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Editor's Note & Introduction:
Does chronic Chlamydia pneumoniae (Cpn) infection play a role in the pathogenesis or symptoms of some patients with Chronic Fatigue Syndrome, Fibromyalgia Syndrome, and other unexplained illnesses? It's a distinct possibility, based on a never-published trial conducted by leading CFS clinical researchers Peterson, Cheney, Bell, and Stratton in the late 1990's. Here's the story of that research and an opinion on its implications for CFS and FMS patients, written by James Kepner, a leader of the Cpn patient community.

Who is Jim Kepner? He is an active Chlamydia pneumoniae patient advocate, and owner/founder of CpnHelp.org, "a website devoted to the understanding and treatment of Chlamydia pneumoniae, an infectious bacteria implicated in a number of human illnesses." It is a non-commercial site "run and supported by volunteers, and does not take monetary or other assistance from any other sources." In the following article Mr. Kepner refers extensively to the work of Charles W. Stratton, MD,¹ Associate Professor and Director of Clinical Microbiology at Vanderbilt University School of Medicine in Nashville, Tennessee. Dr. Stratton's research focus is the pathogenesis of Cpn, with a present emphasis on its possible role in Multiple Sclerosis. Other researchers at Johns Hopkins, the Mayo Clinic, and elsewhere have been similarly focused on investigating Cpn's possible role in a range of illnesses, from Coronary Artery Disease and Rheumatoid Arthritis to Interstitial Cystitis.

What is Chlamydia pneumoniae? Extensive information about this organism and associated research is offered at the Cpnhelp.org site and in this article. Briefly, Chlamydia pneumoniae is a bacterial organism first described in 1988 that is most commonly contracted by breathing droplets floating in the air after a person who carries it has coughed - as with the organism that causes tuberculosis. Cpn can then infect the "mucous-moving" cells lining the airways. It can paralyze those cells because it survives by stealing their energy, and may cause a serious respiratory infection. Then, if the body's immune response is unable to kill the invading Cpn bacteria, they can be disseminated via "mononuclear cells" in the bloodstream to infect other cells in the body, such as those that line the blood vessels, nerve tissues, brain, muscles, and even immune cells. There again Cpn bacteria metabolize and damage these cells by "stealing" energy. Further, the Cpn bacteria are drawn to newly formed mononuclear blood cells, which tend to be generated where there is inflammation in the body - and where the Cpn can cause a secondary infection. And finally, Cpn passes through three forms in its life cycle, so that research indicates a combination of antibiotics may be necessary to kill it off in all forms.

"If you have inflammation, a spider bite, a viral joint infection, viral meningitis, or encephalitis," Dr. Stratton has said, "it doesn't matter what it is, if a Chlamydia-infected cell happens to end up in that inflamed area, you may have just started yourself a Chlamydia farm." In which case Chlamydia may not be the cause of the disease, but may play an important role in its progression.^1A

Chronic Fatigue Syndrome (CFS), also called Chronic Fatigue Immunodeficiency Disorder (CFIDS), or called Myalgic Encephalomyelitis (ME) in Great Britain, affects 1 million Americans, with "tens of millions" more who have a fatigue condition that doesn't meet the strict criteria for CFS². According to the Centers for Disease Control and Prevention (CDC), which considers CFS an accepted medical condition³, there is no officially known cause or cure for CFS or for the related, and often co-occurring, condition of Fibromyalgia Syndrome (FMS)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 its sufferers when, naively seeking medical assistance, they find that their doctor doesn't believe that their symptoms are from a "real disease" or merit medical treatment. That there is no known "test" for Chronic Fatigue Syndrome that can conclusively demonstrate its existence is one of the difficulties here.

