Looking for the missing ME/CFS puzzle pieces

Dr Michael VanElzakker from Harvard Medical School and Dr Rogier Louwen, assistant professor at the Department of Medical Microbiology and Infectious Diseases of Erasmus MC, both conduct research into ME/CFS. They discuss the complex puzzle that this disease forms and the role that researchers with different areas of expertise can play in the new research programme.

Rogier, what did you think when you heard that the Netherlands is going to make 28.5 million euros available for ME/CFS research?

Rogier: ‘I was very pleased to hear that. We desperately need research into this disease. A great number of people suffer from ME/CFS. I think it is very good that the Dutch government will now fund biomedical research to learn more about the disease.’

Michael: ‘I knew that patient representatives in the Netherlands had campaigned hard for this. But when I heard that that effort had succeeded, I was nevertheless surprised. It is impressive how patients in the Netherlands make their voice heard. I hope that we will now at last be able to set up systematic research because something like this has not yet been achieved anywhere in the world. That would give research into ME/CFS a considerable boost.’

You are both personally motivated to do something for people with ME/CFS. How did that come about?

Rogier: ‘My connection with ME/CFS started in the summer of 2013 when my wife developed a sort of flu with a high fever. She recovered, but the symptoms rapidly returned and seemed to be neurological in nature. A few months and many tests later, we still did not yet know what she was suffering from. She tried to continue with daily life, but things slowly deteriorated. A year later, she could no longer go for a normal walk and after exertion, she had to recover in bed. Our GP then referred us to the CFS/ME centre in Amsterdam. That is where she received the diagnosis. Meanwhile, we had already discovered that carnitine and vitamin D were favourable for a more rapid recovery after exertion. Now she can fortunately work again for nine hours per week, whereas, initially, she had to keep to her bed a lot and needed a wheelchair. The supplements are really helping her, although I want to emphasise that this does not mean she is cured of the disease. She still needs to be careful not to tax herself beyond her limits.’

Michael: ‘It must be very difficult to struggle like that with this disease. Your search for answers is not just due to curiosity, but is also highly personal.’

Rogier: ‘That’s right. Many patients with ME/CFS are, unfortunately, even worse off than my wife. After a study of the scientific literature, I discovered that a lot is still unknown and the patients are stigmatised. During this deep dive into the literature and my personal experience with ME/CFS, I saw parallels with the Guillain-Barré Syndrome that I had worked on in the past. This is a neurological disease in which the immune system attacks the nerve cells after infection. It is a sort of autoimmune response for which there are now indications that this is what happens in the case of ME/CFS as well. That is how I became involved in the research into ME/CFS. Because of these indications, I have come to think that this disease runs along the axes of microbiology, immunology and neurology.’

What is your connection with ME/CFS, Michael?

Michael: 'I have a connection because a friend of mine, who I’ve known since junior high school, has ME/CFS. In college I re-established contact with her via social media. She told me that she had been forced to drop out of law school when she became rapidly and seriously ill. She got a high fever and within a week could no longer climb the stairs. About a year prior, she had a pretty severe chickenpox infection, and I personally think that infection and the later illness were related to each other despite the time interval. My friend has severe ME/CFS and therefore is bedbound most of the time. That's hard enough for a bright person who want to be active, but patients also have to deal with stigma against the chronically ill. Here in the United States ME/CFS was even referred to as yuppie flu, after the outbreak in the Incline Village tourist town. The idea persists that this condition only affects rich, white people who are complaining about mild health problems. I hadn't planned on spending my career studying ME/CFS, but it was really my friend who inspired me to think about the problem and search for answers.'

Which contribution are you making to the research into ME/CFS?

Michael: 'My group's research is centered in a neuroimaging laboratory where we use a wide range of techniques such as PET scans, MRI scans, MR spectroscopy and EEG. However, brain scans can only tell us so much. During an autopsy we can directly study brain tissue, but brain scanning is the best alternative to noninvasively investigate the brain of living people. Neuroimaging can establish the presence of things like inflammation or vascular problems but these are outcomes not root causes, and the brain scans cannot necessarily tell us why they are happening in the first place.

'Therefore we try to work with researchers who investigate tissue, blood, and saliva. With microbiologist Amy Proal and geneticist Kris Fobes, I started the PolyBio research foundation with the intention of attracting researchers with diverse expertise. In this way, we can conduct deeper research into the mechanisms of diseases such as ME/CFS. Otherwise we will remain stuck in different competing theories, each of which only explains part of the illness. I personally don’t think that the root cause of ME/CFS symptoms are the exact same for everybody. The shared symptoms may instead revolve around the fact that a wide range of things can trigger the neuro-immune system and that this subsequently leads to an overlapping presentation. It's a complex difficult truth, and you would prefer to be able to find just one cause and just one treatment too. Unfortunately, I don’t think that is how things are playing out.'

