Advice to Non-Medical Newcomers

Why are you here?  The reason is the same for all of us.  Either you or someone you care for is sick, so you're looking for something, anything to help.  Maybe it's MS^{i [113]}, CFS^{i [92]}, ME, FM, Lupus, Alzheimer's, unrelenting fatigue, pain and inflammation^{i [110]}, or something else.  You might  be desperate because you're up against a wall built of words like incurable, untreatable, and of unknown origin.  Perhaps a cutting-edge medication has been tried and failed.  With the media full of news about medical breakthroughs, you're frustrated that a meaningful treatment has not been found for your illness.  You're thinking that surely the answer lies somewhere out there in the vast body of knowledge that makes up modern medicine...someone just hasn't connected the dots yet.  You surf the internet and find websites offering support and education on the illness. You read articles about research and new treatments.  Much of it is written in medical-ese, and you may feel overwhelmed, even handicapped in your ability to milk the meaning out of the information you find.

I am a caregiver and care advocate for my husband who has a degenerative illness.  I have no medical background and I'm cyber-challenged.  If, like me, you're stubborn enough to keep struggling with all those research and treatment articles, and if you can make any sense out of them, a bigger picture emerges.  When you step back to assess the various bits of information collectively, you will find a gaping hole.  Something huge is missing.  The problem is that most of the current research and emerging treatments focus on "tinkering" with the disease process, not on addressing the root cause of the disease.  Why is that?

Things they forgot:  Entertain some what ifs with me.  What if research into the disease had been underway for several decades?  What if, in those early days, research efforts were concentrated on finding a microbe as the villain?  After all, the immune^{i [114]} systems of the people afflicted with the disease seemed to be attacking something that shouldn't have been there.  What if, after no infectious agent was found, the research community embraced the theory that the body sometimes goes nuts and attacks itself via a defective immune system?  What if this interesting autoimmune concept led researchers into some limited success in developing drugs that "tinker" with the immune system to some benefit for some of the afflicted some of the time?  Limited success is better than no success.  What if herd-mentality caused a stampede of researchers in one direction?  What if, in the meantime, there had been advances in microscopy and lab techniques that might have enabled those early researchers to find what they had been looking for?  What if the majority of the research/medical community had somehow lost track that the model of autoimmunity^{i [115]} was an unproven theory, and they had comfortably incorporated it into their thinking and efforts as though it were a given fact?  What if new technology applied to old ideas could result in the hope of treating the disease at its core rather than just "tinkering" with the disease process?

My husband's illness has been rubber-stamped as autoimmune.  Like you, I was searching, and like you, I am a relative newcomer to this website.  Most of the material on cpnhelp.org is very understandable, but you will eventually run into unfamiliar medical terms and processes.  Advice from other users, resource tips gleaned from their blogs, and my own experience have helped me develop a system for digesting the cpnhelp.org material and for understanding the medical-ese I encounter elsewhere on the internet as I investigate my husband's illness.  I'm offering you a shortcut.  Please let me help you in your quest to get the most out of this website, lits linked websites, other websites you are already visiting, and those you will visit in the future (especially those research articles).

THE SYSTEM:

Once over lightly - Follow the advice on the Homepage by reading Cpn Simple and The Basics Page in the Cpn Handbook...go back to the Handbook and skim through the sections concerning treatment just to know what's there.  Be sure to read the disclaimer and privacy statement.

Prepare to go deeper - Very simple, free, not much time, and so worth the effort.

• If you think you might want to try my system, print it and keep it handy.
• Build a small foundation of knowledge and understanding.  I can't emphasize enough how helpful this is.  After you do it, you'll want to revisit those research articles that were so befuddling.
• Click on this:  http://health.howstuffworks.com/immune-system.htm [116].  Read each short section.  Print it and keep it handy.  You will use it over and over again.
• Click:  http://en.wikipedia.org/wiki/Inflammation#Characteristics [117].  Read the entire page with particular thought given to the dysfunction aspect of inflammation.  Under the Outcomes heading, see if you don't recognize "collateral damage"  as it's called by the military.  Print it and keep it handy.

Read the entire Homepage again.

Read the Handbook.

• Read it all the way through or click on the topics in the Table of Contents found on the left side of the screen to read specific information.
• Use the glossary on the left side of the screen (you may need to use the up/down slide bar to locate it).
• Some terms in the Handbook will be marked with a highlighted " ⁱ  " at the end.  Click on the " ⁱ " for a definition or a comment about that term.
• For terms not found in the glossary, minimize the active cpnhelp.org page by clicking its identifying tab in the bar at the bottom of the screen.  Then go to medterms.com, wikipedia, or even howstuffworks.com (it's good, but has its limits).  You will discover other resources to use for the same purpose.
• After reading the definition(s) on the other websites, minimize the resource page(s).  Keep these resources at the ready in the bottom bar to pop up for future use.  Then click the appropriate bottom bar tab to restore the cpnhelp.org page.
• You may want to print the entire Handbook for portable reading.  Follow the printing instructions on the introduction page, especially the part about The Table of Contents.  A printed copy of the glossary is a good take-along aid as well.

Visit other cpnhelp.org resources by clicking the tabs found at the top of the screen.  The Patient Stories are sure to be a favorite resource.

Find out what the website users are blogging about by clicking recent posts on the left side of the screen.  If you spot a blogger that may be of interest because you suspect you have an illness in common, click on that user's highlighted name.  This will take you to a window where you can track other comments made by that user.

Navigate your way to the older posts; they are still new to you.