As the causal factors of CFS are considered unknown, conventional medical treatment for it and for Fibromyalgia Syndrome are all palliative [addressing symptoms] 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

Chronic Fatigue Syndrome is often disparaged as being a "syndrome," merely a collection of symptoms, not a disease - that is, not 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 diagnosis of "pneumonia" does not tell 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 beyond conventional medical ignorance about CFS. These combine both symptomatic treatment and a 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 CFS is that of bacterial or viral infection. Especially "occult infections" - that is, those organisms that are either typically overlooked or difficult to test for, or tend to evade the immune system.⁷ Within this causal possibility are infectious organisms such as Chlamydia pneumoniae.

My purpose here will to be present the information that argues for the involvement of Chlamydia pneumoniae in at least a subset of CFS and FMS 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 CFS.

At the outset it should be said that Chlamydia pneumoniae (Cpn) is not the only infectious agent that has been implicated in CFS/FMS. We certainly don't know if it is involved in all or in a subset, or is 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 to correct this ignorance, and place Chlamydia pneumoniae more clearly in the realm of possible sources for these devastating conditions.

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 Stratton and his lab on Chlamydia pneumoniae was actually not first directed at Multiple Sclerosis, as is more commonly believed, but looked at Cpn in Chronic Fatigue Syndrome. The first grant monies received by Dr. Stratton for Cpn research, using the highly sensitive tests they have developed, were from the Massachusetts Chronic Fatigue Foundation in the mid to late 1990s.

Dr. Stratton was asked to test blood samples submitted by the well-known Chronic Fatigue Syndrome physicians Paul Cheney, MD, Daniel Peterson, MD, and David S. Bell, MD to explore the possible involvement of Cpn in their CFS 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.

In this research, Doctors Cheney, Peterson, and Bell sent blood samples from their own CFS patients to Dr. Stratton's Vanderbilt Chlamydia pneumoniae Research Lab for testing. According to Dr. Stratton, they tested hundreds if not thousands of such blood samples. These were tested using both ELISA-based serologic methods and PCR [polymerase chain reaction] testing using the tests developed by Stratton, et al. at the Vanderbilt Cpn lab. Dr. Stratton's lab found that the majority (almost 100%) of CFS patients were PCR positive for Cpn in blood samples.

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

Of course, this in and of itself does not mean Cpn is the cause of CFS. The presence of Cpn could be due to some third factor that is part of CFS (such as immuno-suppression, etc). But such a high correlation with one specific organism outweighs every other 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 criterion used to select those patient samples sent to Vanderbilt. This remains unknown as of this writing.

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

The obvious next step was to try courses of antibiotics known to be anti-chlamydial and see if reduction of PCR signal for Cpn correlated with reduction in CFS symptoms. This was done by Doctors Cheney, Peterson, and 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 the CpnHelp.org 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 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 Cpn 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 the CpnHelp.org website) would completely eradicate Cpn 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), 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.

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 Doctors Cheney, Peterson, and Bell, as well as by Dr. Stratton with his own CFS 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 or CAP for CFS was very high. Many patients were unable to see it through to the endpoint of the whole 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.

It was quite a challenge for the CFS 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 For those patients (a small number) whom Dr. Stratton treated personally and who continued after the end of the study through the full course of the protocol there was, says Dr. Stratton, "100 percent improvement of symptoms."

Why did the eradication of Cpn cause such a 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 because it attacked all of the phases of the Cpn life cycle. A single antibiotic only kills Cpn in one of its life phases. The symptoms of CFS are related to Cpn's toxic and inflammatory impact on the body. The more you kill at once, the greater these reactions.

Second, 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 Cpn bacterial load 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 that...

The longer one has had the disease,

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 CFS patients. There ensued a deluge of protest from medical colleagues who objected to research with CFS being conducted at Vanderbilt. According to Dr. Stratton, the objections were "quite heated."

