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In January 2021, the World Health Organization (WHO) revised its guidelines for COVID-19 treatment to include a recommendation that all patients should have access to follow-up care in case of long COVID. However, despite ongoing studies to better evaluate this serious emerging phenomenon, long COVID is not yet fully understood.

Most people recover from COVID-19 in a matter of days or weeks. Only about 1 in 10 infected with the virus will develop symptoms of long COVID, which patients experience as a cluster of symptoms such as brain fog, muscle pain, and fatigue that persist or appear after acute infection with SARS-CoV-2. Of that 10% who experience it, vaccinated adults with breakthrough infections and young children are significantly less likely to develop long COVID syndrome.

While highly effective vaccines are indeed good news for those in countries that can access them, experts caution against jumping to conclusions about who might be vulnerable to long COVID.

“The incidence of long COVID for vaccinated adults and for children seems to be low, but these numbers are not insignificant,” said Avindra Nath, MD, clinical director of the National Institute of Neurological Disorders and Stroke. “For example, other complications of COVID-19 can be worse in children, like multisystem inflammatory syndrome. And their immune systems are still developing, meaning they may not be capable of mounting the kind of ramped up inflammatory response we see in adults with long COVID.”

Lucette Cysique, PhD, senior research fellow at the University of New South Wales School of Psychology in Sydney, whose research focuses on how infectious diseases affect the brain and cognition, said early reports of long COVID’s impact on the immune system and cognitive function seemed similar to the effects she saw in her work with HIV. “To me, this meant there might be chronic, possibly life-long consequences to COVID-19 infection that we need to understand,” Cysique said.

Racing to Help Patients While Definitions Evolve

We now have a better understanding about who is more susceptible to long COVID, but clinicians and laboratorians have until recently been working without a universally accepted definition of the syndrome, as well as no definitive methods of detecting and treating it.

When asked how he would define long COVID, Nath said, “I think it’s fair to say when you see it, you know it.” This may seem offhand, but Nath very seriously calls long COVID “a major health crisis.”

Since Nath spoke with CLN, WHO issued a more formal definition on October 6, referring to it as a post-COVID-19 condition. This “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. “Common symptoms include fatigue, shortness of breath, cognitive dysfunction, and others which generally have an impact on everyday functioning. Symptoms may be new onset, following initial recovery from an acute COVID-19 episode, or persist from the initial illness. Symptoms may also fluctuate or relapse over time. A separate definition may be applicable for children.” WHO added that data show 10%–20% of patients experience lingering symptoms for weeks to months following acute SARS-CoV-2 infection.

The long COVID patient population has been notoriously hard to characterize because oftentimes clinicians do not have information about the initial COVID-19 diagnosis; for example, the patient did not have access to testing when their symptoms started or received false-negative results. Nikolina Babic, PhD, associate professor of pathology and laboratory medicine at the Medical University of South Carolina, said these patients “can show up at their doctor’s office months later when they are probably in a long COVID situation, but we can’t look back at earlier tests to confirm it, so we don’t have a baseline to serve as a point of reference.”

One of the leading hypotheses for what causes long COVID is centered on hyperactivity and dysregulation of the innate immune response caused by viral persistence or proteins from the virus. An innate immune response, unlike an adaptive response, is, in a word, aggressive. It is also hard to stop once it gets going.

Cysique is one of the researchers that has linked this increased immune response to neurocognitive difficulties in people with long COVID. However, her work is still in its early days. “I’m still analyzing data from 2 months and 6 months postinfection,” she said. “I’m just starting to look at 12 months postinfection data.”

Diagnostic Dilemmas

The first hurdle clinicians face in diagnosing long COVID is confirming an initial COVID-19 infection. If they can confirm an initial infection, the next move is to rule out other diseases that may present with similar symptoms, such as rheumatoid arthritis or lupus. After that, the syndrome is usually diagnosed based on a continued process of elimination. Treatment options are typically directed at individual symptoms and involve existing immunotherapeutics, including plasma exchange, steroids, antiinflammatories, as well as antiviral and interferon medications.

Now, researchers are working on several laboratory-supported approaches to diagnosing long COVID by identifying biomarkers that pop up with post-COVID-19 uncontrolled immune system activation. Potential targets include inflammatory cytokines, like IL-6 and IFN that can be detected in blood tests, and monocytes—a type of white blood cell deployed by the innate arm of the immune system—that can be measured with flow cytometry.

