What We Know about Long COVID So Far

This syndrome is getting to be just a little bit creepy — especially for those of us who are under 50 (–as well as those over 50 who sometimes feel like we’re still younger than 50). 😉
What We Know about Long COVID So Far

Maggie Fox

September 27, 2022

Editor’s note: Find the latest long COVID news and guidance in Medscape’s Long COVID Resource Center.

Long COVID: The name says it all. It’s an illness that, for many people, has not yet stopped.

Eric Roach became ill with COVID-19 in November 2020, and he’s still sick. “I have brain fog, memory loss,” says the 67-year-old Navy veteran from Spearfish, SD. “The fatigue has just been insane.”

Long COVID, more formally known as post-acute sequelae of COVID (PASC), is the lay term to describe when people start to recover, or seem to recover, from a bout of COVID-19 but then continue to suffer from symptoms. For some, it’s gone on for 2 years or longer. While the governments of the U.S. and several other countries formally recognize the existence of long COVID, the National Institutes of Health (NIH) has yet to formally define it. There’s no approved treatment, and the causes are not understood.

Here’s what is known: Long COVID is a post-viral condition affecting a large percentage of people who become infected with the coronavirus. It can be utterly debilitating or mildly annoying, and it is affecting enough people to cause concern for employers, health insurers, and governments.

First, the Many Symptoms

According to the CDC, long COVID symptoms may include:

Tiredness or fatigue that interferes with daily life
Symptoms that get worse after physical or mental effort (also known as “post-exertional malaise”)
Difficulty breathing or shortness of breath
Chest pain
Fast-beating or pounding heart (heart palpitations)
Difficulty thinking or concentrating (sometimes referred to as “brain fog”)
Sleep problems
Dizziness when standing
Pins-and-needles feelings
Change in smell or taste
Depression or anxiety
Stomach pain
Joint or muscle pain
Changes in menstrual cycles

“People with post-COVID conditions may develop or continue to have symptoms that are hard to explain and manage,” the CDC says on its website. “Clinical evaluations and results of routine blood tests, chest x-rays, and electrocardiograms may be normal. The symptoms are similar to those reported by people with ME/CFS (myalgic encephalomyelitis/chronic fatigue syndrome) and other poorly understood chronic illnesses that may occur after other infections.”

Doctors may not fully appreciate the subtle nature of some of the symptoms.

“People with these unexplained symptoms may be misunderstood by their health care providers, which can result in a long time for them to get a diagnosis and receive appropriate care or treatment,” the CDC says.

Health professionals should recognize that long COVID can be disabling,the U.S. Department of Health and Human Services says. “Long COVID can substantially limit a major life activity,” HHS says in civil rights guidance. One possible example: “A person with long COVID who has lung damage that causes shortness of breath, fatigue, and related effects is substantially limited in respiratory function, among other major life activities,” HHS says.

How Many People Are Affected?

This has been difficult to judge because not everyone who has had COVID-19 gets tested for it and there are no formal diagnostic criteria yet for long COVID. The CDC estimates that 19% of patients in the U.S. who have ever had COVID-19 have long COVID symptoms.

Some estimates go higher. A University of Oxford study in September 2021 found more than a third of patients had symptoms of long COVID between 3 months and 6 months after a COVID-19 diagnosis. As many as 55% of COVID-19 patients in one Chinese study had one or more lingering symptoms 2 years later, Lixue Huang, MD, of the China-Japan Friendship Hospital in Beijing, and colleagues reported in the journal Lancet Respiratory Medicine in May.

According to the CDC, age is a factor. “Older adults are less likely to have long COVID than younger adults. Nearly three times as many adults ages 50-59 currently have long COVID than those age 80 and older,” the CDC says. Women and racial and ethnic minorities are more likely to be affected.

Many people are experiencing neurological effects, such as the so-called brain fog, according to Ziyad Al-Aly, MD, of the Washington University School of Medicine and the VA St. Louis Health Care System, writing in the journal Nature Medicine in September. They estimated that 6.6 million Americans have brain impairments associated with COVID infection.

“Some of the neurologic disorders reported here are serious chronic conditions that will impact some people for a lifetime,” they wrote. “Given the colossal scale of the pandemic, and even though the absolute numbers reported in this work are small, these may translate into a large number of affected individuals around the world — and this will likely contribute to a rise in the burden of neurologic diseases.”


It’s not clear what the underlying causes are, but most research points to a combination of factors. Suspects include ongoing inflammation, tiny blood clots, and reactivation of what are known as latent viruses, or those that linger quietly in your body without causing damage. In May, Brent Palmer, PhD, of the University of Colorado School of Medicine, and colleagues found people with long COVID had persistent activation of immune cells known as T-cells that were specific for SARS-CoV-2, the virus that causes COVID-19.

COVID-19 itself can damage organs, and long COVID might be caused by ongoing damage. In August, Alexandros Rovas, MD, of University Hospital Munster in Germany, and colleagues found patients with long COVID had evidence of damage to their capillaries. “Whether, to what extent, and when the observed damage might be reversible remains unclear,” they wrote in the journal Angiogenesis.