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

At that time, the late 1990's, the diagnosis of CFS 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 on 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 that 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 toward an area of research on Cpn with less diagnostic controversy, and where Vanderbilt did have its own disease-based clinic. Dr. Stratton and his colleagues, spearheaded by Dr. Subramaniam Sriram, MD, 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 Wheldon, 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 use of 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 combination antibiotic protocol 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 Persistence 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 that 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:

n No improvement - leading to the assumption that no bacterial presence is involved.
n 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.
n 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.

n 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.
n 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 is 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-cysteine and amoxicillin.

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 metronidazole 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 cytokine reactions, including inflammation, 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 porphyria¹¹ that engenders further misery and suffering. Reports of strong reactions to antibiotics, and particularly to metronidazole, have led 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 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.

CFS/FMS 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 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.

Intracellular Energy Parasite. Cpn reproduces by entering the host cell of your body tissue and stealing the ATP energy molecules that your cells function with. [ATP, or Adenosine triphosphate, transports chemical energy within the body’s cells.]

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 [the deep red iron containing component of hemoglobin], requires lots of ATP to come to completion. ATP depletion results in incomplete heme production and a build up of the incomplete byproducts called porphyrins. Porphyrins are neurotoxic and have numerous deleterious effects on the nervous system including anxiety, depression, bowel and digestive disturbance, and interference with sleep, rapid pulse, and even psychosis.

Chlamydial Endotoxins. Chlamydia pneumoniae contains a number of endotoxins in its structure, such as LPSi and HSPi-60. These endotoxins cause widespread inflammation (cytokine cascades) and a host of other metabolic disturbances. These are released chronically in small amounts in Chlamydia pneumoniae infection and in large amounts when Cpn cells are killed.

Cytokine Cascades. Cytokine responses (inflammatory immune reactions) are rampant in Chlamydia pneumoniae infection from a number of sources: to Cpn endotoxins; to the bacterial envelopes left behind by dead Chlamydia pneumoniae bacteria in tissue, which cause a variety of inflammatory reactions; and even the death of neighboring non-infected healthy cells.¹²

Antibodies to Vitamin B-12. B-12 is an important co-factor in a number of energy and detoxification processes in the body. One of the unique findings of Dr. Stratton's group was that antibodies to vitamin B-12 develop in many Chlamydia pneumoniae infected patients. This means that normal blood levels of this vitamin are insufficient, as it is bound to antibodies and useless to body functions affecting energy production and detoxification (methylization).

With these in mind, let's look at how these, and other factors about Cpn, might explain some of the otherwise mysterious symptoms of Chronic Fatigue Syndrome and Fibromyalgia.

General, Unrelieved Fatigue

n This is the most characteristic feature of CFS and, other than pain, of FMS.

n ATP depletion from Chlamydia pneumoniae parasitism simply leaves less energy available for body functions.

n Fatigue is a main symptom of porphyria.

n Cardiac infection: Cpn infects the cardiac system, and is a major culprit being investigated as a source of cardiac disease. Parasitization of cardiac muscle by Chlamydia pneumoniae would reduce heart efficiency and contribute significantly to fatigue. A recent paper found evidence of Cpn throughout myocardium, the heart muscle wall. These infected muscles would presumably be functioning at lower efficiency because of ATP depletion, resulting in a chronic cardiac insufficiency. This is consistent with findings of cardiac insufficiency in CFS patients (see Peckerman).^13,14

n Cytokine cascade in CFS.¹⁵ The typical malaise and fatigue of a cold or flu is caused by the flood of cytokines that are generated in the innate immune response. Chlamydia pneumoniae infection tends to stimulate a chronic innate immune response and this chronic cytokine cascade is an additional source possible in CFS fatigue. This has been called "sickness behavior" - i.e., the behavioral responses to an immune cascade. (See "Cytokine dysregulation, inflammation and well-being" in references²⁹).

Tender Axillary or Cervical Lymph Nodes

One of the main routes by which Cpn is carried through the body is the lymphatic system via infected immune cells. Chlamydia pneumoniae infected lymphocytes and/or infection of the lymphatic system itself would easily account for this clinical finding in CFS.^16,17 These lymph nodes in particular drain the upper respiratory system (sinuses, throat, etc), and these areas are a major entry point for Cpn into the body via sinus infection, laryngitis, and so on.

