Reprinted with the kind permission of Cort Johnson and Health Rising.
Dr. Unger and Dr. Montoya are in the middle of some of the biggest studies ever produced in chronic fatigue syndrome. They talked about their respective programs on the PCOCA call about a month ago.
Dr. Elizabeth Unger
The Multi-Center ME/CFS Experts Study
Unger’s statement that the seven site ME/CFS experts study will help produce an evidence-based definition makes one wonder how long any definition is going to last. We’ve never, after all, seen a study this big (@470 patients) and this comprehensive looking at the symptoms and characteristics of people with chronic fatigue syndrome.
The studies must be very complex. Two years ago, Unger presented some if its findings at the FDA Workshop. A year ago at the IACFS/ME Conference she stated they were “scrubbing” the data. Now she’s reporting they’re beginning to write the papers. Maybe all good things do take time.
The delay is also probably in part because they’re moving forward rapidly on the second larger part of the study. She broke the study up into three groups.
Group #1: the Big Tent
If my notes are right, the first group in the second consists of ME/CFS, fibromyalgia, Lyme disease and hepatitis patients. Nobody has ever jammed this many different types of patients into a major study before, and it’s about time somebody did. Not contrasting ME/CFS patients with other disease groups was a key critique leveled at the field in the AHRQ draft report. Only by contrasting ME/CFS with other similar disease groups can we get at a good definition or diagnostic biomarker. Contrasting ME/CFS patients with a group with an active infection (hepatitis patients) was a great idea.
Most of the ME/CFS patients and over half of the Lyme patients have gone through the first part of the study.
Exercise and Cognition Test
With about 260 people slated to do the one-day exercise test, this is easily the biggest exercise study ever done in ME/CFS. They’ll get their blood taken for gene expression tests and have their cognitive functioning studied.
Yes, it’s too bad it’s not a 2-day test. As difficult as a two-day exercise test is on patients, a two-day study would have nailed the metabolic limits to exercise found in ME/CFS. It could have presented a unique and very disturbing finding to the medical world. I believe it could have broken the doors wide open on this disease, but it’s not to be.
A big study that finds that exercise dramatically alters gene expression patterns and reduces cognition will be big news. In contrast to other studies, this study is big enough to reveal subsets of patients with altered gene expression patterns. Finding reduced cognition after exercise would be another feat, and, of itself, would be an excellent demonstration of post-exertional malaise. Demonstrating that a short exercise session measurably impacts cognition a day later would be big news.
Group #2: the Kids
A big pediatric cohort (130 patients!) is next. You can probably count the number of pediatric studies done on ME/CFS on the fingers of two hands. The kids are less numerous and harder to find, but they had gotten through about 20% of the group as of the time of the call.
Group #3: the Missing Pieces
The CDC is not slacking on this study. They’re going after the “hidden” and hard to get at elements of ME/CFS like no one has before.
The third group consists of bedridden patients and patients with recent onset. The bedridden group shouldn’t need exercise to tweak their systems into showing something unusual – they just need to get tested. Studying the recent onset patients just got a whole heck of a lot more interesting after the Lipkin/Hornig Chronic Fatigue Initiative study suggested their different immune signatures differ markedly from later stage patients.
They’ve gotten IRB approval, and this study should begin soon.
Health Care Survey
The CDC has also been able to get ME/CFS questions folded in some very large ongoing medical surveys in five states. The participants will be answering if they’ve ever been diagnosed with ME/CFS, if they still have it, and other questions associated with the quality of the health care they’ve received.
Developing a Curriculum for Medical Schools
The CDC is in the process of finalizing case examples or “scripts” involving ME/CFS patients. These appear to be ways to portray vividly what happens in this disease. The University of Colorado is evaluating how effective they are. They plan to send them to medical schools with the intention of getting them inserted into the curriculum.
Dr. Montoya: Leader of Stanford ME/CFS Program
Dr. Montoya didn’t mince his words. Chronic fatigue syndrome, he said, is a complex, chronic and highly variable disease, and it will take a highly multidimensional approach engage many disciplines to understand it. It can be done, however. Montoya asserted – hold your breath – a 100 million dollars a year in funding would make it possible to conquer ME/CFS in our lifetimes.
Since Montoya is probably around fifty, that would probably include my lifetime but probably at the end of it. Later Montoya asserted, though, that they’d be able to produce good treatments much more quickly than that if they had more money.
Although the timeline for eradication is a long one, Montoya’s statements give one the sense he feels he’s beginning to understand the broad outlines of what’s going on.
