Autonomic Dysregulation Redux - Here we go Again!

This morning I noticed another article seemingly trying to dismiss the findings of the Whittemore Peterson institute by going back to the neuroendocrine model of CFS.  The so called "Paper" titled "How XMRV Retrovirus Findings May Fit With The Amygdala Hyperarousal Model for ME/CFS is written by Ahsok Gupta, a self-proclaimed expert on ME/CFS who states that he cured himself of ME/CFS after being struck by a viral-like illness after his second year of Economics at Cambridge University.  The irony of it is that Mr. Gupta is neither a medical doctor, molecular biologist, or biochemist.

This theory in itself does not seem to hold water - in studies where a drug was injected into the amygdala, the animals had better memory for retaining the task - quite the opposite of memory impairment seen in ME/CFS.  In his paper, he also blames overstimulation of the autonomic nervous system - which would be typically characterized by anxiety, hypertension, and digestive disturbances (Something that occurs with use of cocaine, crystal meth, or even too much caffeine) - quite the opposite of ME/CFS!  He also goes on to theorize that the XMRV virus is simply a passive opportunistic infection which establishes itself due to general suppression and dysfunction of the immune system from autonomic dysregulation and amygdala hyperarousal (Would manifest itself as mania and hypersexuality).  Once again, this theory brings ME/CFS back to the forefront as a fire of unknown origin.

I stand firm that XMRV directly causes the symptoms of ME/CFS, FM, and Gulf War Syndrome - much like HIV causes AIDS.  Gupta quotes "There are two broad aspects to the immune system, Th1 and Th2.  Th1 involves Natural Killed (NK) cells whose job it is to identify and destroy viruses.  The Th2 side of the immune system involves amongst other things antibodies which respond to threats.  There is evidence in the litterature that patients with ME/CFS are Th2 biased..."  Enough said - some of this is partially true, but it does not meet the definition of a cause.  Years of AIDS research has already given us a heads up on what could be happening in XMRV infections.  HIV infects by latching on to the CD4 molecule for entry, much like I postulate that XMRV uses the CD8 Molecule found on NK cells, explaining why NK function is disrupted - saying that if the Th1 arm of the immune system is attacked, the Th2 system is going to be predominant.

To dissect this further, Gupta goes on to state that "The XMRV virus may simply represent one of many viral and bacterial infections present in the blood of ME/CFS patients, and that many of these previous infections (including EBV) have been previously prematurely suspected as the root cause of ME/CFS."  My take on this is look no further than HIV - as the disease progresses to AIDS, titers of CMV, EBV etc. rise dramatically - to the point where some AIDS patients have to take Valcyte to prevent sight-threatening CMV infections.  You also see that RNASE-L is elevated, and the uber-powerful cleaved version is present because RNASE-L functions to keep viral pathogens at bay until NK cells are summoned - unfortunately no one is there to answer the call

I also believe that the autonomic disruption in ME/CFS, FM, and Gulf War Syndrome is a direct result of infection with XMRV.  We've seen this in HIV - AIDS Dementia Complex.  The action of certain cytokines on the nervous system is also of note - anyone who has had the flu can tell you just how tired they are, and feel "spacey" - persons receiving interferon report the same.

I will finish by saying that ME/CFS, Fibromyalgia, and Gulf War Syndrome patients have been bombarded for years with faith healers, alternative/complimentary medicine theories, and psychiatric explanations for their symptoms.  No currently approved treatment has produced any satisfactory improvement in any of this group of patients, although some improvement has been noted with anti-virals targeting herpesviruses such as HHV-6, EBV, CMV lending to the credence that EBV exacerbates symptoms of an XMRV infection.  It will be interesting to see early results of AZT trials, and hopefully more HIV drugs will show efficacy - hopefully the integrase inhibitor Isentress will show efficacy against XMRV due to its lack of delitirious side effects like lipodystrophy, hypercholesterolemia and hyperglycemia found in protease inhibitors and some RTI's.