Immune Deficiency¹⁸

n Chlamydia pneumoniae can infect bone marrow.¹⁹ That is where our immune cells (macrophages, monocytes, neutrophils) are produced. Infected bone marrow will produce infected and thus poorly functioning immune cells, resulting in a low-grade immunodeficiency.

n Co-infections resulting from poor immune functioning from opportunistic organisms - viruses, bacteria, mycoplasms, fungi & yeasts and such - are more likely gain a foothold. These further confuse the clinical picture as to what is cause and what is effect or co-factor, and add to further immune burden and further reduced immune function. The more organisms the immune system (already infected itself) has to deal with, the less resources available for any one thing.

Cardiac Insufficiency

Cardiac insufficiency has been identified in CFS patients as a significant correlate to symptom severity²⁰ �?so much so that Dr. Paul Cheney (yes, the same one who participated in the CFS/CPN study) has focused on this as his cause celebre for CFS recently.²¹ As we have noted, Cpn is parasitic and steals ATP, the energy molecule, from the infected host cell to subvert it for its own replication process. Heart muscle is one of the most ATP demanding cells. Cp infection of heart muscle as discussed previously is likely to result in reduced heart efficiency, explaining the results of the Peckerman study and giving a causal element to Dr. Cheney’s observations of cardiac dysfunction in CFS. Why Dr. Cheney has ignored the earlier work he participated in, which implicates an organism that is becoming well known for its involvement in cardiac disease, is a real curiosity.

Exercise Intolerance and Post-Exertional Fatigue

Cardiac Insufficiency. See cardiac infection comments previously noted. Impaired performance on treadmill commonly noted in CFS/FMS could be similarly explained by this as well as other factors.

Muscle and General ATP Depletion. Chlamydia pneumoniae is an ATP parasite in infected cells, leaving of this energy molecule for host cells. In a broad based Chlamydia pneumoniae infection stores of ATP would be generally depleted, such that high output exercise would leave a significant ATP deficit in some systems such as the muscular system.

Porphyrins. Porphyrin load increases after exercise or exertion because ATP stores, already in short supply because of Cpn parasitism, are used up at rapid rate by muscle activity. This makes even less ATP available for heme production resulting in incomplete heme and its byproducts, porphyrins. An inadequate supply of ATP means that only the amount of exercise up to the ATP limit at that particular moment can be tolerated. The increased porphyrin byproducts result in post-exertional fatigue and long recovery time. This is the "over-exert one day, payback for three days" report common to many CFS patients.

Gastrointestinal Problems

n CFS and FMS patients often have concomitant gastrointestinal problems, ranging from Irritable Bowel Syndrome, poor nutrient absorption, and other problems.

n Cpn infects endothelial tissues, as its preferred home, including the endothelial tissues of the gut. Some of the micrographs of Cpn infected cells which can be viewed on this website are of stained intestinal endothelial tissues.²²

n Porphyria is notorious for causing chronic gut distress: nausea, intestinal cramping, etc. Chlamydia pneumoniae infection of gut endothelial tissue.

n Gut co-infections from fungi, bacteria, or yeast resulting from general immunosuppression, or specific Cpn infected gut-immune system will further add to gastrointestinal problems.

