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Introduction
It is naïve to think that such a complex multivariate illness as chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) could be caused by a single pathogen. But that has not stopped us from repeatedly looking for that smoking gun.
This complex syndrome has been given many names over the years. CFS/ME is one of the most widely used today. However, for the purpose of this discussion, I will use a popular name from years ago, CFIDS (chronic fatigue and immune dysfunction syndrome). It is still relevant, and it better represents the focus of this article.
As a general practitioner with 30 years of experience, I have seen many trends in the effort to correlate infectious disease and CFIDS. From the beginning of the chronic fatigue epidemic, viruses have been the primary suspect. There have been waves of interest in viral etiologies (e.g., mid-1980s and early 1990s), but none compares to the current intense activity being generated in research and treatment.
In this article, we will summarize various aspects of CFIDS in relation to emerging ideas about viruses, review recent lab tests used to monitor viral activity, and consider new aspects of immune system dysfunction and treatment possibilities.
Personal Learning Curve for CFIDS
Those of us committed to the treatment of CFIDS have followed many leads to help people with this disabling illness. In the 1980s, it was about Epstein-Barr virus (EBV); back then we had ineffective remedies. The therapeutic focus in the early 1990s shifted to yeast and the gastrointestinal tract. During this time, functional medicine was born, along with laboratories that emphasized function over structure to evaluate metabolic and optimum individual biochemistry. With this renewed focus of treating fatigue by optimizing function, we took a fresh look at hormones, gluten sensitivities, food allergies, and heavy metals, using a broader array of natural products. Yet it did not solve the CFIDS puzzle.
The challenge of solving this medical mystery pushed us into new horizons, such as consideration of possible new etiological agents. In the mid-1990s, Lyme disease and the coinfections eclipsed other possibilities as the cause of CFS. For those of us "lucky enough" to live in a Lyme-endemic area, we were forced to appreciate the role that it can play in fatigue. Antibiotics, not antivirals, became the weapon of choice when dealing with CFIDS patients. The awareness of the prevalence of neurotoxin bacteria was a significant step. A few of my patients resolved their fatigue on antibiotic treatment. For about a decade, I thought that everyone with a CFIDS diagnosis had a tick-borne infection.
Many years of being confronted with the chronic "fatiguelike" illness patients, who didn't get better in spite of all of the above, brought us full circle to appreciating the viral etiologies of CFIDS. Meanwhile, the number of chronic viruses to consider continued to expand, including herpesvirus 6 (HHV-6), cytomegalovirus (CMV), Coxsackie virus, parvovirus B19, echovirus, and hepatitis (HCV) – to name a few.
Laboratory Consideration
Over the past 30 years of treating CFIDS, high EBV titers were a disconcerting presence and a cause for reflection. We could discount the high IgGs, NA, and VCAs as postviral infection with poor correlation with the patient's symptomatic presentation. But the stone in the shoe was the high early antigens (> 1:640), which didn't make sense in the chronic patient. These high EBV early antigens also seemed associated with the higher IgG titers (from 1:640 to 1:1280 and even 1:2560) in our sickest patients. It has been speculated that the presence of elevated early antigen could indicate viral load.1 Over the years, when evaluating the probable Lyme patient, these high titers were hard to overlook and difficult to explain in the "fatiguelike" patient.
