Chronic Fatigue Syndromei, Fibromyalgia & Chlamydia Pneumoniae[1]

Introduction

Chronic Fatigue Syndrome (CFS), also called Chronic Fatigue Immunodeficiency Disorder (CFIDSi), or called Myalgic Encephalomyelitisi (ME) in Great Britain. CFS affects 1 million Americans, with "tens of millions" more who have a fatigue condition that doesn't meet the strict criteria for Chronic Fatigue Syndrome.[2] According to the Center for Disease Control (CDC), which considers CFS an accepted medical condition,[3] there is no officially known cause or cure for CFS or for the related, and often co-occurring, condition of Fibromyalgia Syndrome (FMSi).[4]

Despite the CDC's affirmation, the syndrome and its diagnosis is still considered controversial even in this day and age. Some doctors continue to insist that Chronic Fatigue Syndrome is not a "real" disease entity. It may be rather a surprise to it's sufferers when, naively seeking medical assistance, they find that their doctor doesn't believe that their symptoms are from a "real disease" or merits medical treatment. That there is no known "test" for Chronic Fatigue Syndrome that can conclusively demonstrate its existence is one of the difficulties here.

Perhaps another difficulty is that medical practitioners are socialized to believe that feelings of their own helplessness are a sign of personal failure. A solution to this psychological conundrum is to blame the patient by "psychologizing" the problem i.e. "It's in your head." Fortunately, acceptance of the legitimacy of the disease has increased in recent years, even if conventional medical treatment for it continues to have little to offer of help.

As the causal factors of CFS are considered unknown, conventional medical treatment for it and for Fibromyalgia Syndrome are all palliative (symptomatic) in nature: antidepressants for mood and pain associated with it, medications for sleep, stimulants for the fatigue, behavioral strategies, and so on. These can help make life bearable but don't fundamentally change the condition. [5]

Disease Syndromes: more common than you think -

Chronic Fatigue Syndrome is often disparaged as being a "syndrome," merely a collection of symptoms, not a disease i.e. a causal entity. Of course, a critique applying to one syndrome should apply to them all, yes? A syndrome is a collection of signs and symptoms (Sign= something you can measure; Symptom= patient reports) that appear to have diagnostic consistency. A syndrome tells you nothing per se about the cause of the problem. Many different causes, and sometimes more than one cause at the same time, can result in a syndrome. Interestingly, the diagnosis of "Pneumonia," just like Chronic Fatigue Syndrome, is actually a syndrome, though it is not referred to as "Pneumonia Syndrome." The diagnosing "pneumonia" does not tell you what is causing it, which can be variously viral, bacterial, food aspiration and so on.

Similarly, diagnosing Chronic Fatigue Syndrome doesn't tell you about possible causes until further investigation is done. There could be a variety and/or combination of potential causes. There are examples of modern, multi-factorial and case-individualized approaches to CFS/FMS that go far beyond conventional medical ignorance about CFS. These combine both symptomatic treatment and search for possible causal contributors for each specific patient.[6]

The various causal factors being looked into are amply discussed elsewhere and can be found in any web search. One of the proposed causal mechanisms for at least a sub-set of Chronic Fatigue Syndrome is that of bacterial or viral infection. Especially "occult infectionsi" i.e. those organisms that are either typically overlooked, difficult to test for, or tend to evade the immunei system[7]. Within this causal possibility are infectious organisms such as Chlamydia pneumoniae.

My purpose here will be to present the information that argues for the involvement of Chlamydia pneumoniae in at least a sub-set of Chronic Fatigue Syndrome and Fibromyalgia Syndrome patients. I will outline how Chlamydia pneumoniae's known biology and impact on the body could explain some of the characteristic symptoms and signs of Chronic Fatigue Syndrome.

At the outset it should be said that Chlamydia pneumoniae is not the only infectious agent that has implicated in Chronic Fatigue Syndrome/Fibromyalgia Syndrome. We certainly don't know if it is involved in all, a subset or merely a co-condition of such cases. But there is good reason to look further at this particular organism's involvement. Most of the argument discounting Cpn's involvement in CFS/FMS has been based on ignorance and poor understanding about the organism itself and the difficulties of testing and treatment for it. This is an attempt at trying to correct this ignorance, and place Chlamydia pneumoniae more clearly in the realm of possible sources for these devastating conditions.