Search for a specific topic in the Search slots located in the upper right and lower left sides of the screen.

Check out what's happening on the right side of the screen.  Click around here and there and you'll soon become an expert navigator.  You will eventually want to participate, or perhaps you will want to go where only a user can go.  Welcome aboard, it's time to REGISTER!

 

 

 

 

Cpn Simple

 

Cpn^{i [90]} Simple- The shortest explanation we could think of!

Cpn has been clearly proven to have persistence^{i [108]} in the body despite “standard” antibiotic treatment (two weeks of a single antibiotic).

Cpn has been implicated in a wide variety of diseases^{i [1]} (see bottom of this page).

Blood tests and cultures are not reliable indicators of whether Cpn is part of your disease.

If you have any of the diseases in which Cpn has been implicated, it may be worth trying an “empirical” (based on symptoms alone) combination antibiotic protocol (Link).

Most doctors are not familiar with this, and you will have to present a rational and evidence based case to them for prescription of the appropriate antibiotics^{i [111]} through information such as on this site.

Is this right for you? 

Four indicators can be used to help you determine if an empirical test of the full combination antibiotic protocol is useful for you. You should be on it for for a minimum of 6 months to a year. The first three suggest that you have Cpn and you should continue this treatment.

1. You experience distinct reactions to the antibiotics indicative of Cpn die-off (see Reactions to Treatment link).

2. You have improvement of disease symptoms.

3. You have noticeable halting of symptom progression.

4. Nothing at all and decide this isn’t for you.

Diagram from David Wheldon^{i [118]} (http://www.davidwheldon.co.uk/killing.jpg [119]) used by permission. 

Phases of the Cpn bacteria and what agents effect those phases:

EB’s- Elementary Body What are they? EB’s are spore-like forms which are infectious and metabolize minimally (aren’t using nutrients, replicating, exchanging with the environment, etc.). They are tough, tiny and reside in the intercellular^{i [120]} tissues (outside of actual body cells). What do they do? EB’s attach to your body’s cells and invade them. Since there can be more EB’s than can get into cells, EB’s build up in local tissues causing inflammation^{i [110]} and immune^{i [114]} response.

What kills them? They are killed by amoxicillin^{i [121]}, which is transformed to penicilamine in your own body, and destroys the bonds which hold the EB cell wall together. An amino acid NAC^{i [122]} (N-acetyl cysteine) also is used for this purpose. What happens? When you kill them, they release toxin into the tissues in which they have built up, and you get inflammation and pain there, which can last for days or weeks afterwards before you feel relief of symptoms. Most people taking NAC report a period of flu-like feeling of malaise, achyness, nunning nose, perhaps coughling.

RB's- Reticulate Body What are they? Once an EB enters a host cell it transforms into a form which can replicate new EB's^{i [123]} which is called a Reticulate Body or RB. The RB has no energy source of it's own for this, so it must steal energy (ATP) from the host cell, leaving the host cell weakened and less functional. The RB also inhibits the natural cell death^{i [124]} of the host cell so that it can survive while it replicates. After the production of many new EB's the host cell bursts and dies, spreading the infectious new EB's into the surrounding tissue.RB's are inhibited in replicating by various antibiotics such as doxycycline, azithromycin, roxythromycin and others, and subject to this will convert into the Cryptic (and nonreplicating) form where they can be killed by metronidazole^{i [125]}. RB's are prevented from forming by rifamcin^{i [126]}.

Cryptic form^{i [127]} What are they? When RB’s face an environment which threatens their survival inside a cell (lack of food, antibiotic attack, etc) they can transform into a “Cryptic” form which stays inside the cell, but is in hibernation, so to speak. What do they do? In this form it is not vulnerable to regular antibiotics and can reside there until conditions change, then become an RB again and start to replicate and reinfect with EB’s. What kills them? Flagyl (metronidazole) or Tinactin^{i [95]} (tinidazole) are used to kill the cryptic forms of Cpn. Nitrofurantoin, an old urinary tract infection drug, also has antichalmydial effect in this phase. These drugs can be hard to tolerate for various reasons, and so are commonly “pulsed” by taking a course for 5 days every 3-4 weeks, rather than taken continuously. Some protocols^{i [2]} may eventually have one of these drugs taken continuously for some period as the patient can tolerate. Patients may experience fatigue, nausea, bowel upset, deep joint achyness and muscle pain as the cryptic orgnanisms are killed and the immune system engages in clean up.

Much of the discomfort from treating Cpn is a combination of the organism's endotxin itself, and the inflammation caused by your own immune system (cytokine^{i [128]}) reactions to that.

SUMMARY

Amoxicillan and NAC kills the infectious spore-like EB forms which build up in the tissues.

Rifamcin kills EB’s transforming to RB’s in a vulnerable enzyme transformation phase.

Doxycycline and either Rozithromycin or Azithromycin, are used in combination to interfere with the RB’s ability to replicate. Two are used which work on different proteins to minimize creating resistance.

Supplements^{i [5]} are recommended to help counter the impact of Cpn on the body, and of the inflammatory effect of the die off during treatment.

Treatment can take months to years to completely eradicate Cpn from the body.

What diseases has it been implicated in?

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CAP^{i [4]i [4]} for Cpn^{i [90]} 11/04. Dx^{i [91]i [91]}: 25yrs CFS^{i [92]} & FMS^{i [93]i [93]}. Currently: 250 aithromycin mwf, doxycycline 100mg BID^{i [94]i [94]}, Tini^{i [95]} 1000mg/day pulses; Vit D2000 units, T4 & T3, 12mg Iodoral

Slide Presentation on Cpn from Charles Stratton

Although focused on respiratory disease^{i [130]}, this slide show provides and excellent summary of Cpn^{i [90]} in general, and why combination antibiotic therapy is so important.