Sleep Disorder

n Porphyrins block GABA receptors, a main cause of anxiety and agitation in porphyria, and likely to interfere with sleep.

n Melatonin serves a number of functions that are related to protecting cells from oxidation²³ as well as binding inflammatory endotoxins²⁴ and activating immune functions.²⁵ Melatonin depletion from it being used up for antioxidant and other metabolic purposes resulting from Cpn infection could result in inadequate amounts left for neurotransmitter production and its influence on inducing sleep.

n Hypothalamic infection and disturbance by Chlamydia pneumoniae could be a contributing factor.

n Cytokine disturbance of sleep regulation.²⁶

Anxiety & Depression

n Porphyrins- noted previously for causing anxiety, depression, even psychosis.

n Depletion of melatonin noted above causes depletion of serotonin in the brain. Inadequate serotonin results in depression, as well as increased pain sensitivity.

n Cytokine depression - cytokines are clearly linked to causing depressive symptoms.²⁷

Endocrine Disturbance (Thyroid, Periods, Etc.)

n Infection of endocrine gland cells: thyroid, pancreas islet cells, pituitary, pineal, etc.

n Glucose disturbance. Chlamydia pneumoniae steals ATP that requires the host cell to absorb and metabolize more glucose. This disturbs glucose homeostasis. "Hypoglycemic" symptoms (must have food now, worsening of inflammatory and porphyric symptoms when get depleted of glucose or during fasting, etc.) are common in CFS/FMS and are quite notable in those suffering from disseminated Chlamydia pneumoniae infection. Anecdotally, Chlamydia pneumoniae patients on the CAP report significant lessening of episodes of these hypoglycemic symptoms over the course of treatment.

Headaches

n Porphyrins. One of the neurotoxic effects of porphyrins is headaches.

n Vascular disturbance direct and indirect. Cpn infects the vascular system leading to high blood pressure (from rigidified vascular walls), headaches, inflammation of blood vessels (including those in the brain), etc.

n Sympathetic nervous system over activation from chronic upregulated innate immune response caused by infection.²⁸

“Sickness Behavior�?/B>

Mentioned earlier, sickness behaviors are the innate, the behavioral responses to cytokines that have been stimulated by infection: feeling lousy, withdrawal, depression, movement avoidance, and energy conserving, etc.²⁹

Cognitive Dysfunction (Brain Fog)

This is one of the most frustrating features of CFS/FMS, and one with little explanation in the domain, despite its being one of the most life-impacting symptoms for the sufferer. Cpn infection explains this very well.

n Secondary porphyria induced by it and the impact of porphyrins on brain functioning.

n Cerebral inflammation from circulating cytokines.

n Brain infection.

n Endotoxins.

FIBROMYALGIA SYMPTOMS

All of the above plus�?

Musculoskeletal Pain and Inflammation

n Soft tissue infection by Chlamydia pneumoniae and subsequent inflammation.

n Fibromyalgia Syndrome often starts after injury/accident. In the normal response to tissue repair, injured and inflamed areas attract macrophages. Chlamydia pneumoniae infected macrophages can leave Chlamydia pneumoniae behind in injured/inflamed area. Infection then becomes progressive gradually spreading from that area. As generalized inflammation increases (from free circulating cytokines) these sites are further infected by parasitized macrophages drawn to increasingly inflamed sites, etc. See http://www.cpnhelp.org/how_chlamydia_pneumoniae_

n Porphyrins blocking GABA receptors will also lower pain tolerance.

n Generalized cytokine load causes broad based "feels lousy all over."

SUMMARY CONCLUSION

The case for Cpn in CFS does not prove that Cpn is always the causal element. As a syndrome, CFS may originate from a variety of causal factors, and these could be different for different patients. But in a disease where modern medicine has had no curative treatment to offer, it is clearly a causal factor worth looking into. Even with negative blood tests for Cpn, an empirical trial of the CAP for Cpn is worth exploring.

In future articles I hope to discuss some of the potential complexities of treating Cpn in CFS/FMS patients with the Combination Antibiotic Protocol, and some considerations that make treating this different from other Cpn related diseases.

* * * *

References

1. My deep appreciation to Dr. Charles Stratton for his review and consultation in formulating this article. Beyond that, my tender deepest respect to him for bravery under fire. My thanks also to Marie Rhodes, for saving me some grammatical embarrassments!

1-A. See "Chlamydia pneumoniae not caught like you thought," Vanderbilt Medical Center Reporter, April 23, 1999.

