Long COVID: The latest in a series of unexplained post-acute infectious syndromes?

by Ya’el Courtney
figures by Gracyn Mose

COVID-19, the disease caused by the SARS-CoV-2 virus, has killed over 1 million Americans from 2020 to 2024. This number is startling, especially considering that the harm of COVID-19 extends beyond loss of life and even beyond the symptoms of acute infection. While most people recover fully from SARS-CoV-2 infection within a week or two, in February 2024, 6.8% of Americans aged 18 to 65 (over 17 million people) reported “long COVID,” or symptoms attributable to SARS-CoV-2 infection that lasted for months beyond the initial active infection. Furthermore, around 4 million of those people are unable to work, which is 1.5% of the working-age population. The economic impact of these lost wages is currently ~$200 billion a year and is expected to rise. If you factor in the cost of medical care and lost quality of life, long COVID costs the US an additional $544 billionannually. These statistics mean that millions of Americans are dealing with a frustrating, debilitating set of symptoms that make participating in day-to-day life more difficult.  

Long COVID is characterized by symptoms that include feeling tired quickly, difficulty concentrating (“brain fog”), sensory problems, difficulty breathing, heart rate changes, sleep problems, and symptoms worsening after exercise. Asymptomatic, mild, and severe COVID-19 cases can all lead to these long-lasting symptoms. Long COVID has no specific treatment, and its exact cause is not yet understood. However, it closely resembles the poorly understood chronic illnesses caused by several other viruses, collectively termed post-acute infectious syndromes (PAIS). It’s possible that there may be similar causes underlying many of these syndromes, and noting these similarities could help researchers better understand and develop effective treatments and cures for long COVID. 

What other viruses are known to lead to post-acute syndromes – and what do they have in common? 

The first well-documented observation of PAIS was Post-Polio Syndrome in the 1870s, where people developed muscular degeneration and weakness 15-40 years after infection with poliomyelitis. Since then, PAIS has been noted after infection by many viruses – from influenza to the common cold to Epstein-Barr Virus (EBV) (also known as ‘mono’ or glandular fever). It was not until the 1980s that doctors began to recognize similar chronic conditions as serious medical problems, and a new diagnosis was born: myalgic encephalomyelitis/chronic fatigue syndrome, or ME/CFS. However, attempts to identify a single infectious agent as the cause of ME/CFS have been unsuccessful, complicating efforts to find a cure. This brings us to a compelling proposition: could ME/CFS be more accurately described as a spectrum of post-acute infectious syndromes? This perspective suggests that various infectious agents could trigger a prolonged, systemic response, manifesting in remarkably consistent symptoms across different cases. The COVID-19 pandemic has provided a unique opportunity to explore this hypothesis, as the similarities between long COVID and ME/CFS are striking. Both conditions share a core set of symptoms (Figure 1), highlighting the possibility that SARS-CoV-2 might act as one such infectious trigger. 

What might viral infections have in common that leads to similar long-term symptoms? The scientific community has identified four similar features in most PAIS patients (Figure 2): tissue damage, in which viruses damage body tissues that are not repaired correctly due to prolonged symptoms, pathogen reservoir/remnants, in which there is still virus causing problems in deep tissues despite no detection of viral presence in blood or nasal swab tests, autoimmunity, and reactivation of latent viruses, which are discussed in sections below. While PAIS and long COVID patients frequently have all of these features, it’s unclear which pathways are the cause of continuing symptoms and which are more of a side effect. Scientists will need to figure out which of these features are the driving causes of long PAIS, as well as which might be able to be targeted with therapeutics to help patients. 

Common features of PAIS: Autoimmunity

The immune system must react strongly during viral infection to create antibodies to destroy virus-related material. However, in PAIS, infection can trick the immune system into attacking healthy tissue and promoting inflammation. A critical insight into this process is the role of molecular mimicry, first described in 1965, where viruses have features that closely resemble the body’s proteins. Molecular mimicry is a problem during acute infection because it makes it harder for your immune system to tell the difference between viral material and your own body, leading the immune system to attack the body’s own tissue. For example, in multiple sclerosis (MS), an autoimmune disorder, research has found antibodies in patients that react to both a viral protein from the EBV and a protein found naturally in the brain. This suggests a direct link between EBV infection and the autoimmune attack leading to MS symptoms. This mechanism may be at play in developing several other autoimmune diseases as well, including Guillain–Barré syndrome, type 1 diabetes, and systemic lupus erythematosus.

