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Tag: Women’s Hospital

  • The Big COVID Question for Hospitals This Fall

    The Big COVID Question for Hospitals This Fall

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    Back in the spring, around the end of the COVID-19 public-health emergency, hospitals around the country underwent a change in dress code. The masks that staff had been wearing at work for more than three years vanished, in some places overnight. At UChicago Medicine, where masking policies softened at the end of May, Emily Landon, the executive medical director of infection prevention and control, fielded hate mail from colleagues, some chiding her for waiting too long to lift the requirement, others accusing her of imperiling the immunocompromised. At Vanderbilt University Medical Center, which did away with masking in April, ahead of many institutions, Tom Talbot, the chief hospital epidemiologist, was inundated with thank-yous. “People were ready; they were tired,” he told me. “They’d been asking for several months before that, ‘Can we not stop?’”

    But across hospitals and policies, infection-prevention experts shared one sentiment: They felt almost certain that the masks would need to return, likely by the end of the calendar year. The big question was exactly when.

    For some hospitals, the answer is now. In recent weeks, as COVID-19 hospitalizations have been rising nationwide, stricter masking requirements have returned to a smattering of hospitals in Massachusetts, California, and New York. But what’s happening around the country is hardly uniform. The coming respiratory-virus season will be the country’s first after the end of the public-health emergency—its first, since the arrival of COVID, without crisis-caliber funding set aside, routine tracking of community spread, and health-care precautions already in place. After years of fighting COVID in concert, hospitals are back to going it alone.

    A return to masking has a clear logic in hospitals. Sick patients come into close contact; medical procedures produce aerosols. “It’s a perfect storm for potential transmission of microbes,” Costi David Sifri, the director of hospital epidemiology at UVA Health, told me. Hospitals are on the front lines of disease response: They, more than nearly any other place, must prioritize protecting society’s vulnerable. And with one more deadly respiratory virus now in winter’s repertoire, precautions should logically increase in lockstep. But “there is no clear answer on how to do this right,” says Cameron Wolfe, an infectious-disease physician at Duke. Americans have already staked out their stances on masks, and now hospitals have to operate within those confines.

    When hospitals moved away from masking this spring, they each did so at their own pace—and settled on very different baselines. Like many other hospitals in Massachusetts, Brigham and Women’s Hospital dropped its mask mandate on May 12, the day the public-health emergency expired; “it was a noticeable difference, just walking around the hospital” that day, Meghan Baker, a hospital epidemiologist for both Brigham and Women’s Hospital and Dana-Farber Cancer Institute, told me. UVA Health, meanwhile, weaned staff off of universal masking over the course of about 10 weeks.

    Most masks at the Brigham are now donned on only a case-by-case basis: when a patient has active respiratory symptoms, say, or when a health-care worker has been recently sick or exposed to the coronavirus. Staff also still mask around the same subset of vulnerable patients that received extra protection before the pandemic, including bone-marrow-transplant patients and others who are highly immunocompromised, says Chanu Rhee, an associate hospital epidemiologist at Brigham and Women’s Hospital. UVA Health, meanwhile, is requiring masks for everyone in the hospital’s highest-risk areas—among them, certain intensive-care units, as well as cancer, transplant, and infusion wards. And although Brigham patients can always request that their providers mask, at UVA, all patients are asked upon admission whether they’d like hospital staff to mask.

    Nearly every expert I spoke with told me they expected that masks would at some point come back. But unlike the early days of the pandemic, “there is basically no guidance from the top now,” Saskia Popescu, an epidemiologist and infection-prevention expert at the University of Maryland School of Medicine, said. The CDC still has a webpage with advice on when to mask. Those recommendations are tailored to the general public, though—and don’t advise covering up until COVID hospital admissions go “way high, when the horse has well and truly left the barn,” Landon, at UChicago, told me. “In health care, we need to do something before that”—tamping down transmission prior to wards filling up.

    More specific advice could still emerge from the CDC, or individual state health departments. But going forward, the assumption is that “each hospital is supposed to have its own general plan,” Rhee told me. (I reached out to the CDC repeatedly about whether it might update its infection-prevention-guidance webpage for COVID—last retooled in May—but didn’t receive a response.)

    Which leaves hospitals with one of two possible paths. They could schedule a start to masking season, based on when they estimate cases might rise—or they could react to data as they come in, tying masking policies to transmission bumps. With SARS-CoV-2 still so unpredictable, many hospitals are opting for the latter. That also means defining a true case rise—“what I think everybody is struggling with right now,” Rhee said. There is no universal definition, still, for what constitutes a surge. And with more immunity layered over the population, fewer infections are resulting in severe disease and death—even, to a limited extent, long COVID—making numbers that might have triggered mitigations just a year or two ago now less urgent catalysts.