More novel techniques are in the works, as well. Nath and his colleagues are looking at signs of vascular damage caused by COVID-19 proteins as potential indicators of long COVID. “With more data, we hope to enable laboratory diagnoses using a battery of tests related to the immune response that will be a signature of long COVID,” he said. Nath’s team is also developing antisense molecules to prevent SARS-CoV-2 replication, which could in turn eliminate the viral proteins believed to trigger the overactivation of the immune system that causes symptoms.

Cysique is lead author on a recently published collection of culturally standardized neurocognitive and mental health tests to assess people with long COVID. “This is more than just a research exercise,” stressed Cysique. The NeuroCOVID International Neuropsychological Society Special Interest Group, which Cysique chairs, hopes the data will eventually help inform treatment decisions for people with long COVID.

The group started their standardized collection of data on COVID-19 long-term neuropsychological effects early in the pandemic. Their findings culminated in neurocognitive tests for establishing a baseline for cognitive function in people with acute COVID-19 and postinfection. The tests are designed to be easy to administer bedside or virtually, and range from basic to more thorough neurocognitive assessments for different stages of the disease.

Although still in its early stages, Cysique said they are starting to see trends in the data. “It looks like people with impaired cognitive function postinfection are undergoing an abnormal immune response and inflammation, and women are more likely to experience neurocognitive symptoms.” 

The group is developing a free, access-controlled repository to share their data with clinicians and researchers around the globe.

A Call for Lab Expertise and Insights

Accessible, affordable, and early COVID-19 testing appears to be the keystone to improved detection and care for people with long COVID.

“If a COVID-19 infection is properly documented at the outset, we can better diagnose and treat the patient if they are present with continuing or new symptoms several months out,” Bacic said. “I do sincerely hope that we will soon have information that will help us better identify the patients at higher risk for long COVID but also to properly manage them quickly to minimize the degree and length of their suffering.”

Nath expects that laboratory medicine researchers developing new or more refined assays related to SARS-CoV-2 will make all the difference.

“The researchers and clinicians in medical laboratories play a very important role in solving the mysteries of long COVID,” Nath said. “These innovative minds are going to develop new standardized versions of the immunoassays we are currently investigating for long COVID. And if we can make these standardized tests widely available, it will have a huge impact on the health of people with long COVID.”

Sarah Michaud is a freelance writer who lives in London. +Email: [email protected]

NIH Initiative Supports Long COVID Research

The National Institutes of Health (NIH) launched the Researching COVID to Enhance Recovery (RECOVER) Initiative to investigate the long-term effects of COVID-19. The national effort includes diverse scientists, clinicians, patients, and caregivers working collaboratively to collect real-world data to answer the following questions:

  • What does recovery from COVID-19 look like for different populations?
  • How many people experience symptoms after the acute stage of COVID-19 infection?
  • How many people experience new symptoms  after acute COVID-19 infection?
  • What causes long COVID?
  • Why do some people develop long COVID and others do not?
  • Does COVID-19 trigger changes in the body that increase the risk of other health conditions, such as chronic lung, heart, or brain disorders?

Earlier this year, NIH awarded four RECOVER infrastructure awards, listed below, to facilitate the initiative’s organizational framework around which research will be conducted. These centers are tasked with building and supporting the RECOVER Initiative, its participant pool and team of investigators, and ensuring data are standardized and shared among researchers and the public.

Clinical Science Core: New York University, Langone Health, New York City

Build the RECOVER Consortium, a group of lead investigators to harmonize and coordinate data, develop methods for monitoring protocols, and guide communication and engagement with stakeholders.

Data Resource Core: Massachusetts General Hospital, Biostatistics Center, Boston

Help enable tracking and searchability across all data sources and provide expertise in statistical analysis and data standardization, access, and sharing.

Biorepository Core: Mayo Clinic, Biospecimens Accessioning and Processing Core Laboratory, Rochester, New York

Receive, manage, and make available to researchers a diverse range of biospecimens obtained from RECOVER research studies.

Administrative Coordinating Center: RTI International, Research Triangle Park, North Carolina

Provide oversight and monitoring support in addition to communication, work group, protocol development, and implementation support.

The RECOVER Initiative is asking for volunteers to participate in studies throughout the United States. Learn more at recovercovid.org