Dr. Klimas on the Immune System, Treatment Options, Recovery and the Future (2008)

We take advantage of a recent paper, a Prohealth chat and Name Change Campaign Profile with Dr. Nancy Klimas, professor, physician, researcher, and advocate to do a review of the recent immune findings, treatment options and see what Dr. Klimas believes the future looks like for chronic fatigue syndrome (ME/CFS). First we’ll take a look at her paper and then at Dr. Klimas’s Prohealth chat and her profile. 

Nancy G. Klimas, MD, and Anne O’Brien Koneru, MSN, 2007. Chronic Fatigue Syndrome: Inflammation, Immune Function, and Neuroendocrine Interactions. Current Rheumatology Reports. Vol. 9, #6, pp 482-487

What’s up in the immune systems of ME/CFS patients? One thing that appears to be up is viral reactivation.

Viral Reactivation

Note that this section is not called ‘viral attack’ but ‘viral reactivation’ – a very different scenario. The first (viral attack) suggests a pathogen has entered an otherwise healthy body and simply needs to be destroyed. The chief problem there is finding, identifying and then killing the pathogen – sometimes, as we shall see, a very difficult task. The second problem (viral reactivation) suggests the immune system has been weakened enough that latent (or inactive) viruses that humans carry dormant within them have become ‘reactivated’. In the first case the pathogen is primary; in the second immune dysfunction is. The second case appears to be more common in chronic fatigue syndrome.

Dr. Klimas noted that a study employing several different methods of assessing viral persistence found that 40% of chronic fatigue syndrome (ME/CFS) patients had evidence of a herpesvirus infection. The Dubbo studies found that CFS (post-viral fatigue) was a common outcome of a serious infection. Dr. Chia also recently found a high persistence of enteroviral infection in the gut.

It appears that viral reactivation occurs in at least some chronic fatigue syndrome (ME/CFS) patients. Why might this be so? Dr. Klimas first outlines evidence that the immune system (T-cells) is overly activated (probably by a pathogen) but out of balance.  She then spells out recent evidence suggesting ME/CFS patients have immune system abnormalities that open holes in our lines of defense that pathogens may be able to take advantage of.  That’s where we’ll pick up the discussion.

Hole #1 – Poor T-cell Activation

Recent studies by Dr. Maes, a Belgium researcher, suggest that ME/CFS patients’ immune systems are not functioning properly. Dr. Maes, a well-known researcher specializing in depression is a relative newcomer to the chronic fatigue syndrome research field, but he’s made up ground fast; he’s quickly become one of our most active researchers.

Dr. Maes has found evidence suggesting that the important pathogen killing machines, T-cells, are having trouble activating themselves. This problem appeared to be correlated with decreased levels of the antioxidant zinc, an important T-cell co-factor. Low levels of antioxidants suggest that increased oxidative (i.e. oxidant/free radicals) stress in ME/CFS patients have damaged their anti-oxidant systems.

Personal Note – Zinc is rarely discussed in connection with ME/CFS but zinc solution was the first substance that I, after 10 years of no results from anything, first reacted favorably to.

Where is this oxidative stress coming from? Much oxidative stress (free radical damage) is a by-product of inflammation and the fatty acid levels of Dr. Maes patients suggested increased inflammation was indeed present. Where do these fatty acids come from? They appear to come from damaged cellular membranes.

Dr. Maes found evidence that the immune systems had mounted an attack against these damaged bits of cellular membranes. The fact that the degree of cellular damage was correlated with symptom severity suggested oxidative stress is an important factor in this disease.

Dr. Klimas tied this together with viral activity by noting that some researchers believe the membrane damage Maes found is caused by viral activity. We started out with evidence of increased immune activation and Maes has now outlined two immune stimulants: damaged bits of cellular membranes that the immune system attacks and the viruses themselves.

We can start to build a scenario; viruses attack and damage cell membranes releasing factors that increase immune activation and cause further inflammation (i.e. oxidative stress). This increased oxidative stress depletes the antioxidant system leading to reduced zinc levels, which in turn impairs T-cell activation. Impaired T-cell activation results in greater viral activity and the cycle continues

  • Dig Deeper: Dr’s. Chaudhuri and Behan believe that viral damage may be responsible for the choline peaks they see in their brain imaging studies. See “A Neurological Channelopathy In CFS?” for their findings. Caution – very technical!