Click This Link [131] for a powerpoint presentation by Charles Stratton^{i [132]} on Cpn.

It includes great pictures of the organism at different life phases, and links Cpn various diseases^{i [1]}.

Download a .pdf file of the slide show, thanks to Red (!) CLICK HERE [133]

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CAP^{i [4]i [4]} for Cpn^{i [90]} 11/04. Dx^{i [91]i [91]}: 25yrs CFS^{i [92]i [92]} & FMS^{i [93]i [93]}. Currently: 250 aithromycin mwf, doxycycline 100mg BID^{i [94]i [94]}, Tini^{i [95]i [95]} 1000mg/day pulses; Vit D2000 units, T4 & T3, 12mg Iodoral

The Basics Page

Hello and Welcome!

This site is focused on treatment of chronic disease like Multiple Sclerosis (MS^{i [113]}) Chronic Fatigue Syndrome^{i [134]} (CFS^{i [92]}) and Fibromyalgia (FMS^{i [93]}) an many other diseases^{i [1]} with antibiotics^{i [111]}. Recent research indicates that Chlamydia Pneumoniae (CPn^{i [90]}) plays a role in these diseases.

Here are the basics that make it easier for people new to the site to get going (if your brain isn't ready for even this much right now-- we've all been there-- read Cpn Simple [135] first):

Is this a sexually transmitted disease? No. this is chlamydia pneumoniae, a bacteria that can cause pneumonia. It may soon be called chlamydiophilia (meaning in the family of).

Is chlamydia pneumoniae (CPn) rare?

No it is a common cause of respiratory illness, but it has an interesting and abnormal way of existing because it can change forms and inhabit the very cells of your body. It can go into your monocytes (a blood cell), your macrophages ^{i [136]}(an immune^{i [114]} cell), microglia (a brain cell that causes immune reaction) endothelial cells (blood vessels) and others and actually take over.  We say then it has parasitized the cell. Your cell can't do the work it was meant to do now because it's busy supporting the CPn, all the energy of the cell going to make energy for the CPn and it using that energy to make new CPn cells.  For all intents and purposes, your cell is no longer a functional cell and cannot do what it was designed to do.

How does it spread?

From person to person when in the respiratory tract it is spread by droplets; in a cough for example. The form that goes from one to another is the elementary body (EB), a tough, little tiny bacteria. It may actually cause pneumonia in the respiratory tract. In some cases once inside, the EB will look for a home (cell) to parasitize so it can have an energy source. Once inside the cell the EB turns into a reticular body (RB) which can produce new infective cells (EB's^{i [123]}) that can find and parasitize other cells. Gradually the cells of your body lose the ability to do what they were meant to do. They are now supporting CPn lifecycle and not taking care of your lifecycle. If it's a monocyte that's infected for example, it is now a factory for EB's not a functional monocyte.  We say then the CPn has parasitized the cell.

Click here for a detailed explanation of [107]of Cpn [107]

Why doesn't my immune system kill it?

This is a complex question. It depends on where the infection is and how advanced it is and what cells have been infected. People who get CPn as a form of pneumonia and do have an active immune response to the bacteria in that instance, though as a form of pneumonia it is mild. Often it is referred to as "walking pneumonia" because people, while ill, are not prostrate with it. Since most people get CPn in their lifetime and get over it as evidenced by rising titers to the bacteria, we can assume that most of the time the immune response is effective enough to for all intents and purposes "get over it."

In some people however, perhaps because of their genetic makeup or some other factor, the bacteria is carried in blood or immune system cells In this case it "goes underground" and infects the tissues far from the origin of the lungs. Key to this discussion is that your immune system cells are some of the ones that now have these nasty little bacteria hiding in them, so where the immune system goes, the CPn goes too and over time may render the immune cells less effective.

Second, the germ is INSIDE the cells. Your immune system can't see them in there. Your immune system "sees" what is "you" and what is "foreign" by looking at the proteins on the outside of the cell wall. The outside of this cell is you. For all your system knows, it is a friendly cell, so your immune system is quiet and unexcited. Meanwhile the stealthy pathogen is hiding, slipping into the cells and taking over one cell at a time, and one cell at a time they are now CPn factories not whatever they were meant to be.

While in some cases CPn is a fairly "benign" germ under certain conditions such as when it is attacked by antibiotics or "starved" it becomes cryptic or shuts down so it can't be harmed or detected. When cryptic it is so quiet and hidden in the body, your body does not really notice it. It then becomes active at some later time causing a "new" infection, perhaps in new parts of the body.

Changing forms of Cpn

This bacteria diabolically can change from any form, EB, RB, Cryptic or persistent, to any other form based on the environment. It will choose the form least affected by whatever is threatening it! If you take an antibiotic, let's say for a bladder infection, the CPn will hide in a non replicating and non metabolizing form until the threat is over and your internal environment is less hostile. Virtually all people will have rising titers to CPn over their lifetime, meaning they have been exposed and make antibodies to it from the occasional experience with it as a respiratory pathogen, but also perhaps because they harbor this cryptic form^{i [127]} which later "wakes up" and then subsides or is treated. But as a cryptic pathogen we know little about it. It is just emerging as a known cause of disease. The Centers for Disease Control list it as an Emerging Pathogen in atherosclerosis. See the slides to see pictures of these germs in the cells.here [131]

Why do steroids help MS then? This question was asked to Dr Wheldon and Dr A. The answer is found here [137]

Why is it true that your doctor does not tell you about this?