The Early Vanderbilt Work: Chlamydia pneumoniae in Chronic Fatigue Syndrome-

The Incomplete Research-

There is some published work linking Chlamydia pneumoniae to Chronic Fatigue Syndrome/Fibromyalgia Syndrome in medical research journals.[8] But perhaps the most important research in this regard never reached publication. This article is the first thorough description in a public information setting.

The original initial work at Vanderbilt by Dr. Charles Strattoni and his lab on Chlamydia pneumoniae in human disease was actually not first directed at Multiple Sclerosis, as is more commonly believed, but looked Chlamydia pneumoniae in Chronic Fatigue Syndrome. The first grant monies received by Dr. Stratton for Chlamydia pneumoniae research, using the highly sensitive tests they had developed, was from Massachusetts Chronic Fatigue Foundation in the mid to late 1990's.

Dr. Stratton was asked to test blood samples submitted by the well-known Chronic Fatigue Syndrome physicians Cheney, Peterson & Bell to explore the possible involvement of Chlamydia pneumoniae in their Chronic Fatigue Syndrome patients. As I understand it, the grant was given to these doctors, and the determination of patients was by their own diagnostic selection. This research was never published, for reasons that will be explained later. The lack of publication and follow through of this work may be one of the great tragedies in a long line of them in the history of Chronic Fatigue Syndrome. Many patients may have suffered needlessly from this disease because the strong link between CFS and Cpn has remained largely unknown.

A remarkable finding:

In this research Dr.'s Cheney, Peterson & Bell sent blood samples from their own Chronic Fatigue Syndrome patients to Dr. Stratton's Vanderbilt Chlamydia pneumoniae lab for testing. According to Dr. Stratton, they tested 100's if not 1000's of such blood samples. These were tested using both ELISA-based serologic methods and PCRi testing using the tests developed by Stratton, et al. at the Vanderbilt Chlamydia Research Laboratory. Dr. Stratton's lab found that the majority (almost 100%) of Chronic Fatigue Syndrome patients were PCR positive for Chlamydia pneumoniae in blood samples.

That the selected patient group of Chronic Fatigue Syndrome patients had almost 100% positive PCR tests for Chlamydia pneumoniae (actual proteins, which means actual presence of the bacterial particles not only an antigen response which could be remnant from prior infection) is an extraordinary finding. Further, the majority also had either elevated IgM or IgGi antibodies to Chlamydia pneumoniae major outer membrane protein cross-confirming the PCR based findings.

Of course this in-of-itself does not mean Cpn is the cause of CFS. The presence of Chlamydia pneumoniae could be due to some third factor that is part of Chronic Fatigue Syndrome (such as immuno-suppression, etc). But such high of a correlation with one specific organism outweighs every other or biological finding to date in CFS research. No other single variable in the CFS literature even comes close to being found in near 100% of CFS patients. Now, there are some unknowns here, especially the criterian used to select those patient samples sent to Vanderbilt. This remains unknown as of this writing.

The first research problem:

They also discovered that many of the randomly selected "healthy controls" were also Cpn PCR positive. This would tend to call into question the tests themselves, i.e. suggesting that the tests are generating false positives. So, they tested a random sample of blood donors to have a larger pool of healthy controls from which to get a baseline comparison for the study's original control group. They found that, of "healthy blood donors" about 20% were Chlamydia pneumoniae positive! This percentage was higher than expected at the time, as it was not yet understood how ubiquitous Cpn is.

However, it turns out that this matches the figures of Cpn found in recent research with healthy, young blood donors.[9] That these earlier Vanderbilt studies found the percentage of Chlamydia pneumoniae occurring in healthy donors replicating the current accepted findings (which range from 18-25%) lends credence to the accuracy and sensitivity of the tests used to study this original Chronic Fatigue Syndrome sample. In other words, post hoc data suggests that their finding of an incidence of Cpn in healthy "controls" was an accurate one, not an artifact from an inaccurate test.

The next problem- treatment:

The obvious next step was to try courses of antibioticsi known to be antichlamydial and see if reduction of PCR signal for Cpn correlated with reduction in CFS symptoms. This was done by the by Dr.'s Cheney, Peterson & Bell with a sample of their patients. It turned out that no single antibiotic agent eradicated the Chlamydia pneumoniae PCR signal. So, Dr. Stratton's lab, having laboriously developed the PCR susceptibility tests (described quite elegantly in the patent materials which can be found linked elsewhere in this website) now had to use them to discover which agents or combinations of agents were required to eradicate Cpn completely, such that no PCR signal was evident in blood samples. This is called "sensitivity testing."