The "Normal" 4% Living XMRV Postive

In the findings by the Whittemore-Peterson Institute, roughly just under 4% of the normal control population tested positive for XMRV.  It would be really interesting to take these so called "normal" subjects in another study, and further examine them.  I hypothesize that a segment of these people are asymptomatic, much like many HIV positive individuals live asymptomatically for many years before developing AIDS, and I would not be surprised to see an alarming number of this 4% of the "Normal" controls demonstrating some mild symptoms that would not be enough to meet the diagnostic criteria for XMRV Neuroimmune disease.  Some of the mild symptoms that I postulate would be found include, but are not limited to:

• Autistic Spectrum Disorders (Asperger's syndrome, Pervasive Development Disorder)
• Mild fatigue previously attributed to depression
• Intolerance to cold
• Intolerance to physical activity
• Lack of libido
• Mild immune deficiency (ie: Picking up every cold or flu going around)

A thorough study of the "Normal" XMRV positive individuals should be performed to broaden our understanding of the disease process.  Eventually, we might be able to answer the question that if XMRV is the primary insult to the immune system setting the wheels in motion for XAND disorders, what factors contribute to developing full-blown disease?  The answer might be as simple as having too many simple viral infections like the cold or flu over a short period of time - meaning that the immune system of XMRV positive individuals functions in a near-normal manner, until it is brought to a threshold where there are not enough healthy Natural Killer cells to keep XMRV in check, allowing the total viral load in the body to slowly build with other persistent viruses like EBV, HHV-6 - contributing to symptoms.  This probably explains why Valcyte has shown a limited response in some individuals with Chronic Fatigue, though it has not produced dramatic improvements.  It shows that there is some truth in the statement made by Dr. Marshall that XMRV is not responsible for all the symptoms of Chronic Fatigue, but I still firmly hold my belief that XMRV is the cause, and that other Co-infections increase the cytokine burden, but there are not enough healthy NK cells to respond to the alarm, leaving a smouldering fire, which is Chronic Fatigue or Fibromyalgia.  It leads me to believe that after being treated with an antiretroviral for a fixed length, the immune system could be once again competent to keep XMRV in check, and that simply monitoring viral load afterwards and resuming an antiviral if the viral load exceeds a certain threshold could make a big difference.

Chronic Fatigue Advisory Committee Meeting

This week, the Chronic Fatigue Advisory Committee will meet, and listen to the findings of Dr. Daniel Peterson.  The advisory committee has representation from the FDA, CDC, NIH, HRSA, and Social Security Administration.  The event is essentially a make-or-break event - will the evidence be strong enough to persuade the various agencies to start paying more attention to Chronic Fatigue Syndrome, that is the question that remains to be asked.

Over the years, the CDC has finally begun to realize that this disorder is reaching alarming proportions.  However, the system failed patients - the CDC essentially works hand in hand with the NIH - if the CDC doesn't believe something, the NIH does not grant research funds to institutions into that particular field of interest.  Precisely, this is what happened with the findings of Defreitas et. al years back - no research dollars flowed to anyone wanting to search for a virus responsible for CFIDS.  Without this, no drug companies are willing to invest in something that is unproven.

The current findings basically confirm earlier findings from research done be Dr. Elaine Defreitas.  This time, the difference is that Dr. DeFreitas did not actually isolate and characterize the virus, but found clues to its existence - this time we have a virus.  Hopefully, millions of dollars in research grants will flow to studying XMRV, rather than studying various neurological phenomena.

