Long Covid “is a phenomenon that is really quite real and quite extensive,” Anthony Fauci said earlier this month.
When Heather-Elizabeth Brown spiked a fever in April in Detroit, the only reason she was able to get a coronavirus test was because she was volunteering as a police chaplain and was therefore considered an essential worker. Her results came back negative, and she was relieved. But then, she says, “I just got sicker and sicker.”
After being turned away from overcrowded ERs twice, Brown was eventually admitted on her third try. She finally tested positive, and by that point, she was severely ill. She was put on a ventilator and spent the next 31 days in a medically induced coma.
Before Covid-19, Brown was a healthy, active Black woman in her 30s. “But when I came off the ventilator, they had to coach me how to breathe.” The smallest pleasures — like eating a sliver of ice after her feeding tube was removed — became something to treasure.
Six months later, Brown is still very ill. She has been hospitalized for blood clots and has lingering heart problems, nerve pain, and extreme fatigue. “Even making breakfast is now out of the question,” she says. Most troublingly, she’s still experiencing severe brain fog, which makes it hard for her to return to work.
Brown is just one of many previously healthy people whose life has been derailed after a Covid-19 infection. While early research on Covid-19 focused on its respiratory symptoms, we now know its impacts — both direct and indirect — can be much more extensive and relentless.
On December 3, the National Institutes of Health held a two-day seminar on what has come to be called long Covid, or long-haul Covid — cases of lingering symptoms that can last for weeks or months after an initial infection. The Centers for Disease Control and Prevention (CDC) recently created a list of some of the persistent symptoms patients are experiencing, which include chest pain, brain fog, fatigue, and hair loss — with patients reporting many others as well.
Because these patients don’t all have the same symptoms, they will need different kinds of post-Covid care. And the NIH made clear that there are still many more questions than answers — including whose symptoms might linger for months, and how to treat them.
Almost a year into the pandemic, there have not yet been thorough, large-scale studies to determine the true prevalence of long Covid. But preliminary research suggests that somewhere between 10 percent and 88 percent of Covid-19 patients will experience at least one symptom for many weeks or months. Some of these can be life-altering; one study found that 50 percent of non-ICU patients reported a significant change to their cognitive functioning.
Doctors at the seminar said they were surprised by the scope of long Covid and its potential socioeconomic impacts. “This is a phenomenon that is really quite real and quite extensive,” said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, who spoke at the event.
Even if the prevalence ends up being on the lower end of the 10 to 88 percent range, the sheer volume of people getting sick means there are already millions of Americans who have, and will soon have, long Covid. Despite the staggering numbers, “we’re a hidden group of people,” Brown says. This can make getting treatment from skeptical physicians challenging. Long-Covid patient Anthony Campbell, for example, had a doctor refuse to sign a work disability form unless he was treated for anxiety rather than for his actual persistent symptoms.
Interviews with dozens of patients like Brown and Campbell provide a closer look at long Covid’s devastating impact — and the clues the latest research offers into what might be causing all these symptoms, including erectile dysfunction, hormonal imbalances, hallucinations, and dementia-like effects that can severely impact daily life.
Menstrual changes and erectile dysfunction
One of the most surprising new findings about long Covid’s effects is that both women and men have reported sexual and reproductive system symptoms following a Covid-19 infection.
The Patient-Led Research Group, a team of researchers who are also Covid-19 patients, conducted a survey of 640 long-Covid patients and recorded more than 200 total symptoms, including testicular pain, urinary problems, and menstrual changes.
“A lot of people with long Covid notice that their symptoms get worse just before their period happens,” when estrogen levels are lowest, says Louise Newson, a general practitioner and menopause specialist. She says an additional sign hormones may be involved are long-Covid symptoms like “brain fog, fatigue, dizziness, joint pain — these are also symptoms of menopause.”