John Chia and the Stomach Biopsy
Dr. John Chia has done quality research on EBV and Coxsackie for years. He expanded his focus to include enterovirus. He finds an 82% positive enterovirus on stomach biopsy in his CFIDS patients. Normal controls tested at 20%. He has challenged the belief that enterovirus is a transient, weak pathogen. He has proved that it survives in gastric cells chronically, and he has postulated its chronic presence in many other tissues in the body.3
Nagalase Serum Levels
The Europeans have introduced us to the serum/plasma lab test Nagalase, which is a marker for innate immune suppression. It has been a proven marker to efficacy of treatment for certain viral infections, including HIV, influenza virus, and possibly other retroviruses. They have been using it to monitor HIV and cancer for a decade. In the wake of the XMRV (xenotropic murine leukemia virus-related virus) debate, it became a marker of CFIDS.14
The test measures the activity of alpha-N-acetylgalactosaminidase (Nagalase) in the blood. It is an intrinsic component of the envelope protein of various virions, such as HIV and the influenza virus, thus secreted from virus-infected cells. Nagalase deglycosylates the vitamin D3-binding Gc-protein. The Gc-protein is a precursor for the major macrophage-activating factor (MAF). This deglycosylated Gc-protein can no longer convert to MAF. Macrophage activation for phagocytosis and antigen presentation is the first step in the immune development cascade. Lost precursor activity leads to immune suppression.15
For a year, I have measured Nagalase in patients whom I believe have viral activity related to their CFIDS. The reference range for this Health Diagnostics serum test (South Amboy, NJ, 732-721-1234) is .30 to .95. Of the +/−100 patients tested, I have had only 2 patients in the normal range. The statistical high for my patients outside the reference range is 2.0, with many patients from .95 to 2.0, and a large number from 2.0 to 3.0. I have 8 patients in the 3.0 to 4.0 range, 5 patients between 4.0 and 5.0, and 4 patients with the highest Nagalase level above 5.0. It appears to me that the higher the Nagalase level, the more likely that the patient has a viral-dominate pathogen. As I successfully treat them, their Nagalase level normalizes.
Overall, I have found Nagalase to be a good diagnostic marker for viral activity and treatment management.
Immune System Dysfunction
The research community has been hard at work to understand what is happening in the immune system, and why viruses such as CFIDS can malfunction in some patients but not in others.
We know that the innate immune system is not enough to defend against these chronic viruses. We rely on lymphocyte coordination between B cells (humoral immune) and T cell response (cell mediated). Immunological synapse is the process wherein antigen (peptides) are recognized by T cell receptors, resulting in the activation of T helper cells. These T helpers activate specific B cell components, the adaptive immune system. The B cell receptor is able to bind specifically to the viral antigen. After activation, the B cells mature and split into plasma B cells that work on the current invader and memory B cells, which stay in the system for years to recognize and respond to the same antigen. T regulatory cells (Tregs) are the built in brake to the system. They downregulate the immune response and regulate autoimmunity.16
Professor Michael P. Pender from Queensland, Australia, has extensively studied EBV and autoimmunity. He is looking at how this sophisticated system can misfire, causing RA, SLE, and other autoimmune illnesses. This proposed mechanism of action postulates that the susceptible patients start with a CD8+ T cell deficiency (also called cytotoxic T cell) and are lacking in natural killer cells when infected with EBV. Due to the deficiency of T cell control, the EBV load increases, as do the anti-EBV antibodies. As EBV infects the target organs, there is a disproportional rise in clonal expansion of EBV-infected autoreactive B cells in the immune-suppressed patient (CD8+ T cell deficiency). These autoreactive B cells accumulate in the target organ, where they produce pathogenic autoantibodies.12
This chronically infected B cell produces excessive IgG and early antigen IgG. Unfortunately, the virus is then able to integrate into DNA of infected B cells. Normally the Tregs tell the B cells that their job is done and turn them off. As antibodies increase ineffectively, there is a corresponding decrease in Treg cell activity. These infected B cells suppress Treg feedback, thus allowing the infection to continue.16
There is a flurry of interest about how to suppress this B cell activity. These EBV-infected B cells need cytotoxic T cells (CD8+) that destroy virally infected cells and tumors. But these, along with the Treg cells (a regulator of autoimmunity), can be inactivated. Much research is going on to find the disruptor in this system.
David Dreyfus from Yale is also looking at the underlying autoimmune mechanism. Again, he finds that the B cells are a reservoir for chronically active EBV, which brings another possibility to the discussion. The pathogenic EBV in the B cells may activate endogenous human retroviruses (HERV) as an additional stressor to the immune system.7
HERV are retroviruses that are embedded in our genome from generations past. They are single-strand RNA viruses that reverse-transcribe their RNA into DNA for integration into the host's genome. Thousand of endogenous retroviruses are present in human DNA (or 8% of the human genome).10 Many are inactive mutations and others can be activated to stimulate an autoimmune response. EBV and probably other chronic viruses hiding in the B cell have been implicated.