    Read: The future of long COVID

    Further clouding the forecast is the fact that much of the data that experts once relied on to monitor COVID in the community have faded away. In most parts of the country, COVID cases are no longer regularly tallied; people are either not testing, or testing only at home. Wastewater surveillance and systems that track all influenza-like illnesses could provide some support. But that’s not a whole lot to go on, especially in parts of the country such as Tennessee, where sewage isn’t as closely tracked, Tom Talbot, of Vanderbilt, told me.

    Some hospitals have turned instead to in-house stats. At Duke—which has adopted a mitigation policy that’s very similar to UVA’s—Wolfe has mulled pulling the more-masking lever when respiratory viruses account for 2 to 4 percent of emergency and urgent-care visits; at UVA, Sifri has considered taking action once 1 or 2 percent of employees call out sick, with the aim of staunching sickness and preserving staff. “It really doesn’t take much to have an impact on our ability to maintain operations,” Sifri told me. But “I don’t know if those are the right numbers.” Plus, internal metrics are now tricky for the same reasons they’ve gotten shaky elsewhere, says Xiaoyan Song, the chief infection-control officer at Children’s National Hospital, in Washington, D.C. Screening is no longer routine for patients, skewing positivity stats; even sniffly health-care workers, several experts told me, are now less eager to test and report.

    Read: What COVID hospitalization numbers are missing

    For hospitals that have maintained a more masky baseline, scenarios in which universal masking returns are a little easier to envision and enact. At UChicago Medicine, Landon and her colleagues have developed a color-coded system that begins at teal—masking for high-risk patients, patients who request masked care, and anyone with symptoms, plus masking in high-risk areas—and goes through everyone-mask-up-everywhere red; their team plans to meet weekly to assess the situation, based on a variety of community and internal metrics, and march their masking up or down. Wolfe, of Duke, told me that his hospital “wanted to reserve a little bit of extra masking quite intentionally,” so that any shift back toward stricter standards would feel like less of a shock: Habits are hard to break and then reform.

    Other hospitals that have been living mostly maskless for months, though, have a longer road back to universal masking, and staff members who might not be game for the trek. Should masks need to return at the Brigham or Dana-Farber, for instance, “I suspect the reaction will be mixed,” Baker told me. “So we really are trying to be judicious.” The hospital might try to preserve some maskless zones in offices and waiting rooms, for instance, or lower-risk rooms. And at Children’s National, which has also largely done away with masks, Song plans to follow the local health department’s lead. “Once D.C. Health requires hospitals to reimplement the universal-masking policy,” she told me, “we will be implementing it too.”

    Other mitigations are on the table. Several hospital epidemiologists told me they expected to reimplement some degree of asymptomatic screening for various viruses around the same time they reinstate masks. But measures such as visiting restrictions are a tougher call. Wolfe is reluctant to pull that lever before he absolutely has to: Going through a hospital stay alone is one of the “harder things for patients to endure.”

    A bespoke approach to hospital masking isn’t impractical. COVID waves won’t happen synchronously across communities, and so perhaps neither should policies. But hospitals that lack the resources to keep tabs on viral spread will likely be at a disadvantage, and Popescu told me she worries that “we’re going to see significant transmission” in the very institutions least equipped to handle such influx. Even the best-resourced places may hit stumbling blocks: Many are still reeling from three-plus years of crisis and are dealing with nursing shortages and worker burnout.

    Coordination hasn’t entirely gone away. In North Carolina, Duke is working with the University of North Carolina at Chapel Hill and North Carolina State University to shift policies in tandem; in Washington State, several regional health-care organizations have pledged to align their masking policies. And the Veterans Health Administration—where masking remains required in high-risk units—has developed a playbook for augmenting mitigations across its many facilities, which together make up the country’s largest integrated health-care system, says Shereef Elnahal, the undersecretary of Veterans Affairs for health. Still, institutions can struggle to move in sync: Attitudes on masking aren’t exactly universal across health-care providers, even within a hospital.

    The country’s experience with COVID has made hospitals that much more attuned to the impacts of infectious disease. Before the pandemic began, Talbot said, masking was a rarity in his hospital, even around high-risk patients; many employees would go on shifts sick. “We were pretty complacent about influenza,” he told me. “People could come to work and spread it.” Now hospital workers hold themselves to a stricter standard. At the same time, they have become intimately attuned to the drawbacks of constant masking: Some have complained that masks interfere with communication, especially for patients who are young or hard of hearing, or who have a language barrier. “I do think you lose a little bit of that personal bonding,” Talbot said. And prior to the lifting of universal masking at Vanderbilt, he said, some staff were telling him that one out of 10 times they’d ask a patient or family to mask, the exchange would “get antagonistic.”