Accessibility to New Treatments

Even if treatments were to be approved by the FDA, or the medicines and health products regulatory agency, likely the such drugs would be well out of reach for most people. Since most people with Chronic Fatigue, or Fibromyalgia are already significantly disabled, their ability to earn income is severely curtailed. HMO's, PPO's, primary care trusts (UK), and provincial health care plans (Canada) are unlikely to foot the bill for some time. For pharmaceutical companies, it could provide a considerable disincentive for developing new medicine - likely drugs from the current HIV portfolio will be screened for efficacy initially. Currently, these drugs vary in price from $263 a month, to $2314.50 a month. If approved, Ampligen is expected to cost around $1300 to $1500 a month.

An approach that has been seen by many providers has been to restrict access to medications using certain criteria. In the case of XAND (XMRV associated Neuro Immune Disease) such as Fibromyalgia, Chronic Fatigue Syndrome, the approach insurers may likely take would be to demonstrate a certain level of disability, and have failed other drugs beforehand. A primary care trust for example might require a certain disability score and fail to respond to a course of Lyrica and Ritalin. For insurers, the cost of treatment remains to be determined, and the following questions need to be addressed over time:

• Is the new drug more effective than the old one?
• What benefit does the drug have in terms of quality adjusted life years score?
• Will a lifelong course of medication be required as in HIV?
• Will other antivirals be required to treat co-infections, such as cytomegalovirus, EBV, HHV-6?

Current and Future Approaches to Treatment

Treatment options for Fibromyalgia and CFIDS sufferers are currently few and far between. There are no FDA approved medications specifically indicated for treating Chronic Fatigue Syndrome, and Lyrica is the only drug approved for Fibromyalgia thus far, with few options coming down the pipeline. Drugs currently prescribed for the condition include:

• Amitryptilline - Based on the theory that Chronic fatigue is caused by a neurotransmitter imbalance, Amitryptilline is frequently part of the drug regiment offered to Chronic Fatigue patients, whereby it is postulated that it helps regulate sleep, as it is thought that in CFS or FM, very little time is spent in stage 4 sleep. Controlled blind studies show that it is not very effective, providing only a slight benefit over placebo.
• Ritalin (methylphenidate), Desoxyn (methamphetamine), Dexedrine (dextroamphetamine), Provigil (Modafinil) - Drugs in this category act as CNS stimulants. The first three have the effect of raising blood pressure, and are indicated in treating postural hypotension, and promote wakefulness in CFIDS individuals. Modafinil does not address postural hypotension, therefore it is of limited use. For these patients, stimulants make it possible to perform daily tasks, however they do not seem to have an appreciable effect on cognitive impairment.
• Lyrica (Pregabalin) and Gabapentin - Gabapentin is a drug used to treat epilepsy, which gained off-label use to treat neuropathic pain, Lyrica being the active metabolite of Gabapentin. Lyrica was the first drug approved for Fibromyalgia, until the approval of the antidepressant Cymbalta (duloxetine). Response to Lyrica has not resulted in statistically significant improvement in quality of life in FM patients. The cost of the drug is high, and many insurers will not cover its cost, and the opioid analgesics like Dilaudid (hydromorphone), and fentanyl seem to confer the greatest benefits. Lyrica is known to cause marked weight gain, and can be very sedating (CNS depressant).

Current experimental treatments have shifted towards anti-viral compounds. Anti-virals currently being prescribed off-label include Valtrex (Valacyclovir), Valcyte (Valgancavir), and Acyclovir - all targeted towards herpesviruses. Some patients note significant improvement, lending to the theory that having high viral titers of herpesviruses adds to the disease burden of XMRV. Equally significant results have been obtained with Isoprinosine, which is available on both sides of the border at a reasonable cost. Valcyte has the distinction of being extraordinarily expensive - >$1500 a month, and it is not without severe side effects. Ampligen is a drug if approved that would be the first drug approved specifically for treating Chronic Fatigue Syndrome - it is expected to cost ~$1500 a month for treatment.