Newson has 842 patient responses so far to a pilot survey, and she says the results “confirm my thoughts that long Covid is likely to be related to low hormone levels (estrogen and testosterone), which so far have been neglected with research.” Estrogen plays a key role in women’s health, and having abnormally low levels can lead to infertility, osteoporosis, lack of sex drive, and depression.
Newson says that anecdotally, patients with long Covid from her menopause clinic have improved with the right dose and type of hormone replacement therapy. “They all had low oestradiol and low testosterone results before treatment,” she says.
Long Covid can also significantly impact male reproductive systems and testosterone levels. “Absolutely, reproductive systems have been overlooked during the pandemic,” says Geoff Hackett, a professor of sexual medicine at Aston University in Birmingham, UK. He explains that during acute illness, the testes can be attacked by the virus directly.
“The testes are one of the highest sites of ACE2 expression,” writes the British Society of Sexual Medicine (BSSM) in its position paper on Covid-19. (This ACE2 enzyme is the primary way SARS-CoV-2 enters cells.) The BSSM adds that SARS-CoV-2 also damages cells on the inner surface of blood vessels called endothelial cells, a condition which is “frequently present in men with erectile dysfunction and testosterone deficiency.”
Several recent studies have pointed to testosterone, which in men is produced in the testes, as playing an important role in coronavirus patients: A study in Germany found that the majority of men admitted to the hospital with Covid-19 had low testosterone levels and high inflammatory markers. (This study was unable to determine if these low testosterone levels predated their coronavirus infection.)
A similar study in Italy found low testosterone levels predicted worse outcomes in hospitalized patients. A third study, in Wuhan, China, also found low testosterone levels in coronavirus patients, which they said required “more attention to gonadal function evaluation among patients recovered from SARS-CoV-2 infection, especially the reproductive-aged men.”
Hypogonadism, when sex organs don’t produce sufficient hormones, affects both the production of testosterone and sperm. Another recent paper, published in The Lancet, found the production of sperm was impaired in Covid-19 patients, which they said might be explained by an immune response in the testes. In some patients, they also found auto-immune orchitis, or inflammation of the testis with specific anti-sperm antibodies. “There does seem to be some evidence for relative infertility afterward,” Hackett says, though he cautions it’s too early to say if it would be permanent.
In general, “attacking the cells of the testes will have an adverse effect on erections,” Hackett says. Even beyond a direct effect, endothelial disorder and inflammation may affect the arteries in the penis, making erections more difficult. “Erectile dysfunction is going to be highly prevalent, particularly if you look at the groups at high risk of Covid-19,” Hackett says. “Seventy-five percent of diabetics have erectile dysfunction anyway.” Based on anecdotal evidence, the next Patient-Led Research Group survey will include questions on shrinkage, erectile dysfunction, and testicular pain.
Erectile function is a sign of overall health, and urologist Ryan Berglund of the Cleveland Clinic recently made a statement that for young and healthy people who develop this problem after having Covid-19, “this can be a sign of something more serious going on.”
The BSSM is concerned that these reproductive effects may have lasting implications, warning that low testosterone levels in men “are associated with increased mortality,” and that those “who may have survived the current pandemic … may be at considerable risk from second and third wave infection, or future viral pandemics.”
Beyond Covid-19, research suggested a connection between viral infections of the central nervous system and pituitary dysfunction. A significant number of viruses have previously been associated with the onset of Type 1 diabetes, and it appears there may have been an increase in diabetes diagnoses during the pandemic.
Recognizing these impacts may help doctors find effective treatments; Hackett says a common erectile dysfunction treatment, Tadalafil, improves all markers of endothelial disease. “If it didn’t give men an erection, it would be treated as a serious cardiovascular drug,” he says. He notes that mountain climbers often take Tadalafil before big climbs to avoid altitude sickness, as it lowers pulmonary artery pressure and improves the endothelium of arteries — effects that might significantly help Covid-19 patients.