    Read: The pandemic’s legacy is already clear

    When lifting mandates, many of the hospital epidemiologists I spoke with were careful to message to colleagues that the situation was fluid: “We’re suspending universal masking temporarily,” as Landon put it to her colleagues. Still, she admits that she felt uncomfortable returning to a low-mask norm at all. (When she informally polled nearly two dozen other hospital epidemiologists around the country in the spring, most of them told her that they felt the same.) Health-care settings aren’t meant to look like the rest of the world; they are places where precautions are expected to go above and beyond. COVID’s arrival had cemented masks’ ability to stop respiratory spread in close quarters; removing them felt to Landon like pushing those data aside, and putting the onus on patients—particularly those already less likely to advocate for themselves—to account for their own protection.

    She can still imagine a United States in which a pandemic-era response solidified, as it has in several other countries, into a peacetime norm: where wearing masks would have remained as routine as donning gloves while drawing blood, a tangible symbol of pandemic lessons learned. Instead, many American hospitals will be entering their fourth COVID winter looking a lot like they did in early 2020—when the virus surprised us, when our defenses were down.

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    Katherine J. Wu

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  • A Genetic Snapshot Could Predict Preterm Birth

    A Genetic Snapshot Could Predict Preterm Birth

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    This article was originally published by Knowable Magazine.

    For expectant parents, pregnancy can be a time filled with joyful anticipation: hearing the beating of a tiny heart, watching the fetus wiggling through the black-and-white blur of an ultrasound, feeling the jostling of a little being in the belly as it swells.

    But for many, pregnancy also comes with serious health issues that can endanger both parent and child. In May, for example, the U.S. Olympic sprinter Tori Bowie died while in labor in her eighth month of pregnancy. Potential factors contributing to her death included complications of preeclampsia, a pregnancy-specific disorder associated with high blood pressure. Preeclampsia occurs in an estimated 4.6 percent of pregnancies globally. Left untreated, it can lead to serious problems such as seizures, coma, and organ damage.

    Preeclampsia and preterm birth are relatively common conditions that can put both the mother and her baby at risk of health issues before and after birth. But doctors don’t have a good way to determine whether an individual will develop one of these complications, says Thomas McElrath, an ob-gyn at Brigham and Women’s Hospital, in Boston. Currently, physicians primarily look to a woman’s prior pregnancies, medical history, and factors such as age and ethnicity to determine her risk. These measures are useful but limited, and may fail to identify problems early enough to enable effective treatment, McElrath says. “They’re not as precise as I think most of us, as clinicians, would really want.”

    That may soon change. Scientists are learning that free-floating bits of genetic material found in a pregnant person’s blood may offer a way to detect complications such as preeclampsia and preterm birth—although some experts caution that it’s too early to determine how useful these tests will be in the clinic. In the meantime, the tests are providing researchers with a new way to unravel the underlying biology of these inscrutable ailments.

    All of us carry bits of our own genetic material—both DNA and its more evanescent cousin, RNA—around in our bloodstreams. During pregnancy, these free-floating fragments, known as cell-free DNA and RNA, are also released from the developing fetus into the mother’s blood, primarily via the placenta. For more than a decade, clinicians have used cell-free DNA from blood to screen the fetus for genetic abnormalities.

    But DNA provides a largely static view of the genetic content within our cells. RNA gives a snapshot of which genes are turned on or off at a specific point in time. Because gene activity varies across cells and over time, researchers realized that they could use RNA to glean a more dynamic view of the changes that occur within the mother’s body during pregnancy. RNA enables scientists to look beyond the fixed genotype to factors that change over the course of pregnancy such as prenatal complications, says Mira Moufarrej, a postdoctoral researcher at Stanford University who co-authored a paper in the 2023 Annual Review of Biomedical Data Science on noninvasive prenatal testing with circulating RNA and DNA.

    Read: The pregnancy risk that doctors won’t mention

    To screen for possible complications, scientists have been looking at cell-free RNA in pregnant women’s blood that originates from both mother and child. Some of the earliest studies of this kind emerged in the early 2000s. In 2003, for example, Dennis Lo, a chemical pathologist at the Chinese University of Hong Kong, and his colleagues reported that in a study of 22 pregnant women, a specific RNA released from the placenta was much more abundant during the third trimester in those who had preeclampsia than in those who did not. Over the years, Lo’s group and others have looked at broader changes in RNA during pregnancy in larger groups of people.

    In a 2018 study, Moufarrej, who was then a doctoral student; her adviser Stephen Quake, a biophysicist at Stanford University; and colleagues reported that cell-free RNA could help determine when labor would occur. The researchers recruited 38 pregnant women in the United States known to be at risk of preterm birth, and then drew a blood sample from each. By comparing cell-free RNA in those who eventually delivered prematurely with that in those who gave birth at full term, they were able to identify a set of RNAs that appeared up to two months prior to labor that could pinpoint about 80 percent of premature births.