This is new understanding and it's not well defined yet. For example why is it cryptic in some people? We are not certain at all. The CPn was first seen in 1965 and was identified as the cause of an outbreak of pneumonia in the early 80's. Before that time we had no research or concept about bacteria with lifecycles that included changing forms from one to another and hiding inside the cells of your body. Bacteria were seen as one form either a cocci, or a spirochete, or a rod and you were given one antibiotic and it would go away. Everyone who was trained in medicine was taught this and spent long hours studying these facts.

Now, research on CPn indicates it plays a role in several chronic diseases by using these peculiar and not well understood ways of being in the body. We have to go back to the books and learn a whole new kind of bacterial science where germs evade and hide from our treatments in ways that seem impossible or outlandish based on prior learning and understanding. New knowledge takes time to filter into the mainstream because physicians spend so many years studying biochemistry and microbiology that they feel like experts. This is so different that it sounds "wrong". Also some other research seems to find it is not a factor in chronic illness, which gives the individual physician a sense this is too new to act on yet.

For example, some research in CPn in multiple sclerosis (MS) does not find an increased incidence of CPn in the nervous system in people with MS while other research does find CPn DNA in the nervous system of people with MS. This creates doubt in the minds of physicians and a sense that we need to wait for more definitive research before acting. And finally, medicine is extremely slow to change paradigms.

We have a superb example of this in helicobacter pylori, a bacteria, in peptic ulcer disease. This bacteria was discovered in 1982 by Barry Marshall. He produced a large amount of good research on h. pylori^{i [138]} causing peptic ulcers that went largely ignored. Why? Because "everyone knew" that bacteria could not survive in the stomach (wrong) and he literally had to swallow the bacteria himself and prove that it then caused him an ulcer. When he healed it with antibiotics others to finally accepted his research. It's very difficult to get medicine in general to accept new science, even if it's absolutely correct.

I bet you're thinking that everyone gets antibiotics for ulcers these days, but you'd be wrong. Up to 9 out of 10 ulcers can be healed by treating with appropriate antibiotics for 2 weeks. Yet today, 23 years after the discovery that ulcers are caused by bacteria, not lifestyle or stress, over 50% of ulcers are STILL treated with proton pump inhibitors (medicines that decrease stomach acid)or other palliative measures that do not kill the bacteria, which also may play a role in gastric cancer. This link is to the American Centers for Disease Control detailing these facts HERE [139]There is a serious "blind spot" in medicine about potential infectious causes of chronic disease. Clearly, even a proven fact can still be ignored by doctors.

Why does research say it's not a factor sometimes?

The fact of the matter is that CPn in cryptic form, that means in the cells in an unmetabolizing and non relicating form, is hard to detect. It's virtually impossible to detect without extremely complicated procedures and even in the infectious form it is hard to detect with sensitive DNA (PCR^{i [140]}, below) tests, let alone less sensitive antibody tests. You cannot just see if the person is making antibodies to the bacteria as you would in other infections^{i [129]} and as mentioned above, people have rising titers (rising numbers of antibodies) to CPn over their lifetimes as most all of us are exposed repeatedly.

Instead of checking for antibodies a newer advanced kind of technique must be done called polymerase chain reaction (PCR) to see if CPn is in the tissue. This technique uses small amounts of DNA to detect the presence of the bacteria, not the old method of just screening the blood to see if you have antibodies to CPn.

The trouble with this is that just like our understanding of CPn is growing so is our understanding about how to detect it. Labs are developing ways of finding and testing for the DNA fragments, however this is still early days. Some labs use one part of the DNA for detection; others use another. This accounts for discrepancy in results as it has not yet been agreed upon by everyone that one lab's approach is the clear winner for accuracy.

It appears at this time that the Vanderbilt University test is the best at detecting the DNA via PCR. They have doccumented that they have concordance with split samples. In other words, samples tested as positive are positive and negatives are negative in a second test done at another lab. VU finds CPn in the majority of MS cases.

Another reason we have confusion about whether CPn is in chronic disease or not is some research almost inexplicably seems to be set to NOT find it. For example, just testing the antibody titers of people with MS or CFS or FM and people who have no chronic disease is sure to result in no difference between the groups since this is a common bacteria we all will be exposed to over our lives. Yet we still see some "research" doing exactly this; saying that the titers were the same in both the chronic illness group and the normal group and reaching a conclusion that CPn plays no role in the disease. This is silly! The question is not have you been exposed to CPn and do you have a high titer, the question is whether it is an active infection and or whether it has gone cryptic in your particular case. There is no consensus yet as to how to determine that all important question. However evidence is emerging, and in some areas it's substantial (as it is in the area of atherosclerosis) that CPn is the cause of chronic illness. The CDC lists CPn as an emerging pathogen in the cause of atherosclerosis.

What is empirical treatment for Cpn?