But Hackett says even as the UK National Health System rolls out long-Covid clinics, he’s been disappointed to see these symptoms overlooked. “Their strategies include things like eating healthy, hydrating, and mindfulness,” he says. “How is this going to go down with seriously ill people? All they’re offering is platitudes.”
Long-Covid symptoms can be very diverse and are often not limited to one part of the body, making them hard to understand. One of the reasons long-Covid patients are struggling to do high-quality research through their illnesses, says Hannah Davis, a long-Covid patient and a member of the Patient-Led Research Group who helped design the survey, “is that we need answers.”
She’s tired of being told that no one knows how to help treat her symptoms, or how many others might be experiencing something similar. “We’re going to get answers faster than anyone else because we’re living this experience,” Davis says. One recent study of 201 long-Covid patients in the UK found that even in a young, low-risk population, 66 percent had impairments to one or more organs four months after their initial symptoms.
Being sick enough to be ventilated, like Brown was, often comes with its own complications; one study found that 81 percent of ventilated patients develop delirium, and one in five patients with acute respiratory distress syndrome — a common lung condition in ICU patients — experience long-term cognitive impairment. But even coronavirus patients with milder symptoms or no initial symptoms at all can develop long Covid.
Long-term lung problems are perhaps the most straightforward long-Covid symptom, as the virus can directly inflame the lung tissue, filling air sacs with fluid and making them less elastic and harder to expand as you breathe. Even at the beginning of the pandemic, it was known that previous coronavirus epidemics had caused lung scarring in some patients. One 15-year study of 71 SARS patients from a 2003 outbreak found a third had reduced lung capacity; a third of MERS survivors in a 2017 study also had long-term lung damage.
New research suggests that around half of asymptomatic Covid-19 infections can also cause damage to the lungs.
In early November, a study published in The Lancet on 41 autopsies of Covid-19 patients offered a possible reason: It found that the virus caused major structural changes in the lungs, including extensive blood clotting, scarring of respiratory tissue, and the fusion of many smaller cells into larger cells. (Based on the fact that these were autopsies, these were all severe cases, limiting the implications that can be drawn.)
The authors suggest that, unlike other types of pneumonia, these structural changes may stem “from the persistence of infected and dysfunctional cells in the lungs” — which may help explain why some of these symptoms linger. Though we still don’t know the exact mechanics, continuing lung symptoms are perhaps the most common of them.
It’s still unclear how long these symptoms might last; some long-Covid patients have reported improvements in their breathing, although much slower than they would have liked. One study of mildly ill patients in China found that 70 percent had abnormal lung scans three months after their initial illness.
Blood clotting and other cardiovascular issues
Early in the pandemic, doctors noticed that many Covid-19 patients were having serious blood clotting problems, with reports of clogging dialysis machines and clots in the arms and legs called deep vein thromboses. But some patients, like Brown — who went back to the hospital with blood clots three months after her initial symptoms — are also experiencing clots weeks or months later.
Large blood clots can cause tissue damage, requiring amputations. Smaller clots can restrict blood flow in the lungs, impairing normal oxygen exchange. If clots travel to the brain or heart, they can also cause strokes or heart attacks, as 23-year-old Riley Behrens recently suffered after a coronavirus infection. “Before this, I was a healthy young athlete with no major medical conditions,” she tweeted after a Covid-related stroke. “Now, I’m being told I will likely never return to contact sports because of lasting lung and brain damage. The risk for a second stroke will always be there.”
It’s hard to know how common clotting problems are in Covid-19 patients, but reports of conditions linked to clotting have certainly increased: A study published in Annals of Vascular Surgery recently found a twofold increase during the pandemic in major amputations, which are sometimes required after a clot is found. And multiple researchers have reported a spike in the number of stroke patients, including young people like Behrens who would not normally be at high risk for strokes, as well as in patients who didn’t know they’d had the coronavirus but later tested positive for antibodies.
