to assess how symptoms impact patients’ daily living.
The team also grapples with the challenges of classifying symptoms that may seem focused on a specific organ system, but are actually emblematic of a body-wide problem. Researchers noted that some simplification needs to occur to make it possible to analyze the reams of data that can be collected.
But sometimes it’s unclear what’s causing someone’s symptom — so researchers can’t classify symptoms by underlying cause. What then?
Members also keep an eye on trends in the wider scientific community to see if they can align with areas of growing consensus, the better to compare their results with other studies.
But sorting out the logistical challenges of classification is just the first step. Long COVID-19 researchers want to understand why symptoms develop and who’s at risk. Why do some symptoms affect some patients but not others? Who will have a mild course, and who will suffer greatly? A deeper understanding, they hope, will shed light on why symptoms linger so long for some people, and how to predict how a patient’s experience will unfold.
UW neurologist Dr. Payal Patel is focusing on the cognitive symptoms of PASC.
“I want to know, what is the cause of the symptoms we see in PASC,” said Patel, who studies the continuing effects of infections of the central nervous system, including HIV. “We know PASC affects different organ systems. I’m trying to get a better clinical understanding of how it affects the brain.”
Without this, it’s difficult to give worried patients a clear picture of what they can expect from long COVID. Patel wants to better understand how long such symptoms last, who’s most at risk, and what’s causing them. Is brain fog caused primarily by immune dysfunction? Or could the clotting problems associated with COVID-19 have damaged the cells lining blood vessels in the brain? Patel and a team of scientists have studies underway to answer these questions.
This type of location-specific question can be very difficult to address, Chow noted. It’s relatively easy to take blood samples and look at general patterns of immune cells or antibodies floating through the blood. But what about problems that are occurring at a hard-to-reach spot, like tiny blood vessels in the brain or lungs?
Some working group members focus their research questions on specific areas of the body. With Patel, Andrews is trying to understand who’s most at risk for cognitive and physical impairments after COVID. Some patients’ fatigue is related to muscle wasting, known medically as sarcopenia, and Andrews wants to know what’s behind that and who’s at risk.
Since it became understood that an overactive immune response (known as a “cytokine storm”) lurks behind some of COVID-19’s most dire complications, scientists have begun digging deeper into how the immune system responds to SARS-CoV-2. Macnofsky herself participated in a Benaroya Research Institute study looking at the immune response to the novel coronavirus.
Bender Ignacio's working group is drawing on the Hutch’s longstanding expertise in immunology and infectious diseases and looking to the immune system for answers.
“We’re studying what natural infection looks like over time,” said Fred Hutch immunologist Dr. Maria Lemos, who studies immune responses in mucosal tissue like vaginal and nasal surfaces, where we first encounter many viruses. “People could have cold symptoms for nine days, then four moths later they’re diagnosed with a lung condition or a heart condition.”
To understand why, she and others on McElrath’s team are mapping the immune response to SARS-CoV-2 infection as it unfolds over months. With collaborators at Emory University in Atlanta, they’re charting the rise and fall of antibodies against the virus and how different immune-cell populations grow, shrink and morph over time.
By describing how these responses differ between people who did and did not develop long COVID-19, the researchers hope to identify key biomarkers, like specific inflammatory proteins, that help predict which patients will have persistent problems. Such biological predictors could help doctors intervene early, either to help connect patients with the right services to help them deal with symptoms, or (once scientists crack this problem) stave it off entirely.
McElrath’s team, with collaborators at Emory University and the Seattle-based Allen Institute for Immunology, has revealed some tantalizing immunological patterns, Lemos said, which the group posted on the preprint server biorxiv.org. The immune trajectory in many long-haulers looks startlingly unlike that seen in people who recover quickly and permanently.
“The alarm system of the immune system doesn’t get turned on as quickly in these people — but surprisingly it seems to remain on for way longer,” Lemos said. They’re currently putting together a paper for peer review at a scientific journal.