    That proof-of-concept investigation spurred the researchers to look further and examine whether cell-free RNA could also predict preeclampsia. Other groups had previously reported RNA-based signatures of preeclampsia—in 2020, for instance, scientists working with the California-based biotech company Illumina reported dozens of RNA transcripts that were unique to a small cohort of pregnant women with the condition. But Moufarrej, Quake, and their colleagues wanted to track RNA changes throughout pregnancy to see whether it might be possible to identify people at risk of preeclampsia during early pregnancy, before symptoms began.

    In a study published in 2022, the researchers recruited several dozen mothers at heightened risk of preeclampsia and drew blood from them four times: at or before 12 weeks, in weeks 13 to 20, at or after 23 weeks, and after birth. Afterward, the researchers compared cell-free RNA for women who indeed developed preeclampsia against that of those who did not. The team identified RNAs corresponding to 544 genes whose activity differed in those who developed preeclampsia and those who did not. (The study did not differentiate between maternal and fetal RNA, but because the majority of cell-free RNA in a pregnant person’s blood is their own, Moufarrej says that most of these RNAs are likely maternal in origin.)

    Then, using a computer algorithm, the researchers developed a test based on 18 genes measured prior to 16 weeks of pregnancy that could be used to predict a woman’s risk of developing preeclampsia months later. The test correctly identified all of the women who would later develop preeclampsia—and, equally important, all of the women who the test predicted wouldn’t develop preeclampsia did in fact escape the disease. (About a quarter of the women who were predicted to develop preeclampsia did not get the disease.) The same 18-gene panel also correctly predicted most cases of preeclampsia in two other groups totaling 118 women.

    The team also took a closer look at which tissues the RNA of interest originated from. This included the usual suspects, such as the lining of the blood vessels (also known as the endothelium), which scientists already know is associated with preeclampsia, as well as other, more unexpected sources, such as the nervous and muscular systems. The authors note that, in the future, this information could be used both to understand how preeclampsia affects different parts of the body and to assess which organs are at highest risk of damage in a particular patient.

    According to Quake, studies like these from both his team and others are starting to reveal the diversity of changes throughout the body that contribute to pregnancy complications—and providing evidence for something that clinicians and researchers have long suspected: that both preeclampsia and preterm birth are conditions with a range of underlying causes and outcomes. “There are now strong indications that you should be defining multiple subtypes of preeclampsia and preterm birth with molecular signatures,” says Quake. “That could really transform the way physicians approach the disease.”

    Research teams elsewhere are also looking at other pregnancy complications such as reduced fetal growth, which can cause infants to be at higher risk of problems such as low blood sugar and a reduced ability to fight infections. Some of these tests are now being validated in large studies, while others are still in the early days of development.

    RNA-based tests for both preeclampsia and preterm-birth risk are inching their way toward the clinic. Mirvie, a company co-founded by Quake in South San Francisco, is focused on developing both. Last year, the company published a study of a preterm-birth test with hundreds of pregnant individuals as well as one on a preeclampsia test with samples from more than 1,000 women. Both studies had promising results. The company is now in the middle of an even larger study of the preeclampsia test that will include 10,000 pregnancies, Quake says. (Quake and Moufarrej are both shareholders of Mirvie.)

    Cell-free RNA-based tests for preeclampsia are leading the way, says McElrath, likely because preterm birth has more subtypes and more potential causes—including carrying multiples, chronic health conditions such as diabetes, and preeclampsia—which make it a more complicated issue to address. (McElrath is involved in validating Mirvie’s tests; he serves as a scientific adviser to the company and has a financial stake in it.)

    Read: Childbirth is no fun. But an extremely fast birth can be worse.

    Still, questions about these tests remain. An important next step, says Moufarrej, is determining what’s behind the RNA changes associated with a heightened risk for these pregnancy complications. All of the studies conducted to date have been correlative—linking patterns in RNA with risk—but to provide effective treatment, it will be important to determine the cause of these changes, she adds. Another open question is how important maternal versus fetal RNAs are to determining the risk of pregnancy complications. To date, most studies have not distinguished between these two sources. “This remains an active area of investigation,” McElrath says.

    Erik Sistermans, a human geneticist at Amsterdam UMC, says that although  researchers can learn a lot from cell-free RNA, it’s still too early to judge what the power of these RNA-based tests will be in clinical practice. He notes that he and other researchers are also investigating the possibility of using cell-free DNA to determine the risk of pregnancy complications such as preeclampsia. For example, some groups are looking at chemical modifications to DNA known as epigenetic changes, which occur in response to age, environment, and other factors.

