Interview with Dr. Luis Nacul: Part Two

Last month ME/FM Society of BC volunteer, Howard Searle, interviewed Dr. Luis Nacul, Medical Director of BC Women’s Hospital Complex Chronic Diseases Program (CCDP), at his apartment for an article for our Society’s Giving Tuesday December fundraiser.

Howard was a registered ER nurse in his life before ME, and his background and health experience inform his interview.

There were so many great questions and answers in this interview that we have published it in 2 parts:

Part 1 focuses on the CCDP and clinical aspects of the diseases . Read here
Part 2 focuses on research. Read below.

Interview with Dr. Luis Nacul, Part 2 : Research

by Howard Searle

Howard:

As well as being the Clinical Director for BC Women’s Complex Chronic Diseases Program (CCDP), you are also the new Clinical Research Director for the Program, and this comes with dedicated time and funding for research. Do you plan to invite CCDP patients to suggest what their priorities might be for the research that is conducted at the CCDP?

Dr Nacul:

This is already happening. We have two pieces of research in preparation that were initiated by the ME/FM Society of BC. One relates to an MRI imaging study to look at neuro-inflammation, of which there is some evidence that it occurs in ME. We have submitted an application for funding and are waiting for a response. We located a very good radiologist who specializes in MRIs at Fraser Health and so we will use their expertise and state-of-the-art equipment with selected patients in our program.

The second research proposal that originated from our patients also came from the ME/FM Society of BC who felt it was important to conduct a Needs Assessment Study to look at the needs of patients with complex and chronic diseases and to evaluate how these needs are met or unmet by the various services that are available.

This is an area that I am particularly interested in, as I have experience in studying the needs of patients with ME and other conditions, and so we hope to submit a proposal on this soon. The needs assessment may incorporate epidemiological information such as how common both ME and Fibromyalgia (FM) are, how severe they are, how disabling they are, and then to look at the composition of health services that are available, and how they respond to the burden of disease in the population. These are two vertices of a triangle, and the third is to determine what are the most cost-effective services that should be delivered by the health system, by social services, and other providers. The goal is to determine if these services are being delivered to the patient population according to their needs. So, by understanding the needs in an objective way, then we can plan how to meet these needs in priority order by coordinating with all stakeholders, patients, and decision-makers for services.

Howard:

What lines of inquiry into ME do you find most compelling?

Dr Nacul:

I’m very interested in looking at the burden of disease in the population. I think we have very little information about that in Canada. The structure of health services and how well they are dealing with problems they are being faced with, is a big problem here and internationally. I think there are too few services that specialize in people with complex and chronic diseases, so there is a mismatch between demand and service provision. I think if you ask patients what they want most, they want to be respected, to receive diagnostic tests, and to receive treatment. Therefore, I think searching for biomarkers of these diseases, and for treatments, should be the main focus of research. This links to the fairly widespread misunderstanding of ME and FM: once you have found a biomarker that definitively shows that someone has the disease, then it will be believed and you can go forward from there.

Howard:

Do you think ME is one disease or a group of diseases?

Dr Nacul:

I think it may be one disease with a number of sub-groups. I think it is primarily a neuro-immunological disorder that seems to be triggered by a viral infection, but the body responds in inappropriate ways. There is bi-directional communication between the immune system and the central nervous system. I believe that this is where the problem starts, and then there are many different consequences that follow from that, such as metabolic abnormalities.

Howard:

Do you see a similar dramatic loss of muscle strength on subsequent attempts in other diseases?

Dr Nacul:

Interestingly enough, there has been a lot of research in hand grip strength in cardiovascular disease. People with heart disease tend to have lower grip strength, and so the conclusion is that the hand grip strength is not necessarily an indicator of the hand muscles themselves, but it is a good indicator of the person’s overall health and fitness.

In a way, it may relate to frailty, and that is why we may have seen the striking result we did in those severely affected by ME. Just to give you an example, if you have a stroke, and you lose strength in your left arm, your right arm will not be affected. However, if you measure hand grip strength in the non-affected right arm, it will be less than before the stroke, which shows it is not a result of a localized problem, but instead is a reflection of a generalized problem. Although in the case of ME, it could be a localized problem, but I suspect that it is more than that. It might be used as an objective measure of change in disease severity, for example following a clinical trial in which you treat patients with drugs.

Howard:

In April 2019 one of the papers you co-authored found markedly reduced serum creatine kinase (CK) levels in patients with severe ME. Do you plan to further investigate the question as to whether CK can be used as a reliable biomarker for severe ME?

Dr Nacul:

I’d love to, but of course we’d need to have the required infrastructure in place.

One thing I’d like to do is for those who have relatively low CK values, to do an exercise challenge, to see how the CK responds to that exercise challenge, and why this is the case. CK is very much related to the energy production by muscles. If you’re not using your muscles much, your CK is bound to be lower. But if you’re an athlete in training, then you’re going to have a high CK.

So I’d like to find out if the CK level will increase in ME patients who engage in exercise, compared to controls. My suspicion is that it will not in the same way as it does in healthy individuals, and I say that because there was a similar study done in the Netherlands that showed an increase in CK after exercise in healthy controls, but a lower rise in CK in those affected by ME. However, that study was done with a small number of subjects, and the difference was not statistically significant. So I think it would be very interesting to look at this again, especially now that we have a specific hypothesis. One possibility would be to do muscle biopsies and look at CK levels inside the muscles. So there are many things that could be done, but when you look at them individually, they are not so easy to carry out.