Future treatment will likely involve treatment with anti-retrovirals. As the link between Chronic Fatigue Syndrome and XMRV becomes more clearly established, likely more practitioners will be willing to try current anti-retrovirals on Chronic Fatigue and Fibromyalgia patients. Three potential viral targets might include reverse-transcriptase, XMRV polymerase, and intergrase. Initially, AZT has shown activity in vitro against XMRV, however the toxicity of AZT limits its use - it's fine for someone who would otherwise die of AIDS, but it leads to an ethical dilemma when prescribing it in a situation where the side effects may be worse than the disease. Most NRT's and NNRT's are fraught with side effects such as lipodystrophy - which can be quite disfiguring. Protease inhibitors are slightly more benign, although some are known to cause dramatic increase in blood lipids. Integrase inhibitors are prehaps the most benign, being well tolerated, producing few metabolic abnormalities. Protease inhibitors may not work against XMRV, as the catalytic site may be sufficiently different than the HIV protease - being the case, it would require determining the atomic structure of the XMRV protease, in order to develop effective drugs. As the function of other proteins of XMRV become unravelled, other drug targets could conceivably be developed - one of these being the androgen responsive element or ard.

How is XMRV acquired?

Without doing further studies, it is difficult to establish exactly how XMRV is acquired. Being a retrovirus, it is as sure as the setting sun that tainted blood products, and injection drug use being some of them. A study by Umberto Tirelli in Archives of Internal medicine "Clinical and Immunologic Study of 205 patients With Chronic Fatigue Syndrome: A Case Series From Italy", seems to indicate some interpersonal mode of transmission between household members and casual contacts, appear to have been infected with a virus related to HTLV-II.

The initial onset of the disease with flu like symptoms seem to suggest an acute phase, where perhaps the virus is spread by droplets much like influenza. A certain amount of credence must be given to such a scenario, given that a number of young catholic nuns at a convent in Monterrey, Mexico were afflicted with the disease in 2003-2006, complaining of general malaise, and body aches which upon physical examination revealed little. This brings into question that maybe XMRV is spread through saliva as well, meaning that sharing utensils could transmit the disease.

The possibility of an insect vector cannot be ignored. Mice being a reservoir of XMRV, leads to the distinct possibility that blood sucking insects such as mosquitoes, sandflies, horse flies, and ticks could transmit the disease to humans.

The CDC Failed CFS Sufferers in 1991 And Continues to do so Today.

In a landmark paper written by DeFreitas et. al, "Retroviral sequences related to human T-lymphotrophic virus type II in patients with chronic immune dysfunction syndrome", the authors stated that an association had been made by a yet unidentified retrovirus, and Chronic Fatigue Syndrome. It was during my tenure with the CDC in Atlanta that the CDC quickly jumped to the occasion and refuted the findings in the paper, pouring cold water on the retrovirus link. For the next 18 years, many theories surfaced about Chronic Fatigue Syndrome, with no answers - the phrases "hypothalmic dysregulation", "Neuropsychiatric disorder", "Neurally mediated hypotension" being all too common.

Meanwhile, a scandal was unfolding with our neighbors to the north where just two years ago the Canadian Government announced $150 million in compensation for those infected with HIV through blood products, and around the time the paper written by DeFreitas, details began to emerge about persons contacting Hepatitis C from tainted blood. A similar blood scandal like those of our Canadian neighbors was the last thing the CDC wanted - when the word "Retrovirus" was uttered, fear struck among the top brass of the CDC - notably Dr. Brian Mahy, prompting director William Roper to convene an emergency meeting with Louis Sullivan, then Secretary of US Department of Health and Human Services, and the director of the National Institutes of Health.