If you are tested as positive for Cpn either through antigen or PCR testing, then you clearly know you need to treat it. In that case, know that the standard two week course of a single antibiotic may be inadequate to kill the Cpn in some of it’s life-phases, and re-infection can occur unless a combination antibiotic protocol such as the Vanderbilt or Wheldon protocols^{i [2]}, is followed. But if you have any of the diseases in which Cpn has been implicated (see list on Home page), it may be worth doing an “empirical” (based on symptoms) course of a combination antibiotic protocol even if your tests for Cpn are negative or uncertain. The antibiotics used are not considered harmful, even for long courses. If you have Cpn involved in your disorder and try this protocol you will likely experience the following: an inflammatory reaction or worsening of some of your symptoms (caused by the bacteria dying and releasing it’s toxin in larger amounts), followed by a gradual improvement in your disease symptoms. Reactions to treatment can range from mild, if your load of Cpn is not great, to very strong and uncomfortable. In the latter case, you have to go very slowly to get to full dose of the protocol. Similarly, improvements in your condition depend on how long you have been infected, and what your total load of Cpn is, and how much permanent damage it might have created to your body.

Why are there so many antibiotics?

CPn exists in your body in several different forms. The first is the elementary body. It is small hard and is not actively replicating or metabolizing. It is "looking" for a cell to adhere to and be absorbed by. At this stage amoxicillin^{i [121]} can force the EB into the cells.

Once inside a cell, the EB goes through a transformation becoming metabolically active and replicating. To make this transformation, proteins are used and reassembled to cause the change. It grows huge compared to it's EB size and when the transformation is complete, it takes over the cell's energy system, robbing all the energy for it's own purposes. At this point the tetracycline antibiotics block one of the proteins used in the transformation process (that's how antibiotics work; by blocking proteins used to replicate) so the EB is stuck halfway transformed to an RB (replicating body).

Now, one of the problems we have with antibiotics in general is that bacteria are very crafty and they have "learned" to resist different antibiotics by replicating using different pathways than before so the blocked protein is no longer needed. This is what we mean by resistance. A certain bacteria is no longer stopped by a certain antibiotic from replicating. The concern about CPn resistence can be stopped in it's tracks by adding a macrolide antibiotic such as rifampin, azithromycin or roxithromycin in addition to tetracyclines because it blocks protein synthesis in a second part of it's pathway. It is effectively impossible for CPn to develop resistance with this double whammy.

Both the tetracyclines and the macrolides are considered bacteriostatic. They do not kill germs outright, but stop replication so your body can clean up and win the battle without a growing bacterial population to deal with. In the case of CPn however, the EB is stuck halfway converted. It is not able to take over the cell's energy system, so it's on it's own. It has some rudimentary ability to survive on it's own in this anaerobic (without oxygen) state, but not much. As a result a number of the CPn germs will die causing an endotoxin^{i [141]} reaction (see below) even though at this stage you are only taking bacteriostatic drugs.

However a good number of the bacteria will survive even though many die under the stress of living stuck halfway between EB and RB, reducing the overall bacterial load^{i [142]} by a good margin. This brings us to flagyl (metronidazole^{i [125]}). This antibiotic kills the CPn outright, causing for some people a big reaction to the endotoxin, depending on how extensive the bacterial load still is for them as they begin it's use. For this reason, many people wait a number of months after starting the bacteriostatics before taking their first dose of flagyl. Then, they may take flagyl for only one dose the first time they take it, then wait for the body to recover a bit before dosing again. Pulsing the flagyl kills off some germs,  then gives the body and tissues reacting to the released LPS^{i [143]} a rest.

The Wheldon regimen recommends using the flagyl for 5 days once every three weeks while continuing to take the other antibiotics. Effectively the CPn is stuck by the bacteriostatic agents waiting to be killed by your next flagyl pulse, though some die simply waiting. The VU protocol recommends flagyl without rest in between and amoxicillin to force the EB's into the cells where they can be killed by the flagyl. This can result in a fairly vigorous LPS reaction (below). Dr A stated in his interview he has no probelm with people pulsing flagyl if they wish to do so.

What is endotoxin and how is that related to "herxheimer"?  

Endotoxin is a lipopolysaccharide^{i [144]} (LPS), the protein that is on the outside of every gram negative bacteria.  A gram negative bacteria is one that does not take gram stain.  LPS is very immunogenic meaning it causes a brisk reaction by the immune system to it's presence.  When gram negtive bacteria die, either naturally or by antibiotic, the resulting load of LPS floating around is toxic to the person. "Toxic shock syndrome" is a reaction to LPS in a gram negative bacteria.  The kinds of reactions to LPS vary a bit depending on the bacteria in question, some being more toxic than others.  CPn LPS is not very toxic as far as LPS goes, though it does cause a noticable reaction, it's not threatening as other LPS can be. 

Syphilis as another gram negative bacteria.  When antibiotics were first applied to this dread disease, the patients got markedly worse as the LPS built up in thier systems.  This was named for the doctors that described it as "Jarisch Herxheimer Reactions".  It has been specualted that the phrase "you have to get worse before you get better" came from this phenomenon.  Today the term herxheimer or herx has been in common usage to mean any reaction to a gram negative bacteria.  I have even heard of people using the phrase in relation to the die off of candida after appropriate anti-yeast drugs have been taken.

What diseases has it been implicated in?

Multiple sclerosis [98]

Chronic fatigue [99]

Asthma [100]

Arthritis

Fibromyalgia [101]

Chronic refractory sinusitis

Cardiac disease [102]

Interstitial cystitis [103] 

Prostatitis

Crohn's disease

Inflammatory bowel disease^{i [106]}

Alzheimer's disease [105]

Additionally: chronic obstructive pulmonary disease, uveitis, optic neuritis, radiculitis, nerve deafness, transverse myelitis, sarcoid, myocarditis, pericarditis, culture-negative endocarditis, atheromatous arterial disease, aneurysm, giant-cell (temporal) arteritis, polyarteritis nodosa, Wegener's granuloma, primary sclerosing cholangitis, reactive arthritis, Reiter's syndrome, Behcet's disease, cutaneous vasculitides including pyoderma gangrenosa. Wheldon adds: "Conditions which may suggest the possibility of flare-ups of chronic Chlamydia pneumoniae infection deserving serological investigation include the following — a multiplicity being more strongly suggestive: recurrent sinusitis, recurrent chest infections, chronic fatigue (especially if following a respiratory infection), focal neurological deficits, myalgia, muscle fasciculation's, recurrent episodes of bronchospasm, unexplained pleuritic pain, angina, recurrent arthralgia, unexplained recurrent abdominal pain, unexplained menorrhagia, recurrent fistula-in-ano, recurrent cutaneous vasculitides, achalasia, intestinal dysmotility."

