Infectious Disease

Solving the riddles of long COVID

September 30, 2022

10 min read


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Al-Aly, Block, Fryhofer and Glatt report no relevant financial disclosures.


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Although the general understanding of long COVID has improved in the past year, many questions about the persistent sequelae experienced by some people after an acute SARS-CoV-2 infection remain, according to experts.

“Initially, people assumed this was only brain fog and fatigue, but now, in this last year, a slew of issues related to long COVID have emerged,” Ziyad Al-Aly, MD, FASN, chief of the research and development service at the Veterans Affairs Saint Louis Health Care System, told Healio. “This includes neurologic and mental health disorders, heart and cardiovascular conditions, increased risk of diabetes, and so on.”


“Long COVID improved our awareness that viruses produce long-term consequences,” said Ziyad Al-Aly, MD, FASN, a leading long COVID researcher. Source: Mary-Dale Amison/Public Affairs, U.S. Department of Veterans Affairs

One recent study assessing data published through March 2022 found that the global estimated pooled prevalence of long COVID-19 was “substantial” at 43% — equal to approximately 200 million people who have had post-COVID-19 health consequences, the researchers reported.

Another study found that nearly 6% of children who tested positive for SARS-CoV-2 after seeking care at an ED reported lasting effects from their infection, 10% of whom were hospitalized for the condition.

Helping patients with long COVID has not been simple.

“Early in the pandemic, most people had not heard of long COVID, so a major focus was on validating those experiencing such symptoms and educating others,” Brian L. Block, MD, assistant professor of medicine in the division of pulmonary and critical care at the University of California, San Francisco, told Healio. “Thankfully, long COVID is now more broadly known, but understanding how and why it develops remains elusive.”

‘A combination of similar syndromes’

In October 2021, WHO published a clinical case definition of long COVID that says the condition “occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually 3 months from the onset of COVID-19 with symptoms that last for at least 2 months and cannot be explained by an alternative diagnosis.”

According to WHO, the most common symptoms include fatigue, shortness of breath and cognitive dysfunction, plus others that can generally have an impact on everyday functioning.

The CDC considers a patient to have long COVID — it generally uses the term “post-COVID conditions” — if symptoms persist 4 weeks after the acute phase of illness, although it notes that “many patients continue to recover between 4 and 12 weeks.”

“Although standardized case definitions are still being developed,” the CDC says, “in the broadest sense, post-COVID conditions can be considered a lack of return to a usual state of health following acute COVID-19 illness. Post-COVID conditions might also include development of new or recurrent symptoms or unmasking of a pre-existing condition that occurs after the symptoms of acute COVID-19 illness have resolved.”


Researchers in the United Kingdom developed a novel tool called the Symptom Burden Questionnaire for Long COVID, a patient-reported outcome measure that was created using data from 13 patients but was then field tested by 274 adults with long COVID. The researchers determined it was accurate, made it available for clinicians and researchers worldwide and said it can assess the symptoms of long COVID and help deliver clinical care.

In addition to pinpointing symptoms, researchers have begun determining what pre-existing conditions contribute to the possibility of developing long COVID.

One study found that pre-existing type 2 diabetes, SARS-CoV-2 RNA in the blood, Epstein-Barr virus DNA in the blood and the presence of certain autoantibodies could anticipate a patient developing long COVID. The study showed the autoantibodies decreased protective SARS-CoV-2 antibodies as they themselves increased, suggesting a relationship between long COVID, autoantibodies and an elevated risk for reinfection.

“It remains hard to predict which people will have more persistent symptoms of long COVID, and which will have a better trajectory. I think some of this is because what we have been calling long COVID — as if it is just one disease with one mechanism and one expected outcome — is actually a combination of similar syndromes, each of which may have its own cause, expected trajectory, and outcome,” Block said.

“Having more granularity about long COVID, such as being able to say a person has a certain subtype, will make it easier to predict what will happen to a certain patient, and tailor treatments appropriately,” he said.

One thing experts know for certain is that caring for patients with long COVID requires a collaborative effort.

“Patients with long COVID continue to benefit from a multidisciplinary approach where they can see a physician with expertise in the symptoms they are feeling, along with critical team members such as a physical therapist, psychiatrist, social worker, and others for support,” Block said.