A study published in Science in mid-November may have identified one of the reasons for this abnormal clotting: In half of 172 hospitalized coronavirus patients, the scientists found autoantibodies — proteins that are supposed to defend against invaders that instead start to attack the body’s own cells. When these autoantibodies were injected into lab mice, the animals developed blood clots. The researchers suggest that these proteins could be sparking a dangerous loop between clotting and hyperinflammation. A December preprint also found a significant percentage of Covid-19 patients developed autoantibodies, and the more severe their symptoms, the more autoantibodies they had.
But Covid-19’s cardiovascular impacts don’t end with coagulation. Half of 1,216 Covid-19 patients in one study also had heart abnormalities, and one in seven had severe cardiac issues.
“People can present without any lung symptoms, and have just heart or brain involvement,” says Eric Topol, a professor of molecular medicine and director of the Scripps Research Translational Institute. These can include cardiomyopathy, a disease of the heart muscle that makes it harder for your heart to pump; myocarditis, or inflammation of the heart muscle; and pericarditis, inflammation of the pericardium, the two thin layers of tissue that surround the heart and help it function. One study on 54 college athletes who’d had mild Covid-19 cases found that a third had pericarditis, even though about the same number had been asymptomatic.
Many long-Covid patients are also experiencing persistent heart concerns months after their initial illness. Kate Meredith of Beverly, Massachusetts, for example, first got sick in March. Now, she has tachycardia, or an abnormally elevated heart rate. “If I get up to do the dishes, it jumps to 140 [beats per minute],” she says.
Leticia Soares and Israel Slick, of Ontario, both also got Covid-19 in April. They each independently reported heart palpitations and tachycardia to the same doctor, who speculated Slick’s condition might be related to his Covid-19 infection, while Soares, who is Latina, was told to seek counseling. (Many Black and brown long-Covid patients say they’ve experienced gaslighting and medical racism when they try to seek treatment.)
Cardiovascular symptoms may arise from the coronavirus directly impacting the endothelium. These cells control vascular functions, including enzymes that direct blood clotting. The endothelium is also important for proper immune function, and its imbalance could help explain the cytokine storms seen in many patients with severe Covid-19 cases. “There’s no shortage of ways by which this virus can hurt the heart,” Topol concludes.
Damaged endothelial cells can also stimulate mast cells, a type of blood cell that’s part of the immune system. Their job is to defend against foreign bodies by releasing chemicals like histamines. Activated mast cells were recently found in autopsies of Covid-19 patients and are linked to clots and pulmonary edemas.
Some long-Covid patients are reporting symptoms and inflammation similar to mast cell activation syndrome (MCAS), a chronic, multisystem condition that causes allergic responses, GI problems, and neurological issues.
Frances Simpson, a psychology lecturer at Coventry University in the UK, says she and her 5- and 9-year old were infected with Covid-19 in March and have had long-Covid symptoms since, including new allergic reactions. “When you read about possible mast cell activation syndrome,” she says, “we can tick all of the symptoms off between us” — things like headaches, rashes, and extreme fatigue. Moreover, some of the drugs that have been shown to help with severe Covid-19 cases, like famotidine and aspirin, inhibit mast cell activation.
Immunology is very complicated, but it also appears that T cells, an important component of the immune system, may also play a role in long Covid, as they do in other inflammatory and autoimmune conditions.
The CDC is now calling a particular set of inflammatory symptoms in multiple organs after an initial infection multisystem inflammatory syndrome in adults, or MIS-A — after a similar post-viral condition that was first reported in children, called MIS-C. Both children’s and adults’ symptoms in these cases overlap with MCAS, with problems like chest tightness, abdominal pain, rash, and inflammation, strengthening the argument that mast cells may be involved.