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On CAP^{i [4]i [4]} since Sept '05 for MS^{i [113]}, RA^{i [145]}, Asthma^{i [146]}, sciatica. EDSS^{i [147]i [147]} at start 5.5.(early cane) Now 6 (cane full time) Originally on: Doxy^{i [148]i [148]} 200, Azith 3x week, Tini^{i [95]i [95]} cont. over summer '07, Revamp of protocol in Summer '08 by Stratton due to functional loss; clarithromy

How Chlamydia Pneumoniae Causes Such a Plethora of Diseases

The following is a condensation of a slightly longer post which can be found at this link.

Jim K

Chlamydia pneumoniae and Rosacea: A potential link?

 

While the exact pathology of rosacea is not completely understood or widely agreed upon, recent studies suggest that chronic inflammation likely plays a role in many of the symptoms associated with this disease.

 

Background

Rosacea^{i [192]} is a chronic disorder of still unknown cause that affects an estimated 14 million Americans.¹ Rosacea^{i [193]} often initially presents itself with transient flushing and redness of the cheeks, nose, forehead and chin, but it may also involve other areas of the body, including the ears, neck, and chest. With time the transient flushing becomes more frequent, the transient redness tends to become more persistent, and papules, pustules, and visible blood vessels called telangiectasias may also appear. Facial swelling, or edema, also often accompanies rosacea, as do burning or stinging sensations of the affected areas. In addition, many people with rosacea often also have the concomitant chronically irritated eye and eyelid symptoms of ocular rosacea and blepharitis.²

The exact pathology of rosacea is not completely understood or widely agreed upon, but recent studies suggest that chronic inflammation likely plays a role in many of the symptoms associated with this disease. And the chronic inflammation and blood vessel involvement in this disorder may well point to involvement of gram-negative bacteria, or more particularly their endotoxins, which have been shown to elicit similar response upon entry into the bloodstream.

While several gram-negative bacteria, including H. pylori and B. oleronius (found in Demodex folliculorum) have been associated with rosacea in the past, they have not been shown to enter the bloodstream, and thus they are unlikely to play anything more than a secondary role in the disease. Chlamydia pneumoniae, however, has been associated with rosacea in one small study, and studies in other inflammatory diseases in which it is being studied closely indicate that it is quite capable entering and persisting in the bloodstream, as well as producing the type of chronic inflammatory response that has been associated with rosacea. This evidence suggests the potential for C. pneumoniae's involvement in rosacea, at least secondarily.

 

Evidence

Although the exact pathology of rosacea is still unknown, recent studies suggest that chronic inflammation likely plays a role in many of the symptoms associated with the disease. Supporting the role for chronic inflammation is the host of elevated proinflammatory cytokines (TNF-a, IL-1B), matrix metalloproteinases (MMP-1, MMP-3, and MMP-9), nitric oxide (NO), and reactive oxygen species (ROS^{i [194]}) that have been associated with rosacea in recent studies.³ Rosacea has been associated with elevated vascular endothelial growth factor (VEGF) in recent studies as well.⁴

It is important to note that the discovery of these elevated inflammatory mediators in rosacea may suggest important clues to an underlying disease etiology when comparing them as a whole to other known pathologies. And indeed, the elevated cytokines, MMPs, VEGF, NO and ROS associated with rosacea, match closely with the known pathology of early gram-negative sepsis, an infection of the bloodstream caused by toxin-producing bacteria.⁵

In fact, endotoxins, or rather lipopolysaccharides (LPS^{i [143]}), portions of the outer membrane of gram-negative bacteria, are widely known to induce a variety of inflammatory responses, ranging from mild to severe inflammation (and death), depending on the virulence of the bacteria endotoxins themselves.⁶ Recent studies suggest as well that vascular endothelial growth factor (VEGF) itself may actually be a key biomarker for sepsis.⁷

While gram-negative bacteria such as H. pylori and even B. oleronius (found in Demodex folliculorum) have been associated with rosacea in past studies, since these bacteria have not been shown to enter the bloodstream, one would not expect them to produce pathology similar to early sepsis.⁸ So looking at other inflammatory diseases for clues relating to associated gram-negative bacteria, one such pathogen, Chlamydia pneumoniae, stands out for its association with many inflammatory diseases, including Atherosclerosis, Multiple Sclerosis^{i [113]}, Asthma^{i [146]}, Alzheimer's and other inflammatory disorders.⁹

Interestingly, one small study has linked C. pneumoniae with rosacea directly, detecting serum antibodies of C. pneumoniae in 8 of 10 patients with rosacea and detecting C. pneumoniae specimens in 4 of 10 cheek biopsy.¹⁰ Other studies suggest that infection with C. pneumoniae can lead to pustular rashes (acute generalized exanthematous pustulosis) and increased VEGF production, as in the case with wet age-related macular degeneration.^11,12 These of course are most likely caused as by-products of the chronic inflammation associated with this pathogen, but I point them out since papule and pustule rashes and increased VEGF production are symptoms of rosacea.