This was a greater challenge than most of us would think. Along the way to infecting mice and cell cultures with Cpn and looking for effective combinations of antibiotics, they discovered that the available laboratory mice and commercial cell cultures widely assumed by scientists to be "clean," and thus proper starting points for introducing new variables, were themselves often infected with Chlamydia pneumoniae. This could seriously skew the interpretation of their tests. So Dr. Stratton's lab had to first develop methods to clear the cell cultures of Chlamydia pneumoniae and prove such clearance using their sensitive PCR testing. This is a remarkable bit of science here. Their finding that common biological laboratory materials are contaminated with Cpn appears also to be relatively unknown.

From all of this they managed to find that only certain combinations of antibiotic agents (described elsewhere in this website) would completely eradicate Chlamydia pneumoniae from tissue cultures and laboratory mice, as indicated by clearance of Cpn PCR signal. No single antibiotic treatment, nor any series of antibiotics one at a time, was able to eradicate Cpn. Now that they had the combination antibiotic protocol (CAP) protocol, they could test the impact of eradicating Cpn on the resulting CFS symptoms, and then confirm whether patients were actually clear of Cpn from the blood testing.

And another thing…

As in all research, there is always another problem ahead. This time the problem was with the reactions to the clinical treatment itself being tried by Dr.'s Cheney, Peterson & Bell, as well as by Dr. Stratton with his own Chronic Fatigue Syndrome patients. The treatment was indeed working to kill Cpn, but the toxicity of the Cpn kill was causing existing symptoms to worsen significantly. The dropout rate using the combination antibiotic protocol (CAP) for Chronic Fatigue Syndrome was very high. Many patients were unable to see it through to the endpoint of the whole of the treatment process—where PCR signal was absent for Cpn. As Dr. Stratton put it to me in an interview, "The cure appeared worse than the disease." It was difficult for the treating physicians to keep patients on the protocol long enough to begin to see significant symptomatic improvement. This was due to two major difficulties.

• Die-off reactions- When combinations were used the die-off reactions from this potent mix could be as bad, or worse, than the Chronic Fatigue Syndrome itself. Little was yet known about how to support patients through these reactions, or what exactly their nature was.

• Length of treatment- Moreover, the length of treatment of Cpn with these combination antibiotic protocolsi for Chronic Fatigue Syndrome was very long. It was difficult to get patients to "stay the course" without extraordinary support, or dedication on the part of both the patient and the physician.

It was quite a challenge for the Chronic Fatigue Syndrome physicians, including Dr. Stratton, to know how to manage these responses and how to support their patients to hang in with a treatment that seemed to have little short term gain.[10] Of those patients (a small number) who Dr. Stratton treated personally and who continued after the end of the study through the full course of protocol there was, says Dr. Stratton, "100% improvement of symptoms."

Why did the eradication of Chlamydia pneumoniae cause such reaction in CFS patients? People treated for actual pneumonia caused by Cpn (community acquired pneumonia) don't appear to have severe reactions to their antibiotics after all.

First, the combination antibiotic protocol (CAP) was far more effective than a single antibiotic used in standard treatment of Cpn pneumonia because it attacked all of the phases of the Cpn life cycle. A single antibiotic only kills Cpn in one of it's life phases. The symptoms of CFS disease are related to Cpn's toxic and inflammatory impact on the body. The more you kill at once, the more these reactions.

Secondly, CFS patients appear to have built up a very high load of Cpn, spread through a large variety of tissues: the bone marrow, the connective tissue, the liver, the spleen, the vascular system, heart, and so on. When you have a highly toxic organism being killed in large numbers, in a wide variety of tissues, you have more severity of reactions.

Additionally, the overall Chlamydia pneumoniae bacterial loadi appears to be one of the big determining factors in the length of the therapy needed. The higher the load, the longer the therapy required.

Implied in this also is...

• The longer one has had the disease,
• The more organ systems affected,
• The less resilient the patient from age, additional illnesses, etc.,

...The longer and more challenging is the treatment required.

As a group, patients with Chronic Fatigue Syndrome/Fibromyalgia Syndrome appear to have higher Chlamydia pneumoniae loads in more different organs and tissues, compared to say MS patients, making treatment with the CAP more challenging, longer, and creating a significant dropout rate as it took longer to see the beneficial results versus the immediate term die-off reactions. But further research into this very promising but challenging treatment process was halted before questions about how to improve the treatment process could be answered.

Research is halted-

At about this point in the research, word was getting out in the medical community that they were testing blood samples from Chronic Fatigue Syndrome patients. There ensued a deluge of protest from medical colleagues who objected to research with Chronic Fatigue Syndrome being conducted at Vanderbilt. According to Dr. Stratton, the objections were "quite heated."