What We Learned from XMRV
We have just finished the wild ride that was XMRV. For those who missed it, a prominent retrovirologist, Judy Mikovits, published a very informative article on XMRV in the October 2009 issue of Science. She made a big splash in the scientific community by announcing the discovery of a new retrovirus, adding it to the short list (HIV and HTLV-1) thought to infect humans.4 We at Gordon Medical Associates had a ringside seat as many of our CFIDS patients volunteered their blood to help her refine her testing techniques. She worked long and hard, seeming to be on the verge of a major breakthrough in the laboratory assessment and diagnosis of CFIDS. Sadly, her results were recanted six months ago, after the researchers found an invalidating contaminant. Despite the great expectation but eventual disappointment of XMRV, good has come from the experience.
The benefits coming from the wake of XMRV are twofold: first, practitioners with CFIDS patients have become reinvigorated to the possibility of a viral etiology, and possibly a retrovirus, endogenous or otherwise. Secondarily, the interest in XMRV stimulated an expanded arsenal of weapons to help in the battle against viruses in general.
Paul Cheney has observed a delayed but similar trajectory between the onset and incidence of HIV and CFIDS. If there are other unappreciated slow-growing retroviruses infecting our patients, it could be an explanation as to our lack of success in treating the sickest of those with CFIDS.
Treatment Options
Chia initially used interferon for the treatment of the echovirus that he found in stomach biopsies and Coxsackie antibody titers; however, over time he discontinued it due to toxicity. Since 2008, he has been using the Chinese herbal formula oxymatrine, derived from the Sophora plant. It has antiviral capacities, can reduce viral load, and is a tonic to the liver and circulation. He found that with a flexible dosing schedule, such as working slowly to increase the dose from 4 to 6 capsules daily, 53% of his patients found benefit after three months of treatment.3
Pender, following his EBV-infected B cell model of autoimmunity, has had marginal success using the herpes class drugs Valcyte, Valtrex, Acyclovir, and so on.12 They interfere with replication of the reverse transcriptase enzyme, but only when it is reproducing. These drugs can be marginally effective at reducing viral load and give some relief from symptoms. This is, however, ineffective for the EBV virus hiding in the B cells. This intervention could take decades to affect the viral growth cycle.1,12
I have used this approach at times over the years, hoping that I would find the right patient who would respond. Thinking that the patients with the IgG antigens at > 1:640 could be the ones to benefit, I met with marginal success. My failure in doing so might be not having done it long enough, but it seems a low-yield treatment.3
Pender also thought that a deficiency of vitamin D could have a causal relationship with CD8+ T cell deficient patients. Along with a genetic HLA alleles strand defect that determines which self-antigens the T cell recognizes, vitamin D deficiency could be a trigger for autoimmunity by aggravating T cell deficiency.
Dreyfus postulated that the activation of some unknown endogenous human retrovirus(es) trigger autoimmunity by way of the infected B cell. His theory is to treat with a retroviral integrase inhibitor, such as raltegravir. This broad-spectrum drug could be effective against both retrovirus and herpesviruses.6
A number of studies on the effectiveness of the antiretroviral drugs in patients who tested positive for XMRV and had CFIDS were tried in 2010 by Dr. Joe Brewer, with a 10% to 20% improvement in patients' CFIDS symptoms. There was some wisdom to killing the infected B cells with antiretroviral drugs (ARV). A few patients had a miraculous recovery with ARV, but the expense and side effects were prohibitive for many patients.
With the exception of the herpes and antiretroviral drugs, we have few choices in pharmaceutical agents that would help CFIDS patients. Our pharmaceutical industry has put its viral research dollars into vaccines. Thus, those of us who are committed to helping these patients are forced to look outside the pharmaceutical realm.