Strain on public health

Unfortunately, such care is “resource intensive” and not always available as the health care system continues to experience strain, Block added.

“It’s not an understatement to say the U.S. health care system was stretched thin by the COVID-19 pandemic,” Sandra Adamson Fryhofer, MD, chair of the AMA board of trustees and member of the CDC’s Advisory Committee on Immunization Practices COVID-19 vaccines work group, told Healio.

Sandra Fryhofer“From personal protective equipment shortages and constant battling against misinformation to significant physician burnout, physicians have been asked to do more with less for nearly 3 years,” Fryhofer said.

She said physician shortages were projected to be severe even before COVID-19, and the U.S. is now approaching a public health emergency. How much long COVID is contributing to the strain on health care services compared with other “surging” illnesses is up for debate, Al-Aly said.

“At this point, it’s really hard to disentangle the strain that the health system is experiencing and how much is really due to the influx of patients with long COVID vs. other things,” he said. “I can tell you, anecdotally, if you go to any post-COVID clinic or any COVID clinic, the wait time is unacceptably long.”

Al-Aly explained that if patients go online or call to set up an appointment at a long COVID clinic, they would be lucky to get an appointment within 3 or 4 months.

“There is really a mismatch between demand and capacity, or the ability to provide services,” he said.

Compounding the problem of physician shortages and long patient waits is that fact that no guidelines or official means of diagnosis have been established.

“As is the case in a lot of diagnoses, diagnosing long COVID is often a process of elimination,” Fryhofer explained. “It shows up both in patients who were very sick from COVID and patients who had no symptoms at all. It can show up immediately or months after infection. If a patient had no symptoms before and now has new symptoms, a physician cannot simply label it as long COVID without first ruling out other conditions.”

This extra guesswork can prolong the treatment and care process, creating heavier workloads for doctors and longer waits for patients, which could be detrimental as other public health emergencies emerge.

Aaron Glatt“The U.S. health care system is a very strong system, but it’s breaking in a lot of places,” Aaron E. Glatt, MD, chairman of the department of medicine and chief of infectious diseases at Mount Sinai South Nassau in Oceanside, New York, told Healio.

Glatt listed some infectious diseases that are eating up public health resources in the U.S — COVID-19, monkeypox and influenza among them. Glatt practices in one of the New York counties where poliovirus has been detected in wastewater.

“You’re not catching long COVID from somebody else, so there’s a little bit less of a public health urgency — but that doesn’t mean it’s not an urgent, real concern for the patients who have to deal with this every day,” Glatt said. “Unfortunately, when you’re dealing with debating where we should put limited resources, it is not always easy to give every disease the right funding it needs to solve the issues it presents.”

Treatments? ‘It’s still zero’

There remain no specific treatments for long COVID — and that is not surprising, Al-Aly said.

“If you asked me a year ago for the number of approved therapeutics for long COVID, I would have said zero. And guess what? It’s still zero,” said Al-Aly, who called the lack of treatments “a major deficiency.”

“We really need to promote awareness [of this],” he said. “This is really a sore point. People are hurting with long COVID … and they want treatment yesterday.”

Block said that some centers appear to have standardized treatment protocols that they use for all patients with long COVID, which can range from prescription medications that have been repurposed for long COVID to supplements, recommendations about dietary changes and other protocols.

However, he said, this is not the same at all facilities, including his own.

“At our clinic we do not employ this practice, given our belief that each patient with long COVID requires an individualized treatment plan and given that the evidence base for many of the offered treatments is thin,” he said.

Glatt said there is not really a need to develop a protocol to apply to patients with long COVID.

“If you’re dealing with, let’s say for argument’s sake, shortness of breath, pulmonary and cardiac complications — a generalized protocol [for that] might be inappropriate for someone dealing with loss of smell or people who are fatigued,” he said. “I don’t think it’s a one-size-fits-all protocol.”

According to Glatt, a lot of clinicians treating patients with long COVID are really just monitoring them and gathering data, which is still very important.

“Everybody wants to hear ‘treatment,’ but sometimes the first step is understanding what’s going on and then, once you understand, maybe you have a chance to treat,” Glatt said.

He said long COVID is like other illnesses that are poorly understood — chronic fatigue, for example — making treatment difficult. The first and foremost thing to remember when initiating care and treatment for any illness, including long COVID, is to try to make the patient feel better, Glatt said.