Howard:

Have there been any studies done on the effects on CK levels of graded exercise therapy (GET) to try and better condition a subject?

Dr Nacul:

Not that I am aware of. I don’t think CK has been looked into much, and the reason for this is that there are alarm bells when CK is high, because it is an indicator of muscle inflammation, and what we found was the exact opposite, that the CK was low, and normally people don’t pay attention to that.

Howard:

Human Endogenous RetroViruses (HERVs) are prehistoric pieces of human genetic material that came from exogenous retroviral infections that occurred during the evolution of vertebrates and are now part of our genetic makeup. Most are dormant but some can be reactivated in response to exogenous viruses such as herpes or HIV, stress, or perhaps hormones. It is theorized that HERVs might be a cause of autoimmune diseases. In any case, their potential for immune system deregulation and other pathology is a concern.

One of your most recent co-authored papers found that HERVs type K were over-expressed only in patients with moderate ME but not in patients with severe ME. Does this suggest that HERVs are unlikely to be helpful as biomarkers for this disease?

Dr Nacul:

I wouldn’t agree with that. As we saw with handgrip strength and CK which were abnormal in severely affected ME patients but not in moderate or less severely affected people, HERVs may only be a risk factor for some subtypes of ME and not perhaps a risk factor for severe disease. I think it is all about stratification. I don’t think we’re going to find one biomarker for all cases. HERVs may turn out to be a marker for one subtype of cases which may not be those most severely affected. We all have HERVs, but people with MS for example, have HERVs over-expressed more than other people.

Howard:

Another paper published this year involving your work found that Mucosal-Associated Invariant T-Cells (MAIT cells) were found in increased levels in patients with severe ME, demonstrating that an altered immunological state does exist in ME. . Do you think it is possible that an immune-system modulating treatment may turn out to be a cure for these patients, and is this line of inquiry currently underway?

Dr Nacul:

I think this might be possible. Studies have been done with some immune modulators, such as Rituximab, which overall was found not to be effective. But there may be a sub-group of people who could potentially benefit from Rituximab, maybe those who have some specific B-cell abnormalities.

There is a group of clinicians in Florida who have been trying different treatments using immune modulators. There have been various attempts, but what we don’t have so far is an immune modulator treatment that works for everyone, and maybe we never will have that.

I think it is important that patients are well-characterized in their immunological phenotype and that specific treatments are only offered to that particular subgroup with a unique immunological abnormality.

Howard:

You were involved in the establishment of the Biobank in London as a resource to facilitate research in ME. The Biobank collects blood samples from over 300 ME patients and separates these into serum, plasma, red blood cells, mononuclear cells, granulocytes and RNA, as well as patient data sets, and makes them available to researchers worldwide after their methods have been carefully scrutinised.

Given the large number of patients here, do you see the need for a similar biobank in North America?

Dr Nacul:

I think it would be a very good idea. Researchers here can access samples from the UK Biobank for planned research, as they do around the world. Israel, Spain, Australia, Austria, Brazil and the UK have all been using samples from the UK ME Biobank, for example.

There is another ME Biobank being established in Australia. It would be great to have a bank of samples from our own patient population here, which is important, but also puts you into a position to combine methods with the UK and the Australian Biobank, give support on the development of databases and the standardization of procedures for bio-samples globally. So if you have several ME Biobanks around the world using similar protocols for sample selection and storage, you can potentially get samples from all of these places and not only compare them, but you can replicate studies, and add samples for larger studies as needed.

Howard:

Do Canadian researchers have access to the UK Biobank resources, and are they using the Canadian Consensus guidelines for selecting patients for their samples?

Dr Nacul:

Yes, they first have to submit their research proposal and methods for scrutiny, and if approved, can access samples from the UK Biobank, which is using the Canadian Consensus guidelines, but they are also using the US National Institute of Medicine and the Fukuda protocols. The data collection for these samples permits researchers to select samples according to any of these three protocols. The Fukuda protocol is perhaps less rigorous considering that it does not require the symptom of post-exertional malaise, but it has been widely used in studies, and so it is important to be able to use it in comparisons. But you can modify the Fukuda protocol by making post-exertional malaise compulsory, and then perhaps there would be more use of it.

Howard:

In one of your recent research articles, you found that hand grip strength was markedly reduced in ME patients (especially in severe ME patients) compared with healthy controls. [Link to Dr. Nacul’s research and articles]. You also found that grip strength decreased with each successive performance in a given patient, and this was not seen with healthy controls. Do you hope to do further investigations into the exact mechanisms that would account for this demonstrated reduced muscle power and increased fatigability in ME patients versus controls?

Dr Nacul:

I would like to. Of course every investigation needs to be well planned and funded, but I think it would be very interesting to look into this in more detail. We have colleagues in Germany who were very interested in this study and they are interested in either replicating this study or doing something similar. Our findings need to be confirmed, and we need to go deeper to be able to explain why the phenomenon we found happens. Unfortunately, research funding for this disease is so far not very generous and hard to come by.

Howard:

Dr Nacul, it has been a pleasure talking with you.