The Byron White Formulas (BWF)
The Byron White Formulas, designed for their immune activation against virus (e.g., A-C, A-CM, A-V, A-XM, A-EB/H6) are the best that I have found for these chronic pathogens. These herbal extracts are specifically charged with frequencies that help the immune system counteract the disabling effects of these viruses. In my experience, these formulas are a balance between immune-provoking and systemic support. In my 30 years of practice, I have not found a more useful approach to specific viruses.
Viruses such as EBV, HHV-6, Coxsackie, CMV, influenza, Powassan virus (the Lyme virus or central nervous system virus), and the retrovirus have a systemic effect on the entire matrix of the body. This matrix effect (like a fingerprint) is specific to each virus, and each weakens the body in its own way. A virus's effect on the body's matrix can produce toxins, affect specific organ systems, and cause mental or emotional symptoms, along with general immune dysregulation.
The Coxsackie "fingerprint" can present as a recurrent flu that may progress to viral pneumonia. Organs within this template are the throat, larynx, chest, and – if it becomes chronic – the bone marrow. For patients with this symptomatic pattern, I have found the Byron White Formula A-C (an energized herbal extract) to be very useful. In acute cases, high doses are required; in chronic cases, low doses can be useful, but can be difficult to tolerate if increased too quickly.
When CMV and an imbalanced matrix affect my patients or have a particular symptomatic presentation, I have found A-CM to steady the effect of this matrix of imbalance. It has a purging effect on the liver, offers strong lymphatic support, and strengthens the immune system. On the emotional level, A-CM helps with the hopeless, exhausted feeling that is common with patients who have CMV.
I cannot say enough about A-V. I have found it beneficial for many of my virally affected patients. It has an immune adaptogenic effect and can be helpful for both acute and chronic viral conditions. A-V is superior for patients with chronic viral CNS symptoms, such as headache, dizziness, and cognitive and memory processing. I use it in my viral patients who need blood building and detoxification. It also has therapeutic mushrooms that are regenerative.
The herbs in A-XM have been studied in the use of HIV, being effective with both the retrovirus and the immune system. This formula is very supportive to the detox pathways. I have used it with patients with CFIDS and found it both provoking and regenerative, depending on the patient and dosage.
The strong steady effect of EB-H6 seems to be felt by the patients almost immediately. We prefer to use it with the patient whose system is compromised by the Epstein-Barr/herpesvirus 6 imbalanced matrix. I use low doses with chronic cases, while acute cases can tolerate higher doses. It appears to help immune identification of these viruses and keep them superficial and accessible to the body's defenses. The herbs decrease the damp spleen and help purge the fire that is part of these pathogens' prevailing conditions.
These formulas are a blend of herbal extracts and energetics that counteract the depletion that the virus causes. When the therapeutic whole of the formula matches the imbalanced matrix of the virus, there is the potential for regeneration.
Gc-MAF: Macrophage Activating Factor
The Europeans have tools for the treatment of viruses that are attracting more interest in our country. Some of our doctors at Gordon Medical are working with Paul Cheney, Kenny De Meirleir in Belgium, and Dr. Ruggiero from Italy to better understand the therapeutic potential of Gc-MAF.
Gc-MAF is a naturally occurring powerful immune modulator. Nobuto Yamamoto first published a paper in 1999 on Gc-MAF and its use in mice with tumors. With the increased interest in XMRV in 2010, Gc-MAF was considered for its antiretroviral effect. Gc is a protein, which is also known as the vitamin D-binding protein, as it needs the VDR (vitamin D receptor) to activate macrophages. When a virus attacks the system, the innate immune system responds with a troop surge. The previously sleepy macrophages go to work on the invader. Nagalase is a marker of how successful we are at this process. The higher the Nagalase level, the more the macrophages (innate immune system responders) are being disabled by the virus.
De Meirleir used Gc-MAF with 108 patients with elevated Nagalase levels and CFIDS symptoms. His study ran over 5 to 40 weeks, with CFIDS patients given 100 ng SQ injections weekly. The participants in the study had a 63% improved response rate with corresponding lowering of Nagalase levels.5
Dr. Derek Enlander has made a probiotic/colostrum product available in this country through eBay. It is cultured; used orally; and, according to Enlander, gives an equivalent of 6 ng of Gc-MAF daily. I have just begun recommending this for my CFIDS patients. I am intrigued with the potential of an oral delivery system of a powerful immune modulator to the immune system of the gut.8
Conclusion
We are in an exciting time in medicine. We have the research sophistication to unlock many of the chronic medical problems that have become endemic. We are on the verge of helping patients with CFIDS and other autoimmune disorders.