2. http://www.cdc.gov/cfs/cfsbasicfacts.htm#prevalence

3. CDC Diagnostic Symptoms

Unexplained, persistent fatigue that is not due to ongoing exertion, is not substantially relieved by rest, is of new onset (not lifelong) and results in a significant reduction in previous levels of activity - and four or more of the following symptoms are present for six months or more:

Impaired memory or concentration

Postexertional malaise (extreme, prolonged exhaustion and exacerbation of symptoms following physical or mental exertion)

Unrefreshing sleep

Muscle pain

Multi-joint pain without swelling or redness adults

Headaches of a new type or severity

Sore throat that’s frequent or recurring

Tender cervical or axillary lymph nodes

Other Commonly Observed Symptoms in CFS
The frequencies of occurrence of these symptoms vary from 20% to 50% among CFS patients. �?include abdominal pain, alcohol intolerance, bloating, chest pain, chronic cough, diarrhea, dizziness, dry eyes or mouth, earaches, irregular heartbeat, jaw pain, morning stiffness, nausea, night sweats, psychological problems (depression, irritability, anxiety, panic attacks), shortness of breath, skin sensations, tingling sensations, and weight loss.

4. Estimated by the American College of Rheumatology to affect 6 million Americans.

5. A popular palliative intervention with “cutting edge�?conventional practitioners is Cognitive Behavioral Therapy (CBT). I’m a psychologist by profession and should be fond of my profession’s contributions to a challenging disease. But my personal and professionally informed commentary on the value of CBT as a CFS/FMS treatment is not high. As applied to the condition of Chronic Fatigue Syndrome, CBT may be likened to teaching someone to how to become more relaxed and organized while one is standing upon a sinking ship. Thus, metaphorically, CBT teaches one how to adjust their viewpoint as the horizon tilts; how to stop worrying about the water lapping at their feet, how to counter the emotional responses of impending doom, how to relax so their stress doesn’t add water to the already sinking ship, and so on. Like my stubborn friends here at www.cpnhelp.org dealing with Multiple Sclerosis who were often told there’s nothing that can be done but “get comfortable with your disease,�?finding comfort in my decline has never been personally attractive to me as a solution.

Some studies have found CBT “effective�?in reducing CFS symptom severity. This makes CBT much beloved by conventional physicians as it, a) Is legitimized by scientific research, b) they feel at least they have something to offer these “difficult-to-help-patients,�?and c) CBT still fits comfortably with the continuing vague suspicion that CFS isn’t really a disease at all but is really “all in their head�?after all. I have not spoken a single CFS patient, and I have communicated with many, who has found that CBT did anything of significance for them in terms of their disease. This said, CBT does teach highly valuable relaxation, stress management and cognitive strategy skills. These are useful in a disorder highly impacted by stress and which is very cognitively disorganizing. However like all palliative measures, CBT is only helpful at managing the disease, and in this it is not even profoundly so.

6. “Effective Treatment Of Chronic Fatigue Syndrome (CFIDS) & Fibromyalgia (FMS) - A Randomized, Double-Blind, Placebo-Controlled, Intent To Treat Study,�?Teitelbaum J, et al. Annapolis Research Center For Effective FMS/CFIDS Therapies; Annapolis, Maryland; Anne Arundel Medical Center, Annapolis, Maryland, Gaithersburg, MD; USDA, Beltsville, Maryland. Journal Of Chronic Fatigue Syndrome Volume 8, Issue 2 �?2001

7. “The immune system, atherosclerosis and persisting infection,”[article in Russian] PV Pigarevskii, et al., Vestm Rpss Alad. 2005;(2);17-22. Abstract in English: http://www.cpnhelp.org/?q=node/129