Persistent C. pneumoniae infection of epithelial cells has been shown to produce chronic blood vessel inflammation, resulting in production of a host of cytokines and growth factors such as those found in rosacea as well as promoting a "foci of inflammatory responses in addition to promoting cellular proliferation, tissue remodeling and healing processes".¹³ And additional studies suggest that chlamydiae, while classified as gram-negative bacteria due to their outer LPS coating, are actually a distinct group of eubacteria, with a unique multi-form, intracellular^{i [97]} and extracellular development cycle, allowing them to change between forms and promote the persistent infection that may lead to chronic inflammatory disease.¹⁴

Another clue potentially linking rosacea with C. pneumoniae involves recent studies in the anti-microbial peptides, cathelicidins, and their activity in rosacea. These recent studies have identified unusually high levels of kallikrein activated cathelicidins in rosacea and suggest that these two substances may be in part responsible for producing the papules and pustules associated with rosacea as well as in promoting the angiogenesis associated with the disease.^15,16,17 Some additional studies have shown too that C. pneumoniae seems to invoke unusually high levels of cathelicidin activity and that endotoxins in general activate the kallikrein-kinin system.^18,19 Intriguingly, still other studies suggest that cathelicidins seem to be ineffective in clearing C. pneumoniae infection.²⁰ Potentially this is due to C. pneumoniae's ability to revert between forms, effectively evading the immune response. If this were correct then a C. pneumoniae infection, with the resulting ineffective yet elevated levels of activated cathelicidins, could indeed explain the unusual cathelicidin activity found in rosacea.

Dr. Charles Stratton^{i [132]}, MD, at Vanderbilt University, in a recent interview, ²¹ summarized his observations of some of the emerging research on C. pneumoniae. He noted how C. pneumoniae crosses from the lungs to the bloodstream via infected macrophages. The spore-like Elementary Bodies (EB^{i [123]}'s) then circulate in the bloodstream to infect other organs throughout the body, including the liver, bone marrow, spleen, kidneys and skin.²¹ Potentially this might explain how C. pneumoniae, whose initial entry into the body is via the respiratory system, might arrive in the skin to cause rosacea. This may explain too the discovery of C. pneumoniae in cheek biopsy of rosacea as in the study discussed above.

 

Conclusion

In summary, Chlamydia pneumoniae may be involved at least secondarily in the etiology of rosacea. C. pneumoniae is a persistent, gram-negative bacteria known to enter and exist in the epithelial cells of the bloodstream, and it is known to produce the type of chronic inflammation that can be found in rosacea. Studies suggest C. pneumoniae may be involved with the etiology of many other inflammatory diseases, and intriguingly, a small study suggests a potential link with rosacea itself. Combined, this evidence would suggest more study related to C. pneumoniae's potential involvement in rosacea is necessary.

 

 

References

1. National Rosacea Society. Information for Patients: If You Have Rosacea, You're Not Alone. [195] Rosacea.org.

2. National Rosacea Society. Information for Patients: All About Rosacea [196]. Rosacea.org.

3. Bikowski, Joseph. Examining Inflammation as a Common Factor in Theories of Rosacea Pathophysiology [197]. RosaceaToday.com.

4. Smith JR, Lanier VB, Braziel RM, Falkenhagen KM,White C, Rosenbaum JT. Expression of vascular endothelial growth factor and its receptors in rosacea. [198] Br J Ophthalmol. 2007 Feb;91(2):226-9.

5. Institute for Inflammation Research, Rigshospitalet Univ Hosp, Copenhagen. Diagram: Early events in sepsis [199]. Inet.uni2.dk.

6. Todar, Kenneth. Online Book of Bacteriology: Mechanisms of Bacterial Pathogenicity: Endotoxins. [200] Textbookofbacteriology.net.

7. Prescott, Bonnie. New Study Finds Key Role For VEGF In Onset Of Sepsis [201]. Medical News Today. 21 May 2006.

8. Rebora, A. The management of rosacea [202]. Am J Clin Dermatol. 2002;3(7):489-96.

9. Stratton, Charles W. Association of Chlamydia pneumoniae with Chronic Human Diseases. [203] Antimicrobics and Infectious Diseases Newsletter. 2000 July; 18(7).

10. Fernandez-Obregon A and Patton DL. The Role of Chlamydia pneumoniae in the Etiology of Acne Rosacea: Response to Oral Use of Azithromycin. [204] Cutis. 2007 Feb;79(2):163-7.

11. Manzano S, Guggisberg D, Hammann C, Laubscher B. Acute generalized exanthematous pustulosis: first case associated with a Chlamydia pneumoniae infection. [205] Arch Pediatr. 2006 Sep;13(9):1230-2. Epub 2006 Aug 17.

12. Leach, Mary E. Chlamydia pneumoniae present in eyes with 'wet' age-related macular degeneration [206]. Medical News Today. 13 Nov 2005.

13. Blasi F, Centanni S, Allegra L. Chlamydia pneumoniae: crossing the barriers? [207] Eur Respir J 2004; 23:499-500.

14. Hogan Richard J, Mathews Sarah A, Mukhopadhyay Sanghamitra, Summersgill James T, Timms, Peter. Chlamydial Persistence: beyond the Biphasic Paradigm [208]. Infection and Immunity, April 2004, p. 1843-1855, Vol. 72, No. 4.