New research is also homing in on the many, sometimes severe, neurological symptoms that long-Covid patients have reported. One peer-reviewed paper found that a surprising 40 percent of patients with Covid-19 showed some kind of neurologic manifestation, and more than 30 percent had impaired cognition. These symptoms — including brain fog, extreme fatigue, difficulty with short-term memory, intense headaches, and tingling or numbness — are common in long-Covid patients.
Some long-Covid patients develop dysautonomia, a disorder of the autonomic nervous system that can be triggered by viral infections. The autonomic nervous system controls involuntary functions in our bodies such as heart rate and digestion. When it is damaged by an infection, these functions can go out of whack.
Davis, for example, has been diagnosed with a form of dysautonomia called postural orthostatic tachycardia syndrome (POTS), where blood vessels don’t respond to chemical signals efficiently. When she stands, blood pools in her lower extremities, making her feel faint and exacerbating her brain fog. The nervous system continues to release hormones to tighten her non-responding blood vessels, increasing her heart rate and making her shake.
There’s also increasing evidence that SARS-CoV-2 can actually cross the blood-brain barrier, a layer of specialized cells that protect the brain, and harm the nervous system directly. In April, researchers found that a 40-year-old woman in Los Angeles with headaches, seizures, and hallucinations had RNA from the coronavirus in her cerebrospinal fluid.
One study recently found an explanation for how that may have occurred: The virus can directly enter and damage cells in the brain’s choroid plexus, which has cells with ACE2 receptors. “This can lead to leakage across this important barrier, that normally prevents entry of pathogens into the cerebrospinal fluid and the brain,” says study co-author Madeline Lancaster, a biologist and the group leader at the MRC Laboratory of Molecular Biology in Cambridge, UK.
The brain is normally protected from your blood, so it’s a big problem to have that barrier penetrated. During viral infections, many immune cells are activated and circulating through the body. Lancaster explains that even if the virus itself doesn’t get past the barrier, having “those inflammatory cytokines leak into the brain, where they really do not belong, can have serious repercussions.” One example is encephalitis, or inflammation of the brain itself, as found in this study of 12 Covid-19 patients in the UK.
Lancaster says viruses may penetrate the blood-brain barrier more often than previously thought. “The Covid crisis has shined a light on overlooked post-viral chronic fatigue syndrome (CFS),” she says. “There’s a lot of indication that inflammation of the brain can lead to those symptoms. There’s a huge overlap between those conditions and long Covid.”
But though post-viral symptoms may linger for months or even years, it can be hard for doctors to find clues in neurological tests. While encephalitis can be seen on MRIs, damage to the cerebrospinal fluid might not be visible. (Doctors can, however, look for elevated biomarkers like cytokines.) “Unfortunately, that’s one of the reasons a lot of patients with CFS have been told it’s all in their heads. We’ve let those patients down,” says Lancaster.
Neuro-inflammation can cause emotional and behavioral changes. Sammie, who asked that her last name not be used to protect her privacy, says she and her daughter were both infected in the UK with Covid-19 in March. Since then, her 15-year-old daughter has had headaches, dysautonomia, fatigue, and extreme anxiety and emotional outbursts. “She’s not a crier. She’s normally very stoic,” Sammie says, but over the last few months, “she’s had irrational outbursts, just sobbing her heart out.”
One study of 62,354 patients recently published in The Lancet Psychiatry journal found that one in five were diagnosed with a mental health disorder within three months of testing positive for the coronavirus. “But what’s the chicken and what’s the egg?” Lancaster asks. “It could be that there are people with leakier brains to start with, who when they get Covid-19 are more likely to have viral entry into their brain.”
Neuro-inflammation might also help explain some of the weirder long-Covid symptoms reported by parents of children who have had Covid-19, like something called Alice in Wonderland syndrome, an alteration of visual perception where objects or body part sizes are perceived incorrectly. Simpson says her son’s vision regularly goes blurry, and he describes people’s heads “going small.”