They’re also pretty bold statements given the state of current funding. Does he believe $100 million a year in funding is possible? My guess is that he wouldn’t state something like that if he didn’t believe it was in the realm of reality – maybe not this year or next year, but in the conceivable future. Let’s say private sources and other countries can provide $10 to $20 million dollars a year in funding. That would leave the feds kicking in 80-90 million dollars.
Clearly touched by the human dimension of the illness, Dr. Montoya referred to the suffering and isolation experienced by millions of patients.
His introduction to ME/CFS began in 2004 after he saw one patient with high antibodies to viruses whose life had been devastated by her illness. To his utter surprise, her cognition and fatigue improved significantly on antivirals. (One wonders who was “patient x”? Who initiated that meeting that changed the course of Dr. Montoya’s career and got Stanford into the act? )
In 2006, 9/12 very ill ME/CFS patients in an open-label study improved significantly in a trial of herpesvirus antivirals. Several ended up returning to work after long absences. The next step was a 30 person placebo-controlled double-blinded valganciclovir (Valcyte) trial in ME/CFS patients with high antibody titers for HHV-6 and EBV. They showed significant improvement after six months (but not the dramatic improvements seen in the first study. An analysis suggested, as Dr. Lerner and Dr. Henderson have found, that the longer they were on the drug, the better they tended to do.
[Was the trial asking for too much? Was asking patients with high antibodies to both viruses to get well too much to ask for?]
The results opened the possibility that long-term use of valganciclovir or another antiviral could be helpful in a subset of patients. Widespread skepticism from infectious disease specialists about the use of antivirals in ME/CFS dates, however, back to 1988 antiviral trial by Stephen Strauss. Despite the different drug and short duration of the trial, the failure of the Straus trial has apparently loomed over this part of the field for decades.
The Montoya/Kogelnik trial indicated valganciclovir had produced a surprising and never seen before immunomodulatory shift that increased Th1 functioning in the ME/CFS patients. The antiviral drug had somehow strengthened their antiviral defenses. Dr. Montoya suggested that this unexpected immunomodulatory shift may be crucial and could help explain the benefits the patients received. The cytokine data they’re currently gathering supports their conclusions.
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But why would herpesviruses and not other viruses be such a big deal in ME/CFS? Because of the balky NK cells typically found in ME/CFS: people with poor functioning NK cells are highly susceptible to herpes virus infections.
Montoya drew three broad implications from his findings.
- Herpesviruses – A more in-depth look at herpesviruses themselves is needed. Only eight (eight is not enough?) herpesviruses have been found. Sounding like he knew of some efforts in this area that will bear fruit, Montoya stated it was “very possible” more herpesviruses will be discovered in the next couple of years.
- NK cells – More focus on NK cells is critical.
- NK cell infections – Montoya is beginning study to see if NK cells are the target of known or unknown viruses. Looking for pathogens in NK cells appears to be an entirely new endeavor in ME/CFS. Some attempts have been made to get at the cause of the NK cell problems in ME/CFS, and others are ongoing. Isabel Barao, Ph.D. at the Simmaron Research Foundation is looking at possible genetic underpinnings of NK cell dysfunction.
Why is Dr. Montoya able to do stuff like this? Because of an anonymous donor who gave him unrestricted funds for five years starting in 2009. (If memory serves he gave him $5 million to spend as he wished.) [Note that the five years is up……]
Montoya created a large biobank of 300 ME/CFS patients and corresponding age and sex matched healthy controls. He’s also currently working on a mega immune study that consists of having hundreds of patient samples being tested in Mark Davis’s Human Immunome Project. Ultimately producing more than 25 million data points, this will easily be the most comprehensive overview of immune functioning in ME/CFS ever done. Gene expression, cytokines, pathogens, immune cell makeup – it’s all apparently there in the study.
Jared Younger was one of the stars of the program and Montoya said they missed him greatly. Besides Younger’s groundbreaking studies on low dose naltrexone (LDN) and fibromyalgia, his Good-Day/Bad Day study suggested that leptin could play a major role in ME/CFCS.
It looks like Stanford’s loss may be our gain, however. Younger was quickly able to put a team together in his new Fatigue and Pain lab at the University of Alabama and is engaged in more studies than ever.
An Inflammatory Disease
“Our cytokine data contradicts the erroneous conclusion that ME/CFS is not an inflammatory disease and supports that not only an inflammatory state exists in these patients but it also opens the door for the use of anti-inflammatory drugs or biologics, as it has been done for other inflammatory diseases whose aetiology is still unknown, including in rheumatoid arthritis and systemic lupus erythematosus.” Dr. Montoya
For many years, investigators believed inflammation was not present in ME/CFS, but the tests they were using (SED, CRP) are outdated and do not pick up the kind of inflammation present. Increased levels of IFN-y, IL-7, IL-17 and other cytokines indicate that an inflammatory process is feeding symptom severity in ME/CFS.