    Yalda Afshar, a maternal- and fetal-medicine physician at UCLA, agrees that it’s still unclear whether these tests will provide benefits not available from existing screening methods such as looking for the presence of risk factors. For these screening tests to truly benefit patients, clinicians will first need to understand the underlying biology of these complications—and have effective treatments to offer patients found to be at risk, she adds. (Afshar is an unpaid consultant for Mirvie.)

    There are also ethical questions to consider. Screening tests provide only an estimate of risk, not a definitive diagnosis, Sistermans notes. Before these tests are rolled out to the public, it will be crucial to consider how best to communicate test results, and what next steps to take for individuals who are identified as being in a high-risk category, he says. For preeclampsia, low-dose aspirin can help prevent or delay its onset, while the hormone progesterone may help prevent some cases of preterm birth. But every additional test added to a prenatal screen makes decisions more complicated and potentially stressful for pregnant women. “You shouldn’t underestimate the amount of anxiety these kinds of tests may cause,” Sistermans says.

    Still, researchers are optimistic about the future of cell-free RNA-based tests. The tests for preeclampsia are already more accurate than currently available tests for the condition, according to McElrath. And if researchers succeed in predicting other complications, he adds, future patients will benefit not just from additional information about their pregnancies, but also from the opportunity to receive more personalized care. “Once we start to see success in early preeclampsia prediction,” McElrath says, “it will quickly spread out from there.”

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    Diana Kwon

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  • What Fatigue Really Means

    What Fatigue Really Means

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    Alexis Misko’s health has improved enough that, once a month, she can leave her house for a few hours. First, she needs to build up her energy by lying in a dark room for the better part of two days, doing little more than listening to audiobooks. Then she needs a driver, a quiet destination where she can lie down, and days of rest to recover afterward. The brief outdoor joy “never quite feels like enough,” she told me, but it’s so much more than what she managed in her first year of long COVID, when she couldn’t sit upright for more than an hour or stand for more than 10 minutes. Now, at least, she can watch TV on the same day she takes a shower.

    In her previous life, she pulled all-nighters in graduate school and rough shifts at her hospital as an occupational therapist; she went for long runs and sagged after long flights. None of that compares with what she has endured since getting COVID-19 almost three years ago. The fatigue she now feels is “like a complete depletion of the essence of who you are, of your life force,” she told me in an email.

    Fatigue is among the most common and most disabling of long COVID’s symptoms, and a signature of similar chronic illnesses such as myalgic encephalomyelitis (also known as chronic fatigue syndrome or ME/CFS). But in these diseases, fatigue is so distinct from everyday weariness that most of the people I have talked with were unprepared for how severe, multifaceted, and persistent it can be.

    For a start, this fatigue isn’t really a single symptom; it has many faces. It can weigh the body down: Lisa Geiszler likens it to “wearing a lead exoskeleton on a planet with extremely high gravity, while being riddled with severe arthritis.” It can rev the body up: Many fatigued people feel “wired and tired,” paradoxically in fight-or-flight mode despite being utterly depleted. It can be cognitive: Thoughts become sluggish, incoherent, and sometimes painful—like “there’s steel wool stuck in my frontal lobe,” Gwynn Dujardin, a literary historian with ME, told me.

    Fatigue turns the most mundane of tasks into an “agonizing cost-benefit analysis,” Misko said. If you do laundry, how long will you need to rest to later make a meal? If you drink water, will you be able to reach the toilet? Only a quarter of long-haulers have symptoms that severely limit their daily activities, but even those with “moderate” cases are profoundly limited. Julia Moore Vogel, a program director at Scripps Research, still works, but washing her hair, she told me, leaves her as exhausted as the long-distance runs she used to do.

    And though normal fatigue is temporary and amenable to agency—even after a marathon, you can will yourself into a shower, and you’ll feel better after sleeping—rest often fails to cure the fatigue of long COVID or ME/CFS. “I wake up fatigued,” Letícia Soares, who has long COVID, told me.

    Between long COVID, ME/CFS, and other energy-limiting chronic illnesses, millions of people in the U.S. alone experience debilitating fatigue. But American society tends to equate inactivity with immorality, and productivity with worth. Faced with a condition that simply doesn’t allow people to move—even one whose deficits can be measured and explained—many doctors and loved ones default to disbelief. When Soares tells others about her illness, they usually say, “Oh yeah, I’m tired too.” When she was bedbound for days, people told her, “I need a weekend like that.” Soares’s problems are very real, and although researchers have started to figure out why so many people like her are suffering, they don’t yet know how to stop it.

    Fatigue creates a background hum of disability, but it can be punctuated by worse percussive episodes that strip long-haulers of even the small amounts of energy they normally have.