The result was simply scandalous.  Dr. William Reeves became installed as the head of the CFS/ME research program where under the command of his superiors namely Dr. Brian Mahy, many sinister things began to happen to the CFS/ME research program.  The experiment done by Dr. DeFreitas had essentially been rigged, and the CDC sent Dr. James Gow a standardized primer solution containing a fixed concentration of magnesium - so his lab would report a similar result.  During my tenure at the CDC during my research fellowship, we were told we would not be flying to Philadelphia because there was a lack of funds to buy airplane tickets.  It later turns out that $12.9 million dollars earmarked for CFS/ME research had been misappropriated and funneled to other projects, $8.8 Million was granted to pharmaceutical companies who sat on the money and did nothing with it, and $4.1 million dollars unaccounted for.  The Inspector General of the Department of Health and Human Services confirmed that $13 million in CFS/ME research money was either mismanaged and/or embezzled.  Following this report, the General Accounting Office noted research had declined on CFS at the NIH since 1996, there was a lack of communication between the CDC, and NIH about CFS research, and the leadership of the DHHS was ineffective in leading the CFS coordinating committee.

What ensued would have a profound effect on Chronic Fatigue Syndrome research for the next 15 years. Research funds for the disorder literally dried up overnight, and research came to a standstill. Shortly after the paper authored by Defreitas et. al. came out, the CDC was quick to refute their findings, and no further studies were made to isolate a virus. Basically, after the CDC has published their findings and used Dr. Gow to manipulate the results to appear as inconclusive, the NIH would no longer provide the research team of DeFreitas et. Al with further research funding on the matter or anyone else for that matter - it was case closed - NO RETROVIRUS! Now according to the CDC, CFS was a symptom of unknown etiology that had both psychiatric and neurological influences, and the NIH granted funding to find a neurological basis for the disease, which for the next decade would offer us some insights, but still no answers.

The fact is that we had our man 18 years ago, but we were too quick to rule him out as a suspect, and he's been out on the lam for the last 17 years. Rather than face the music, the CDC chose to stick their heads in the sand, and have it all come back in their at a later time. It begs the question of just how many people have been infected with XMRV through blood products , when we could have been testing our blood supply for at least the last 16 years? Lest not forget that antiviral drugs targetting XMRV would likely be available now had research been pursued.

Plausible disease models

Until now, no good disease models existed to explain to etiology of Chronic Fatigue Syndrome and related disorders. In the 1980's, we called it the yuppie flu, in the 1990's we called it a neuropsychiatric disorder of unknown etiology, then we called Fibromyalgia a pain processing abnormality with hypothalmic disturbances, and for a period of time both conditions became a wastebasket diagnosis. There were no tests available to mainstream medicine that could precisely detect disease markers, although over time various researchers have uncovered slight abnormalities in patient's immune systems.

A good disease model can be explained by the disease pyramid - succeptible host, pathogen, environment, time. My disease model begins with the succeptible host - Man, pathogen - XMRV, environment - stress, and then time. Succeptible host needs some explanation, as does environment, with pathogen and time being constants. I will begin with the host:

Basically, not all human beings are created equal, but being simplistic the prevalence of Fibromyalgia is heavily biased towards women, and chronic fatigue somewhat less. Based on the genome sequence of XMRV, it appears that one gene functions as an androgen responsive element - does it bind androgens and act as a repressor? Further studies will be needed to answer that question, although it provides a plausible explanation. It could also mean that men who have low testosterone levels are more prone to developing disease. Once again, a promising lead that needs to be studied.

Now my model will explain why some people may live symptom free for years. In a state of homeostasis, the immune system efficiently keeps the virus in check.

• Pregnancy - during pregnancy the balance of the immune system shifts towards Th2, likely from the influence of progesterone, this means that the body's defenses towards viruses are diminished.
• Stress - Cortisol is a hormone produced by the adrenal glands in response to stress - small amounts are needed to keep the immune system in balance. Larger amounts will generally tend to suppress the Th1 response more than the Th2 response, thus tipping the balance. Emotional stress, sleep deprivation, caffeine, trauma and over-exertion all increase cortisol.
• Infection - certain infections will favor a Th2 response - extracellular parasites (bacteria, protozoa, etc), and in the process will distract a Th1 response.

