Comparing ME/CFS following mononucleosis with Long COVID, 2026, Jason et al

I told Dr. Jason I was discussing his study on an ME/CFS group and asked if he could address your question. He wrote this for me to share with you:

I want to emphasize that this study is possible because we have a very rare scientific resource: biological samples and self-report data from thousands of college students collected before anyone became ill with mononucleosis. In most ME/CFS and post-viral illness research, investigators can only study people after illness onset, making it difficult to understand what factors may contribute to why some individuals recover while others develop prolonged illness.

Because these data were collected prospectively, before the viral trigger occurred, they provide a unique opportunity to examine possible factors that may influence vulnerability, resilience, and illness progression following infection. We have only begun with our biological investigation of our sample. This kind of pre-illness data is extraordinarily uncommon and may offer insights that retrospective studies cannot.

The goal of this work is not to question the reality or seriousness of the illness, but to better understand mechanisms that could ultimately inform prevention, earlier identification, and improved treatment. We undertook this study precisely because opportunities like this are so rare, and because they may help generate new knowledge about a disease we all want to understand much better. The study is motivated by the possibility of uncovering mechanisms involved in illness onset; knowledge that could help advance earlier identification, prevention strategies, and ultimately treatment.

One of the central questions patients themselves have raised for decades is: why do some people become chronically ill after an infection while others do not? This study is directly aimed at that question. Because we have rare prospective data collected before illness onset, we can investigate this in a way that few studies in the world can.
That answer from Prof Jason seems to be entirely about the IM to ME/CFS study. We have discussed in detail the various papers published about that study. I think all of us appreciate the value of the project he undertook to find out what factors might predict whether someone gets ME/CFS after mono. Though as we have pointed out, there are some serious problems with the analysis of the results, specifically the unhelpful definitions of moderate and severe ME/CFS, and the DSQ's coflation of PEM and fatigabilty. The premise of the study was very worthwhile, and some useful data resulted.

What he has not addressed in his answer is this specific study where data was collected on long covid using a different collection method, a different way of subdividing participants into groups and some inapproriate questionniares, and to draw as a result what I and others have explained are unjustified or unhelpful conclusions that try to compare ME/CFS and Long Covid.
 
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The data used on ME/CFS was collected from 2014 to 2018 for the original mono study. Other students were added using similar data collection methods for the COVID cohort:

We also recruited participants who did and did
not recover from SARS-CoV-2. These partici-
pants were recruited in 2023–2024 by social
media sources and from posters and recruitment
efforts at local universities. Participants recruited
were provided a medical evaluation, and that,
along with self-report questionnaires (see
below) helped determine whether a person had
recovered or not from SARS-CoV-2. Those clas-
sified as Long COVID had continuous, relapsing,
and remitting symptoms affecting one or more
organ symptoms for at least three months follow-
ing acute SARS-CoV-2 infection.
As an epidemiologist, you will know that collection method matters when attemting to get a picture of severity levels across a population, and when comparing populations. It is true that an attempt was made to match the IM/ME/CFS and LC populations by sampling from university students with the same mean age, but the sampling method is not the same.
This was then compounded by not comparing like with like. The IM/ME/CFS group included only those with at least 4 symptoms from a specific list (Fukuda) or even more restricted to only those meeting at least 2 criteria, ie again a minimum of 4 symptoms. There were, according to the numbers, some IM people who were not classed as recovered, and were not included in the ME/CFS groups, so either had fewer than 4 symptoms or were unavailable.
The LC group, by contrast were self selected by advertising and only required to have at least one symptom.
Also LC is an umbrella category rather than a specific diagnosis, with symptoms ranging from breathlessness or loss of taste, to fulfilling ME/CFS criteria.