In the next article, we will focus on treatment and case management considerations, and on the differential diagnosis of neurotoxin illness vs. chronic "fatiguelike" illnesses from a nonneurotoxic etiology.
Notes
1. Balfour HH Jr, Hokanson KM, Schacherer RM, et al. A virologic pilot study of valacyclovir in infectious mononucleosis. J Clin Virol. 2007;39:16–21.
2. Belshaw R, Pereira V, Katzourakis A, et al. Long-term reinfection of the human genome by endogenous retroviruses. PNAS. 2004 Apr.;101(14):4894–4899.
3. Chia JKS. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach J Clin Pathol. 2008;61:43–48.
4. Cohen J. The waning conflict over XMRV and chronic fatigue syndrome. Science. AAA.org. 2011, Sept. 23. Available at http://www.sciencemag.org.
5. De Meirleir K. Mt. Sinai ME/CFS conference – De Meirleir lecture. CFS Patient Advocate. 2011 Nov. 23. Available at http://cfspatientadvocate.blogspot.com.
6. Dreyfus R. Autoimmune disease: a role for new anti viral therapies? Autoimmunity Review. 2011;1188–1197.
7. Dreyfus DH, Kelleher CA, Jones JF, Gelfand EW. Epstein-Barr virus infection of Tcells: implications for altered T-lymphocyte activation, repertoire development and autoimmunity. Immunol Rev. 1996 Aug.;152:89–110.
8. Enlander D. Myalgic encephalomyetis, fibromyalgic, EF/CFS. New York ME/CFS Center. 2012. Available at www.enlander.com.
9. Hall MA, Ahmadi KR, Norman P, et al. Genetic influence on peripheral blood T lymphocyte levels. Genes Immun. 2000;1:423–427.
10. Mosser DM. The many faces of macrophage activation. J Leukoc Biol. 2012 Aug.;73(2):209–212.
11. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-hydroxyvitamin D levels and risks of multiple sclerosis. JAMA. 2006;296:2832–2838.
12. Pender MP. Infection of autoreactive B-lymphocytes with EBV, causing chronic autoimmune diseases. Trends Immunol. 2003;24:584–588.
13. Thorsby E, Lie BA. HLA associated genetic predisposition to autoimmune diseases: genes involved and possible mechanisms. Transplant Immunol. 2005;14:175–182.
14. Yamamoto N. Pathogenic significance of alpha-N-acetylgalactosaminidase activity found in the envelope glycoprotein gp160 of human immunodeficiency virus Type 1. AIDS Res Hum Retroviruses. 2006;22:262–271.
15. Yamamoto N, Urade M. Pathogenic significance of alpha-N-acetylgalactosaminidase activity found in the Hemagglutinin of influenza virus. Microbes Infect. 2005;7:674–681.
16. Yang Z, Novak AJ, Ziesmer SC, Witzig TE, Ansell SM. CD70+ non-Hodgkin lymphoma B cells induce Foxp3 expression and regulatory function in intratumoral CD4+CD25 T cells. Blood. 2007;110(7):2537–2544.
Wayne Anderson, ND, initially practiced in a busy community-based family medical center, for more than 20 years, treating individuals and families from birth to old age. The focus of his practice gradually shifted to a search for effective  interventions for patients experiencing chronic illness. Located in an area where Lyme disease was endemic, he became aware of the prevalence of chronic Lyme and related conditions and came to realize the important role that they were playing in many of the chronic health disorders of his patients.
Ten years ago, he left family practice to work with Eric Gordon, MD, in a practice using both conventional and integrative medicine. Dr. Anderson is a dedicated clinician whose work emphasizes immune support for patients with chronic and neurologic health conditions, including those with Lyme disease and/or Lyme coinfections.
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