    Daria Oller is a physiotherapist and athletic trainer, so when she got COVID in March 2020, she naturally tried exercising her way to better health. And she couldn’t understand why, after just short runs, her fatigue, brain fog, chest pain, and other symptoms would flare up dramatically—to the point where she could barely move or speak. These crashes contradicted everything she had learned during her training. Only after talking with physiotherapists with ME/CFS did she realize that this phenomenon has a name: post-exertional malaise.

    Post-exertional malaise, or PEM, is the defining trait of ME/CFS and a common feature of long COVID. It is often portrayed as an extreme form of fatigue, but it is more correctly understood as a physiological state in which all existing symptoms burn more fiercely and new ones ignite. Beyond fatigue, people who get PEM might also feel intense radiant pain, an inflammatory burning feeling, or gastrointestinal and cognitive problems: “You feel poisoned, flu-ish, concussed,” Misko said. And where fatigue usually sets in right after exertion, PEM might strike hours or days later, and with disproportionate ferocity. Even gentle physical or mental effort might lay people out for days, weeks, months. Visiting a doctor can precipitate a crash, and so can filling out applications for disability benefits—or sensing bright lights and loud sounds, regulating body temperature on hot days, or coping with stress. And if in fatigue your batteries feel drained, in PEM they’re missing entirely. It’s the annihilation of possibility: Most people experience the desperation of being unable to move only in nightmares, Dujardin told me. “PEM is like that, but much more painful.”

    Medical professionals generally don’t learn about PEM during their training. Many people doubt its existence because it is so unlike anything that healthy people endure. Mary Dimmock told me that she understood what it meant only when she saw her son, Matthew, who has ME/CFS, crash in front of her eyes. “He just melted,” Dimmock said. But most people never see such damage because PEM hides those in the midst of it from public view. And because it usually occurs after a delay, people who experience PEM might appear well to friends and colleagues who then don’t witness the exorbitant price they later pay.

    That price is both real and measurable. In cardiopulmonary exercise tests, or CPETs, patients use treadmills or exercise bikes while doctors record their oxygen consumption, blood pressure, and heart rate. Betsy Keller, an exercise physiologist at Ithaca College, told me that most people can repeat their performance if retested one day later, even if they have heart disease or are deconditioned by inactivity. People who get PEM cannot. Their results are so different the second time around that when Keller first tested someone with ME/CFS in 2003, “I told my colleagues that our equipment was out of calibration,” she said. But she and others have seen the same pattern in hundreds of ME/CFS and long-COVID patients—“objective findings that can’t be explained by anything psychological,” David Systrom, a pulmonologist at Brigham and Women’s Hospital, told me. “Many patients are told it’s all in their head, but this belies that in spades.” Still, many insurers refuse to pay for a second test, and many patients cannot do two CPETs (or even one) without seriously risking their health. And “20 years later, I still have physicians who refute and ignore the objective data,” Keller said. (Some long-COVID studies have ignored PEM entirely, or bundled it together with fatigue.)

    Oller thinks this dismissal arises because PEM inverts the dogma that exercise is good for you—an adage that, for most other illnesses, is correct. “It’s not easy to change what you’ve been doing your whole career, even when I tell someone that they might be harming their patients,” she said. Indeed, many long-haulers get worse because they don’t get enough rest in their first weeks of illness, or try to exercise through their symptoms on doctors’ orders.

    People with PEM are also frequently misdiagnosed. They’re told that they’re deconditioned from being too sedentary, when their inactivity is the result of frequent crashes, not the cause. They’re told that they’re depressed and unmotivated, when they are usually desperate to move and either physically incapable of doing so or using restraint to avoid crashing. Oller is part of a support group of 1,500 endurance athletes with long COVID who are well used to running, swimming, and biking through pain and tiredness. “Why would we all just stop?” she asked.

    Some patients with energy-limiting illnesses argue that the names of their diseases and symptoms make them easier to discredit. Fatigue invites people to minimize severe depletion as everyday tiredness. Chronic fatigue syndrome collapses a wide-ranging disabling condition into a single symptom that is easy to trivialize. These complaints are valid, but the problem runs deeper than any name.

    Dujardin, the English professor who is (very slowly) writing a cultural history of fatigue, thinks that our concept of it has been impoverished by centuries of reductionism. As the study of medicine slowly fractured into anatomical specialties, it lost an overarching sense of the systems that contribute to human energy, or its absence. The concept of energy was (and still is) central to animistic philosophies, and though once core to the Western world, too, it is now culturally associated with quackery and pseudoscience. “There are vials of ‘energy boosters’ by every cash register in the U.S.,” Dujardin said, but when the NIH convened a conference on the biology of fatigue in 2021, “specialists kept observing that no standard definition exists for fatigue, and everyone was working from different ideas of human energy.” These terms have become so unhelpfully unspecific that our concept of “fatigue” can encompass a wide array of states including PEM and idleness, and can be heavily influenced by social forces—in particular the desire to exploit the energy of others.