But when the balance tips, the XMRV in Nk cells begins to replicate, and infect other Nk cells, and the immune system becomes weakened as Nk cells become depleted, however does not result in a complete immune collapse, as other lymphocytes can partially fill the role of Nk cells, although with much less efficiency. Nk cells are important in recognizing cells infected with herpesviruses (Eppstein-Barr, Cytomegalovirus, HHV-6, Herpes Zoster, and Herpes Simplex 1 & 2), and with diminished numbers, the various viruses that have been identified in Chronic Fatigue and FM sufferers begin to flourish. A futile cycle ensues, where interferon pathways become activated, where RNase-L destroys cellular RNA in an effort to stop viral replication. Likely the fatigue results from chronic interferon activation, in addition to possibly the presence of a viral protein in the blood which acts as an endocrine disruptor. Confidently, I can say that based on this disease model, XMRV is the puppet master of Chronic fatigue. If you can suppress XMRV, Nk cell function will return, and the immune response will now keep herpesviruses in check. Once the immune system becomes competent, or reconstituted you might say, XMRV will be kept in check, until the host defenses are compromised.

The relationship between HIV and AIDS, XMRV and CFS or FM

The million dollar question is - does XMRV cause Fibromyalgia, or Chronic Fatigue syndrome. Here's the spin - just like HIV patients, I theorize that many persons infected with XMRV can live symptom free for years. Many people report an initial onset of illness which causes symptoms reminiscent of a general viral infection like the flu - probably where the virus grows to very high levels, and then drops after the immune system begins to attack the virus, but later the virus damages the immune system where a competent immune response cannot be attained. If you look at the paper published by the Whitemore Peterson Institute in the Journal Science on Oct. 8th, 2009 - the initial findings are no surprise. Almost all CFIDS patients produced antibodies to XMRV - translation: XMRV beyond a reasonable doubt causes Chronic Fatigue Syndrome. XMRV could be detected in two-thirds of chronic fatigue sufferers - translation: Until a more sensitive assay is developed, the one-third where no virus was detected probably means that viral load was below the limit of detection. XMRV was found in 3.8% of healthy controls - translation: This probably means two things - a small percentage of false positives, and like having HIV doesn't mean you have AIDS, having XMRV does not mean you have chronic fatigue, although at some point in the future you will develop the disease.

A Primer on XMRV

XMRV is a retrovirus - a virus that uses its RNA to copy its genetic material into host DNA. The best known retrovirus is HIV (Human Immunodeficiency virus) - the virus that causes AIDS. XMRV is only the third such retrovirus discovered to infect humans, after the discovery of HTLV. Like HIV, XMRV has 3 genes in common - gag, pol, and env. The gag gene encodes the capsid and matrix proteins, the pol gene encodes a single protein which is cleaved into three separate proteins by the viral protease - reverse transcriptase, viral protease, and integrase, and the env gene encodes the envelope glycoproteins. The XMRV also contains an androgen response element gene, which I will discuss a theoretical role in a future post. The XMRV genome is somewhat smaller than the HIV genome - 8161 base pairs as opposed to ~9500 base pairs in the HIV genome. Based on initial findings, it appears that XMRV infects the immune system in ways that are all too familiar in HIV. The envelope glycoproteins likely bind to some yet unknown immune system protein like HIV binds to the CD4 receptor, and co-receptor, possibly CD8, CD 16 or CD 56 on the surface of NK cells.

A New Era of Hope

This week's publication in the journal Science literally blew me away! Not in the sense that it's just another virus, but in the sense that the findings about XMRV show an eerie resemblance to those made by Dr. Robert Gallo, and Luc Montaignier in 1984. Though the results are still very preliminary, there seems to be an arrow pointing at Chronic Fatigue syndrome, and an even bigger arrow pointing back at XMRV. I think this time we've got our fugitive, and in time he will be found responsible for more than Chronic Fatigue Syndrome and Fibromyalgia. He's already a suspect in Autism.