Why would microbiological research, as hard-science an aspect of the medicine as one could imagine, stir such heated outrage?

At that time, the late 1990's the diagnosis of Chronic Fatigue Syndrome was hugely controversial. Even more than it is today. Despite having a CDC case definition, a significant number of physicians believed that Chronic Fatigue Syndrome did not exist as a real medical entity or diagnosis. They believed that it was a false, catchall "syndrome," essentially representing psychiatric problems. Therefore it was not considered a legitimate area of serious scientific medical research.

The expressed concern was that the reputation of Vanderbilt University, and by extension the protesting physicians who were associated with Vanderbilt, would be sullied by sponsoring work such a medical "non-entity" and be seen as fostering specious science. This kind of reaction was not just reflective of physicians only associated with Vanderbilt of course. In general at this time, scientists or institutions associated with any kind of Chronic Fatigue Syndrome research were seen as incompetents, and were often made pariahs to conventional medicine. CFS research was often a career ender for career scientists. The reactions from potential publication journals at this time were similar. Please remember that this was only 10 or 12 years ago, and these attitudes still exist today in medicine.

At about this time the grant money for this study ran out. As Dr. Stratton was serving only as the testing laboratory, he did not have access to the patient data himself to have adequate controls over patient selection and the like to make for publishable results. Vanderbilt itself did not have a CFS clinic to draw from.

As Dr. Stratton's expertise was in Chlamydia, not in CFS, he turned his research interests towards an area of research on Cpn with less diagnostic controversy, and where Vanderbilt did have it's own disease based clinic. Dr. Stratton and his colleagues, spearheaded by Dr. Siram in neurology, shifted the focus of their research to Multiple Sclerosis. This was done in part to have a widely accepted, "legitimate" nosological (diagnostic) entity for research. As an accepted neurological disease, no one could call MS a psychological problem. As many of us know, this research has turned out to be almost as controversial, although for different reasons than the CFS study.

While one might wonder at Dr. Stratton's penchant for seeking controversy, the reality is that any research that cuts across accepted conventional viewpoints in medicine is likely to face rejection and derision. Anyone who knows Dr. Stratton would know that controversy is not at all a motivator in picking his research areas, Chlamydia is the motivator. Dr. David Wheldoni, a colleague and friend of Dr. Stratton's, noted Dr. Stratton's avoidance of the limelight by saying that he "Tends to hide his considerable light under a bushel."

There are probably other factors operating here as well. Any treatment process requiring a combination of three to four antibiotics for a very long period of time is anathema to most conventionally trained MD's. Most physicians have only the rudiments of microbiology in their training, and no basis to understand the complexities of treating multiple life-phase infectious agents.

As well, the development of antibiotic resistant strains of bacteria has created a kind of phobia about the long term use of antibiotics amongst most practicing MD's. This attitude is even more true for the use of multiple antibiotics at the same time. It is ironic that physicians who see nothing wrong in pumping patients full of multiple chemotoxic agents for cancer treatment will balk at the suggestion of far less harmful multiple antibiotic agents, calling it "polypharmacy." Ironically too, it is actually the use of multiple antibiotics in the CAP for Chlamydia pneumoniae that truly minimizes the chance of developing bacterial resistance, while repeated courses of single antibiotics, the "conventional medical" approach, creates much higher risk for developing bacterial resistance.

At any rate, these very interesting findings were never pursued. We still don't know what percentage of CFS patients are PCR positive for Chlamydia pneumoniae, and exactly how much Cpn is the origin of symptoms in this disease syndrome. What we do know is that those of us who have diagnosed CFS/FMS and have positive blood tests for Cpn have benefited, slowly, gradually, but significantly in many of our symptoms from the CAP for Cpn based on Dr. Stratton's work. This improvement is true as well for a number of CFS/FMS patients who, while not testing positive for Cpn using standard tests that are not as sensitive as those used by Dr. Stratton's lab, have evidenced typical die-off reactions to the CAP antibiotics, suggesting Cpn infection. Is it the case for all CFS/FMS? No one knows.

Chlamydial persistencei and antibiotic response-

Cpn has some unique characteristics which make it both an adaptive parasite, and difficult to eradicate. While over the years, some clinicians treating Chronic Fatigue Syndrome/Fibromyalgia Syndrome patients have tried the use of monotherapy (single) antibiotics with the notion that there might be an occult (hidden) bacterial infection involved in the disease, response by patients has been inconsistent. Some CFS/FMS patients may even have found their own symptoms temporarily improving when on incidental antibiotic treatment, say for ear infections and the like, but improvements not lasting.