    As the historian Emily K. Abel notes in Sick and Tired: An Intimate History of Fatigue, many studies of everyday fatigue at the turn of the 20th century focused on the weariness of manual laborers, and were done to find ways to make those workers more productive. During this period, fatigue was recast from a physiological limit that employers must work around into a psychological failure that individuals must work against. “Present-day society stigmatizes those who don’t Push through; keep at it; show grit,” Dujardin said, and for the sin of subverting those norms, long-haulers “are not just disbelieved but treated openly with contempt.” Fatigue is “profoundly anti-capitalistic,” Jaime Seltzer, the director of scientific and medical outreach at the advocacy group MEAction, told me.

    Energy-limiting illnesses also disproportionately affect women, who have long been portrayed as prone to idleness. Dujardin notes that in Western epics, women such as Circe and Dido were perceived harshly for averting questing heroes such as Odysseus and Aeneas with the temptation of rest. Later, the onset of industrialization turned women instead into emblems of homebound idleness while men labored in public. As shirking work became a moral failure, it also remained a feminine one.

    These attitudes were evident in the ways two successive U.S. presidents dealt with COVID. Donald Trump, who always evinced a caricature of masculine strength and chastised rivals for being “low energy,” framed his recovery from the coronavirus as an act of domination. Joe Biden was less bombastic, but he still conspicuously assured the public that he was working through his COVID infection while his administration prioritized policies that got people back to work. Neither man spoke of the possibility of disabling fatigue or the need for rest.

    Medicine, too, absorbs society’s stigmas around fatigue, even in selecting those who get to join its ranks. Its famously grueling training programs exclude (among others) most people with energy-limiting illnesses, while valorizing the ability to function when severely depleted. This, together with the tendency to psychologize women’s pain, helps to explain why so many long-haulers—even those with medical qualifications, like Misko and Oller—are treated so badly by the professionals they see for care. When Dujardin first sought medical help for her ME/CFS symptoms, the same doctor who had treated her well for a decade suddenly became stiff and suspicious, she told me, reduced all of her detailed descriptions to “tiredness,” and left the room without offering diagnosis or treatment. There is so much cultural pressure to never stop that many people can’t accept that their patients or peers might be biologically forced to do so.

    No grand unified theory explains everything about long COVID and ME/CFS, but neither are these diseases total mysteries. In fact, plenty of evidence exists for at least two pathways that explain why people with these conditions could be so limited in energy.

    First, most people with energy-limiting chronic illnesses have problems with their autonomic nervous system, which governs heartbeat, breathing, sleep, hormone release, and other bodily functions that we don’t consciously control. When this system is disrupted—a condition called “dysautonomia”—hormones such as adrenaline might be released at inappropriate moments, leading to the wired-but-tired feeling. People might suddenly feel sleepy, as if they’re shutting down. Blood vessels might not expand in moments of need, depriving active muscles and organs of oxygen and fuel; those organs might include the brain, leading to cognitive dysfunction such as brain fog.

    Second, many people with long COVID and ME/CFS have problems with generating energy. When viruses invade the body, the immune system counterattacks, triggering a state of inflammation. Both infection and inflammation can damage the mitochondria—the bean-shaped batteries that power our cells. Malfunctioning mitochondria produce violent chemicals called “reactive oxygen species” (ROS) that inflict even more cellular damage. Inflammation also triggers a metabolic switch toward fast but inefficient ways of making energy, depleting cells of fuel and riddling them with lactic acid. These changes collectively explain the pervasive, dead-battery flavor of fatigue, as “the body struggles to generate energy,” Bindu Paul, a pharmacologist and neuroscientist at Johns Hopkins, told me. They might also explain the burning, poisoned feelings that patients experience, as their cells fill with lactic acid and ROS.

    These two pathways—autonomic and metabolic—might also account for PEM. Normally, the autonomic nervous system smoothly dials up to an intense fight-and-flight mode and down to a calmer rest-and-digest one. But “in dysautonomia, the dial becomes a switch,” David Putrino, a neuroscientist and rehabilitation specialist at Mount Sinai, told me. “You go from sitting to standing and your body thinks: Oh, are we going hunting? You stop, and your body shuts down.” The exhaustion of these dramatic, unstable flip-flops is made worse by the ongoing metabolic maelstrom. Damaged mitochondria, destructive ROS, inefficient metabolism, and chronic inflammation all compound one another in a vicious cycle that, if it becomes sufficiently intense, could manifest as a PEM crash. “No one is absolutely certain about what causes PEM,” Seltzer told me, but it makes sense that “you have this big metabolic shift and your nervous system can’t get back on an even keel.” And if people push through, deepening the metabolic demands on a body that already can’t meet them, the cycle can spin even faster, “leading to progressive disability,” Putrino said.