I think the only way to do a direct and accurate comparison between the two samples would have been to use the same method of diagnosis of the so called moderate and severe ME/CFS categories with both the IM and the LC groups. Then direct like with like comparison could have been made. Even then, you may have missed out on more severe cases as they would be likely to have had to drop out of univesity so not available to volunteer for the LC group.
Long COVID and ME/CFS are very similar—but not identical
- Both groups had much higher symptoms and impairment than people who recovered.
- This supports the idea that these are related post-infectious illnesses, not unrelated conditions.

Severity matters a lot in ME/CFS
The researchers separated ME/CFS into moderate vs severe. Severe ME/CFS patients were the most impaired overall.
- Long COVID fell in between:
- Worse than moderate ME/CFS
- But not as severe as severe ME/CFS

Symptom burden comparison (key takeaway)
Long COVID had:
- More symptoms than moderate ME/CFS
- Fewer symptoms than severe ME/CFS

Some symptom differences
- ME/CFS (especially severe cases) more often had:
- Sore throat
- Tender lymph nodes
- Flu-like symptoms
- Long COVID more often had:
- Certain neurological, autonomic, and exertion-related symptoms compared to moderate ME/CFS

Functional impact
Long COVID patients had:
- Worse physical functioning and more anxiety than moderate ME/CFS
But across many measures (fatigue, stress, autonomic symptoms), the groups were more similar than different

Big-picture conclusion
- These illnesses likely share overlapping biological mechanisms.
- Studying them together could help explain why some people don’t recover after infections.
_____________________________________

Why this matters (my interpretation)? Long COVID gets exponentially more funding for research, so if similarities between the two can be documented, it will help get more funding to study ME/CFS as a related condition.
Can you not see that all those comparisons are artefacts of the way the researchers chose to subdivide the two samples.

I applaud the intention of showing LC and ME/CFS both include severely sick and disabled people and both need funding. But this study just muddies the water and is so easy to pull to pieces that it discredits the aim.
 
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I know people are mostly disputing the 'severe ME/CFS' diagnosis methodology, but I would equally question it for 'moderate', which on the face of it looks far closer to what people who are classified as 'mild' in the UK (particularly in terms of lack of physical ability).

I found this on the Ammes website:
Dr. Leonard Jason’s team at De Paul University found that eleven symptoms were sufficient to accurately identify ME/CFS patients. These symptoms were clustered in five areas:

  • Profound loss of energy (fatigue)
  • Post-exertional malaise of PEM (symptoms worsen after physical or mental exertion)
  • Cognitive impairment
  • Unrefreshing sleep
  • Pain in joints and muscles, as well as headaches
Doctors often refer to the above symptoms as “non-specific” meaning they are common to a number of illnesses. In fact, healthy people also experience fatigue, muscle aches, and insomnia, as well as many other symptoms on the list, but what marks ME/CFS symptoms as unusual is that they worsen after exertion. They are also distinguished by their severity, frequency and duration. ME/CFS symptoms can be incapacitating, they can be experienced daily, and symptoms may last for years.

SYMPTOMS SCALE

Not all patients experience the same severity of illness. As with any other disease, including the common cold, symptoms can be mild, moderate or severe. Patients often rate themselves on a 1-10 scale, with 1 being bedbound, and 10 fully recovered.

In addition, there are three general levels of illness: mild, moderate, and severe.

Mild: Patients are mobile, can care for themselves, do light housework and work part-time, or even full-time with the curtailment of all other activities. Mildly ill patients experience easy fatigability and loss of stamina and must plan their activities carefully.

Moderate: Patients have reduced mobility and are restricted in all activities of daily living. They have usually stopped work or school. Moderately ill patients feel exhausted after activities.

Severe: Patients are unable to do anything without assistance. They spend most of the day in bed and are sensitive to light and noise. Severely ill patients often feel as if they have the flu.

Patients may suffer relapses at any point in the illness. Even mildly ill patients may become severely ill during a relapse.
This seems to relate to Jasons interpretation of 'moderate'.

I have often noticed that in the US the use of the term 'moderate' is much more on a par with 'mildly affected' .
 