That informal clinical experimenting with antibiotics in CFS/FMS has not resulted in much useful direction of treatment or research has to do with the unique biology and characteristics of Cpn. As these unique characteristics apparently are only known by microbiologists, and little understood by treating physicians, treatment of CFS/FMS with antibiotics has yielded conflicting results. Curiously, this ignorance of important microbiological facts about Cpn (and other infectious organisms) appears to extend to medical Infectious Disease specialists, whose knowledge of microbiology appears shockingly limited, and have not intelligently pursued the possibility of occult infection in these disorders.

Antibiotics in CFS/FMS have resulted in the whole range of responses:

• No improvement—leading to the assumption that no bacterial presence is involved.
• Improvements followed by a return of symptoms after the antibiotic is withdrawn. Since long-term use of antibiotics is discouraged, with the fear of creating resistance, further treatment is often discouraged.
• Symptoms worsening—leading to the assumption that they are having toxic or allergic effects, and leading to halting antibiotic treatment.

If, in fact, Cpn causes even a subset of CFS/FMS, the lack of consistency to antibiotic treatment has to be explained. This inconsistency becomes understandable if you know some key features about the biology of Chlamydia pneumoniae.

• No improvement- the antibiotics used may not be effective antichlamydials. Thus a "trial of antibiotics" using the incorrect agent would be expected to yield negative results in the disease symptoms. The sensitivity tests done by Stratton, et al demonstrated clearly that a number of commonly held "high power" antibiotics are not effective against Chlamydia pneumoniae.
• Temporary improvement- One of the great scientific puzzles about Chlamydia pneumoniae has been its ability to persist and reinfect, even treatment by antibiotics. It does this, and evades the immune system and threats such as starvation, by its ability to switch forms and survive in a different life phase that not affected by the particular threat.

There are three known phases or forms of Cpn:

1. The infectious, spore-like Elementary Body (EB): only killed by cysteine reducing agents like N-acetyl-cysteinei and amoxicillini
2. Once the EB invades a host cell it converts to the replicating Reticulate Body (RB)- only antibiotics that interfere with replication, such as protein synthase inhibitors doxycycline or azithromycin, affect it.
3. Finally, Cpn can survive those drugs by converting to the low metabolizing "cryptic" form, which Dr. Stratton's research found is only killed by metronidazolei family drugs.

Thus two weeks, or even two years of a single antibiotic may improve symptoms by suppressing one form of Chlamydia pneumoniae, but symptoms recur as soon as the antibiotic is withdrawn.

• Worsening- Killing Chlamydia pneumoniae liberates significant amounts of bacterial endotoxins which cause widespread cytokinei reactions, including inflammationi, pain, depression, low energy and so on. These are precisely the symptoms of Chronic Fatigue Syndrome/Fibromyalgia Syndrome itself. In addition, Stratton's work found that Chlamydia pneumoniae causes a condition of secondary porphyriai[11] that engenders further misery and suffering. Reports of strong reactions to antibiotics, and particularly to metronidazole, have lead the treating clinicians to misinterpret these reactions as allergy or drug reactions, and to prematurely withdraw the agent. The reality is that it is these bacterial toxins which are a great part of what causes the symptoms in CFS/FMS, and there is no way to kill Cpn without dumping these toxins into the system and feeling worse. The only question is how to pace it, and what measures can be taken to make it more tolerable.

Chronic Fatigue Syndrome/Fibromyalgia Syndrome Symptoms & Chlamydia pneumoniae

When we look at the common symptoms of Chronic Fatigue Syndrome and Fibromyalgia how might they be explained by what we know about Chlamydia pneumoniae biology and infection? In this section I will present a list of the major symptoms and look at how chlamydial biology and our own bodily response to this might generate these often puzzling symptoms.

Features of Chlamydia pneumoniae (Cpn) and Cpn infection:

Multi-Organ Infection- Cpn crosses from the respiratory system and can infect multiple organ systems including the nervous system, liver, heart, bone marrow, immune cells, skin, and so on.

Intracellulari Energy Parasite- Cpn reproduces by entering the host cell of your body tissue and stealing the ATP energy molecules that your cells function with.

Secondary porphyria- Depletion of host cell ATP by Chlamydia pneumoniae means that your cells don't have enough energy to complete their normal biochemical reactions. One of these, the production of heme