People with long COVID have immune responses to other viruses, such as Epstein-Barr — evidence that COVID-19 might reactivate latent viruses. “Our data suggest the involvement of persistent antigen, reactivation of latent herpesviruses, and chronic inflammation,” immunobiologist Akiko Iwasaki, PhD, of the Yale University School of Medicine, and colleagues wrote in a study posted in August that had not yet been peer-reviewed for publication.

This might be causing an autoimmune response. “The infection may cause the immune system to start making autoantibodies that attack a person’s own organs and tissues,” the NIH says.

There could be other factors. A study by Harvard researchers found that people who felt stressed, depressed, or lonely before catching COVID-19 were more likely to develop long COVID afterward. “Distress was more strongly associated with developing long COVID than physical health risk factors such as obesity, asthma, and hypertension,” Siwen Wang, MD, a research fellow with Harvard University’sT.H. Chan School of Public Health, said in a statement. Plus, nearly 44% of those in the study developed COVID-19 infections after having been assessed for stress, Wang and colleagues reported in the journal JAMA Psychiatry.

Vaccine Protection

There’s evidence that vaccination protects against long COVID, both by preventing infection in the first place, but also even for people who have breakthrough infections.

A meta-analysis covering studies involving 17 million people found evidence vaccination might reduce the severity of COVID-19 or might help the body clear any lingering virus after an infection.

“Overall, vaccination was associated with reduced risks or odds of long COVID, with preliminary evidence suggesting that

two doses are more effective than one dose,” Cesar Fernandez de las Penas, PhD, of King Juan Carlos University in Madrid, Spain, and colleagues wrote.

A team in Milan, Italy, found unvaccinated people in their study were nearly three times as likely to have serious symptoms for longer than 4 weeks compared to vaccinated volunteers. Writing in July in The Journal of the American Medical Association, Elena Azzolini, MD, PhD, an assistant professor atthe Humanitas Research Hospital, said the team found two or three doses of vaccine reduced the risk of hospitalization from COVID to 16% or 17% compared to 42% for the unvaccinated.


With no diagnostic criteria and no understanding of the causes, it’s hard for doctors to determine treatments.

Most experts dealing with long COVID, even those at the specialty centers that have been set up at hospitals and health systems in the U.S.,recommend that patients start with their primary care doctor before moving on to specialists.

“The mainstay of management is supportive, holistic care, symptom control, and detection of treatable complications,” Trish Greenhalgh, MD, professor of primary care health sciences at the University of Oxford, and colleagues wrote in the journal The BMJ in September. “Patients with long COVID greatly value input from their primary care clinician. Generalist clinicians can help patients considerably by hearing the patient’s story and validating their experience … (and) making the diagnosis of long COVID (which does not have to be by exclusion) and excluding alternative diagnoses.”

Evidence is building that long COVID closely resembles other post-viral conditions — something that can provide clues for treatment. For example, several studies indicate that exercise doesn’t help most patients.

But there are approaches that can work. Treatments may include pulmonary rehabilitation; autonomic conditioning therapy, which includes breathing therapy; and cognitive rehabilitation to relieve brain fog. Doctors are also trying the antidepressant amitriptyline to help with sleep disturbances and headaches; the antiseizure medication gabapentin to help pain, numbness, and other neurological symptoms; and drugs to relieve low blood pressure in patients experiencing postural orthostatic tachycardia syndrome (POTS).

The NIH is sponsoring studies that have recruited just over 8,200 adults. And more than two dozen researchers from Harvard; Stanford; the University of California, San Francisco; the J. Craig Venter Institute; Johns Hopkins University; the University of Pennsylvania; Mount Sinai Hospitals; Cardiff University; and Yale announced in September they were forming the Long COVID Research Initiative to speed up studies.

The group, with funding from private enterprise, plans to conduct tissue biopsy, imaging studies, and autopsies and will search for potential biomarkers in the blood of patients.


CDC: “Long COVID or Post-COVID Conditions.”

CDC National Center for Health Statistics: “Nearly One in Five American Adults Who Have Had COVID-19 Still Have ‘Long COVID.'”

National Institutes of Health: “Long COVID,” “Long COVID symptoms linked to inflammation.”

PLoS Medicine: “Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19.”

The Lancet Respiratory Medicine: “Health outcomes in people 2 years after surviving hospitalisation with COVID-19: a longitudinal cohort study.”

Angiogenesis: “Persistent capillary rarefication in long COVID syndrome.”

PLoS Pathogens: “SARS-CoV-2-specific T cells associate with inflammation and reduced lung function in pulmonary post-acute sequalae of SARS-CoV-2.”

Lancet eClinical Medicine: “Impact of COVID-19 vaccination on the risk of developing long-COVID and on existing long-COVID symptoms: A systematic review.”

JAMA Psychiatry: “Associations of Depression, Anxiety, Worry, Perceived Stress, and Loneliness Prior to Infection With Risk of Post–COVID-19 Conditions.”

U.S. Department of Health and Human Services: “Guidance on ‘Long COVID’ as a Disability Under the ADA, Section 504, and Section 1557.”

Long COVID Research Initiative:”Introducing LCRI.”

Nature Medicine: “Long-term Neurologic Outcomes of COVID-19.”

The BMJ: “Long COVID—an update for primary care.”

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