8. “Multiple co-infections (Mycoplasma, Chlamydia, Human Herpes Virus-6) in blood of Chronic Fatigue Syndrome patients: Association with signs and symptoms,�?Nicolson GL, Gan R, Haier J. Clin Infect Dis. 1999 Aug;29(2):452-3; and “Chronic Chlamydia pneumoniae infection: A treatable cause of Chronic Fatigue Syndrome,�?Chia JK, Chia LY. Torrance Memorial Medical Center, California, U.S.A.J Infect Dis. 1992 Jan;165(1):184

9. “Detection of Chlamydia in the peripheral blood cells of normal donors using in vitro culture, immunofluorescence microscopy and flow cytometry techniques,�?Cirino F, et al. (E-mail: [email protected]) BMC Infectious Diseases. 2006, 6:23 doi:10.1186/1471-2334-6-23 ; and “Prevalence of viable Chlamydia pneumoniae in peripheral blood mononuclear cells of healthy blood donors,�?Yamaguchi H, et al. Transfusion. 2004 Jul;44(7):1072-8

�?“Thirteen of 70 donors (18.5%) showed the presence of bacterial transcript in cultured PBMNCs. …CONCLUSION: The bacterial transcripts in PBMNCs obtained from healthy donors were detected by the RT-PCR method. Viable C. pneumoniae may be present in healthy human PBMNCs…�?

10. Note - One of the things Dr. Stratton said to me shortly after I started www.cpnhelp.org was that this kind of thing was one of the missing elements in the treatment process: some kind of on-going support community that could help patients through the challenges and confusions of being on a difficult protocol.

11. As far as I know Dr. Stratton’s group are the only ones to have found the link between Chlamydia pneumoniae infection and secondary porphyria. It remains unpublished in the scientific literature and so virtually unknown to most medical practitioners.

12. “Cell death and inflammation during infection with the obligate intracellular pathogen, Chlamydia,�?http://www.cpnhelp.org/?q=cell_death_and_inflammati

13. “Persistent Chlamydia pneumoniae infection of cardiomyocytes is correlated with fatal myocardial infarction,�?by Spagnolie LG, et al. Cattedra di Anatomia ed Istologia Patologica, Dipartimento di Biopatologia e Diagnostica per Immagini, Universita di Roma Tor Vergata, Rome, Italy. [E-mail: [email protected] ] Am J Pathol. 2007 Jan;170(1):33-42. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17200180&dopt=Abstract

14. Additional cardiac findings in CFS consistent with cardiac infection by Chlamydia pneumoniae from “Causes of death among patients with Chronic Fatigue Syndrome,�?by Jason LA, Corradi K, Gress S, Williams S, Torres-Harding S. DePaul University, Chicago, Illinois, USA. Health Care Women Int. 2006 Aug;27(7):615-26. PMID: 16844674

“�?in response to postural stress, 81% of patients with CFS, but none of controls, experienced ejection fraction decreases (suggesting left ventricular dysfunction in the heart) and those with more severe symptoms had greater decreases (Peckerman, Chemitiganti, et al., 2003).

“Patients with CFS might have lower cardiac output, and the resulting low flow circulatory state could make it difficult for patients to meet the demands of everyday activity, and it could also lead to fatigue and other symptoms (Peckerman, LaManca, et al., 2003)…�?

15. “Cytokines and Chronic Fatigue Syndrome,�?Patarca R. E. M. Papper Laboratory of Clinical Immunology, Department of Medicine, University of Miami School of Medicine, Miami, Florida USA. Annals of the New York Academy of Sciences. 933:185-200 (2001). http://www.annalsonline.org/cgi/content/abstract/933/1/185

16. “The immune system, atherosclerosis and persisting infection" [article in Russian], Pigarevskii PV, et al. Vestn Ross Akad Med Nauk. 2005;(2):17-22. PMID: 15776961

17. “Phagocytes transmit Chlamydia pneumoniae from the lungs to the vasculature,�?Gieffers J, et al., Institute for Medical Microbiology and Hygiene, University of Lubeck, Lubeck Germany. Eur Respir J. 2004 Apr;23(4):506-10.