Conundrum: We have a conundrum, however. We started off stating T-cells were overly activated in ME/CFS but Dr. Maes suggested that T-cell activation was impaired.

Hole #2: Natural Killer Cell Dysfunction

Next Dr. Klimas turned to one of the most interesting aspects of immune research, natural killer cells. These cells, which man the front lines of our defense, constantly probe cells to see if they are damaged or infected. If they are they zap them with a substance called perforin which drills small holes into them causing them to die off.

Many immune findings have let us down over time with their inconsistency. Natural killer cell dysfunction has, however, stood the test of time – study after study has shown that natural killer cells are functioning poorly in CFS patients. Dr. Fletcher and Dr. Klimas have over the past 20 years slowly dug deeper into the natural killer cell question in CFS. Their Miami group reported last year that patients with more severe NK dysfunction tend to be more severely ill – and possibly outlined the first immune subset in this disease.

Since natural killer and cytotoxic T-cells – the heavy guns of the ‘acquired immune defense’ defense – use the same machinery to kill infected cells, Drs. Fletcher and Klimas took a look at T-cells as well. Their results suggested that T-cell killing capacity was low as well. Thus it appears that the primary virus killers in the both the early (innate) immune response (natural killer cells) and the late immune response (acquired) (T-cells) were performing poorly.

Why is this happening? Remember the T-cell activation Dr. Klimas noted earlier? The Fletcher/Klimas team has proposed that the poor NK and T-cell performance seen is due to over activation; these cells are working too hard and are essentially running out of ammunition.

Dr. Klimas focused on the treatment implications of low natural killer cell activity. As we just noted recent work suggests that a subset of CFS patients with low NK functioning are more severely ill. If a drug trial underway proves successful it’s possible some relief for at least some of them may be on the horizon. (See below).

One attempt at enhancing NK cell function with a known NK cell enhancer, Biobran, however, failed to produce to results.

Hole #3 – Hormones and Women and Chronic Fatigue Syndrome (ME/CFS)

Dr. Klimas built the case for a hormonal component by noting that more women than men suffer from autoimmune diseases  – which are also thought to have a hormonal component. She pointed to a small study suggesting that estrogen abnormalities could be a reason for the female predominance in CFS. This study suggested that estrogen was having a hard time binding to – and thus interacting with – cells in female ME/CFS patients. Since estrogen has anti-inflammatory effects, low estrogen activity could be contributing to the inflammation/oxidative stress  Dr. Maes just outlined     in ME/CFS.

Focus on Estrogen and Hormones in ME/CFS

Estrogen therapy to treat menopausal symptoms was put into question when studies revealed it increased the risk of breast cancer. Most physicians do not test for estrogen levels in ME/CFS but some ME/CFS physicians make hormonal testing a key aspect in their practice. Practitioners such as  Dr. Teitelbaum, Dr. Holtorf and those associated with the Fibro-Fatigue Centers claim that bio-identical hormones do not have the negative effects traditional hormone prescriptions do. Other physicians do not agree.Click here for Dr. Holtorf’s take on bio-identical hormones and the estrogen question.

Dr. Klimas was a member of the Pharmacogenomics efforts and she gave an overview of these extraordinarily complex efforts. It was  satisfying to see these exploratory studies substantiate themes advanced by CFS researchers which had largely been ignored by the research community. They included ion channel dysfunction, mitochondrial dysfunction, heart rate variability and sympathetic nervous system dysfunction. They also suggested ME/CFS patients have genetic abnormalities that may predispose them to problems with the stress response.

In the aftermath of the Pharmacogenomics studies the CDC focused on the stress response, in particular the HPA axis. Here Dr. Klimas brings up an interesting question. Immune problems don’t necessarily mean the immune system itself is dysfunctional. Given the interconnections the immune system has with other systems, the immune problems seen in chronic fatigue syndrome (ME/CFS) could at least in part result from problems elsewhere.