The COVID-19 pandemic has further highlighted the potential for diseases to trigger autoimmune responses that last far beyond the initial infection. Studies have detected autoantibodies—antibodies that mistakenly target and react with a person’s tissues or organs—during the acute and recovery phases of COVID-19. The persistence of such autoantibodies and their role in long-term symptoms is under investigation.  Early findings suggest that these autoantibodies could disrupt critical neurological and vascular functions, and that specific autoantibodies in patients can even predict whether people will develop long COVID. 

Common features of PAIS: Latent virus reactivation

Latent viruses are viruses still circulating from past illnesses, even from a long time ago, that are no longer actively replicating or causing clinical symptoms because the immune system is actively suppressing them. Most of us carry latent viruses in our bloodstream, including human herpesvirus 6 (HHV-6, >80% of the population), EBV (95%), and human cytomegalovirus (CMV, 70%). During active infections and PAIS, however, your immune system becomes less able to suppress latent viruses in your body, often leading to reactivation of these latent DNA viruses; this means that the virus is no longer inactive and is now replicating and spreading through the body. Tellingly, all viruses whose reactivation has been connected with PAIS or COVID-19 are from the family Herpesviridae. While the specific Herpesviridae species reactivated in PAIS patients varies, one study found that one of the most significant risk factors for long COVID was if patients had high levels of EBV reactivation when they were first diagnosed with acute COVID (Figure 3). When viruses reactivate EBV, levels remain high for 3-6 months, and a whopping 67% of people with long COVID have EBV reactivation! High EBV levels may explain why people with long COVID often report fatigue and cognitive difficulty, as these are the symptoms EBV causes during its acute infection. 

While we don’t know precisely how the reactivation of latent viruses leads to PAIS and long COVID, some research supports that taking general antivirals during acute SARS-CoV-2 infection or long COVID improves outcomes. This improvement could be due to antivirals suppressing SARS-CoV-2 itself, thus limiting the severity of acute inflammation and potential viral reservoirs. Alternatively, the antivirals could prevent latent viruses’ reactivation during acute SARS-CoV-2 infection. 

COVID-19 brought new momentum to PAIS research; let’s keep it up!

The COVID-19 pandemic revealed a lack of understanding about the long-term effects of infectious viral diseases, with conditions like ME/CFS being historically neglected in medical training and research. Before the pandemic, most American medical schools and textbooks did not even teach about ME/CFS. Research funding was disproportionately low, with ME/CFS only receiving $15 million from the National Institutes of Health (NIH) in 2019, a fraction compared to other diseases affecting similar numbers of Americans. However, the emergence of long COVID prompted the NIH to allocate over $1 billion for its research, signaling a shift towards recognizing and addressing post-infectious conditions. This newfound focus offers hope for advancements in understanding and treating chronic disabilities linked to infections. In the meantime, the public must continue doing one thing that is proven to reduce the risk of long COVID: keeping up with vaccinations. 

Ya’el Courtney is a fifth-year PhD candidate in the Neuroscience program at Harvard University. You can find her on Twitter as @ScienceYael.
Gracyn Mose is a first-year PhD student in the Chemical Biology program at Harvard University.

For more information:

• Read here for a more detailed analysis of long COVID and ME/CFS similarities.
• If you are experiencing symptoms of long COVID, here is advice about preparing for an appointment – which can make a positive difference in your evaluation, diagnosis, and treatment.
• Many people treat viral infection as a brief inconvenience. Read more here about why rushing back to work and the demands of everyday life may increase the risk of long COVID and other PAIS. 
• To read about the results of a new, high-powered study focused on understanding ME/CFS symptoms, click here. 
• Not all people diagnosed with ME/CFS have an identifiable viral catalyst, but it is possible that non-viral triggers could lead to the same systemic responses explained in this article. Read here about other types of ME/CFS triggers.