“That’s why we became doctors,” he said. “I may not understand why they have fatigue or shortness of breath, but what can I do to make them feel better? I may not have the pills to make this go away in 5 days, but I can be both a compassionate and sympathetic person and figure out, with the patient, how they can normalize their life.”

Getting the lives of patients with long COVID back to normal is crucial to their mental health because many have an increased risk for depression and depressive symptoms, as well as other mood disorders, studies have shown.

“One question we get in clinic is whether a patient can and should return to work, or an employer may send us disability paperwork to complete,” Block explained. “With a new disease of uncertain pathophysiology and trajectory and limited objective testing, it can be very difficult to prognosticate or make informed decisions about what level of activity is safe.”

This may complicate the decision-making process for people with long COVID and those treating them.

“Considerations include the tradeoff between having more time to rest — when we know some people with long COVID feel worse when they overexert themselves — vs. losing the sense of meaning that can come from work, potentially contributing to a sense of loss or other mood disorder, which can magnify the symptoms of long COVID,” Block said.

Preventing COVID is preventing long COVID

Experts agree that preventing COVID-19 altogether is the key to lessening the burden of long COVID.

“I tell people the best way to not get long COVID is to not get COVID,” Glatt said. “People who are especially at higher risk for serious COVID should be very careful in terms of making sure that they’re fully vaccinated and boosted.”

It is also important to acknowledge that studies have shown that vaccination may not fully protect people from long COVID symptoms if they experience a breakthrough infection.

A study by Al-Aly and colleagues that was published in Nature Medicine in June assessed nearly 34,000 vaccinated patients with breakthrough SARS-CoV-2 infections and found that they had a higher risk for long COVID (HR = 1.5; 95% CI, 1.46-1.54) compared with almost 5 million contemporary controls with no documented infection.

Compared with unvaccinated patients with a SARS-CoV-2 infection, patients with a breakthrough infection had a 34% lower risk for death (HR = 0.66; 95% CI, 0.58-0.74) and a 15% lower risk for incident long COVID (HR = 0.85; 95% CI, 0.82-0.89).

At the time the study was published, Al-Aly said the data showed vaccines “reduce but do not eliminate” the risk of long COVID and called them “an imperfect shield.”

“With every infection, one’s odds of getting long COVID increases,” Fryhofer said. “This is what it’s like to live during a pandemic.”

Fryhofer added that the COVID-19 vaccines are “exceptionally effective at preventing severe disease and death,” but despite this, some communities and segments of the population — particularly children — lag far behind on vaccination rates, especially boosters.

“The new bivalent vaccine is specifically effective at combating the two most dominant strains of COVID circulating today, and I urge everyone to get it as soon as you’re eligible,” she said.

‘The even bigger riddle’

SARS-CoV-2 is not the first virus to cause lasting effects in previously infected people. [Editor’s note: For a story about the persistent symptoms of Ebolavirus infection, turn to page 22.]

“Long COVID improved our awareness that viruses produce long-term consequences,” Al-Aly said. “In the U.S., SARS-CoV-2 is the biggest example, or the most vivid one out there now, to help us understand that infections and viruses [can have lifelong consequences]. In most of the public consciousness, and even in the medical field, people used to regard them as acute events that you can turn the page and move on from as if nothing happened.”

The magnitude of SARS-CoV-2 and its long-term effects has also led to more funding for the study of post-viral conditions.

“This is really important,” Al-Aly said, “not just to solve the problem of long COVID alone, but to solve the even bigger riddle of the post-viral condition to help us address other problems that people have been suffering from for years and decades.”

Block agreed, suggesting that because COVID-19 was a “monumental global event,” long COVID has received more attention and research funding than other post-viral syndromes that preceded it. However, he cautioned that the attention that was given to COVID-19 is waning.

“In the past year, the degree of societal concern about acute COVID has decreased substantially,” Block said. “With this return to normalcy, people experiencing long COVID may feel left behind and marginalized as society ‘moves on’ and they continue to feel sick.”

He said that as COVID “loosens its grip on our collective attention,” people experiencing long COVID may find — like people with other presumed post-viral syndromes — that the attention and support they had has dried up.

“People shouldn’t give up hope,” Glatt said.



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