I know people are mostly disputing the 'severe ME/CFS' diagnosis methodology, but I would equally question it for 'moderate', which on the face of it looks far closer to what people who are classified as 'mild' in the UK (particularly in terms of lack of physical ability).
Indeed. I think that's because @Simon M has already done such a good job of it - see series of posts starting here - and we know he'll come back at some point to update that in light of this study. It seems to be a mix of mild ME/CFS and potentially some people who meet Fukuda criteria but don't actually have new onset or worse symptoms than pre-IM.
 
I am not a scientist
Iam foggy
I can’t read all those walls of text. I can’t follow all those side papers and things.

I was quite interested in the biology as that looked interesting in the before-and-after scenario

Sorry but if you can’t summarise a response in a simple sentence, a few words then I can’t follow, also it makes me question why you can’t do so. It means I lose trust in you.
 
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I have a family health emergency to attend to but I am compiling comments to give to Dr. Jason. I know he appreciates the feedback and I hope that my direct connection and engagement has given you a sense that we are listening and looking for ways to improve our contribution to research.

While I am moderate to severe most of the time myself, I'm still attending school online (Medical Gerontology) and often working from bed to support awareness and advocacy for several chronic diseases.

If I don't respond to additional posts right away I am not ghosting you, just dealing with an unexpected event.
 
I am not a scientist
Iam foggy
I can’t read all those walls of text. I can’t follow all those side papers and things.

I was quite interested in the biology as that looked interesting in the before-and-after scenario

Sorry but if you can’t summarise a response in a simple sentence, a few words then I can’t follow, also it makes me question why you can’t do so. It means I lose trust in you.
Sorry if I've lost your trust. I have done my best to respond to the questions. I also have cognitive challenges and couldn't think of a one sentence answer to satisfy you.
 
Sorry if I've lost your trust. I have done my best to respond to the questions. I also have cognitive challenges and couldn't think of a one sentence answer to satisfy you.

@Janet, I personally appreciated the effort you are putting in to discuss these issues with us, and though not everyone will agree on everything what is important that we can maintain a dialogue.

I hope your family health issue resolves positively.
 
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Apart from confirming infection, biology wasn't evaluated. The study was looking at symptom profiles via questionnaires. There is some discussion about possibilities, eg —

There might be biological mechanisms that are similar between the different postinfectious chronic illnesses studied. For example, following EBV infection, Müller-Durovic et al. found the EBV-encoded transactivator Epstein-Barr nuclear antigen (EBNA) drove induction of indoleamine 2,3-dioxygenase 1 (IDO1), and the activity of the kynurenine pathway was up-regulated in EBV-infected B cells; a similar pathway may be involved in. SARS-CoV-2 pathogenesis. Kynurenine-pathway activation has been linked to inflammation and central nervous system alterations as well, and abnormal levels of kynurenine-pathway intermediates, coupled with significant reductions of serotonin, might be a key factor contributing to fatigue and other symptoms of Long COVID.

concluding —

Behavioral and pathophysiological underpinnings of both ME/CFS following IM and Long COVID are not well understood, although we may be getting closer to understanding their pathophysiology, as explained above.
 
I have a family health emergency to attend to
While I am moderate to severe most of the time myself
I just want to echo @Peter T's sentiments above. Hope things will work out OK with your family member, and hope dealing with it will not impact your health too much.

Just to mention that S4ME allows people like you, who are both researchers and patients, to have two accounts - one for the researcher part of you and another when you just want to be a patient. You may know that already and already have another account. Or you might not want that. But I thought I'd mention it in case you would like to be able to participate in other discussions without feeling like you're in professional mode all the time. Here's how it's described in the rules:

Rule 8: One account per forum member
It is not permitted to have multiple accounts, except in certain situations requiring moderator approval. Typically the exception is due to a forum member being a public figure such as a researcher or advocate, but also needing the freedom to post anonymously about sensitive issues.
 
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