All posts by Cort Johnson

Foremost Virus Hunter Finds Biomarkers, Few Viruses in Big Chronic Fatigue Syndrome Study

Dr.Ian Lipkin collaborated with Dr. Peterson, Dr. Klimas, Dr. Bateman and others

A Surprise Presentation

We will publish data very soon on biomarkers of cytokines. Our evidence now suggests there is ongoing stimulus to the immune system. Dr. Ian Lipkin

You don’t usually get study results in talks like the one put on by  the CDC yesterday but this time Dr. Ian Lipkin spilled the beans on the results from the big pathogen studies sponsored by the Chronic Fatigue Initiative (n=200) and Dr. Montoya (400).  (From notes taken on the talk)

Virus Study Results Revealed

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The Simmaron Foundation provided a rare resource: sixty cerebral spinal fluid samples

Viruses have always been the elephant in the room in ME/CFS; everybody has wondered about them but until the Chronic Fatigue Initiative came along, few major studies had been done.  This landmark  study, using the one of the top virus hunters in the world and epidemiologist  Mady Hornig, and containing hundreds of patients from ME/CFS specialists (Dr. Peterson, Klimas, Montoya, Levine, etc.) from across the country, sets a benchmark for pathogen research in ME/CFS.

A special feature of the study involved Simmaron Research’s spinal fluid samples. Called a ‘unique resource’ earlier by Dr. Mady Hornig, these samples allowed the researchers to get as close to the brain – long thought to be a key area in chronic fatigue syndrome – as they could.  And the spinal fluid results were spectacular.

The Studies

virus cartoon

This study funded by the CFI, using top labs, and involving hundreds of people with ME/CFS, is a benchmark in ME/CFS research.

The studies looked at both pathogen presence and  the immune response in hundreds of people with chronic fatigue syndrome.

Pathogens

  • First Phase – Screens for 18 specific pathogens already implicated in ME/CFS (herpesviruses, HTLV, enteroviruses, West Nile Virus, etc.) were done on blood from Montoya’s patients and the CFI’s group (Dr’s Peterson, Klimas, Bateman, Levine, etc.).  Dr. Lipkin was looking for the virus, not a indication it was present, but the virus itself. Any finding of a virus in the blood would indicate it was active.  The same screen was done on Dr. Peterson’s sixty spinal fluid samples.
  • Second Phase – The second phase involved sequencing all the DNA/RNA in the blood to identify  known and unknown viruses. Dr. Lipkin’s lab has been able to identify hundreds of novel viruses using this technique.
  • Third Phase – Any finds in the second phase are confirmed/denied by more accurate testing.

Immune Response

A ‘multiplexed immunoassay’ looked at 50 proteins associated with immune activation/inflammation and oxidative stress.

Active Viruses Strike Out

Four of the 285 ME/CFS blood  samples tested positive for HHV-6B.  One of the sixty spinal fluid samples tested positive for a virus (HHV-6B).  None of the other viruses commonly associated with ME/CFS (Epstein Barr-Virus, enteroviruses, the cytomegalovirus, etc.) commonly associated with ME/CFS showed up in the first pathogen screen.

The high throughput screening designed to look for any viruses including novel viruses drew a blank as well. Dr. Lipkin was confident in his results stating his lab had found over 500 new viruses using this technique.

Infections

Lipkin’s search for 18 viruses and for novel viruses in hundreds of people with chronic fatigue syndrome largely turned up empty

The  news – that fewer than 2% of patients  with infectious onset – tested positive for viruses in the blood was stunning but not without precedent.  Dr. Unger reported earlier that  the first stage of the CDC’s BSRI pathogen study  drew a blank.  A spinal fluid study also turned up no viruses, and PCR analyses done by the Dubbo group were unable to find evidence of a virus in their post-infectious cohort.

With two large sample sets turning up negative in the lab of one of  most acclaimed virus hunters on the planet, it’s probably safe to say that the hunt for an virus in the blood of people with ME/CFS is over.

(Lipkin did report 85% of pooled samples possibly showed evidence of a retrovirus but believes they will not be related to CFS. He also dismissed earlier rumors that a novel infectious agent had been found.)

Infectious Agent Still Proposed

That doesn’t mean an infectious agent is not involved. In  fact, Dr. Lipkin stated he didn’t doubt that an infectious agent was involved.  He didn’t say where and he didn’t say it was still present.  His allusion to the importance of finding evidence of a past infection (“researching the shadows”) suggested  he could  be leaning to the ‘hit and run’ hypothesis where a pathogen sweeps in, does its damage, and then gets removed by the immune system.

The Dubbo studies’ finding that high cytokine levels early in the infection were strongly associated with getting ME/CFS later on suggested an overactive immune system may have a blown a few fuses somewhere.

On the other hand, Dr. Lipkin specifically alluded to an ‘agent’ driving the immune activation he found in both the blood and spinal fluid of ME/CFS patients (but not the healthy controls).

Localized Infections Still Appear to Be a Possibility

Dr. Lipkin didn’t discuss this possibility. The blood is the most convenient place to search for an virus and active viruses usually do travel through the blood but central nervous system or localized infections may not show up in the blood or the spinal fluid.

Some evidence of localized infections in the gastrointestinal tract has been found in ME/CFS. A De Merileir team found evidence of HHV-6, EBV and parvovirus B-19 in 15-40% of gut biopsies. Eighty-two percent of stomach biopsies tested positive for a protein associated with enteroviruses in Dr. Chia’s 2008 study. Dr. Chia reports enteroviruses are found much more readily in the stomach than the blood (but he is able to find it in the blood). No enterviruses were found in the present study.

Vanelzakker proposes that a localized vagal nerve infection is causing the symptoms in ME/CFS.  It’s not clear what these results mean for Dr. Lerner’s theory that an aborted EBV infection is spilling viral  proteins into the blood that are sparking an immune result.

The Three Year Breakpoint 

Data suggests there may be substantial differences in biomarkers in people with less than 3 years of disease and those with more than 3 years of disease. Dr. Lipkin

subsets

Two recent research findings suggest the immune systems of people with recent onset and longer duration ME.CFS are significantly different.

Echoing similar recent findings from the Broderick/ Klimas team at NSU, Dr. Lipkin stated the immune system in ‘newbies’  (patients with recent onset), and patients with a longer case of  ME/CFS was different.  Dr. Lipkin’s ability to independently differentiate ‘newer’ from ‘older’ patients using  cytokine results is pivotal, and points to the central and progressive role the immune may play in this disorder.

With Broderick suggesting that two distinct illnesses emerge over time, and Lipkin proposing treatment options should reflect illness duration, it was clear these changes were significant indeed.

Natelson, on very different track, is finding changes over time as well with more POTS in his adolescents and a different kind of orthostatic intolerance in older patients.  Studies are underway to understand why this might be so.

An Early Allergic Response

Allergy is not usually mentioned in association with ME/CFS but eosinophils and other markers suggested to Dr. Lipkin that  the allergic response was enhanced in ME/CFS early on. The cast of immune characters Lipkin’s biomarker search fleshed out was refreshingly familiar with IL-17, IL-2, IL-8 and TNF-a leading the list.

IL-17

Levels of Il-17 were raised in recent onset ME/CFS patients. Lipkin suggested immunomoculators able to bring IL-17 levels down might be a treatment option at some point.

No mention, interestingly, was made of autoimmunity, but Lipkin, pointing at the high IL-17 levels in the newbies,  embraced the idea (only after further validation) of using immunomodulators in some ME/CFS patients  to turn down the fire in the immune system.  Immunomodulators exist now, he said, that can bring that IL-17 cytokine  down.  (He stressed, however, that there is not enough research to start using them on patients.)

The spinal fluid, interestingly enough, showed a very different pattern. It showed a consistent profile of immunological dysregulation in CFS, regardless of duration of illness. Dr. Lipkin identified increased IL-10 and IL-13 levels suggesting enhanced Th2 activation and increased IL-1B, IL-5 and IL-17 suggesting Th1 (proinflammatory) activation. Dr. Lipkin was obviously intrigued by the differences in cytokine findings between spinal fluid and blood.

A Focus on the Gut

I think the gut microbiome is going to be where the action is (in chronic fatigue syndrome). Dr. Ian Lipkin

Lipkin’s prime focus at this point is the gut and fecal matter. He  believes the gut microbiome is going to play a, perhaps the key role in ME/CFS.

The Hornig/Lipkin team has had considerable experience with the gut microbiome. They’ve been successful  finding gut abnormalities in autism, a disorder that shares some intriguing commonalities with ME/CFS, including low natural killer cell functioning.  Noting that the gut can modulate immune functioning, not just in the gut, but across the body he asserted the gut is going to be ‘where the action is’ in ME/CFS.

gut picture

Lipkin believes ‘the action’ in ME/CFS is going to take place in the gut microbiome (flora)

Unfortunately, the fecal samples originally collected didn’t provide enough material for analysis so they’re restarting that part of the study.

Even more unfortunately, characterizing the bacteria in fecal matter is extremely expensive and with Lipkin, with just 10% of the money needed to do the job, evidenced considerable frustration at having his hands tied  by lack of money.

Stating that he was not pointing fingers, he then proceeded to point  them everywhere:  at federal politics of funding, at NIH budget cuts, and at the paucity of research funding in our field. As at his last public talk, he urged patients to get active and enlist their congressman in  their cause.  Oddly enough, he also said Dr. Fauci, long considered a kind of ME/CFS nemesis by patients, was supportive of more work in this area.

Reiterating his belief that chronic fatigue syndrome has pathophysiological roots, Lipkin noted his history with it. Dr. Lipkin’s 1999 ME/CFS  study did not find the virus he was researching but it did find a great deal of immune (polyclonal B-cell) activation, a pattern that was recently repeated when he didn’t find XMRV but was impressed by the evidence of immune activation he did find.

Next Up

Lipkin, in close collaboration with his ME/CFS experts, Dr. Peterson, Dr. Montoya. Dr. Klimas, Dr. Komaroff, etc. is following these results with deep sequencing of samples, completion of fecal matter analysis and larger studies to confirm and deepen the understanding of cytokines as biomarkers. Protein analysis was not mentioned but it was part of the original project. Tracking down evidence of past infection was also on the agenda.

Conclusion

The Chronic Fatigue Initiative’s pathogen study set a benchmark for rigor and size in the ME/CFS research field, not the least because of Dr. Lipkin’s leadership. Surprisingly few viruses were found in the blood of ME/CFS patients, yet Lipkin asserted that an infectious agent was likely driving the immune activation he found in the blood and spinal samples.  Cytokine analyses of the blood suggested a different pattern of immune dysregulation was present in  newer onset patients (<3 years) and patients with a longer duration of illness.

Dr. Lipkin believes the “primary cause is likely to be an infectious agent” and the gut microbiome is where ‘the action’ will be in ME/CFS.

Viral Finding May Open Treatment Possibilities for 15-20K Chronic Fatigue Syndrome Patients in the U.S.

More Viral Funny Business in ME/CFS

Persistent human herpesvirus-6 infection in patients with an inherited form of the virus. Pantry, S, Medveczky, M, Arbuckle, J, Luka, J, Montoya, J., Hu, R. Renne, H., Peterson, D., Pritchett, J., Ablashi, D. and P. Medveczky. Journal of Medical Virology.

A lot of interesting viral possibilities have been raised in chronic fatigue syndrome (ME/CFS) over time, but this virus, possibly found in every cell of a persons body, might just take the cake.

ciHHV-6 – The Wrong Kind of Integration

Most people are exposed to HHV-6 early in life and carry a latent form of the virus in their body. Usually benign, immune suppression can allow HHV-6 to become reactivated causing fever, seizures, encephalitis, cognitive problems, heart disease and more.

gene model

Some people have HHV-6 integrated into every cell of their body

ciHHV-6 is different though. Two HHV-6 viruses (HHV-6A and HHV-6B) that probably jumped into the human germ at some unknown point several hundred thousand years ago, now some people carry a copy of it in the DNA of every cell of their body; that’s right – every cell of their body.

Does the thought of having a potentially harmful herpesvirus genome present in the DNA of every cell of your body send a little shiver up your spine? It certainly does mine, but before anyone panics let’s recognize that our DNA is larded with all sorts of weird stuff including many old (mostly beaten up) viruses. (Fragments of retroviruses make up about 8% of our genome) Almost all of us have also been infected by 5-8 of the 9 herpesviruses that can smack us hard if our immune systems let them get out of line. We carry toxic species of bacteria in our guts. We’re full of surprises, but the idea that a potentially damaging herpesvirus exists – fully intact – in some people’s DNA calls for more research.

Studies of approximately 6,000 blood and cord blood donor tests indicate 0.8% or slightly less than 1% of the US population, most of whom are in good health, have ciHHV-6. Tests on people with chronic illnesses are less extensive, but early studies suggest increased rate of ciHHV6 integration are present in numerous neurological disorders including children suspected of encephalitis (3.26%), non-Hodgkins Lymphoma (3.13%) and multiple sclerosis (2.86%).

The first of its kind in chronic fatigue syndrome, this study, led by a respected herpes virus researcher (and in collaboration with Dr. Jose Montoya  of Stanford University and Dr. Dan Peterson of Simmaron Research), determined whether a kind of human herpes virus 6 infection called ciHHV-6A or ciHHV-6B was present in a subset of patients diagnosed with chronic fatigue syndrome.

Misdiagnosis Presents Dangers

Even in its benign, unactivated state ciHHV-6 can produce lab test results that make it look like you have roaring HHV-6 infection when you do not. The high viral loads that are a distinctive feature of ciHHV-6 present a danger when physicians, believing the patient has a raging HHV-6 infection, prescribes unneeded and potentially dangerous antivirals.

stethoscope with question mark

Misdiagnosing ciHHV-6 as an active HHV-6 infection can lead to unneeded and possibly dangerous antiviral -treatment

In fact, high levels of HHV-6 (> 5.5 log10 copies/ml of HHV-6 in whole blood) on quantitative PCR tests are considered a definitive indication that ciHHV-6 is present unless a patient is acutely ill. HHV-6 appears to be largely localized in the tissues in ME/CFS, and therefore doesn’t leak a lot of HHV-6 into the blood. (Very high levels of HHV-6 DNA can be found during primary (or first) infections, but this type of infection is not usually seen in ME/CFS).

Even in primary infections HHV-6 loads will diminish over time in the blood. That doesn’t happen with ciHHV-6.

Since a latent ciHHV-6 infection is contained within the cellular DNA, the result on a serum or plasma PCR test is much lower because the cells are separated from the plasma and only DNA from cells that die in the process will show up.

The Study

Three hundred and thirty seven people suffering from neurological problems and long-term fatigue were tested using quantitative PCR for the presence of ciHHV-6. Very, very high levels of HHV6 indicated that two percent (7/337) had chromosomally integrated HHV-6. mRNA tests indicated the virus was actively replicating in their blood.

Two percent (2.1%) of the ME/CFS population translates into about 15-20,000 people with ME/CFS in the US.

Findings

Not Homegrown After All

This study suggests that, in symptomatic ciHHV-6 patients, infection with an exogenous HHV-6 virus may be a frequent occurrence.

The second part of the study involved four ciHHV6 patients suffering from symptoms consistent with ME/CFS including debilitating fatigue, headache, blurred vision, cognitive impairment, pain, etc. who were given further testing to determine the type of HHV-6 present. All had an active infection of different strain of HHV-6 virus than found in their genome. That suggested their illness was not due to ciHHV-6 reactivation but to another strain of HHV-6 they’d been exposed to.

It also suggested that people with ciHHV-6 and neurological symptoms such as fatigue and cognitive problems may very well have two HHV-6 infections; the ciHHV-6 in their DNA and an outside infection.

Long-Term Antiviral Treatment Provides Hope 

The good news…Is that antiviral drugs improve the severe neurological symptoms, including dysfunction and long-term fatigue, suffered by a certain group of patients with CFS. Dr. Peter Medveczky

Two treatment regimes, a short-term regime (900 mg/valganciclovir 2x’s/day) lasting 3 weeks and a longer term (900 mg/valganciclovir 2x’s/day for first three weeks then 450 mg twice daily for three weeks or more) lasting greater than or equal to six weeks. The short-term treatment had no effect on viral load (U100 RNA) or symptoms while the long-term treatment eliminated both. A blood test five weeks after the end of the treatment for one patient, however, indicated the virus was back in full force.

(Note that Valtrex, an antiherpesvirus drug commonly used in ME/CFS, is not effective against HHV-6)

valcyte molecule

Valganciclovir (Valcyte) is effective against HHV-6; (valaciyclovir) Valtrex is not

Kristin Loomis, the Executive Director of the HHV-6 Foundation, suggested patients with active ciHHV-6 infections may also benefit from supplements that enhance their cellular immune response such as AHCC, ImmunoPro, and Avemar, or the prescription drug Immunovir that can be ordered legally from Canada with a prescription.

Last year Medveczky and Montoya reported successfully resolving the neurological symptoms and fatigue of two ciHHV6 patients experiencing cognitive problems, depression, fatigue, and abnormal qEEG readings. Their qEEG readings normalized and their DNA load declined although, (as expected), it did not disappear. According to the Pantry study they remain symptom free.

Kristin Loomis suggested one reason these patients may need longer than normal treatment regimes is a long lasting immunosuppression caused by HHV-6. She noted that the beta herpesviruses (HHV-6, 7 and CMV (HHV-5)) found in ME/CFS all cause immunosuppression that can last up to six months. Until the immune system is restored, these virsues will continue to reactivate during stressful periods or in response to another illness.

She also encouraged patients with ciHHV6 to join the CIHHV6 registry.

ciHVV-6 Opens The Door?

Why the ciHHV-6 patients were infected with a different HHV-6 strain than they were harboring isn’t clear, but several possibilities exist. Findings of reduced antibody rates to an HHV-6 protein suggest ciHHV-6 may somehow have switched off some immune factors that target HHV-6, thereby opening the door for new HHV-6 infections.

kicking door open

Some preliminary evidence suggests ciHHV-6 could open the door for more HHV-6 infections

Kristin Loomis, the President of the HHV-6 Foundation that helped fund the study, noted that many people with recurring herpesvirus infections (ciHHV-6 or not) probably have an undiagnosed immune deficiency such as hypogammaglobulinemia, impaired CD4 or NK cell responses, reduced lymphoproliferative response and/or low NK cell counts. The following tests at a lab such as Quest can identify these some of these immune ‘holes’.

  • IgG Subclasses Panel
  • Lymphocyte Subset Panel (CD4, CD8, CD3, CD19 and CD16/56)
  • ImmuKnow Immune Cell Function (measures CD4 cell response)
  • Natural Killer Cell Functional Assay, FC

Other causes of viral reactivation include stress. (Hydrocortisone activates virus in the laboratory.)

Drugs Open the Door?

Laboratory cell culture studies suggest the possibility that in some cases drugs may have opened the door for ciHHV-6 reactivation. Antibiotics such as Amoxicillin, Minocycline, Vancomycin, Dapsone, Trichostatin; NSAIDS such as ibuprofen and naproxen; immunosuppressants such as hydrocortisone; anti-inflammatories such as sulfasalazine, anticonvulsants such as carbamazepine, phenobarbital, valproic acid and HDAC inhibitor Trichostatin A have all been found in laboratory culture tests or in case reports, to enhance the risk of HHV-6 reactivation. (Click here for more drugs – Table Four).

Extreme drug allergies (also known as Drug Induced Hypersensitivity Syndrome or DRESS) result in HHV-6 reactivation in about 85% of cases. Steroids can also activate HHV-6; it is unknown if they present a unusual risk to individuals with ciHHV6, however.

Tested Positive for HHV-6? You Probably Have ciHHV-6

A team of ciHHV-6 experts does not recommend routine screening for ciHHV-6 for the general population but does recommend that patients with ‘suspiciously high’ serum or plasma HHV-6 levels get screened using quantitative PCR using whole blood or PBMC’s.

Kristin Loomis suggested ME/CFS patients who’ve tested positive for HHV-6 (via quantitative PCR) probably have ciHHV-6. The question then becomes whether they also have an active infection or if your test merely reflected the fact that you have ciHHV-6.

This is the tricky part. ciHHV-6 infection can result in false positives for active HHV-6 infection but this study involved four ME/CFS patients with inherited ciHHV-6 infection. This suggests ciHHV-6 infected ME/CFS patients may be at greater risk of succumbing to an outside strain of HHV-6.

The Missing Test

We have two questions here. If you’ve tested positive for HHV-6 do you actually ciHHV-6?  And if you have ciHHV-6, do you also have another HHV-6 infection?

Question mark

Since tests to determine if active HHV-6 infections are not available commercially, doctors will have to make informed judgments regarding treatment

The first question is relatively easy to answer. Quantitative PCR tests offered by commercial laboratories can suggest you have ciHHV-6. Since ciHHV-6 is expected to produce high DNA copy numbers, and CFS patients with persistent low-level HHV-6 infections almost always test negative (or fall below the level of detection) for HHV-6, any quantitative PCR DNA lab tests indicating high HHV-6 loads very strongly suggests that you have ciHHV-6.

(Note: This does not apply to persons testing positive on the qualitative nested PCR tests at VIP Laboratories or Redlabs.)

Unfortunately, no commercial laboratories offer tests that can tell if you have an active HHV-6 infection.

Physicians will need to rely on their clinical assessments (ie do your symptoms suggest you  have an active infection? Do immune lab tests suggest your body is fighting off an infection, etc.)  to determine if antivirals are indicated.

Kristin Loomis suggested that those with a positive plasma test in the past should send blood samples to the clinical lab University of Washington to confirm CIHHV6 status, using a form that can be downloaded from the HHV-6 Foundation page on CIHHV6 testing. The University of Washington has a new third generation PCR test that is highly accurate and designed to identify ciHHV6 samples.

Testing Must Be Done on Whole Blood (Not Plasma)

Alternatively, samples can be sent to Viracor or Quest but physicians need to contact the lab director at each lab in advance to request that the testing be done on whole blood instead of plasma.

The test used in this study, a real-time PCR assay for HHV-6 U100 mRNA, can differentiate between latent and active infections but is not available in commercial labs.

A New Subset 

An estimated 15,000 to 20,000 patients with this CFS-like disease in the United States alone may ultimately benefit from … this research including antiviral therapy. Dr. Peter Medveczky

pie chart with subsets

Researchers propose subsetting out a category of ME/CFS patients with ciHHV-6 and HHV-6 infections.

The authors proposed to call ciHHV-6 with an outside HHV-6 infection “inherited herpesvirus six syndrome” or IHS. When asked why the ‘syndrome’ tag, Kristin Loomis replied that too much is unknown to pin the disorder down more. Several different HHV-6 scenarios, it turns out, could be causing similar symptoms. An abortive HHV-6 infection, reactivation of the integrated genome even if it is not fully replicating, or even ciHHV-6’s interference with genetic functioning of the chromosomes its found in, could all potentially cause similar symptoms.

Medveczky explains that IHS patients are:

  1. ciHHV-6 positive
  2. suffer from an illness similar to ME/CFS,
  3.  have HHV-6 mRNA  (late mRNA) present in their blood indicating the virus is active
  4. respond to six weeks of antiviral treatment with the disappearance of the active virus and experience symptom improvement

Since ciHHV-6 is found in all the cells of the body it’s potential to wreak mischief either genetically or through reactivation is high. It will take future studies to determine if it does, however. Medveczky found that HDAC inhibitor Trichostatin A activates CIHHV6 in the test tube. Many of the new cancer treatments, such as Vorinostat, are HDAC inhibitors.

Good Pedigree

The senior author of the study, Dr. Peter Medveczky, has been publishing herpesviruses papers since the 1980’s. HHV-6 Foundation president, Kristin Loomis, noted that Medveczky was completely skeptical when he first heard about ciHHV-6 but he’s now convinced, and he’s actively linking a subset of ME/CFS to a viral disorder. With his long stint of herpesvirus research behind him, Medveczky is the kind of researcher other researchers listen to – a vital need.

Conclusion

Doubled rates of ciHHV-6 in ME/CFS relative to the general population suggest ciHHV-6 could contribute to ME/CFS. The high viral loads in laboratory tests, present in people with benign ciHHV-6 infections, can lead to unneeded courses of antivirals. On the other hand, some evidence suggests ciHHV-6 associated immune dysfunction may open the door for further herpesvirus infections.

This early study indicates new HHV-6 infections may be commonly found (and effectively treated) in ME/CFS patients with ciHHV-6. Further study is needed but the success of long term antiviral treatment regimes (@ 6 weeks)  in these patients suggests from 15-20,000 ME/CFS patients in the U.S. could ultimately benefit from appropriate courses of antivirals. Shorter-term courses are not effective.

Since persistently high levels of HHV-6 are associated with ciHHV-6 status but not chronic HHV-6 infection, further testing, while not definitive, can help determine whether ciHHV-6 is present. Physicians will need to decide on a case-by-case basis if antiviral treatment is warranted. Quantitative PCR tests done on whole blood can suggest whether ciHHV-6 is present. No commercial laboratory tests at this time can determine if an active HHV-6 infections are present.

Further Studies

All one study can do is open the door; it takes confirmatory studies to make the findings stick. If a sub-category of ME/CFS called Inherited Human Herpesvirus Six Syndrome is to take hold substantial research is needed. Small research foundations like the HHV-6 Foundation can only do so much. Thus far the work has been done on a shoestring; now it needs full funding and that means NIH funding.

The Simmaron ME/CFS Physicians Roundtable Pt. II: Talking Treatments

Round-Table

meeting of the minds picture

Some of the top ME/CFS practitioners had a meeting of the minds on how best to treat ME/CFS at the Simmaron Roundable

Simmaron Research likes to get people talking. At the FDA Workshop earlier this year, they booked a room, invited patients and physicians and then held a physicians round-table with some of the field’s top doctors.

Part II of a three-part series focuses on Dr. Peterson of Sierra Internal Medicine /Simmaron Research Institute, Dr. Klimas  – the director of the Center for Neuroimmune Studies at Nova Southeastern University, and Dr. Enlander, the Director of the Mt. Sinai ME/CFS Research Center talking about chronic fatigue syndrome treatment.

Dr. Peterson – Simmaron Research Institute

Dr. Peterson started off the treatment section with some hopeful news. Powerful new immune drugs such as immune modulators and cytokine blockers), he said, that have been and are being developed, can have dramatic effects in the right patients.

upward slope

Immune therapies under development in other fields may be able to help ME/CFS patients in the future.

(Rituximab is an example of a new approach that paid off. The first of its class of drugs (monoclonal antibodies), Rituximab (Rituxan) opened up a new arena of drug development. Similarly, Ampligen and other Toll-like receptor affecting drugs offer new approaches to immune modulation. Drug repurposing efforts that are finding new uses for old drugs present some intriguing possibilities. An abortifacent, mifepristone, for instance, boosts natural killer cell functioning.

Breakthroughs in other fields are providing other opportunities. Studies documenting the role natural killer (NK) cells and the innate immune system play in preventing cancer have piqued drug developers interest enough the  several NK cell boosting drugs are in development.

A Treatment Philosophy

Some ME/CFS patients, believe it or not, are relatively easy to treat. Patients with easily characterized viral infections have a clear treatment protocol waiting for them. If a parvovirus infection is found, for instance, it can be easily treated. Dr. Peterson has found that the ‘wait and see’ approach so often prescribed by doctors with ME/CFS in hopes that the patient will just get better is a mistake.  He’s found that, in his group of patients, treating aggressively early is more effective.

cascade effect

Dr. Peterson proposes more aggressive approaches to ME/CFS early may forestall problems later if the disorder progresses.

(This brings to mind the story of someone I know whose doctor used a less strong antiviral (Valtrex) for a significant period of time only to switch to a stronger but potentially more toxic antiviral (Valcyte) after his patient deteriorated significantly. The patient then experienced a dramatic and lasting recovery.)

We’ll see that fighting pathogens in ME/CFS is not a cut-and-dried, one-size-fits-all process, and that physicians differ somewhat in their approach. In more complicated cases, for instance, Dr. Peterson is experimenting with combining immune and anti-viral treatments, and thus far is getting some encouraging results.

Dr. Peterson’s use of the antiviral Cidofovir (typically used to fight eye infections caused by cytomegalovirus in AIDS patients) demonstrates how differently even this small group of physicians sometimes approaches infections.

Cidofovir (Vistide)

“Cidofovir is not a panacea for this disease, but I think it demonstrates clearly how we should be subsetting and treating the treatable people,” Dr. Peterson.

Dr. Peterson uses Cidofovir regularly in patients with documented HHV6 and cytomegalovirus (CMV) infections.  (Since he employs more spinal taps than the other doctors at the Roundtable, he probably also finds more HHV6/CMV infections.)

Gunnar Gotschalk

Gunnar Gotschalk, Dr. Peterson’s research assistant, reported on Vistide’s results in ME/CFS patients with HHV6/HMV infections

Gunnar Gottschalk, Dr. Peterson’s research assistant, gave an overview of  the Vistide results seen in Dr. Peterson’s practice. Vistide is an expensive drug with potentially serious side effects that requires a rather complex infusion process.  Most patients need to relocate to the Reno/Lake Tahoe area to get at least 12 infusions.  Once they start the infusions they need to get three blood tests a week.  Vistide is difficult to administer, and its no surprise that most ME/CFS docs are not using it.

Gunnar reported, however, that a retrospective analysis indicated that 70% of ME/CFS patients with HHV6/CMV infections achieved a positive response.  He highlighted three patients: two achieved substantial gains in VO2 max and their viral titers dropped to zero, and all three returned to work after being disabled.

The retrospective analysis indicated significant drops in viral titers, increases in VO2 max (but not to normal) in full responders, and increased NK cell functioning in the group as a whole. Of the full responders Gunnar estimated two-thirds were able to maintain their health and one-third had to restart the treatment after 6-8 months.

When asked to compare Valcyte’s side effects with Vistides, Gunnar said that his experience was that people appeared to have a harder time on Valcyte than Vistide.

CMX001

Then there’s CMX001, the lipid-based analogue of Cidofovir produced by Chimerix that appears to be both more potent and better tolerated and which is beginning phase III (final) trials.

herpesviruses

If CMX001 passes muster at the FDA it will present new possibilities for herpesvirus treatment in ME/CFS

Simmaron believes it has patients that will fit Chimerix’s criteria and is trying to get them into the trials.  (Chimerix, by the way, generated $118 million dollars in gross proceeds when it went public a couple of months ago. Chimerix projects Phase III trials for CMX001 treatment of CMV infections in stem cell transplant patients will be finished in 2015. Since the drug is on fast-track status, the FDA will rule on it more quickly than usual once the data is in). Exactly what Vistide is doing (besides knocking down the virus) is unclear.

On the immune end, it’s possible Vistide is relieving pathogen-associated NK cell dysfunction (although Dr. Peterson thinks more than that is going on) but it’s unclear why the VO2 max readings in his patients go up.  Gunnar did allude to the fact that some deconditioning probably was present in these very disabled patients, but Dr. Peterson thinks cytokine induced mitochondrial dysfunction may be occurring.

HHV6 and Chromosomal Integration

The tricky problem of HHV6 chromosomal integration should be noted. People who have HHV6 integrated into their chromosomes will always, whether the virus is active or not, test positive for HHV6 via PCR. Retrospective studies are never proof of a drug’s effectiveness; you need a placebo-controlled, double-blinded study for that. But retrospective studies do provide the pilot data that could support a trial. (I was told that Dr. Peterson’s Paris presentation generated a lot of interest.) This retrospective study is an instance of a doctor combing through and analyzing their past data, and hopefully we’ll see more of it in the future.

Graded Exercise and Cognitive Behavioral Therapy

“I wish graded exercise and cognitive behavioral therapy worked,”said Dr. Peterson. After mentioning the CDC toolkit (which emphasizes CBT and GET and does not suggest ANY laboratory testing be done) Dr. Peterson said he wished CBT/GET worked, and then said it might be helpful for patients who’ve gotten well enough, but that even if it was, it’s simply not available. For all the talk on CBT and GET, Dr. Peterson knew of no trained practitioners in the US, except for one associated with Dr. Klimas’ clinic.

Dr. Nancy Klimas – Director of the Center for Neuroimmune Studies at Nova Southeastern University

“I’m a splitter not a lumper. I try very hard to find …intervention points,” Dr. Klimas

An  Autonomic Nervous System Focus

Earlier this year Dr. Klimas reported that gene expression tests done during and after exercise suggested that the autonomic nervous system ‘tanks’ first in ME/CFS during exercises, and then drags down the immune system with it.  Her research suggests autonomic nervous system problems trigger an ‘inflammatory cascade’ which then causes much of the post-exertional malaise that occurs in this disorder.

autonomic nervous system

Dr. Klimas exercise studies suggest the problems in the autonomic nervous system trigger problems in the immune system

It was no surprise, then, to hear her say that she spends a great deal of time early on with her patients trying to get that ‘volatile’ autonomic nervous system under control.  (This is an example of translational medicine; i.e., translating research results (gene expression findings) into practical applications in the clinic.) This ANS-immune cascade problem, by the way, appears to be independent of pathogen or antibody results; it’s a core issue present in many patients.

Pathogens and Immune Modulation

With regard to pathogens, Dr. Klimas said most of her patients with high antiviral loads/antibodies will be on antivirals, but generally more gentle ones such as Famvir (famciclovir). She noted, though, that a danger lurks when less-strong drugs inadequately control the virus: it can then ‘break free’ and develop resistance not just to that drug but to others in its class.  A virus that develops resistance to Famvir, for instance, will probably also be resistant to Valcyte. Dr. Klimas then made a plug for controlled clinical trials of Vistide in ME/CFS.

“We don’t really know how to distinguish which group is autoimmune and which group has chronic viral activation”

One has the feeling that the only thing keeping Dr. Klimas, an immunologist, from tinkering more with the immune system in her patients was lack of sufficient data. Referring to the weird immune ying/yang often seen in ME/CFS (some parts of the immune system being over-activated and some parts under-activated), she said she’d love to be able to knock down the immune activation present and build up immune cell functioning, but that building up cell functioning in a patient whose immune system is already overcharged could trigger an autoimmune response. Since no autoantibodies have been associated with ME/CFS, it’s difficult to tell if an autoimmune response is already present.

Some indirect tests can help; high CD4/CD8 ratios, for instance, are suggestive of autoimmunity, and high CD8 levels suggest a pathogen is present. If her flow cytometry tests show high CD4/CD8 ratios, she’s ‘very nervous’ about doing anything to bump up the immune system.

Immunovir (Isoprinosine)

Isoprinosine structure

Dr.; Klimas has had good success with Isoprinosine in ME/CFS

Dr. Klimashas seen an 85% response rate to Immunovir biologically, and it can generally double up NK cell functioning. She obtains pharmaceutical grade Immunovir from Canada Newport Pharmaceuticals and a similar and cheaper over-the-counter preparation called Inosine is available in the US.  Anecdotally she doesn’t think she’s getting as good a response from Inosine. Equilibriant – includes mushroom extracts that enhanced NK function in Chinese studies. Got lots of stuff in there.

Monoclonal Antibodies

A group of patients with extraordinary immune readings; i.e., TNF-a levels hundreds of times above normal, are prime targets for monoclonal antibody drugs (such as Etanercept) that target specific immune factors. In these patients, Dr. Klimas usually brings in a rheumatologist to get the drug.

Expect more news on this in the future, as a great number of monoclonal antibodies coming out of cancer research should be hitting the market, some of which may be able to assist NK functioning. Dr. Klimas said there’s “Some pretty cool stuff in the pipeline”.

“I want to make a plug for Low Dose Naltrexone” Dr. Klimas

Low Dose Naltrexone

Low Dose Naltrexone (LDN), not Lyrica or Cymbalta, is Dr. Klimas’ first line treatment for fibromyalgia-type pain.  A recent study found that it reduced FM pain by roughly 60% without the toxicity of Lyrica and Cymbalta.  She called the science behind LDN (which is not produced in a low-dose form by drug companies but is readily available at compounding pharmacies) ‘riveting’. That’s pretty strong endorsement of an ‘underground drug’ that is getting more and more attention despite its Achilles heel of not being marketed in low-dose form by Big Pharma.

Dr. Enlander – Mt Sinai ME/CFS Research Center 

GcMAF

Dr.  Peterson asked about GcMAF. Dr. Klimas said she hasn’t used it, but Dr. Enlander’s been using it for two years–first by injection and now mostly in his own yogurt mixture. Dr. Cheney probably may have started the GcMAF saga in ME/CFS first with a trip to Italy several years.  A yogurt mix was available, but when one of Dr. Enlander’s patients tried to make it the cost was  $3,000. In the end, Dr. Enlander’s bacteriologists at Mt. Sinai produced the mixture (MAF878) (and at a cost of $120!). Dr. Enlander does believe the injections are probably more effective, but he’s gotten good results for both.

Next Up: the Future! Dr. Peterson started off with hope, and in the next section we take a look at the future for ME/CFS physicians, what their three organizations are pursuing, and what they’re looking forward to in the future.

ME/CFS Physicians Roundtable I: ME/CFS Docs Talk Diagnostics and More at the Simmaron Foundation Roundtable

June 18, 2013

Listen in on the field’s top experts at your own pace here!

(Thanks to Anita Patton for her notes from the Roundtable talk)

FDA-Stakeholders-MeetingSimmaron likes to get people talking.  At just about every conference I’ve been to recently, the Simmaron Foundation has rented a room, brought in some food and got patients, doctors and researchers talking.  This time at the FDA Stakeholder’s Meeting they pitched Dr. Peterson, Dr. Klimas, Dr. Lapp and Dr. Enlander questions around a physician roundtable and took questions from the patients present.  We learned a lot in the off-the-cuff wide-ranging discussion that followed.  In this blog we’re going to look at how these doctors diagnose their patients and next up we’ll look at treatment.

Redefining ME/CFS

PetersonPhoto right

“We are on the verge of better diagnostics.” Dr. Peterson

Diagnostics always come first. Before you can treat you must be able to diagnose. Unfortunately the diagnostics in chronic fatigue syndrome have been shrouded, vague, symptom-based definitions. From the myalgic encephalomyelitis to the Holmes to the Fukuda to the Canadian Consensus Criteria,  the chronic fatigue syndrome field has been grasping for definitions for as long as it’s been around.

Problems on the macro level (the definition), of course, lead to problems at the micro level ( the doctor’s office) where  ME/CFS doctors are deluged with all different kinds of ‘chronic fatigue syndrome’ patients. That uncertainty – not knowing just who might step in the door –surely makes for an interesting job.  The qualifications for a good chronic fatigue syndrome physician may look something like this…. good listener, not daunted by complexity, loves to problem-solve, has a wide range of knowledge and is flexible and  willing to try new things…

As Bernard Munos pointed out at the FDA Workshop, in a disorder like this which has few clinical trials, the physicians, more than anyone else are the innovators. Not able to rely on clinical trials, their offices are an ongoing clinical trial.

How Dr. Peterson, Dr. Klimas and Dr. Enlander made sense of their ME/CFS patients was what the first part of the Simmaron Foundation’s Physician Roundtable was all about.  Listening to how the different doctors approached ME/CFS was fascinating.

“I am very concerned about random drug trials that take the first 100 patients who sign up.  It would be a disaster.” Dr. Peterson

Given the many different types of patients Dr. Peterson sees, the idea of drug trials that don’t subset first is simply appalling. The idea that this complex mix of patients are ever going to respond similarly to a drug is nonsense.

For Dr. Peterson, who sees the complexity of the illness daily, diagnosis, whether in a research study, clinical trial or a doctor’s office, always comes first. Since the same symptoms can be produced by many different factors, symptom definitions, while helpful, will always have flaws. What’s needed is to ‘scientifically redefine ME/CFS’; that’s the Simmaron Foundation’s stated goal and each of these physician/researchers is working towards that.

Now onto diagnosing ME/CFS.

Immune System

Dr Enlander

“Like Dan and Nancy, we look at the patient as an immune system problem in order to develop idea of diagnosis.”  Dr. Derek Enlander

Dr. Peterson started off by stating that after screening for the ‘obvious stuff’ he goes after immune markers, primarily focusing on the NK, T and B cells.

Over time he found consistent patterns began to emerge with natural killer (NK) cells playing a major role. (These cells, which play a major role in the early, innate immune response, appear to be ground zero for the immune problems in ME/CFS.  Unfortunately, they’re not particularly well known in the medical community.  Dr. Peterson’s poll of his colleagues in his area a couple of years ago found that few knew anything about them.)

It doesn’t help that natural killer cells are tricky to work with and need to be assessed within four-six hours of sample collection. In an attempt to make them more user friendly, Dr. Peterson is experimenting with freezing live cells in liquid nitrogen.Nancy Klimas

“We are the Gold Standard” Dr. Klimas

Being an immunologist it wasn’t surprising to see Dr. Klimas’s strong focus on the immune system. With one of the top immune labs in the country, Dr. Klimas is at the center of a lot of immune work.

Immune factors are one lab measure you’ve got to get right; tweak the powerful immune system the wrong way and you can cause a lot of trouble. If you’re  using immune altering drugs, and both Dr. Peterson and Dr. Klimas do, the ability to trust your lab is critical. Dr. Klimas said her immune lab is the ‘gold standard’ and Dr. Peterson gets all his cytokine arrays done at Dr. Klimas’s lab.

Dr. Klimas will dig into IGG subclasses if she sees bacterial infections. Dr. Enlander focused on much the same factors;  CD4 and 8 ratios, NK cells and function, (IL2, IL4, IL10) and uses bacterial cultures to rule out other disease entities, like Lyme, etc.

Pathogens

Pathogens were discussed briefly. All three physicians were testing for them (eg; EBV, HHV6, CMV, Parvovirus, Coxsackie and bacteria)  but there were some differences. Dr Enlander did not see a relationship between viral load and disease severity, something that Dr. Peterson, as we’ll see later has found, at least with one group of patients. Dr. Klimas has not found HHV6 to be a good marker either as patients don’t test positive consistently; in fact, she called ME/CFS a ‘good day, bad day viral disease’ as patients may test negative on a good day and positive on a bad one. That’s helpful for her as a physician but is not good enough for the FDA to test treatments against. The FDA needs a test that’s consistently positive.

InfectionsWhat does Dr. Klimas find that tracks with severity?  Natural killer cell functioning and IL-5 levels  might be two markers the FDA could use to assess treatment effectiveness.

We don’t hear alot about IL-5 cells but they boost two immune factors of interest in ME/CFS; mast cells and B-cells.  Overactive B-cells cause autoimmune disorders and, of course, also  harbor EBV as well.

Dr. Enlander will be seeking to confirm/deny Dr. Chia’s enterovirus findings in his exercise study (see below.)

Autonomic Nervous System

With Dr. Peterson stating the amount of autonomic nervous system dysfunction in ME/CFS was ‘huge’ the stage was set  for the autonomic discussion. All three doctors do blood pressure and pulse testing with Dr. Peterson and Dr. Enlander doing 24-hour BP and heart testing, and Dr. Enlander and Dr. Klimas use tilt table testing. Dr. Klimas noted that an autonomic nervous system dysfunction appears to trigger immune dysfunction. She asserted that the sympathetic nervous system a major, major symptom generator in this disorder and she rattled off problems with standing, respiration, poor digestion, etc. that could all be caused by SNS overactivation.

Nervous-SystemIt’s not clear how many of the physicians were measuring blood volume; it may be that they all simply assume blood volume is low, but Dr. Klimas noted the astounding fact that most patients are about a liter of blood low, or about 20% down from normal. With that little blood running through your blood vessels those blood vessels are going to have to squeeze hard  to get it out to the tissues and brain, and right there you have a good reason for the sympathetic nervous system activation Dr. Klimas talked about earlier.

Dr. Klimas gives blood volume a boost with electrolytes and then puts the patients back on the tilt table to see if they’ve improved.

Dr. Enlander is using Dr. Cheney’s cardiac protocols to measure cardiac output, stroke volume, etc. He does it, interestingly enough in a variety of positions (lying down, standing) giving him a great deal of data on cardiovascular functioning.

With the ANS playing a huge role in exercise, onto to exercise testing we go.

Aerobic Testing

“You do better diagnostics when you do exercise challenges.” Dr.Nancy Klimas.

You probably couldn’t get three ME/CFS physicians more knowledgeable or committed to exercise testing in one room than you had at the Roundtable.

The first ME/CFS physician to embrace VO2 max testing, Dr. Peterson made a strong plug for Staci Steven’s test-retest, two day exercise protocol (the Stevens Protocol. This exercise test grew out of the work she did in Dr. Peterson’s office).

Dr. Peterson uses the most rigorous test of all; the aerobic exercise test to determine how well his interventions are working.   At the FDA Ampligen hearing, Dr. Bateman, noted that the VO2 max test, which measures the amount of energy a person can produce, is the hardest to budge of all ME/CFS tests . Since Dr. Peterson finds that low VO2 max scores are often correlated with poor cognition, abnormalities on MRI’s and spinal fluid as well as autonomic problems, bumping up those VO2 max scores even moderately can mean a significant improvement in functionality and well-being.

Exercise-test-cfs

All three practitioners use exercise testing in for research, disability and/or to assess the effectiveness of their interventions

( I asked Staci Stevens if she knew of any  ME/CFS patients who had returned to full VO2 max functioning and she said yes, some patients on antivirals and Ampligen –coming out of, no doubt given her longstanding connection with him, Dr. Peterson’s office.)

Dr. Klimas has been digging deep into exercise in her research, lately, which, in turn is informing her diagnostic work.  (That’s  ‘translational medicine’).  Earlier this year she reported gene expression studies indicated that the autonomic nervous system tanks first during exercise and then drags the immune system down with it.

This major finding, if validated, suggests breakdowns in the ANS, which is ever so tightly intertwined with the immune system, could be at the core of the disorder.

“Now let me tell you what we are really doing at Mt Sinai…” Dr. Enlander

And then there was Dr. Enlander who’s committing  a big chunk of money to a sophisticated exercise testing study at the Mt Sinai Research Center. He’s got a geneticist, an immunologist and a pulmonologist all working together.

After exercise Enlander’s team will be looking at RNA (genes), blood (immune factors, a stool sample, RNA, DNA genome, enteroviruses), brain MRI and SPECT scan. Amongst other things Enlander will be looking to confirm or deny Dr. Chia’s findings of enteroviruse of seven, yes, seven years ago. That’s seven years without a confirmatory study of a virus that was first linked to ME/CFS decades ago…

Spinal Taps and Brain Imaging

Dr. Peterson does spinal taps  to figure out what’s going on with his most cognitively challenged and neurologically impaired patients. (After decades of gathering spinal fluid, Dr. Peterson easily has the greatest store of ME/CFS spinal fluid on the planet. Dr. Mady Hornig has referred to Dr.Peterson’s spinal fluid as a precious resource).

spinal fluid

Dr. Peterson examines the spinal fluid of his more neurologically and cognitively challenged patients

Spinal taps are where Dr. Peterson, Dr. Klimas and Dr. Enlander part ways to some extent. Both Klimas and Enlander do them at times, but Dr. Peterson does them routinely in patients with neurological and brain issues (and he does them himself).  Dr. Klimas said she was astounded that Dr. Peterson found 17% of his patients’ spinal fluid tested positive for a virus.

Both Drs. Klimas and Enlander may be doing them more in the future. Dr. Klimas is waiting on finding the right neurologist, and Dr. Enlander said he was closely following Peterson’s ideas.  If the CFI and PHANU studies using Dr. Peterson’s spinal fluid are positive, we may see more and more doctors turning to spinal fluid to assist with their diagnoses.

Future -Dr. Peterson looked forward to future medical advances that will help him fine-tune his diagnostic protocols.  Genetic technologies are indicating, for instance, that a genetic predisposition to the NK dysfunction may be present in ME/CFS. On the other hand he also finds ‘acquired’ (ie non-genetic) NK cell dysfunction as well. He believes insights gathered from miRNA’s in the spinal fluid of ME/CFS patients, for instance, and the more rigorous pathogen detection techniques will continue to open up this field and inform his diagnostics.

Similarly, Dr. Klimas’ exercise studies are causing her to focus more on improving autonomic dysfunction, and Dr. Enlander will use his big exercise study to inform his understand of his patients. Each of these three physician/researchers is eager to translate their research findings into their diagnostic protocols.

Undefining ME/CFS?

“There is an entire school of thought in the medical profession that if anyone with chronic fatigue has anything objectively wrong with them – they don’t have chronic fatigue syndrome.” Dr. Dan Peterson

After all the talk about how to diagnose ME/CFS, Dr. Peterson brought up a trend towards ‘undefining’ that he found troubling. Undefining ME/CFS consists of putting ME/CFS patients in a different box as soon as something concrete is found.   Stating that this attitude is more forceful than he ever thought, Dr. Peterson explained that a person with ME/CFS with HHV6A in their spinal fluid will be labeled as having HHV6A encephalitis and be determined to never have had ME/CFS.

ME-CFSDr. Klimas acknowledged that while getting a diagnosis that can be treated is great, as a field winnowing large numbers of patients out of the ME/CFS basket could be devastating. For one it condemns ‘ME/CFS’ to be a  a mere placeholder of an illness.

Dr. Klimas noted Dr. Peterson’s finding that 17% of his cognitively dysfunctional patients were culture positive for viruses in their spinal fluid was a clear subset.  (She was reminded of former CDC CFS chief Bill Reeves response “you don’t know that doesn’t belong there” and she laughed and said “Wait a minute . Would it be ok for you to have your cognitively dysfunctional child culture have positive spinal fluid test? I don’t think so”). What a dilemma it was, she said when every time we start to get clarity, part of this disorder gets shuffled off into another column.

The Hidden Epidemic

“The bedridden patients – It’s the hidden epidemic within another epidemic..It’s scary” Dr. Dan Peterson

And then there’s the missing patients; the bed-ridden ones that rarely get to doctors clinics and certainly aren’t in research studies.  How do you define a disease without access to all the patients?  The most severely ill usually get the most attention in most disorders but the opposite is true in ME/CFS.  (Check out the astonishment from a former ICU nurse working with Dr. Kogelnik at the degree of disability she sees in ME/CFS. These patients, she thought, should be in a hospital, not at home.)

“Talk about a forgotten, ignored group of people.” Dr. Peterson

Dr. Peterson noted that we don’t an accurate count of how many people are in this situation. He didn’t have answers. He noted that you needed staff to get to these people and you needed to find them in the first place. Dr. Klimas answer suggested that funds were at the heart of the problem. Ads for an online CBT study did bring in bedbound patients who were unable to make it to the clinic and funding for the ‘good-day/bad-day’study did allow them to make house-calls on the patients bad days. Both Dr. Klimas and Dr. Enlander said they do do house-calls from time to time. (One of Dr. Enlanders house-calls is now up and working…he said there is hope for the severely ill.)

Listen to audio of the Roundtable in 7 parts here, and stay tuned for a blog summarizing the Roundtable discussion about treatments.

Novel Approach to Herpesvirus Infections Could Reap Dividends for Chronic Fatigue Syndrome Patients

Liang Y, Vogel JL, Arbuckle JH, Rai G, Jadhav A, Simeonov A, Maloney DJ, Kristie TM. Targeting the JMJD2 Histone Demethylases to Epigenetically Control Herpesvirus Infection and Reactivation from Latency. Sci Transl Med. 2013 Jan 9. PMID: 23303604.

Common Infections..Sometimes Uncommon Effects

An uncommon common virus

Unlike most viruses once you’re infected with herpesviruses you’re usually infected for life.

Herpesviruses are fundamentally different from most other viruses we come into contact with.  Most viruses  get completely eliminated from our systems  but herpesviruses have found a way to stick around – usually effectively bottled up by our immune system – for a lifetime ride in our cells. Very common in humans, we’ve all been exposed to and almost all of us carry a  latent or inactive herpesvirus infection.

Usually contracted in childhood most herpesvirus infections produce nothing more troubling than a childhood cold but they have a dark side.   A Epstein Barr virus infection that causes a mild cold in childhood often produces  infectious mononucleosis in adolescents and increase one’s risk of later coming down with multiple sclerosis and ME/CFS.  A mild herpes simplex infection during childhood can turn into an  painful case of shingles when we’re older.

Herpesvirus infections may be ubiquitous and usually mild but they  can cause encephalitis, blindness, horrific neurological problems and inflammation if they hit the right person at the wrong time. Not surprisingly, people with impaired immune systems such transplant patients are at high risk of herpesvirus reactivation with sometimes deadly consequences.

Key Viruses in Chronic Fatigue Syndrome (ME/CFS)

herpesvirus

A significant percentage of people may have reactivated herpesvirus infection.

Herpesviruses may play a key role in ME/CFS as well. How many people with chronic fatigue syndrome have a reactivated form of the virus is still unclear but some doctors believe the percentage is substantial. Many people begin their experience with chronic fatigue syndrome (ME/CFS) with a herpesvirus infection in the form of infectious mononucleosis.

Dr. Lerner and Dr. Glaser believe an unusual form of Epstein-Barr  virus is wreaking havoc in many patients. Their model suggests proteins and enzymes produced by a  partial reactivation of the virus are sending  the immune system into a tizzy and causing fatigue and other symptoms. Because the current slate of  herpesvirus antivirals attack the virus in the later stages of it’s development they’re in effect missing the action in ME/CFS.  These drugs work to some degree.  As they slowly lower viral load, the cells harboring the viruses die off over time.

Help Needed 

“there remains a clear need to develop new antivirals”

The problem is that in this model  the road to recovery takes time and lots of it; often a year or more of taking expensive antivirals. Dr. Lerner’s  been looking for a treatment that will hit the virus just as it’s starting to replicate and he’s  not alone. Even when the full virus is present, the present slate of  antivirals still sometimes  arrive too late to prevent blindness, neurological problems, birth defects and inflammation. The current herpesvirus antivirals come too late to the scene to

  1.  block the production of mutant viruses that can give rise to resistant strains of virus
  2.  block the expression of early viral enzymes that effect  and can produce cancer in cells
  3.  block the product of viral proteins that can trigger a damaging immune response (Lerner/Glaser’s theory of ME/CFS)

A Possible Breakthrough

A new approach to treating herpesvirus infections could reap dividend for other viral infections as well. An entirely different way of treating herpesvirus infections could reap dividend for other viral infections as well.

A new approach to attacking hard to treat herpesvirus infections could reap dividend for other viral infections as well.

“Depletion of the JMJD2 members or inhibition of their activity with a new drug results in repression of expression of viral immediate early genes and abrogation of infection. This inhibitor also represses the reactivation of HSV from the latent state in sensory neurons”

That may be changing. Researchers working at National Chemical Genomic Center (NCGC) have a developed  a ‘probe’ that stops herpesviruses from replicating by  pouncing  on the early enzymes they use to build a new virus.   (Ironically the virus uses our genetic machinery to get our bodies to produce the enzymes to build another virus). These researchers were able to design this probe after they figured out what genes these herpesviruses activate early in their life cycle.  This ‘epigenetic’ approach – stopping a virus by targeting the genes it needs to replicate – may very well herald a new era in antiviral therapy.

It’s  death by small cuts. By continually stopping the virus from replicating the herpesvirus will eventually  die when the cell they’re  living in dies. The good news for ME/CFS patients is that this probe could also whack the very enzymes Lerner and Glaser believe are causing ME/CFS. That could  mean no more long, expensive and sometimes dangerous treatment regimens.

The Implications for Chronic Fatigue Syndrome (ME/CFS)

This study focused on two herpesvirus infections (cytomegalovirus (HCMV), herpes simplex) sometimes found in ME/CFS. In Dr. Peterson’s presentation in Paris on the successful treatment of HCMV infections in ME/CFS, he reported that a small subset of ME/CFS patients have an active herpes simplex infection, as did Dr. Montoya at the FDA Drug Development Workshop.

Epstein-Barr Virus and Human Herpesvirus 6?

 Continued elucidation of the mechanisms and components involved in epigenetic regulation of viral pathogens will lead to additional targets for antiviral development

Epstein-Barr Virus (EBV) and Human Herpesvirus 6 (HHV6) are the pathogens most commonly associated with ME/CFS, however. I was unable to determine if the  enzyme targeted by this probe is found in these viruses. The fact that the  herpesvirus family undergoes a process called chromatic assembly and modulation in which the enzyme plays a role  suggests the probe might be effective in other herpesviruses.The fact that the probe worked in both alpha and beta herpesviruses (EBYis a gamma herpesvirus) suggests it may have widespread application but we’ll have to see if it applies to these viruses as well.

Dr. Martin Lerner, a specialist in treating herpesvirus infections in chronic fatigue syndrome has high hope for this approach.

My own research suggest immediate early gene products initiate CFS.  I think this work has great promise in effectively inhibiting many herpesviruses. Dr. Martin Lerner

Even if it doesn’t this discovery provides a new approach to drug treatment  that could be duplicated in other herpesviruses. Indeed these researchers are already looking for other epigenetic targets, one of which is found in Epstein-Barr virus.

This ‘probe’ has still  long way to get to the marketplace. It’s demonstrated its effectiveness in cultured cells and now needs to be assessed in animal models and  humans.

outside the box

This same epigenetic approaches that are effective in cancer are effective with viruses as well.

A New Paradigm for Antiviral Drug Development

There is intensive focus on the development of inhibitors of epigenetic components for the treatment of cancers and other diseases. The study presented here demonstrates that epigenetic inhibitors can also function as antiviral therapeutic agents.

The success of a drug employing a epigenetic approach to infection was big news with the study appearing in the premier scientific journal Science and the authors urging other researchers to pour resources into developing more epigenetic tools to fight infection.

Dr. Peterson Calls for “Therapeutic Strategy” to Develop Drugs for ME/CFS

“We’re Ready”

Dr. Peterson had 2 minutes to get to the point. And he did.

After 30 years of treating approximately 9,000 patients and tired of the ‘therapeutic stagnation’ in this disease, he called on the FDA to ‘execute a therapeutic strategy’ that would pave the way for drug development. No doubt speaking not just to the FDA but to drug company reps listening, he gave them good pragmatic reasons to do so; 1,000,000 sick people in the US, a $9 billion hit to our economy yearly, a market for a diagnostic marker yielding potentially $250 million a year, a drug therapy possibly bringing in billions….PetersonPhoto right

“I implore the esteemed committee to develop a therapeutic strategy for ME/CFS” Dr. Dan Peterson to FDA

Listen to Dr. Peterson at minute 92:00 of this VIDEO.

He didn’t ask the federal government to do it all  on their own. The ME/CFS physician community he asserted is ready to do its part.  They’re already using objective markers such as NK cell functioning, MRI’s, SPECT scans, low VO2 max tests to inform their therapies and they have formed the consortia and networks needed to take on pilot studies and multi-center Phase I, II and III clinical trials.

He was backed up by his longtime colleague, Dr. Nancy Klimas later in the meeting when she said ” much of what is needed to develop drugs for ME/CFS is ‘already in hand’; we have, she said, the ‘clinical trials groups’  who have ‘many, many years of  experience with these…instruments we’ve been talking about’. “There’s really no reason to delay any further”

“There’s  really no reason to delay any further” Dr. Nancy Klimas on targeted clinical trials for ME/CFS at the FDA Stakeholder’s meeting

The key problem is the large heterogeneous population that makes up the ME/CFS community.  Dr. Slagle of the FDA noted that the heterogeneity of the ME/CFS patient population made it necessary for researchers to  define and target specific subsets, but both  Dr. Klimas and Dr. Peterson asserted they’re ready, right now, to bring targeted therapies to bear on just those subsets.

This is all about one thing; scientifically redefining ME/CFS … wherever that takes us … and as long as it leads to treatments.

Scientifically Redefining ME/CFS SR Facebook logo new

Dr. Peterson’s report of Vistide’s success in a retrospective study of severely ill ME/CFS with herpesvirus infections constituted not just an attempt to provide better treatment options but to redefine this illness using biological variables; in this case a subset of patients with active  cytomegalovirus infections who responded to Vistide.

The Chronic Fatigue Initiative’s Hornig/Lipkin pathogen study will, with the addition of Simmaron’s spinal fluid samples, contribute to this process if they illuminate a distinct subset of patients with active viral infections, as suggested by Madie Hornig in Florida.  (Results are due within the next two months.)

Now comes convincing the pharmaceutical industry that it’s worth their while to invest in this disorder, and that’s where Dr. Peterson’s request for a ‘therapeutic strategy’ that will compel pharma to enter the market comes in.  That therapeutic strategy will involve the FDA  identifying endpoints for subpopulations and study designs that industry will have confidence in.Food_and_Drug_Administratio

Is the FDA ready to do that?

We’ll bring you more of the FDA meeting in coming blogs.

Your Brain on Viruses: Study Finds Even Common Viruses Cause Cognitive Declines

The ‘Manhattan Project’

The Northern Manhattan Study is an immense project that’s taking a deep look at health in Northern Manhattan, New York . The project consists of  analyzing basic health characteristics of several  thousand people over time and it’s spinning out studies at a dizzying rate.  The project is not on chronic fatigue syndrome, but because it’s  looking at factors that have shown up in ME/CFS it may shed  some  light on what’s happening there.  In fact it may shed a lot of light.

Manhattan

The ‘Manhattan Project’ is examining health issues in a wide swath of the population. Several findings may have relevance to ME/CFS/FM

For instance, each of the studies below looked at a factor that’s been found (in at least some studies) in ME/CFS and  each of the findings seemed to make sense what we know of ME/CFS.

Increased IL-6 levels were associated with cognitive declines in one study, and increased  soluble tumour necrosis factor receptor 1 (sTNFR1) levels were associated with increased  mortality in another.  Increased levels of daytime sleepiness in the elderly were associated with increased risk of stroke, heart attack and vascular events in another.   Metabolic syndrome was associated with cognitive declines in another. Eating a Mediterranean diet was associated with  reduced ‘white matter hyperintensity volume’ a marker of small blood vessel breakage in the brain and reduced vascular events such as stroke.

Infectious Burden

Neurology. 2013 Mar 26;80(13):1209-15. doi: 10.1212/WNL.0b013e3182896e79.Infectious burden and cognitive function: The Northern Manhattan Study. Katan MMoon YPPaik MCSacco RLWright CBElkind MS.

The most applicable study to ME/CFS, however, is clearly the latest one which determined if infectious disease burden was associated with cognitive declines.  In this study the researchers tested  blood from a broad swath of the population in New York  for antibodies to common bacteria and viruses (three of them herpes viruses) and gave the participants  cognitive tests.  Then they created an index of infectious burden (IB) and determined if more infections meant more problems with cognition…and found they did; the more active infections present, the  worse the cognitive impairment.

Infections

This study suggested that having more infections, active or latent, are associated with reduced cognition.

No ME/CFS studies have attempted to associate pathogen load with cognitive declines but given the increased  rate of infections Dr. Peterson and other immunologically oriented ME/CFS  doctors have found and the documented cognitive impairment in ME/CFS, the finding made sense. Cognitive impairment is  associated with brain issues but the researchers didn’t zero in on the brain; instead they focused on cardiovascular problems which interfered with blood flows to the brain.

It turns out that studies have linked common infectious agents to inflammation, coronary artery disease and stroke and a past ‘Manhattan project’ study found  that high infectious burdens  were associated with an increased risk of stroke and increased carotid plaque buildup.

Many viral pathogens in the herpesviridae family, characterized by latent or persistent infection, were implicated in increased stroke risk.

It appears that chronic infections often play havoc with cardiovascular functioning. Infectious organisms can impact cardiovascular functioning in various ways. They can directly invade the vascular walls. C. pneumoniae and H. pylori DNA was found in aetherosclerotic lesions in 26%  and 37% of cardiac bypass patients in one study.  With regards to pathogens commonly found in ME/CFS, high rates of active HHV6 infection  found in Italian cardiac patients who did not have aetherosclerosis suggested the virus may play a role in heart patients who have idiopathic heart disease.

Cardiovascular Issues

At the 2008 HHV6 Symposium in Baltimore, a German researcher, Dr. Lassner reported that heart biopsies he’d done in German heart patients commonly revealed parvovirus B-19, HHV-6, enterovirus and/or Epstein-Barr Virus infections.  He noted that HHV-6 infection of the blood vessel walls results in the production pro-inflammatory cytokines which can constrict the blood vessels, impair capillary production and reduce heart blood flows. HHV6’s ability to trigger blood vessel wall constriction is intriguing given studies suggesting it may play a key role in ME/CFS.

Blood vessels

Pathogens can affect the cardiovascular system and cardiovascular problems appear to be rife in ME/CFS.

Lassner, interestingly, found antivirals (IVIG-parvovirus, interferon-enterovirus) to be effective in virus infected heart patients, but reported much the same treatment response  pattern found in many ME/CFS patients; improvement while on antivirals followed by relapse when off them.

Infections can also turn on the macrophages which help create the dangerous plaques, they can confuse the immune system into attacking parts of the body and they can help an inflammatory state that is damaging, etc.

These observations, along with the results of this current study lend support to the notion that past or chronic exposure to common infections, perhaps by exacerbating inflammation, may be an important etiologic factor of atherosclerosis.

Simply the presence of active herpesvirus or other infections  can contribute to an inflammatory mileu that can be detrimental.  Katan reported that an inflammatory state could lead to aetherosclerosis, ‘subclinical stroke’ and dementia. Subclinical strokes (ie transient ischemic attacks from which patients recover) primarily effect executive functioning, one of the cognitive processes known to be impaired in ME/CFS.  Changes in mood and  the ability to organize and take on multiple tasks could be a sign of a ‘subclinical stroke‘.  Other symptoms can include feelings of numbness or weakness, double vision, dizziness/vertigo, confusion, inability to speak, loss of balance or coordination.

Cardiovascular issues have been found in ME/CFS and more and more attention is being given to this area. Cardiovascular control is impaired,  reduced cardiac vagal tone is associated with cognitive declines, impaired blood pressure variability,  reduced cerebral blood flows, reductions in stroke volume and cardiac output (all this in the past year and a half)  provide ample evidence of impaired cardiovascular functioning in this disorder.  Interestingly autonomic nervous system issues similar to those found in ME/CFS were correlated with cognitive declines in fibromyalgia.

All in all the finding of decreased cognitive functioning with increased infectious burden in the  Northern Manhattan Study findings may not be surprising for many people with ME/CFS. At the most recent HHV6 Conference in Paris Dr. Peterson reported on several ME/CFS patients who’s cognitive abilities rebounded remarkably following Vistide infusions for herpesvirus infections and Dr. Lerner has reported similar results in his herpesvirus infected patients.

Conclusions

The latest Manhattan project study should be helpful in highlighting not only the cognitive declines but the cardiovascular risks that are associated with common or  chronic latent or active infections. Since active infections are part and parcel of ME/CFS, this study’s important association of decreased cognitive function with increased infectious burden suggests that measuring both those factors in ME/CFS should be routine, and may offer objective measurements of treatment efficacy.

Report From Paris: Peterson Reports Antiviral (Vistide) Effective in Treating Herpesvirus Infected Chronic Fatigue Syndrome (ME/CFS) Patients

PetersonPhoto right

“These results show objective endpoints, subset selection, and recovery. There were complete responders and partial responders among severely ill CFS patients with HHV6 or CMV. These are encouraging results for this subset and further well-designed trials should be pursued to confirm them.” Dr. Dan Peterson

At the HHV6 Conference in Paris, France today Dr. Peterson reported on the results of a retrospective study following 65 severely ill chronic fatigue syndrome patients given a course of Vistide from 2005-2012 for HHV6 and/or HCMV infections.  Despite the interest in pathogens in ME/CFS, antiviral studies are rare and this is the first one reported for this drug.

Virus from vistide presentation


Dr. Peterson has three decades of experience treating immunologically challenged ME/CFS patients.

Vistide (Cidofovir) gets a lot less press than other antivirals and immunomodulators (Ampligen, Rituximab, Valcyte,  Valtrex) used in this disorder  probably because the drug requires a  complex infusion protocol,  frequent blood tests because of the rare but real possibility of  serious kidney side effects and is expensive  (although it can be covered by insurance).

This combination – infusions, frequent blood tests and expense – requires close physician follow-up. With Dr. Peterson’s specialized focus on patients with dysfunctional natural killer cells, however, he may be most consistent about testing for herpesviruses, which are known to be active in ME/CFS patients.

After three decades of focusing on immunologically challenged ME/CFS patients, Peterson may be more experienced at pathogen detection and treatment than any other practitioner in the field, and so it’s not surprising to find the first Vistide study coming from his office.  In an interview, a former patient of his said, ‘he leaves no stones unturned’; when he finds something he goes after it ‘aggressively’.

In his presentation he stated  almost 30% of  his patients test positive for  active HHV-6 or human cytomegalovirus (HCMV) (PCR, rapid culture, antigenemia), and a whopping 50% test positive for active Epstein-Barr virus (EBNA) infection.

Serious Drug For A Serious Illness

Vistide (Cidofovir) is  FDA approved for the treatment of cytomegalovirus (CMV) in patients with AIDS. (Cytomegalovirus is a member of the herpesvirus family.) and it’s been used off-label to treat  human papillomavirus, BHK virus, herpes simplex virus, vaccinia virus infections. The Black Box warning on Vistide speaks for itself

 ‘Cases of acute renal failure resulting in dialysis and/or contributing to death have occurred with  few as one or two doses of Vistide. The “recommended dose, rate, frequency of Vistide injections must not be exceeded.”

The Study

A positive response was denoted by a negative pathogen test, improved fatigue and cognitive functioning determined by an interview with Dr. Peterson and  the patient’s self reports after the trial.

Response

  • Full Responders – Patients were deemed to be full responders if they were able to completely return to work or to work-related activities
  • Partial Responders – demonstrated significant improvement of symptoms but were unable to return to work or work related activities.
  • Non-Responders – Did not demonstrate any measurable improvement post-treatment

Results

Seventy percent patients improved

Seventy percent of ME/CFS patients with HHV6 and/or HCMV infections improved significantly on Vistide

Dr. Peterson reported that seventy percent of patients were full  (able to return to work) or partial (significant increase in functionality) responders; a very high rate of success in a illness characterized by a poor response to treatments.  Only thirty percent of Vistide recipients did not have a significantly positive response to the drug. No serious side effects were seen; ironically the minor side effects seen were attributed to a drug, Probocenid, used to ensure Vistide was safe.

It’s not clear what percentage of ME/CFS patients will test positive for HHV6 or cytomegalovirus in other practices but this type of response suggests the drug may be  being under-used. With the FDA Stakeholder’s meeting  coming up in three weeks and the Chronic Fatigue Initiative’s pathogen discovery study results due to be published later this year, Dr. Peterson’s presentation is timely. (Unfortunately, Dr. Peterson was not invited to present at the FDA Stakeholder’s Meeting.)

Dr. Peterson called for placebo-controlled, double-blinded multi-center studies that address Vistide’s efficacy, examine its effects on the immune system and study the mechanisms of increase in VO2 max scores in ME/CFS.

Sample Cases

Dr. Peterson reported on several cases, all of whom were men – something Dr. Peterson has said he likes to do to break up the notion that only women get this disorder.

  • A 27 year old college graduate  unable to work because of  constant flu-like symptoms, weakness and marked cognitive decline (math!) presented with low NK functioning, low VO2 max and HHV6 and cytomegalovirus infection. He was able to return to work after 24 weeks of bi-weekly infusions. His VO2 max on the exercise test went up went up 23%,  his NK cells a remarkable 400% and he tested negative for both viruses at the end of treatment. He had had ME/CFS for three years.
  • A 54 year-old former high school teacher unable to work due to extreme fatigue, flu-like symptoms and cognitive problems severe enough to keep him from being able to grade his students papers presented with active HHV6 and cytomegalovirus infections and low NK cell functioning and VO2 max. He was able to return to work after 24 weeks of bi-weekly infusions. His VO2 max increased 47%, his NK function test went up 20% and he tested negative for both viruses. He had had ME/CFS for five years.
  • The third patient had classic, acute onset ME/CFS which progressed to seizures. Both serum and cerebral spinal fluid tested positive for HHV6. At the end of the Cifodovir trial the  viral load in his cerebral spinal fluid dropped from 3670 copies/ml to undetectable levels. Serum HHV6 was dramatically reduced (47,000 copies/ml to 3,000 copies/ml). Still symptomatic and experiencing cognitive problems, he was nonetheless able to return to work.

Conclusions

The retrospective study indicated Vistide (cifodovir) can have dramatic effects on functional capacity in HHV6 and/or HCMV infected ME/CFS patients.

Increasing VO2 max appeared to be critical to increasing functionality as the partial responders did not increase their VO2 max while on Cifodovir. At the FDA Advisory Meeting for Ampligen Dr. Bateman noted that VO2 max test results probably were, given the exertional problems in ME/CFS, the most difficult to ‘move’ test result in this disorder.

VO2 max levels in Dr. Peterson’s patients prior to Vistide administration were exceedingly low; they appeared to in the ‘very low’ range even for people for 65 years of age and older. Vistide moved those test results about 20% on average; leaving them still, it appeared, below normal but sufficient enough for a significant increase in functionality.

A Vistide Example

Vistide_CFSThe VO2 max tests suggested most patients had not returned to full health and Dr. Peterson has said he knows of few complete recoveries. I interviewed a former patient of Dr. Peterson’s several years ago. Faced with the loss of his career and the ability to care financially for his family Vistide turned out to be a godsend.

Cut down by acute onset ME/CFS, his VO2 max score topped out at an unbelievably low 15 (which qualified him for heart disease) and he was a ‘2’ out of 10 on his own energy scale (had trouble sitting up to eat).  Within a month on Vistide he was at a ‘4’; the next month he was a ‘5’ and sleeping soundly for the first time since he’d gotten sick. The next month he was a ‘7’ and his VO2 max tests had doubled to 28; still far below the 44 expected at his age, but an amazing increase, never the less.  Three months later he was at ‘90%’, back at work and able to do everything except exercise.

CMX001 – The Future Vistide? 

Dr. Peterson didn’t report on CMX001 in Paris, but sitting in the background of all this is a analogue of Vistide called CMX001 which appears to be a safer and more effective,  if not yet available, version of it. A  2012 review named CMX001 as one the ‘ten hot topics’ in antiviral research.

Chimerix Pharmaceuticals modified Vistide so that it can easily be taken up into the  tissues. That means no need for infusions, no worries about kidney problem and according to Chimerix, dramatically increased effectiveness.

CMX001 has been in development for  some time but just this March the FDA awarded the drug ‘fast track’ status for the prevention of cytomegalovirus infection.  Phase II trials are finished  and Phase III trials will get underway this year.

Given Dr. Peterson’s success with Vistide, FDA approval of CMX001 could be very good news for ME/CFS patients with HHV6, HCMV and/or possibly EBV infections.

Wrap Up

In a retrospective study Vistide proved to be  effective  in treating severely ill ME/CFS patients with HHV6 and HCMV infections. Dr. Peterson called for double-blinded, placebo-controlled studies to further study Vistide’s efficacy and mechanism of effect.  The CFI’s pathogen discovery studies due out this year should shed light on what percentage of ME/CFS patients could benefit from Vistide.

A Vistide analogue under development called CMX001 which does not require infusions and does not effect the kidneys could be boon for ME/CFS patients with herpesvirus infections if it is approved by the FDA. CMX001 was given fast-track status by the FDA earlier this year.

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Simmaron Research Mobilizes Unique Assets to Push ME/CFS Field Forward: A Look Back at the First Year

April 4, 2013

We envision a world where ME/CFS is treatable and well-understood. To get there, we are scientifically redefining ME/CFS.

Simmaron focuses on chronic fatigue syndrome research

Simmaron has moved quickly in the past year and half and is involved in a variety of potentially groundbreaking studies.

The latest addition to the ME/CFS Research Foundation scene, the Simmaron Research Foundation started off small. There were no huge endowments, no connections to major academic centers; in fact, Simmaron was located in little Incline Village off of Lake Tahoe, a locale rich in chronic fatigue syndrome (ME/CFS) history but definitely not known for its medical resources.

What Simmaron did have was Dr. Daniel Peterson, a practitioner whose deep experience and extensive biobank is unparalleled in ME/CFS. Since the early days of the Incline outbreak in the early 1980’s Dr. Peterson has been immersed in chronic fatigue syndrome.  Now with the Simmaron Foundation’s support he had the opportunity to put his experience and samples to the test. It turned out that the ME/CFS research community was very interested in what he had to offer.

After just a year and a half, the Simmaron Foundation is making its mark.With studies underway that will help to redefine ME/CFS and how it gets researched and treated, Simmaron has quickly become perched on the front lines of ME/CFS research.

A Vital Resource – Finally Hitting Stride

Dr. Peterson quickly knew something had gone very wrong with the sick patients crowding his  door in Incline Village in the 1980’s, and early on  he began collecting samples for the studies he felt had to come.  It took decades but that time has come, and given the technology and the quality of the researchers  he and Simmaron Foundation are working with now, it was probably worth the wait.

Chronic Fatigue Initiative Pathogen Study

Simmaron Research provided 40  patient and 40 control samples to the biggest, most  rigorous and comprehensive ME/CFS pathogen study ever –  the Chronic Fatigue Initiative’s Pathogen Discovery project. Lead by Dr. Mady Hornig and Dr. Ian Lipkin, this project will set the stage for pathogen research in this disorder for years to come.

Simmaron’s eighty samples will join samples from four other ME/CFS clinics in a search that will:

  1. screen for 18 viruses, bacteria or protozoa  already associated with ME/CFS. If that hunt proves unsuccessful they will
  2. sequence everything in the blood to look for known and unknown viruses
  3. then develop tests for any new pathogens they find as well as
  4. look for unique protein signatures and
  5. analyze 50 markers of immune activation/inflammation/oxidative stress

The well-characterized, rigorously documented samples Simmaron is providing will play a key role in this study.  Of all the clinics in this project, Dr. Peterson’s stands out in its focus on immunologically challenged patients.  If the Lipkin/Hornig team finds pathogens, they will likely show up in the Simmaron samples.

The results from these studies are coming in and  by the end of this year we’ll finally have some answers to one of the biggest questions facing ME/CFS researchers and patients for over twenty years – what role pathogens play in this disorder.

ME/CFS Cerebral Spinal Fluid Samples – Meet Top Pathogen Experts in the World

The large pathogen discovery study funded by the Chronic Fatigue Initiative will dramatically increase our knowledge of the role pathogens play in ME/CFS but, for all the tissues it was studying (tears, saliva, blood and fecal samples), it was missing an important one – perhaps the major one – until Simmaron stepped in.

Cerebral spinal fluid circulates around the brain stem and the outside margin of the brain. When it’s collected, down near the tailbone, it bears traces of its path through the brain. If pathogens, unusual proteins or inflammatory markers are present in the brains, as so many believe,  the CSF is the best way, short of an autopsy or biopsy, to find them. CSF fluid analysis is used to assist with diagnosis in a number of neurological disorders.

Watch Cerebral Spinal Fluid Circulate Around the Brain

The Director of the HHV6 Foundation, Kristin Loomis, considers the Simmaron spinal fluid samples critical to the CFI project’s success because many of the viruses suspected in chronic fatigue syndrome simply don’t show up in the blood, the saliva, etc.  She noted that several theories suggest the pathogens present (HHV6, EBV, enteroviruses) have assumed unusual forms that make them difficult to trace in the blood.

It wasn’t just the size of Simmaron’s spinal fluid contribution – 60 of these difficult to collect spinal fluid samples – something Dr. Mady Hornig called ‘unparalleled’ – but who they’re from that makes them so special. Dr.  Peterson doesn’t routinely do spinal fluid tests; these samples are from patients -often the illest of the ill – he suspected had neuro-inflammatory problems and his superb diagnostic skills means the CFI can have confidence in what kind of patients they’re looking and that’s unusual in ME/CFS research.

This study is not just about pathogens; the Center for Infection and Immunity will be looking cytokines and other biomarkers that could tell us more about the health of ME/CFS patients’ brains. Recent successes documenting  unusual proteins in ME/CFS patients cerebral spinal fluid suggest  the spinal fluid may indeed be the place to look.

Dr. Hornig, the leader of the CFI’s pathogen discovery effort, called the Simmaron spinal fluid samples ‘a really unique opportunity’. It’s no surprise Simmaron made funding this study a top priority.

ME/CFS Cerebral Spinal Fluid Samples –  Meet the Top Natural Killer Cell Experts

natural killer cells

The extensive immune analysis given to Simarron’s spinal fluid samples will provide insights into the immune status of the brain in ME/CFS

We journey halfway across the world down to the Southeast coast of Australia for Simmaron’s next spinal fluid study where the ME/CFS research group led by Sonya Marshall-Gradisnik, PhD, now centered at Griffith University, will be digging deep into the immune profile of the same samples CFI researchers are analyzing for pathogens.

Griffith is now ground zero for  natural killer cell research in ME/CFS.  Griffith researchers recently contributed a chapter on natural killer cell dysfunction in ME/CFS and at the Ottawa conference they  documented the NK cell dysfunction present in ME/CFS,  identified miRNA’s contributing to the NK cell  dysfunction, documented the same dysfunction in T-cells, and identified cytokine abnormalities in the blood. Now they’ll look for these abnormalities in Simmaron’s spinal fluid.

These two studies put the Simmaron Foundation’s spinal fluid samples at the heart of a  double-barreled research effort.  CFI researchers will  determine whether pathogens/markers they’ve found in the blood, saliva, etc. are also in the spinal fluid, while Griffith researchers will determine whether their immune abnormalities show up in the  spinal fluid.  At the end of this process not only will we know a lot more about the brain in ME/CFS, we’ll know much more about where to look for the biomarkers this disorder needs so badly to move forward.

A Multi-Site Clinical Assessment of ME/CFS

CDC multi-site CFS study

Dr. Peterson’s unique focus on immunologically challenged patients will pay dividends in the CDC multi-site definition study.

How to define properly  Chronic Fatigue Syndrome is another issue that’s plagued the field for decades. Perhaps no issue is more important to the field. Inadvertently involving different types of patients, for instance, in research studies could explain the inconsistent research and treatment trial results that have stifled interest in this disease for decades. Drug companies are reluctant to enter into treatment trials for an  illness they don’t feel has a real definition.  The list of negative effects from having a vague definition goes on and on.

With their participation in the Center For Disease Control’s Multi-Site Assessment study, however, the Simmaron Foundation and Dr. Peterson’s Sierra Internal Medicine, will be helping to provide answers to this perplexing and important question.

In this study led by the Open Medicine Institute, Simmaron joins seven other clinical sites to provide electronic data on diagnostic procedures, test results, treatments and outcomes on over 800 patients to the CDC for analysis. The project will, for the first time, produce statistically based analyses of the different subsets ME/CFS practitioners are likely seeing and will bring  the practices and insights of ME/CFS professionals to the fore in scientific publications for the first time.

Once again, Dr. Peterson’s unique focus on immunologically dysfunctional patients will play a vital role in highlighting this significant subset of patients. Promising first results have lead the CDC to refund and expand the project to include more physiological measures.

Charting Long term (gulp) ME/CFS Prognosis

Few studies have looked at a vital subject for most ME/CFS patients; what they can expect in the future.  Is ME/CFS progressive and, if it is, what does it progress to? Some researchers believe ME/CFS may progress to range of other disorders and a recent study found significant fatigue predated the development of multiple sclerosis in many patients. This study will catch up with patients seen at least 10 years ago in Dr. Peterson’s practice and see how they are doing.  The results could profoundly effect our understanding of ME/CFS and will provide physicians important clues how to best manage it.

Post-Infectious Cardiomyopathy Study

Simmaron’s identification of  four  patients in its surrounding community with mysterious  heart problems (cardiomyopathy) provides a new opportunity learn more about the possible role of infection in this heart condition.

Simmaron has recruited the Centers for Infection and Immunity at Columbia University to dig into these patients serum, plasma and other biological samples to see if they can figure why they developed this unusual form of heart disease.  Possible infections will be given a particularly close look.

This study should be published this year.

Conclusion

Dr. Peterson’s years of experience and his extensive data bank have brought new opportunities for Simmaron and for the ME/CFS research field. With collaborative efforts ranging from New York to Atlanta to Australia, the Simmaron Foundation, located in little Incline Village, has developed world-wide connections and is engaged in studies that could redefine ME/CFS, provide vital insights into its longterm prognosis and its neuroinflammatory nature.  Simmaron has been indeed been rising.

 

Infection, Autoimmunity and PANDA’s: Dr. Hornig on Chronic Fatigue Syndrome at Dr. Klimas’ NSU Conference

Quite the Resume

Dr Mady Hornig comes with quite a resume. She and Dr. Ian Lipkin MD direct the Center for Infection and Immunity at Columbia University in New York, and Dr. Hornig is directing the Pathogen Discovery and Pathogenesis Program at the Chronic Fatigue Initiative (CFI).

The Hornig/Lipkin lab at Columbia University is involved in numerous ME/CFS studies

The Hornig/Lipkin lab at Columbia University is involved in numerous ME/CFS studies

An MD and immunologist with a background in neuropsychiatry, Dr. Hornig’s been focused throughout her career on uncovering immune dysfunctions associated with mood and developmental disorders such as autism, PANDA’s, ADHD and schizophrenia. Her current work on the MIND (Microbiology and Immunology of Neuropsychiatric Disorders) Project constitutes the largest examination yet of the role the immune system and viruses play in mood disorders and schizophrenia. She’s currently a lead investigator for  the Autism Birth Cohort study determining how development, genes and environmental factors combine to produce autism.

Dr. Hornig has quickly become a major chronic fatigue syndrome investigator and said she and Dr. Ian Lipkin were using all the tools available to them including gene expression studies, immune and stress markers and proteomics using mass spectroscopy.Check out the ME/CFS studies her lab is or has been involved in….

Chronic Fatigue Syndrome Studies at Dr. Hornig’s Laboratory

  • 200/200 Cases and controls with Chronic Fatigue Initiative  – 18 pathogens identified, then unbiased high throughput sequencing – pretty much tell us anything that is in there
  • 150/150 cases/controls in XMRV study
  • 400/400 cases/controls in huge Montoya Stanford study
  • 60 cases/60 controls Simmaron Spinal Fluid Study

Dr. Hornig focused in on the Simmaron Institute spinal fluid study calling it ‘really intriguing’, calling the number of well-characterized spinal fluid samples  ‘unparalleled’, and stating the study was a ‘unique opportunity’.

We’ll get another chance to see her at the 2013 Invest In ME Conference in May.

The Talk – Infection, Autoimmunity and Illnesses

Placing chronic fatigue syndrome into the category of ‘neuropsychiatric disorders’ (disorders that effect cognition and mood among other things) Dr Hornig started off her talk demonstrating how attacks of insanity seem to have swept over populations, not suggesting that she’s studying a group of insane people, but demonstrating how infections can generate symptoms we don’t generally associate with them.

Mom???

Dr. Hornig believes three factors, timing – a window of opportunity,  a genetic predisposition, and an environmental insult probably come  together to cause chronic fatigue syndrome.  That window of vulnerability could have occurred at any time but Dr. Hornig zeroed in on pregnancy:  a time, it appears, when many chronic disorders are  set into motion.

Mom? The roots of some chronic illnesses appear as far back as pregnancy

Mom? The roots of some chronic illnesses appear as far back as pregnancy

She suggested, but did not say, that chronic fatigue syndrome could be triggered as early as pregnancy and then not show up for 20 or  40 or 50 years until  another window of vulnerability opens up – perhaps during a stressful period, another infection, toxic overexposure. (She noted that the stress response is similar in all these cases).   Indeed, that model of disease, she said,  could apply to outbreaks of autism and ADHD in early life, multiple sclerosis, schizophrenia and ME/CFS in middle life and Parkinson’s and Alzheimer’s disease in later life.

Cannabis triggered schizophrenia during adolescence is an example of the three factors combining in a perfect storm to cause a devastating  disease.  It turns out that bringing together one form of a COMT gene (the COMT gene, oddly enough is implicated in ME/CFS), the tumultuous physiological time of  adolescence, and an environmental factor (cannabis) you get an increased risk of (gulp) schizophrenia.  Basically smoking pot when you’re an adolescent increases your risk of  schizophrenia (it happened to one of the my best friends) but smoking it when you’re an adult – even if you have this particular form of this gene- doesn’t increase your risk at all.

She described an incredible and rather frightening study in which researchers examined pro-inflammatory cytokine levels (IL-6 and IL-1b) in the blood of mothers collected 40-50 years ago. Skipping  forward they found that women whose mothers had high cytokine levels during pregnancy  tended to be depressed and have reduced  brain activation in middle age. This suggested those high levels of pro-inflammatory cytokines changed the circuitry of female fetus’s brain enough to make those women more vulnerable to depression later on.  She noted that some of the same stress-circuitry showing up  in those women is implicated in ME/CFS as well.

The Immune Side of Neuopsychiatric Disorders

Hornig is an immunologist and she  explained that many ‘neuropsychiatric disorders’ may be explained by immune problems; the list  she presented was not a particularly pretty on; besides fibromyalgia and ME/CFS it included Tourette’s syndrome, autism, obsessive compulsive syndrome, ADHD, anorexia nervosa, narcolepsy, major depressive disorder, bipolor disorder and schizophrenia (and probably should have included irritable bowel syndrome, interstitial cystitis and other disorders that co-occur with ME/CFS. ).

There are several  groups in here; the heavy psychiatric disorders – depression, bi-polar disorder, compulsive obssessive disorder and schizophrenia; the CFS-like disorders (ME/CFS, FM….IBS, IC, etc.) and then autism and ADHD.

The Infection Autoimmune Connection

The infection/autoimmune connection is a strong one with many autoimmune disorders showing up shortly after infections…but..(there’s always a but :))  she noted that other autoimmune disorders  can take years to show up making it difficult to determine the trigger.  If it was a pathogen, it could’ve  and may very well have done it’s damage and then disappeared, leaving a chronically disrupted immune system in its wake.

PANDAS – A Possible  Model for ME/CFS

“Several studies suggest autoimmunity may play a role…”

PANDA's - a childhood disorder associated with Streptooccus infection could be a model for ME/CFS

PANDA’s – a childhood disorder associated with Streptooccus infection could be a model for ME/CFS

Hornig  then described an infection triggered neuropsychiatric disorder called PANDAS that could be a model for ME/CFS.  Children with PANDAS don’t eat eucalyptus leaves for lunch, but they do display dramatic changes in behavior including obsessive-compulsive behavior, tics, mood swings and anxiety soon after a staphyloccus infection. They also display the kind  of ‘ vigilance’ and arousal that shows up in some people with chronic fatigue syndrome.

Hornig has become deeply involved in PANDAS. Much is controversial about PANDAS but it’s believed to be an autoimmune disorder that targets the basal ganglia in the brain (which is, yes, also under consideration in ME/CFS…). Working with Dr. Lipkin, Dr. Hornig found that mice injected with strep   engage in obsessive compulsive behaviors (they flip themselves over backwards again and again) and that simply injecting  antibodies to streptococcus  into mice caused problems with learning and memory, coordination, and social interactions.  Then, in a nice Koch-like test, they found that  removing the antibodies from the mice  resulted in the return of  normal behavior.

General Stress Response Affected

That made it pretty clear  it’s the antibodies; eg. the immune response that’s the problem and what they found next confirmed that; they found that the antibodies to strep mistakenly cross-react (ie  target  for destruction) two important parts of  the  immune system; C4 complement and heat shock proteins.

Why would we, with ME/CFS, be interested in these factors?  Because both  appear, Dr. Hornig said, to be general responses to infections and stressors of all sorts, with all its different triggers, chronic fatigue syndrome could be associated with a basic derangement of the stress response (to  infection, trauma, etc.).

Dr. Hornig didn’t mention it both C4 and heat shock proteins  have (yes, yes, yes :)) been implicated in chronic fatigue syndrome at one time or the other

Dr Hornig noted that children with  PANDAS can respond to IVIG, antibiotics and other immune agents.  That’s a bit controversial (no surprise there) with  the American Heart Association (AHA)  recommending that strep not be tested for in children with PANDAS or that they attempt IVIG  treatment despite the fact that one preliminary  study has found IVIG effective.

It’s more of the old, we need more studies before we do or recommend anything without providing the money to do them leaving potential helpful treatments on the shelf while patients suffer (sound familiar?). (PANDAS is way down on the NIH’s priority list.

Key Partners – The Stress Hormone-Immune System Interactions

Hornig noted the immune- stress response connection with PANDAS and now she enlarged on it. Proper central nervous system functioning is dependent on having  balanced immune and stress responses; throw those responses in just one part of the system-  tryptophan degredation – into disarray can cause you to not be able to lay down a memory. Tryptophan is a possible candidate with ME/CFS but she was most interested in the biggest bundle of nerves outside the brain – the enteric nervous system or gut….

Getting Down With The Gut

Hornig then directed us out of the brain and downwards into the gut.  On a very, very basic level this makes sense since  everything  that our bodies run on (except for the gases) comes from our food which means we better be able to digest it well. Stopping the flow of anti-oxidants  (selenium, cysteine, glutathione) from our food out of the gut into our body, for instance, results in increased levels of oxidative stress,  pro-inflammatory cytokines and auto-antibodies  (autoimmune reactions).

Get increased auto-antibodies and you can have problems showing up in literally any part of the body. Just to get our attention, Dr. Hornig noted that an  autoantibody attack of folate receptors could show up in problems with  metabolism,  methylation and B-12.

Then she shifted upwards – back to the brain.  So far our dysfunctional gut has left us with low levels of anti-oxidants, high levels of pro-inflammatory cytokines,  and high levels of autoantibodies in our blood.  Send all that stuff up to the precious (and fragile) blood-brain barrier  protecting our brain and….you have the possibility of a rip exposing the brain to all sorts of bad actors. Depending on which part of your brain gets attacked there goes your  sex drive, appetite, motivation, energy levels, etc….and to think it all could have started with bad flora in your gut.

More Floral Than Viral?

Lest we think this is some researcher’s fantasy, Hornig described her work with autistic kids.  Hornig’s group did not find evidence of measles in autistic children but they did find levels of digestive enzymes so low to be almost non-existent. The autistic kids couldn’t break down milk products because they were lacking the enzyme for that but that hardly mattered as their guts were so deficient they couldn’t have gotten the milk protein into their bodies even they could have broken it down.

Not only was their gut flora massively different but they also they harbored a rare bacteria called Sutterella not present at all in the healthy controls.  Sutterella was not just present,  it was flourishing, accounting for up to  7% of all gut bacteria. Usually a very minor component of the gut microbiome, Suttarella was the third most common bacteria found in these kids.  That really raised some eyebrows.

Could ME/CFS be More Floral than Viral? An upcoming CAA study should be revealing. These bacteria were cultured from yogurt

Could ME/CFS be More Floral than Viral? An upcoming CAA study should be revealing. These bacteria were cultured from yogurt

Still, it’s not clear if Sutterella itself is whacking the kids or if its crowding out good gut flora or if its doing nothing but  we do know that Sutterella thrives in low oxygen  environments and has been linked to inflammatory bowel disorder, Crohn’s disease and ulcerative colitis. (It  can also, though, sometimes be found in healthy individuals.) Hornig’s ability to find an antibody to Sutterella in about 50% of the children indicated they had mounted an immune response to it.

Bacterial imbalances in the gut have been observed in gut disorders such as irritable bowel syndrome (IBS) and inflammatory bowel disease but its become clear that  bad gut bacteria could wreak havoc far outside the gut. The first non-gut disorder associated with bad bacteria appears to have been arthritis.  (Check out a horrifying and fascinating New York Times story of  young child’s battle with rheumatoid arthritis.)  Cesareans appear to  put children at increased risk for asthma because they prevent children from picking up important gut bacteria as they pass they through the birth canal.   Bacterial imbalances in the gut appear to be associated with increased obesity in people with  type two  diabetes .

Researchers have identified three main types of gut composition in humans and they know that diet can influence gut flora. They know that  cutting out sweets and processed foods and using prebiotics and probiotics can help some people reduce or eliminate  inflammation.  Fecal transplants may actually be more effective because they contain more of the bacteria that’s actually populating our guts.

Hornig noted how  important the small intestine is for so many different type of phenomena – for cognition, anxiety and even for sleep. Did you know that if you’re not getting peristalsis (small gut movements pushing the food along)  during the night then you’re missing some sleep enhancing molecules.

Major Chronic Fatigue Syndrome Gut Study Out This Year

The Shukla CFIDS Association gut metagenome study is looking more exciting all the time. This study, which study started several years ago and should be published soon, sought to characterize the entire  gut microbriome before and after exercise in people with ME/CFS.

By studying the gastrointestinal microbiome, Shukla’s work will determine if the ratio of normal to pathogenic (illness-causing) bacteria is off-kilter in CFS patients and if exercise causes harmful bacteria to travel into the body from the gut, creating the postexertional symptoms that are such a prominent feature of the illness. The results have the potential to yield microbial biomarkers for CFS as well as targeted treatments aimed at rebalancing the ratio of bacteria. From CFIDS Chronicle Winter 2009

  • Xafaxan: Gut Rebalancer Extraordinaire –  Suffering from gut issues? Check out a new page Health Rising has on Xafaxan, a gut antibiotic used to snuff out small intestine bacterial overgrowth (SIBO) problems. One person with ME/CFS ended six years of gut turmoil with one short course of Xafaxan…

 Q & A Period

Is Chronic Fatigue Syndrome Infectious?

She thought perhaps, but if so probably mostly during the initial stage of the illness, and that it was highly unlikely it was  infectious in later stages of the illness.  Hornig is following the same model as Klimas in her research; she’s  looking for an infectious agent but finding  immune and stress response factors indicative of a pathogenic attack (at some point) is a major focus.

With a kind of immune system hypervigilance twist she stated its possible an initial infection sensitized the system so that further infections, even very mild ones, might be  throwing it  into a tizzy.   If ME/CFS patients have a problem with infection in general; that is, if any infection has the potential to trigger a kind of overwrought immune response, then she felt it was more important the source of that than to look for a specific virus.  With all the known infectious triggers for ME/CFS she believes some genetic susceptibility/immune issue was present.

One reason for Hornig’s interest in ME/CFS may be due to her work in autism. Hornig believes innate immune system problems during maternity may play a role in the development of autism, and the innate immune system  – the early immune response system involving NK cells, dendritic cells and others – is getting more and more attention in ME/CFS.  Interestingly, Hornig found that infection induced inhibition of the same Toll-like receptors (TLR3) Ampligen effects lead problems with sensorimotor gating responses as adult.  Check out this blog for a treatment of sensory gating issues in chronic fatigue syndrome.

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Clin Invest Med. 2008 Dec 1;31(6):E319-27. Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndromepatients and matched healthy controls. Thambirajah AASleigh KStiver HGChow AW.

J Intern Med. 2009 Aug;266(2):196-206. doi: 10.1111/j.1365-2796.2009.02079.x. Epub 2009 May 19.Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses. Jammes YSteinberg JGDelliaux SBrégeon F.

Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins. Jammes Y, Steinberg JG, Delliaux S. J Intern Med. 2012 Jul;272(1):74-84. doi: 10.1111/j.1365-2796.2011.02488.x. Epub 2012 Jan 4.

Mol Psychiatry. 2010 Jul;15(7):712-26. doi: 10.1038/mp.2009.77. Epub 2009 Aug 11. Passive transfer of streptococcus-induced antibodies reproduces behavioral disturbances in a mouse model of pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection. Yaddanapudi K, Hornig M, Serge R, De Miranda J, Baghban A, Villar G, Lipkin WI.

J Allergy Clin Immunol. 2003 Aug;112(2):397-403. Complement activation in a model of chronic fatigue syndrome. Sorensen B, Streib JE, Strand M, Make B, Giclas PC, Fleshner M, Jones JF.

Mol Med. 2009 Jan-Feb;15(1-2):34-42. doi: 10.2119/molmed.2008.00098. Epub 2008 Nov 10. Transcriptional control of complement activation in an exercise model of chronic fatigue syndrome. Sorensen B, Jones JF, Vernon SD, Rajeevan MS.