What We Know But Still Have to Learn About Long COVID

Since the start of the COVID-19 pandemic, the persistence or appearance of neurologic symptoms after clearance of SARS-CoV-2 infection has become a serious health challenge for patients and clinicians worldwide. The effects of postacute sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID, can be debilitating and persist for months after infection. Some of these symptoms can include fatigue, neuropsychiatric sequelae, sleep disturbances, sensorimotor symptoms, cognitive impairment/brain fog, hypoguesia/hyposmia, hearing loss, and ocular symptoms.

As emphasized by the research and experts in the field, currently there are no specific tests for the diagnosis of Long COVID, and clinical features such as laboratory findings and biomarkers may not specifically relate to the condition. It is important to develop and validate biomarkers for the prediction, diagnosis, and prognosis of Long COVID and its response to therapeutics. Regardless of age or preexisting health conditions, Long COVID can affect anyone, highlighting that this condition is not restricted to any specific demographic and does not discriminate, even against the healthiest individuals.

Recently, we conducted a Long COVID roundtable in collaboration with NeurologyLive.com to continue our roundtable video series where we delve into important clinical neurological disease topics with a comprehensive discussion with clinicians in the field. Despite growing knowledge about Long COVID, many questions remain unanswered. In this last episode, experts acknowledged the significant progress in recognizing and studying this condition, particularly in areas like endothelial and neuroinflammatory changes.

In this discussion, the panel highlighted how advances such as the use of AI for drug repurposing and proteomics may offer hope for new treatments. However, much is still unknown, including the exact mechanisms of Long COVID, who is most susceptible, and why recovery varies widely among patients. The pandemic has spotlighted long-standing post-infectious syndromes, driving further research into how infections impact neuroinflammation, neurodegeneration, and public health.

Our panel of clinicians include:

• Ravindra Ganesh, MD, MBBS, FACP, Dip ABOM, general medicine doctor at the Mayo Clinic and leader of their Long COVID clinic.
• Svetlana Blitshteyn, MD, FAAN, clinical associate professor of neurology at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences, director of the Dysautonomia Clinic.
• Monica Verduzco-Gutierrez, MD, physical medicine and rehabilitation physician, professor, and chair of rehabilitation medicine at UT Health, leader of the Long COVID clinic.

Transcript edited for clarity.

Ganesh: I think the more we’ve learned about Long COVID, the more questions I’ve had. It’s been extremely validating to have an infection-associated chronic illness taken seriously by the government, the NIH, and larger academic bodies. It’s been good to see funding coming in and great to see the data supporting what we’ve suspected for years—that there are endothelial changes, neuroinflammatory changes, and that testing, along with all of this research, is being used to better delineate a pathophysiology that, honestly, has been pretty mystifying for the last 40-50 years as we’ve studied these diseases. Some of the things we’re seeing, such as the application of AI to repurpose orphan drugs and the proteomics research for Long COVID, are promising. Hopefully, this will lead to therapeutic trials that can help our patients.

What do we need to learn? Everything. We have a clinical definition, but we don’t have a unified pathophysiology. We don’t have clear delineations—like, this is what it looks like if you have Long COVID with an endothelial predominance or Long COVID with both endothelial and neuroinflammatory components—and how to treat them. We also don’t know exactly who is susceptible. We have ideas based on hypermobility, family history, and responses to previous infections, but we don’t yet have a genetic signature that could predict who will be at high risk after exposure to SARS-CoV-2. We also don’t know how long each person’s illness will last. I still don’t understand how I can have two patients in my clinic, both six months post-infection and equally sick, but one recovers in a year while the other remains chronically ill for four years, with nothing making them better.

I think this has raised more questions than answers, but the attention and the amount of data we’ve collected are incredibly encouraging.

Verduzco-Gutierrez: I still think we don’t know what we don’t know. It’s one of those Dunning-Kruger effects—there’s still so much we don’t understand, even for people like us who care for these patients regularly.

Blitshteyn: I agree with my colleagues. COVID has uncovered longstanding issues with post-acute infectious syndromes that have existed for decades, if not centuries, but were never properly studied or addressed. We pushed these patients aside. Now, with the Long COVID pandemic affecting millions, we’re saying, “What do we do now?”

The silver lining of this pandemic, which is truly a human disaster, is that we can finally address these unknown pathophysiologies. We’re uncovering that not only does SARS-CoV-2 impact the brain, but so do multiple viral or bacterial infections, leading to both neuroinflammation and neurodegeneration. New science now tells us that even multiple sclerosis has a causative link to the Epstein-Barr virus. I was taught during my residency that EBV was too common to cause multiple sclerosis, but this understanding has shifted.

There’s going to be a whole new field focused on how infections impact human health and disease, particularly the brain. We’ll need to study the genetic predispositions that make some individuals more susceptible to these adverse outcomes. We’ve always had cases of post-acute Lyme syndrome, post-mono syndrome, and post-flu syndrome. Now, we’re also seeing similar symptoms after vaccinations in some cases. All of these unknowns are coming to light, and we are being forced to study them.

Before, we could ask, “How many of these patients are there, really?” Now we know that millions of people are affected. Even if you apply the smallest estimate—3.5% to 4% of those with long COVID, even with Omicron—that still means millions of people worldwide are impacted. These are young people who are unable to work or go to school. The impact is enormous, affecting public health, disease management, and the economy.

The silver lining is that we may finally get some answers. But I don’t think we’re going to like what we learn. What we do with that information will be critical. In the past, it was easier to remain in the unknown—it’s like the saying, “What you don’t know can’t hurt you.” But now, we’ll know, and we’ll have to act on that, likely at both a public health and policy level.