ME/CFS’s Kissing Cousin: Systemic Inflammatory Response Syndrome (SIRS)
A gene expression study indicated that the disease ME/CFS looked most like was “systemic inflammatory response syndrome (SIRS)”. In fact, at the gene expression level, ME/CFS doesn’t look somewhat like SIRS – it looks almost exactly like it.
First described in 1983, SIRS is an inflammatory state that affects the whole body. Sometimes it’s produced in response to an infection and sometimes not. Related to sepsis, SIRS contains both pro and anti-inflammatory elements.
The pathways leading to this condition have been highlighted in ME/CFS before. Fifteen years ago, Dr. David Berg proposed that the same coagulation problems preceding SIRS (fibrin deposition, platelet aggregation, and coagulopathies) characterized ME/CFS as well. All but forgotten now by most practitioners, Dr. Holtorf is still putting Berg’s findings into practice. At the recent LDN conference, he called heparin one of his favorite treatments for ME/CFS/FM.
As ME/CFS gets worse, the inflammation present in it worsens. Montoya asserted that the inflammatory state found in ME/CFS opens the door for the use of anti-inflammatory drugs being used in autoimmune disorders such as lupus and rheumatoid arthritis. Herpesvirus suppression is just one component – an important one – but just one of apparently, a well-rounded and holistic program for fighting this disease. He suggested that there will never be a drug for ME/CFS.
But what about the recent Lipkin.Hornig study? That studies results suggested that ME/CFS in it’s later stages is a disease of reduced immune activation. How does that fit the picture of an inflammatory disease? Montoya stated Lipkin found evidence of both increased and reduced inflammation.
Could targeted treatments aimed at reducing IL-17 work – at least in recent duration patients? It’s (hopefully) significant that IL-17 has popped up in three important and impressive research groups; Columbia and Stanford and although he didn’t mention it, Dr. Klimas’s group. Montoya said it’s still too early to tell how IL-17 is.
Montoya said one thing about the longer duration patients that made sense in light of the Lipkin/Hornig results: a complex network of changes takes place as the disease gets worse.
MEANINGFUL Treatment Options
Montoya then asked “the question” – what will it take to find meaningful treatment options? Options that consistently move the bar for patients? Given a hundred million dollars a year in funding, he believed consistently effective treatment options could be developed in a few years.
The IOM Report
Critics of the IOM report have not been in short supply, but Dr. Montoya was clearly a fan. As a doctor and researcher working in a well-respected academic institution, he felt this report coming from “serious institution” was going to help him at Stanford.
- The report has the potential to change the narrative of the disease in the US.
- So far, every one of his patients at Stanford has met the criteria.
- He appreciated the calls made for funding but was disappointed they did not come with a number. (Neither did the P2P (yet). Nor did CFSAC. Why is everyone letting the federal government pick a number?) .
Is ME/CFS or SEID is contagious?
Montoya said there is no good evidence that it is transmissible. Patients are not passing it on to their loved ones.
He agreed that there have been well-documented outbreaks and noted that an infection can have both epidemic (easily spread) and endemic (not easily spread in its later stages) characteristics. He suggested that an undetected infectious agent able to reactivate other infectious agents such as EBV and Q could be present in an epidemic environment. In its endemic form –which is the form we almost always see it in – patients should not worry about ME/CFS being transmissible….
Will the CDC follow the recommendations of the IOM report on the definition and alter the CDC toolkit?
Dr. Unger simply said revisions will take time to be developed and posted. [Note that the CDC is a member of the DHHS, and it will, of course, follow DHHS guidelines or outcomes coming out of the report. [It’s possible that the CDC’s multi-site study may end up changing the Tool Kit the most.]
Is the CDC Testing Dr. Chia’s samples?
Yes, they are. Dr. Chia’s samples are finally getting beyond his laboratory. The CDC Picornavirus laboratory has received 30 samples from Dr. Chia and began in March. It’s taken, what a decade, for another laboratory to finally examine Dr. Chia’s samples – an unbelievably long time for a good hypothesis not to get examined. Good for the CDC to take this on.
The big news for me was
- The next stage of the CDC multi-site study includes a very wide array of disease groups and ME/CFS subsets
- The CDC is trying to get ME/CFS into the curriculum of medical schools
- Dr. Chia’s samples are finally getting tested
- Dr. Montoya is looking for pathogens in natural killer cells
- He’s convinced herpesviruses play an important role and that new herpesviruses may be found in the next couple of years
- He believes immunomodulation is going to be key
- ME/CFS is an inflammatory disorder
About the Author: Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising.