All posts tagged Klimas

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.

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.

Great Start – Big Plans Ahead: Dr. Klimas at her NSU Coming Out Party

Dr. Klimas has big plans for her new Institute on Neuroimmune Research at NSU

Dr. Klimas has big plans for the new Institute on Neuroimmune Research at NSU

A Coming Out Party

The coming out party for Dr. Klimas Institute for Neuroimmune Research at Nova Southeastern University (NSU) on January 26th was a year in the making.   In 2011 NSU had made her an offer she couldn’t refuse –  the opportunity to break down what she called the  silo’s that separated researchers, clinicians and educators  – and in  Dec 2011 she announced, after decades or work at the University of Miami, she was leaving to  create a new Institute at NSU.

In the Institute’s first public event, a  Patient Conference,  she brought together members of the Institute to talk about it. After the Dean’s short introduction, Dr. Klimas  gave the first presentation.

The Big Plan : Finding Effective Therapies

 (Warning…I frequently take riff’s on  the presentations (see Waziry and EBV below) ; if something in these blogs turns out to be incorrect, it’s probably due to  my riff :))

Dr. Klimas’  presentation was titled a BIG PLAN and it’s a plan  that is  focused towards one goal…”Finding Effective Therapies”. Dr. Klimas’ effort is fundamentally oriented towards finding effective therapies and we’ll see how that’s going to work in a later presentation.

The mission statement pointed out just what kind of disorder Dr. Klimas believes chronic fatigue syndrome is…a “neuro-inflammatory” disorder; a nervous system disorder involving inflammation; ie  immune activation.

Dr. Klimas emphasized that the reason she came to NSU was to create an integrated program that has the  clinicians, researchers and educators  all working together in a tightly knit group.  Each person, she said is  engaged in all of it; the doctors are talking with the researchers who are informing the educators.  In fact the way the building is structured they have to communicate; everyone eats and meets in the same central meeting/ conference room.

The Institute focuses on two groups, people with chronic fatigue syndrome and people with Gulf War Illness (GWI)

Gulf War Illness (GWI)

Introducing Gulf War Illness Dr. Klimas stated the  remarkable fact that fully 1/4 of the Gulf War Vets (that’s 200,000 people and some estimates are higher)  returned with a chronic, often disabling multisystem illness ….(sounds like ME/CFS?)…that looks like ME/CFS but is biologically very  different.  What happened? It appears that a  toxic cloud of elements from gas fires, pesticides, vaccines, uranium etc.  with the major contributor probably being something we’ve all been exposed to at times;  pesticides.

  • Dig Deeper: Check out a  recent fascinating New York Times article  suggesting that contaminated dust and  Sarin, a close cousin of organophosphate pesticides, were  key factors in GWI.

That toxic insult is probably long, long gone but that initial insult  appears to have reset many GW participants systems permanently and Dr. Klimas is trying to figure out how to reset  the reset button.

Chronic Fatigue Syndrome (ME/CFS)

Dr. Klimas’s test results suggest an insult is still present in ME/CFS. (More on that later). Calling it a terrible illness Dr. Klimas noted that 1/4 or more of people with ME/CFS are fully disabled and many more are partially disabled and that the disease with the funny name is as debilitating  as heart disease, end stage kidney disease, AIDS (AIDS !!!) and MS.

She laughed at one idea she  come across at times; that people with ME/CFS  want to be on disability and the poverty level income that provides them instead of having access to their income they enjoyed previously; yes, she laughed , what a great tradeoff that would be.

The People

Dr Waziry will focus on determining what pathogens are doing to the cells of people with chronic fatigue syndrome

Dr Waziry will focus on determining what pathogens are doing to the cells of people with chronic fatigue syndrome

Thus  far the Institute has on board researchers specializing in  gene expression (Nathanson),  viral effects (Waziry), clinical research (Dr. Klimas) and two computational biologists,  (Broderick and Cradock) and, I’ve been told, may be adding an animal modeler.

Pathogens

Waziry specializes in a key, key area – detecting how  viruses muck up how cells operate. If  viruses are present you, of course,  want to get at them but if the viruses are gone or are hard to find  then finding some sort of viral fingerprint could inform you how the damage occurred, where to target treatments and  what viruses to look for would be very helpful and that’s what Waziry is doing.

Given the common infectious trigger in this disorder  this slant makes  sense; something, after all, happened way back when and for many people it involved a pathogen.  If  Waziry finds a signature unique to cells that  Epstein Barr Virus mutilated, for instance,  you’d know your pathogen without having to resort to expensive and not always accurate blood tests.  It’s also possible, given the many  infectious triggers documented in ME/CFS (EBV, parvovirus, coxsackie, West Nile Virus, Giardia, etc.) that they’re all tweaking the system in the same way.  If that’s what’s happening then  finding a common immune signature will allow the team to develop simple diagnostic tests for a significant portion of ME/CFS patients.

Computational Biology

The computational biologists are trying to stop the illness cascade in its tracks in chronic fatigue syndrome

The computational biologists are trying to stop the illness cascade in its tracks in chronic fatigue syndrome

Dr. Klimas has fully  embraced a new branch of  biology called computational biology that uses sophisticated data mining techniques to analyze  how our internal  systems operate.  In fact Dr. Klimas has so fully embraced this type of research that her computational biologists are doing cutting edge work not being done in any other disease.

The computational biologists (Broderick and Crawford) play clean up. Every piece of  research and clinical data gathering ultimately ends up in their hands. They’re trying to do something unique in medicine;  using data mining techniques to target the molecular source of this disease in time.  Think of it as isolating the pebble the started the snow slide that ended creating an avalanche.  This isn’t about symptom amelioration anymore; this is about getting at the very beginnings of the system-wide ‘collapse’ that occurred and is still occurring  in people with ME/CFS.

The computational biologist are the ones, Dr. Klimas explained, that will ultimately be able to tell her that  tweaking this  patients HPA axis here, and prodding their  immune system over here and here,  should stop the cascade of system-wide dysfunction that  causes chronic fatigue syndrome…Essentially she wants to cut a relapse or flare  off at it’s …er…..start.

We’ll learn more about this approach in Broderick’s talk.

Speeding Up the Process

Dr. Klimas wants to move quickly. No more of this  waiting two years for the NIH to respond;  Dr. Klimas – through a process Dr. Broderick will outline later – hopes to produce multiple small-scale, phase-1 type clinical trials in house to get the  data needed to get pharmaceutical companies interested in drugs that will help ME/CFS patients.

The Institute

At this point the Neuro-immune Institute has  11 staff members including 6 researchers/research assistants, a research coordinator, a Director of Medical Education, two Nurse Practitioners (one of whom has ME/CFS) plus researchers from the University of Miami, University of Alberta, Wright State,  and the CDC . And they’re busy with no less than seven different active studies going on at the moment.

Accomplishments of the Past Year

Dr. Klimas announced two encouraging signs; (a)  they’d achieved more in the past year than expected and (b) Nova kicked in more than she expected.

In the first year the Institute for Neuroimmune Research has been involved in

Research

  • a really large DOD grant
  • Genomic studies
  • Gene expression and immune regulation study
  • Gene expression exercise study
  • GWI animal modeling
  • CDC – multisite ME/CFS physician study
  • Chronic Fatigue Initiative Pathogen Study – Dr. Klimas stated that the CFI, which  is the most well-endowed ME/CFS research foundation,  is motivated to come up with answers quickly as well, and that the pathogen samples in the big Lipkin/Hornig study are being analyzed now. She stated the Institute would  continue their work with CFI, suggesting that further studies are around the corner.
  • Epidemiological Study – stating this has never been done before, this study has tracked people back as far as  10 years and asked them how they’re doing now; thus far 1,000 people have answered the questionnaire. Smiling broadly she said they did it on student stipends; $8,000 (a site?) – a ridiculously low figure  – and they’re getting important, never before seen data.
  • Ampligen Study

Treatment

  • Doubled the clinical space at their  Kendall clinic
  • Created a  new clinic at Davie

An Effective Team – Dr. Klimas mentioned how effective she and  Mary Fletcher, whom, she said does not sleep and works weekends (we’ll see evidence of that later :)), were at writing and getting NIH grants. That’s very true; while other ME/CFS researchers have given up on the NIH and few get grants, these two always seem to be in the mix at the NIH.   Their ability to consistently get grants for this  disorder is extraoardinary and is partially because of the interest in the cutting-edge computational biology approach they’ve taking.

Goals for this Year

Next Dr. Klimas went over their goals for this year.

We’re going to be able to collect huge mountains of data on normal care and make the evidence happen….Dr. Nancy Klimas

 Turn the Clinical Database into A Research Database (and then analyze the heck out of it)

The plan, is to integrate her clinical databases into her REDCAP  research database, providing her sophisticated  tools to analyze treatment effectiveness in her patients, past and present. If you’re part of her clinic (with your permission) you’ll become a research partner as well.

Integrating her clinical database into her research database could allow Dr. Klimas to answer many question about treatment effectiveness

Integrating her clinical database into her research database could allow Dr. Klimas to answer many question about treatment effectiveness

This is big stuff. By putting her patients into  a research database made for, well, research and analysis – Dr. Klimas is opening up thousands of records and patient outcomes to  analysis. Over time this will bring  treatment outcomes  out of the fog of individual guesswork and intuition into the clarity of statistically derived analysis.  No more waiting for for someone spend two years convincing the NIH to fund a small treatment trial….those trials have effectively been underway in ME/CFS specialists offices for decades; they’re just waiting to be uncovered.

Doxepin elixir is commonly used to aid sleep in chronic fatigue syndrome but how effective is it really? Are there certainly types of patients it works better in?   Would some patients do better with Ambien? Nobody really knows the answers to these questions but given the staff and funding  they are answerable with this technology.

If this really works, this work, and Dr. Kogelnik at the Open Medicine Institute has similar plans, would be a bonanza for both patients and doctors. Since the CDC doesn’t seem to be able to handle non evidence-based data, we could anticipate an entirely new CDC Toolkit, for example, coming out of  this work.  Dr. Klimas said they were  going to try and sell the project to Medicare.

The ability to do this kind of work is one of the dreams of the electronic digital revolution spreading across the medical field.  Only time will tell but hopefully it will deliver on its promise.

How did Dr. Klimas get this project up and running? She walked into an NSU office…and asked them “Do you think we could????” and it was borne. That’s the difference between working in a pro-active environment that is eager for you to succeed and in an institution (my words, not hers) that tolerates your existence but isn’t going to go out of its way to support you.

Other Goals

  • Establish a Translational Research Program
  • Begin the DOD modeling studies (see later presentation)
  • Establish a Nanostring (Gene Expression)  Laboratory
  • Integrate DOD and NIH programs at the new lab
  • Apply to NIH for Program Project Funds to Pull Everything Together
  • Train Young  Researchers

Five Year Goals

  • Be a self sustaining unit without the need for extra University funding
  • Develop funded training program for young faculty
  • Creating an endowment that supports the program
  • Broaden international collaborations
Dr. Klimas goal is to create a environment that fosters communication and innovation

Dr. Klimas goal is to create a environment that fosters communication and innovation

Conclusion

Dr. Klimas is getting good support, the Institute is growing rapidly, it’s involved in many studies and it’s got big plans. 2012 was a good first year for the Institute for Neuroimmune Research.

Next up: Dr. Hornig on Autoimmunity and ME/CFS