    Other factors might also be at play. Compared with healthy people, those with long COVID and ME/CFS have differences in the size, structure, or function of brain regions including the thalamus, which relays motor signals and regulates consciousness, and the basal ganglia, which controls movement and has been implicated in fatigue. Long-haulers also have problems with blood vessels, red blood cells, and clotting, all of which might further staunch their flows of blood, oxygen, and nutrients. “I’ve tested so many of these people over the years, and we see over and over again that when the systems start to fail, they all fail in the same way,” Keller said. Together, these woes explain why long COVID and ME/CFS have such bewilderingly varied symptoms. That diversity fuels disbelief—how could one disease cause all of this?—but it’s exactly what you’d expect if things as fundamental as metabolism go awry.

    Long-haulers might not know the biochemical specifics of their symptoms, but they are uncannily good at capturing those underpinnings through metaphor. People experiencing autonomic blood-flow problems might complain about feeling “drained,” and that’s literally happening: In POTS, a form of dysautonomia, blood pools in the lower body when people stand. People experiencing metabolic problems often use dead-battery analogies, and indeed their cellular batteries—the mitochondria—are being damaged: “It really feels like something is going wrong at the cellular level,” Oller told me. Attentive doctors can find important clues about the basis of their patients’ illness hiding amid descriptions that are often billed as “exaggerated or melodramatic,” Dujardin said.

    Some COVID long-haulers do recover. But several studies have found that, so far, most don’t fully return to their previous baseline, and many who become severely ill stay that way. This pool of persistently sick people is now mired in the same neglect that has long plagued those who suffer from illnesses such as ME/CFS. Research into such conditions are grossly underfunded, so no cures exist. Very few doctors in the U.S. know how to treat these conditions, and many are nearing retirement, so patients struggle to find care. Long-COVID clinics exist but vary in quality: Some know nothing about other energy-limiting illnesses, and still prescribe potentially harmful and officially discouraged treatments such as exercise. Clinicians who better understand these illnesses know that caution is crucial. When Putrino works with long-haulers to recondition their autonomic nervous system, he always starts as gently as possible to avoid triggering PEM. Such work “isn’t easy and isn’t fast,” he said, and it usually means stabilizing people instead of curing them.

    Stability can be life-changing, especially when it involves changes that patients can keep up at home. Over-the-counter supplements such as coenzyme Q10, which is used by mitochondria to generate energy and is depleted in ME/CFS patients, can reduce fatigue. Anti-inflammatory medications such as low-dose naltrexone may have some promise. Sleep hygiene may not cure fatigue, but certainly makes it less debilitating. Dietary changes can help, but the right ones might be counterintuitive: High-fiber foods take more energy to digest, and some long-haulers get PEM episodes after eating meals that seem healthy. And the most important part of this portfolio is “pacing”—a strategy for carefully keeping your activity levels beneath the threshold that causes debilitating crashes.

    Pacing is more challenging than it sounds. Practitioners can’t rely on fixed routines; instead, they must learn to gauge their fluctuating energy levels in real time, while becoming acutely aware of their PEM triggers. Some turn to wearable technology such as heart-rate monitors, and more than 30,000 are testing a patient-designed app called Visible to help spot patterns in their illness. Such data are useful, but the difference between rest and PEM might be just 10 or 20 extra heartbeats a minute—a narrow crevice into which long-haulers must squeeze their life. Doing so can be frustrating, because pacing isn’t a recovery tactic; it’s mostly a way of not getting worse, which makes its value harder to appreciate. Its physical benefits come at mental costs: Walks, workouts, socializing, and “all the things I’d do for mental health before were huge energy sinks,” Vogel told me. And without financial stability or social support, many long-haulers must work, parent, and care for themselves even knowing that they’ll suffer later. “It’s impossible not to overdo it, because life is life,” Vogel said.

    “Our society is not set up for pacing,” Oller added. Long-haulers must resist the enormous cultural pressure to prove their worth by pushing as hard as they can. They must tolerate being chastised for trying to avert a crash, and being disbelieved if they fail. “One of the most insulting things people can say is ‘Fight your illness,’” Misko said. That would be much easier for her. “It takes so much self-control and strength to do less, to be less, to shrink your life down to one or two small things from which you try to extract joy in order to survive.” For her and many others, rest has become both a medical necessity and a radical act of defiance—one that, in itself, is exhausting.

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    Ed Yong

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