On top of this project, Moodie is working with investigators the Allen Institute to identify immunological signatures, including cellular features like proteins and gene expression, that distinguish long COVID-19 from acute COVID-19. Some patients — including Macnofsky — report improvement of symptoms after vaccination for COVID-19, and Moodie and her collaborators want to understand how vaccination may help their bodies resolve their chronic, damaging immune responses.
(Whether prior COVID-19 vaccination helps protect against developing long COVID-19 is still being explored. A recent study in The Lancet suggests that vaccinated people are less likely to have long-lasting symptoms after SARS-CoV-2 infection.)
Macnofsky said she’s recently been helped by six months of weekly pulmonary rehab sessions. It’s possible that early access to rehabilitative therapies could help prevent or alleviate severe long COVID-19 in others.
It is taking time for scientists at the Hutch and elsewhere to get a clear enough picture of what’s driving long COVID-19 to open clinical studies to address patients’ problems, but a few have begun.
The Seattle arm of a multi-center, Phase 2 trial of a drug called RSLV 132, is administered through the CCRC and headed by Andrews. (People interested in participating can contact the CCRC.) Developed by biotech company Resolve Therapeutics, the drug has already shown promise against fatigue in people with autoimmune diseases like Sjögren syndrome, and scientists hope long COVID-19 patients will also benefit.
“One of the exciting things about this study is that it’s taking a targeted therapy approach to treating symptoms,” Andrews said. “It’s targeting the mechanism behind fatigue — chronic inflammation — to see if it helps.”
In addition to testing whether RSLV 132 outperforms a placebo when it comes to alleviating fatigue in long COVID-19 patients, researchers will collect tissue samples that they’ll study to get a better picture of how it might be working (if it does), he said. If it turns out that some patients respond and some don’t, such samples could also help investigators figure out why.
And, if there’s a similar biological process underpinning the fatigue seen in long COVID and other diseases and syndromes, the study could benefit a wide array of patients, Andrews said.
That’s a hope that other members of the working group also harbor. One of the big questions, said Chow, is whether long COVID-19 patients are suffering from the same immunologic problems as patients with chronic fatigue syndrome, autoimmune diseases, or other virus-associated chronic damage. Or is there something unique about the biology behind long COVID-19?
Bender Ignacio sees potential for the close ties between the CCRC and the long COVID-19 working group to help fast-track promising treatments or treatment strategies that emerge from group members’ projects.
One thing Chow hopes come from the studies is more predictability. Right now, clinicians struggle to determine whose symptoms will last, and whose will resolve. A better understanding of long COVID-19 subgroups will help clinicians guide patients toward the best therapies for them. Improving doctors’ ability to diagnose and clinically characterize long COVID-19 will also help improve insurance reimbursement, he said. Right now, he stressed the need to recognize and validate what patients with long COVID-19 face.
Macnofsky, who at one point couldn’t take a phone call from a friend without falling back into a zombie sleep, feels fortunate. She joined Facebook groups organized by long COVID-19 sufferers, where many reported not just horrible symptoms but job loss and crushing debt. Macnofsky’s leave of absence from her career was fully supported — emotionally and financially — by her husband. She’s recovered enough now to step back into some job duties, though not at her previous level. But she knows other patients who continue to suffer, with no idea when — or if — their symptoms will ever improve.
On top of everything else, her uncertain future is one of the biggest challenges Macnofsky faces Luckily, she said, her "keep calm and carry on" attitude (and compassionate family) are helping her ride her waves of symptoms.
“There’s a mental health component to being so ill,” Czartoski said. She still encourages patients to treat themselves gently and take it one day at a time. While most will improve with time, a few will worsen — and she still can’t tell someone which patient they’ll be. The answer will only come with more data.
“I’m still collecting everything I can,” Czartoski said.
Sabrina Richards, a staff writer at Fred Hutchinson Cancer Center, has written about scientific research and the environment for The Scientist and OnEarth Magazine. She has a Ph.D. in immunology from the University of Washington, an M.A. in journalism and an advanced certificate from the Science, Health and Environmental Reporting Program at New York University. Reach her at email@example.com.
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