18. “Causes of death among patients with Chronic Fatigue Syndrome,�?Jason LA, et al., DePaul University, Chicago, Illinois, USA. Health Care Women Int. 2006 Aug;27(7):615-26.

19. “Detection of Chlamydophila pneumoniae in the bone marrow of two patients with unexplained chronic anaemia,�?Nebe CT, et al., Central Laboratory, University Hospital Mannheim, Mannheim, Germany. Eur J Haematol. 2005 Jan;74(1):77-83.

20. “Abnormal impedance cardiography predicts symptom severity in Chronic Fatigue Syndrome,�?A Peckerman, et al., Department of Neurosciences, CFS Cooperative Research Center, University of Medicine and Dentistry of New Jersey, Newark, New Jersey. Am J Med Sci. 2003 Aug;326(2):55-60.

21. http://www.cfids-cab.org/MESA/Lerner.html

22. http://www.cpnhelp.org/cpn_in_gi_tract_tissue_1

http://www.cpnhelp.org/cpn_in_gi_tract_tissue_2

http://www.cpnhelp.org/cpn_in_gi_tract_tissue_3

23. “Melatonin as Antioxidant Under Pathological Processes,�?Cristina Tomas-Zapico C, Coto-Montes A, Departamento de Morfologia Y Bilogia Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain. Recent Patents on Endocrine, Metabolic & Immune Drug Discovery. 2007, 1, 63-82. http://www.bentham.org/emi/samples/emi1-1/Tom%E1s-Zapico.pdf

24. “Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats,�?Crespo E, et al. FASEB J. 13, 1537�?546 (1999). http://www.fasebj.org/cgi/reprint/13/12/1537.pdf

25. “Activation of human monocytes by the pineal hormone melatonin,�?KM Morrey, et al., Department of Molecular Pharmacology and Biologic Chemistry, Northwestern University Medical School, Chicago, Illinois. J Immunol. 1994 Sep 15;153(6):2671-80.

26. “The Role of Cytokines in Physiological Sleep Regulation,�?Kruegera JM, et al., The Role of Neural Plasticity in Chemical Intolerance - Annals of the New York Academy of Sciences, 933 (1), 211�?21.

27. "Is There a Biologic Connection Between Inflammatory Disease and Depression?" Stong C, NeuroPsychiatry Reviews, September 2004, Vol. 5, No.7. http://www.neuropsychiatryreviews.com/sep04/sep04_npr_inflammatory.html

28. “Migraine: A Chronic Sympathetic Nervous System Disorder,�?Perouta SJ. Headache. 2004 Jan;44(1):53-64. http://www.medscape.com/viewarticle/466937_1

29. “Illness, cytokines, and depression,�?Yirmiya R, et al., Department of Psychology, Hebrew University, Hadassah Hospital, Jerusalem, Israel. Ann N Y Acad Sci. 2000;917:478-87.

“Cytokine dysregulation, inflammation and well-being,�?Elenkov IJ, et al., Division of Rheumatology, Immunology and Allergy, Georgetown University Medical Center, Washington, DC, U.S.A. Neuroimmunomodulation. 2005;12(5):255-69.

30. In 1990, the American College of Rheumatology, the official body of doctors who treat arthritis and related conditions, finally legitimized Fibromyalgia in the medical community by presenting its criteria for diagnosing it. It is diagnosed when you display the following symptoms: 1) a history of widespread pain (pain on both sides of the body and above and below the waist) that is present for at least three months; and 2) pain in at least 11 of 18 tender-point sites. http://www.arthritis.org/conditions/DiseaseCenter/Fibromyalgia/fibromyalgia.asp

An excellent review of infectious issues �?“Fibromyalgia: Is there an infectious connection?�?�?can be found at: http://www.roadback.org/index.cfm/fuseaction/education.display/display_id/135.html

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