Long COVID and its relationship to MS

If intermittent EBV reactivation drives long COVID and MS, it should respond to EBV antiviral strategies. I am aware that many pwMS have started taking antivirals off-label to manage their MS ....

Long COVID is defined as a clinical syndrome of persistent symptoms after acute COVID-19 that last longer than 12 weeks. The symptoms associated with long COVID are numerous and include (see NHS website for more information on long COVID):  

• extreme tiredness (fatigue)

• feeling short of breath

• problems with your memory and concentration ("brain fog")

• heart palpitations

• dizziness

• joint pain and muscle aches

• loss of smell

• chest pain or tightness

• difficulty sleeping (insomnia)

• pins and needles

• depression and anxiety

• tinnitus, earaches

• feeling sick, diarrhoea, stomach aches, loss of appetite

• cough, headaches, sore throat, changes to sense of smell or taste

• rashes

Many of these symptoms overlap with multiple sclerosis, chronic fatigue syndrome, and post-viral fatigue syndromes, which are common to numerous viruses, including Epstein-Barr virus (EBV). While the exact mechanisms driving long COVID are still unclear, several sources suggest that EBV reactivation could contribute. This is when I became very interested. Could long COVID be the gateway to developing effective antiviral treatments for EBV and MS? 

Like long COVID, EBV-associated infectious mononucleosis (IM) is also a post-acute infection syndrome.  It features similar symptoms, including fatigue and muscle pain (myalgia), low mood, cog-fog, insomnia and other mental health problems (depression and anxiety). EBV typically enters a latent phase after the initial infection, be it symptomatic (IM) or asymptomatic, but can reactivate under certain conditions, including acute infections, severe illnesses, or immunosuppression. Several studies have shown evidence of EBV reactivation in COVID-19 patients, which includes:

• The presence of detectable EBV viraemia during the acute phase of COVID-19 is predictive of persistent symptoms. 

• An association between increased seroreactivity to EBV early antigen (EA) and viral capsid antigen (VCA) and the development of long COVID.

It is important to stress that the link between EBV and long COVID is currently an association and not necessarily causal. To prove causation, more research will be done, including trials targeting EBV with antivirals as a potential treatment for long COVID. It is important to note that EBV reactivation can occur in various immune dysregulation contexts, not just long COVID, which some would argue that these findings are non-specific. Intermittent reactivation occurs in MS, and it is this intermittent cycling between latent and lytic infection that may be driving MS disease activity. 

Ancher, Michael, "The Sick Girl", 1882, Statens Museum for Kunst

As a young general medical registrar or trainee, I was always struck by how tired and ill people were with chronic or persistent infections, be it tuberculosis, hepatitis or HIV in the pre-antiretroviral era. I later learnt about sickness behaviour, a complex behavioural syndrome in response to inflammation, be it from infection or another inflammatory stimulus such as that which occurs with autoimmune diseases. What long COVID is, and probably MS, is a form of sickness behaviour, which is why the symptoms of these two diseases overlap so much. If intermittent EBV reactivation drives long COVID and MS, it should respond to EBV antiviral strategies. I am aware that many pwMS have started taking antivirals off-label to manage their MS. It is remarkable how many pwMS have contacted me to tell me how well they are doing on antivirals. This is reassuring and supports our efforts to develop antiviral therapies for MS. Are you taking antivirals? Which ones? Have any of you noted any response?  

Please note that I can not sanction the use of off-label antiviral medications to treat MS. Antivirals need to be tested in well-designed, randomised controlled trials. Without class 1 evidence, we will not be able to get antivirals licensed to treat MS, nor will payers pay for these treatments. Prescribing medications off-label comes with many risks to pwMS, the prescriber and the healthcare system the prescriber works in. 

For more information on sickness behaviour, I would recommend an earlier MS-Selfie newsletter on this subject: ‘ Do you suffer from cog-fog, fatigue or sickness behaviour?’ (19-Oct-2021).

The review article that triggered me to write this newsletter below discusses the current understanding of long COVID and the persistent symptoms experienced by some individuals following a SARS-CoV-2 infection. You may find this article of interest; it is accessible to download. The authors discuss the various challenges in defining and researching long COVID, including its wide range of symptoms, variability in symptom severity, and potential mechanisms. The review explores multiple possible causes, such as persistent viral reservoirs, dysregulated immune responses, direct viral damage, and vascular endothelium activation. The article also examines the progress of animal models and clinical trials aimed at understanding and treating long COVID, highlighting the need for more extensive human studies to confirm the effectiveness of various therapeutic approaches.

Paper

Antar & Cox. Translating insights into therapies for Long Covid. Sci Transl Med. 2024 Nov 13;16(773):eado2106.

Long Covid is defined by a wide range of symptoms that persist after the acute phase of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Commonly reported symptoms include fatigue, weakness, postexertional malaise, and cognitive dysfunction, with many other symptoms reported. Symptom range, duration, and severity are highly variable and partially overlap with symptoms of myalgic encephalomyelitis/chronic fatigue syndrome and other post-acute infectious syndromes, highlighting opportunities to define shared mechanisms of pathogenesis. Potential mechanisms of Long Covid are diverse, including persistence of viral reservoirs, dysregulated immune responses, direct viral damage of tissues targeted by SARS-CoV-2, inflammation driven by reactivation of latent viral infections, vascular endothelium activation or dysfunction, and subsequent thromboinflammation, autoimmunity, metabolic derangements, microglial activation, and microbiota dysbiosis. The heterogeneity of symptoms and baseline characteristics of people with Long Covid, as well as the varying states of immunity and therapies given at the time of acute infection, have made etiologies of Long Covid difficult to determine. Here, we examine progress on preclinical models for Long Covid and review progress being made in clinical trials, highlighting the need for large human studies and further development of models to better understand Long Covid. Such studies will inform clinical trials that will define treatments to benefit those living with this condition.

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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.