Gretchen Drown of Portland, Maine, also says that her 15-year old son, who got Covid-19 in March, describes “things looking weird,” and that during these episodes, his pupils get strangely dilated. Drown’s son also now has headaches and extreme fatigue, which worsen after he overexerts himself, making it hard to keep up with school.
Damaging the blood-brain barrier also hurts its ability to make cerebrospinal fluid, which is important for providing nutrients to the brain and removing its normal waste. Lancaster calls the cerebrospinal fluid the plumbing system of the brain. “Imagine your house with all your toilets clogged — a similar thing can happen in the brain,” she says.
Much of this fluid cycling normally occurs during sleep, so Lancaster suggests that Alice in Wonderland syndrome — and possibly other common neurological symptoms in long Covid, like extreme fatigue and insomnia — might be related to the virus compromising the body’s ability to generate and manage this fluid.
Children and long Covid
As the pandemic began, it appeared most children had mild cases of Covid-19. But while clinicians have not been tracking long Covid in children, it’s clear from the many parents Vox interviewed that children of any age can and do experience persistent symptoms that can completely alter their ability to function.
That no one seems to be paying attention to pediatric long-Covid cases is a source of extreme frustration. Multiple parents reported that during their efforts to get their children care, medical providers accused them of Munchausen syndrome, a psychological disorder where someone pretends to be ill.
Sammie says when a nurse suggested it to her, “I literally think if I hadn’t had a mask on, my jaw would have fallen off. I felt so broken — it makes me feel emotional talking about it now.” Since then, she’s complained to the clinic and actually gotten a letter of apology. But her experience demonstrates the hurdles parents face in getting their children the care they need. “I think there are a lot more children who are ill, and who no one is connecting the dots for,” Sammie says.
While it’s hard to quantify something no one is tracking, the American Academy of Pediatrics suggests about 11 percent of US Covid-19 cases are children, with over 1,460,905 children contracting the virus as of December 3. It’s easier to count more acute Covid-19 consequences, like MIS-C: In one study of kids under 18 with MIS-C, 14.8 percent exhibited new neurological symptoms like headaches, muscle weakness, and reduced reflexes. The youngest child with persistent symptoms Vox found was 18 months; the oldest was 15.
While some of the symptoms parents have reported in children are similar to adult long-Covid cases — headaches, extreme fatigue, difficulty concentrating or forming new memories, anxiety, depression, tachycardia, dysautonomia, lingering or recurrent fevers — others differ. Some parents in the long-Covid kids online group Sammie formed, for example, have been reporting frequent nosebleeds.
Some of the parents, like Simpson, are themselves suffering from long Covid. “In many families who have kids with long Covid, there’s a mother or father who has it as well. People should be tripping over themselves to research if this is genetic,” she says.
But in the meantime, for parents like Sammie, Simpson, Meredith, and Drown, there are few resources to help their children recover. Though it hasn’t been easy, Sammie hasn’t given up trying to get her daughter into more specialized care. “If I don’t advocate for my child, who the hell is going to do it?” she asks.
Parents worry about how their children’s lives might be impacted by the long-term effects of this disease. For adult patients, too, the repercussions are potentially huge.
One doctor, whose family asked that her name be withheld for privacy reasons, first got sick this spring. She eventually despaired of finding treatment for her long-Covid symptoms. She recently drove to New York — because she wanted to be near the best researchers she knew of — before ending her life. She donated her body to science.
For those who survive, like Brown, the questions are pervasive. “How will this affect me when I want to have a baby?” Brown asks. “What is next? We have no idea. No one can tell me anything specific.” She’s frustrated that friends her age still assume that if they get infected, they’ll recover.
“You might be okay, but you might not,” Brown says. She says she’s angry about how the pandemic has been measured in deaths rather than in lives disrupted. “The disparities are shocking. And more will be lost if we don’t make adjustments.”
Lois Parshley is a freelance investigative journalist. Follow her Covid-19 reporting on Twitter @loisparshley.
Author: Lois Parshley