Rogier: ‘That is what I also think. Various triggers are known, such as certain viruses and bacteria. In the Netherlands, we had the Q fever epidemic, which caused similar symptoms. Now we have COVID-19, as a result of which a few percent of the patients develop persistent symptoms that are similar to ME/CFS. It is a very complex pathology.’

What will your research contribute to solving the puzzle, Rogier?

Rogier: ‘I am assiduously searching the literature for different pathogens. There are indications for a role of retroviruses, the group of viruses that has stored its genetic material in RNA, and that touches upon the type of research I’m currently doing. I’m also looking for pathogens in blood cells. Something is going on in these cells too. Within Erasmus MC, we are now preparing research so that we can apply for funding later this year. Then we will be able to better describe the role of such pathogens, among other things.’

How do you see the future of ME/CFS research?

Michael: ‘I hope that possibilities will present themselves, perhaps even in the Netherlands, to draw up a detailed case history and to exchange data between different labs. We need to tailor the research to the individual patient. Perhaps this will enable us to subsequently discover patterns in different groups of patients. I also think that some pathogens result in a higher chance of long-term consequences. My dream is that the Netherlands can develop a research pipeline in which patients receive more extensive investigation than in their own hospital.’

Rogier: ‘I’m also thinking about a two-way approach: fundamental research at the university as well as research into treatments for which we collaborate with, for example, private clinics and patient organisations. This is already the way we work at Erasmus MC in some cases. First of all, we try to find a good treatment for each individual patient. After a while, we hope to be able to distinguish groups of patients with the same symptoms who benefit from the same treatment. We also adopt a more academic approach in which we investigate whether we can distinguish groups straightaway.’ 

Michael: 'Another important point is that the statistical methods that are most commonly used in brain research are not optimal. In the vast majority of neuroimaging studies, patients are binned into a single group in order to discover a single shared abnormality. As a result, there is a significant chance that you will find no effects because individual effects are lost due to variation among patients. That is why we want to look both an individual analyses and subgroup analyses. I think it would be great if we could collaborate with researchers in the Netherlands. Your new research budget could mean a considerable step forwards if the research is set up in a thoughtful manner.'

Rogier: ‘Perhaps we can indeed work together.’

In which way could you two work together, and with other researchers?

Michael: 'That’s an interesting question. For a brain scan, I need patients to physically visit my lab, but we can send blood and tissue samples fairly easily. It would be really valuable if we could exchange samples from the same patient between labs. For example, we are currently working with a research group in South Africa.  They search for microorganisms in blood samples, specifically within fibrinogen and fibrin. We are also working on analyzing tissues samples from ME/CFS patients. There are some researchers who are very are good at research with next-generation sequencing and while others are good at studying blood coagulation, et cetera. If we can share samples across labs, we will learn much more about what is happening in patients. Otherwise, we will continue to work in isolation, each with our own competing theories.'

Rogier: ‘Some patients are bedridden and so they cannot easily go somewhere for research. So, it would indeed be better to take material and investigate that at different places using the same methods. That will also enable us to strengthen our claims. If we find the same things in several labs, then we have more evidence at our disposal. Blood, urine and brain fluid are relatively easy to transport.’

Michael: 'In the US, there are mobile MRI scanners that can be taken to patients who are bedridden. This would theoretically create possibilities to investigate patients at home. And we could also collect and store blood samples drawn at home for further research. This group of bedridden patients is really important because they have the most severe symptoms. For studies to be meaningful and replicate, it's crucial to optimize methods. My advice is to either call collaborators who are already using a technique, or do not use that technique at all. Otherwise, we will continue to add noise to the literature due to sub-optimal methods and inconsistent results.'

Some of the patients with COVID-19 continue to suffer from severe fatigue symptoms after that infection. Does the corona pandemic offer opportunities for ME/CFS research?

Michael: 'It certainly does, and there is increased attention for ME/CFS-related symptoms, but we also need to be careful. Many COVID patients take a long time to recover, but do not have ME/CFS. Some patients recovering from COVID benefit from exercise, and if we improperly associate a longer COVID recovery with ME/CFS, many will incorrectly conclude that ME/CFS can easily be treated by forcing exercise. That would cause old arguments about ME/CFS treatment to resurface. So we should be careful about that.'

Is there anything else you would like to say to researchers interested in ME/CFS?

Rogier: ‘I’ve noticed that many researchers do not know the disease but they have heard about the stigma. Once I take the discussion further than the stigma, I notice there’s a lot of interest. It is a debilitating disease but, scientifically speaking, very interesting. That is because it brings many research areas together and that is incredibly exciting. This is perhaps one of the last severe illnesses for which an adequate scientific explanation has been missing for so long. Patients cannot wait until we have found it. I therefore hope that many researchers will join the new programme!’