Because cortisol is an immune suppressant, for instance, insufficient cortisol levels could result in excessive immune activation and inflammation. Dr. Klimas’s colleague, Dr. Fletcher, is currently exploring whether the other major stress response system – the sympathetic nervous system – is contributing to NK cell problems ME/CFS?. Do the immune dysfunctions in ME/CFS start in the immune system or elsewhere?

We started out with evidence of viral reactivation. Now we arrive at its counterpoint: if chronic fatigue syndrome (ME/CFS) patients have problems with viral reactivation/activation then antiviral trials should be successful.

Antiviral/Antibacterial Trials

Perhaps some researchers can explain away isolated immune findings but it’s hard – very hard – to explain away successful treatment trials and the best evidence that the immune system plays an important role in ME/CFS comes from successful antiviral trials. Besides the high rates of success of the better known Montoya and Lerner antiviral trials Dr. Klimas pointed out how successful a (small) trial of the immunomodulator azithromycin was; most patients achieved 80% of their former functioning.

(While the patients were reported to regain 80% functioning we had to rely on the author’s words for that; no measurements backed up that finding. This is definitely a preliminary finding.)

The caveat with the antiviral trials is their selectivity; in order to enter them chronic fatigue syndrome (ME/CFS) patients had to have levels of infection that only a subset of patients may meet. Nevertheless the results were startling. If the follow-up Montoya trial is successful one should expect our federal agencies (CDC and NIH) to acknowledge the likelihood that a chronic infection subset exists in ME/CFS and begin to fund research in that area. Both the Lerner and Montoya trials are being funded by pharmaceutical firms, the federal government having lost interest in this area several years ago.

Dr. Hanna of the NIH has, in fact, recently expressed interest in re-opening the pathogen question. The CDC largely dismissed Dr. Chia’s effort but it collaborated with Dr. Montoya on his study.

Putting the Science to Work – Treating Chronic Fatigue Syndrome: The Prohealth Chat and Profile

Prohealth provides a great boon to the ME/CFS community with their frequently chats and interviews with ME/CFS physicians and researchers.

“The progress has been very significant in the past few years. Learning about ME/CFS with the new tools we have available really will bring effective therapy.”

Dr. Klimas, a member of the Name Change Campaign, recently appeared in a ProHealth chat and in a Name Change Campaign Profile. In her paper Dr. Klimas characterized several immune problems that may face ME/CFS patients and she pointed to three potential treatment pathways; targeted therapies to impact immune function, HPA axis activity, and persistent viral reactivation in CFS patients. In the Prohealth articles she talks about some of these treatments.

Not An Easy Situation  Dr. Klimas’s Chat on Prohealth.com demonstrated how complex treating ME/CFS can be. (Since it was in response to audience questions it does not present a full overview of her thoughts of this subject.)

  • Dig Deeper - Check out the Chat! There’s lots more to her chat than is featured in this newsletter

Pathogen identification Since, “when the immune system lets one virus out it can let out many,” she believes identifying any pathogens present is important. She noted that Epstein-Barr virus, the virus responsible for infectious mononucleosis – a common trigger for post-viral fatigue/ chronic fatigue syndrome (ME/CFS) – is particularly tough on the immune system.

Immune System Boosters

Since the predominant pathogen problem in ME/CFS appears to be viral reactivation one could assume the primary problem is an immune dysfunction that allows latent pathogens to proliferate. Indeed Dr. Klimas’s statement “when the immune system lets one virus out…” suggests that the core problem in CFS is poor immune performance. Later she will observe that “immune boosting drugs may be very important” in treating this disease.

But when asked if the immune system of a chronic fatigue syndrome patient should be boosted or tamped down Dr. Klimas made it clear that the situation is complex indeed stating “you want better antiviral function but less inflammation and immune activation. That’s not easy and immune-based therapies have to be careful not to immunosuppress.”

This suggests that immune activation is tricky in ME/CFS. Several researchers are exploring neuro-endocrine-immune interactions in this disease. Does treating ME/CFS require rebalancing several systems at once? Dr. Klimas states the evidence suggests this illness ‘involves cellular dysfunction and interactions between the physiologic stress response and inflammation’. Her colleague Dr. Fletcher is exploring ways the sympathetic and immune system are interacting in ME/CFS.

She went on to say that “every patient is different and immune system problems could result from (and lead to) persistent viral reactivation or could come from more of an autoimmune problem.”

A Tangled Web

A patient with an under performing immune system would benefit from an immune booster. An immune booster might be the last thing you’d want to give, however, someone with an already overactive immune system (autoimmune problems). This is quite complex but this is CFS.

Obviously one solution to this problem is identifying subsets and Dr. Klimas noted that UK  physician/researcher Dr. Kerr is using gene expression studies to do just that. In a Prohealth interview with Karen Richards she stated that gene expression studies “give us the potential to subgroup people very accurately into physiologic subgroups that would be potentially responsive to treatments which takes away this mess we’ve had of lumping everyone together and then being surprised when a therapeutic approach fails to pass clinical trials level standards.” (i.e. they can use gene expression tests to target specific therapies to specific types of ME/CFS patients). Thus far Dr. Kerr has identified seven subsets, two of which he appears to be treating with immune drugs.
Subset # 1.   Dr.  Kerr has identified a subset of ME/CFS patients with over-active immune systems. These patients appear to have increased production of the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-a). He’s treating them with the drug Etanercept to turn down their TNF-a levels.

Dr. Kerr believes the problem in this particular set of patients is not a pathogen – it is immune dysfunction. He believes their immune systems are turned on when they shouldn’t be. Since this approach requires turning the immune response down it cannot be used in patients with active infections; these patients are presumably pathogen free.

Subset #2. Dr. Kerr is using an immune booster (interferon-b) on another subset of patients who presumably have pathogen problems. Because interferon-B is able, among other things, to increase natural killer cell activity, it could assist ME/CFS patients who have low NK cell activity.  Interferon-B is a strong drug that can (in the wrong kind of patient) cause the same symptoms found in chronic fatigue syndrome. It’s unclear how big this subset of patients is.

A Breakthrough Technology for ME/CFS?

When asked “Do you think we are close to cracking the cause of ME/CFS?” she stated “Yes I do (!)”. Where will these breakthroughs come from? Perhaps not surprisingly given Dr. Kerr’s and her own work she believes gene expression studies hold the key. She states these studies have given researchers “amazing insight(s)” into chronic fatigue syndrome (ME/CFS).

Gene expression studies illustrate the genetic activity going on in the body right now. Genetic studies, on the other hand, illustrate the genetic endowment each of us is born with.

The Holy Grail: A Biomarker

She also believes gene expression technology will give us another holy grail in chronic fatigue syndrome (ME/CFS); diagnostic biomarkers. She noted that this work is already far enough along that a company in Boston is trying to move it through the FDA.

Recovery???

When asked if people recover from ME/CFS she stated “Absolutely! And complete resolution. It happens but not often enough to make promises.”

The best advice Dr. Klimas could give, interestingly enough though, at least on surface, had nothing to do with the immune system. It involved what Dr. Friedbergs calls ‘lifestyle management’. She says “Number one is hope – just the word hope. The progress has been very significant in the past few years. We’ve really made big gains. Learning about ME/CFS with the new tools we have available really will bring effective therapy. Number two is pace yourself. It’s the single best thing anyone can learn to do.”

Pacing may not seem to be related to immune problems but a team of Dutch researchers recently released a theory paper suggesting how they might be related.

They propose that chronic activation of the stress response system causes it to ‘switch’ to a dysfunctional state.When ME/CFS patients overdo it, i.e. do not pace themselves these researchers believe they activate that dysfunctional stress response system and that causes their symptoms.

(Van Houdenhove, B. et. al. 2007. Rehabilitation of motor performance in chronic fatigue syndrome: should we treat low effort capacity or reduced effort tolerance. Clinical Rehabilitation 1121-1142) Thus stressing the stress response by stepping outside of ones ‘energy envelope’ exacerbates the immune and other problems already present.

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