15. National Rosacea Society. Is Rosacea Like an Allergy? [209], Rosacea.org. Aug 2006.

16. Koczulla Rembert, von Degenfeld Georges, Kupatt Christian, Krotz Florian, Zahler Stefan, Gloe Torsten, Issbr¸cker Katja, Unterberger Pia, Zaiou Mohamed, Lebherz Corinna, Karl Alexander, Raake Philip, Pfosser Achim, Boekstegers Peter, Welsch Ulrich, Hiemstra Pieter S, Vogelmeier Claus, Gallo Richard L, Clauss Matthias, Bals Robert. An angiogenic role for the human peptide antibiotic LL-37/hCAP-18 [210]. J Clin Invest. 2003 June 1; 111(11): 1665–1672.

17. Nizet Victor, Gallo Richard L. Cathelicidins and Innate Defense Against Invasive Bacterial Infection [211]. Scand J Infect Dis. 2003; 35: 670-676.

18. Edfeldt K, Agerberth B, Rottenberg ME, Gudmundsson GH, Wang XB, Mandal K, Xu Q, Yan ZQ. Involvement of the antimicrobial peptide LL-37 in human atherosclerosis [212]. Arterioscler Thromb Vasc Biol. 2006 Jul;26(7):1551-7. Epub 2006 Apr 27.

19. DeLa Cadena Raul A, Suffredini Anthony F, Page Jimmy D, Pixley Robin A, Kaufman Nathan, Parrillo Joseph E, Colman Robert W. Activation of the Kallikrein-Kinin System after Endotoxin Administration to Normal Human Volunteers [213]. J Amer Soc Hematology. 1993; 81(12), 3313-3317.

20. Donati Manuela, Di Leo Korinne, Benincasa Monica, Cavrini Francesca, Accardo Silvia, Moroni Allessandra, Gennaro Renato, Cevenini Roberto. Activity of Cathelicidin Peptides against Chlamydia spp [214]. Antimicrobial Agents and Chemotherapy, March 2005, 49(3), 1201-1202.

21. Jim K. Recent Observations by Dr. Charles Stratton on Chlamydia Pneumoniae (Cpn) Infection [215]. Cpnhelp.org. Aug 2006.

 

 

Chlamydia Pneumoniae in CFS/ME & Fibromyalgia

Chronic Fatigue Syndrome^{i [134]}, Fibromyalgia & Chlamydia Pneumoniae[1]

Introduction

(Note: the original page for this became non-functional for some reason. This copy is identical except for some minor text layout details)

Chronic Fatigue Syndrome (CFS), also called Chronic Fatigue Immunodeficiency Disorder (CFIDS^{i [216]}), or called Myalgic Encephalomyelitis^{i [217]} (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 (FMS^{i [93]}).[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 infections^{i [129]}" i.e. those organisms that are either typically overlooked, difficult to test for, or tend to evade the immune^{i [114]} 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^{i [90]}'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 Stratton^{i [132]} 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 PCR^{i [140]} 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 IgG^{i [218]} 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 antibiotics^{i [111]} 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^{i [4]}) 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 protocols^{i [2]} 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 load^{i [142]} 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 Wheldon^{i [118]}, 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 persistence^{i [108]} 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-cysteine^{i [122]} and amoxicillin^{i [121]}
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^{i [125]} 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^{i [128]} reactions, including inflammation^{i [110]}, 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 porphyria^{i [219]}[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.

Intracellular^{i [97]} 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^{i [220]}, 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 it's structure, such as LPS^{i [143]} and HSP^{i [221]}-60. These endotoxins cause widespread inflammation (cytokine cascades) and a host of other metabolic disturbances. These are released chronically in small amounts in Chlamydial 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 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-

* This is the most characteristic feature of CFS and, other than pain, of FMS.
* ATP depletion from Chlamydia pneumoniae parasitism simply leaves less energy available for body functions.
* Fatigue is a main symptom of porphyria.
* 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]
* Cytokine cascade in CFS[15]- the typical malaise and fatigue of a cold or flu is caused by the flood of cytokines^{i [222]} 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 references).

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 deficiency[18]

* 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.
* 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 severity[20], 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 it's own replication process. Heart muscle is one of the most ATP demanding cells. Cpn 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 recover time. This is the "over-exert one day, payback for three days" report common to many CFS patients.

Gastrointestinal problems

* CFS and FMS patients often have concomitant gastrointestinal problems, ranging from Irritable Bowel Syndrome, poor nutrient absorption, and other problems.
* Cpn infects endothelial tissues, as it's 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]
* Porphyria is notorious for causing chronic gut distress: nausea, intestinal cramping, etc. Chlamydia pneumoniae infection of gut endothelial tissue.
* Gut co-infections from fungi, bacterial, or yeast resulting from general immunosuppression, or specific Cpn infected gut-immune system will further add to gastrointestinal problems.

Sleep disorder

* Porphyrins block GABA receptors, a main cause of anxiety and agitation in porphyria, and likely to interfere with sleep.
* Melatonin^{i [223]} serves a number of functions that are related to protecting cells from oxidation[23] as well as binding inflammatory endotoxins[24] and activating immune functions[25]. Melatonin depletion from it being used up for antioxidant^{i [224]} and other metabolic purposes resulting from Cpn infection could result in inadequate amounts left for neurotransmitter production and it's influence on inducing sleep.
* Hypothalamic infection and disturbance by Chlamydia pneumoniae could be a contributing factor.
* Cytokine disturbance of sleep regulation.[26]

Anxiety & depression

* Porphyrins- noted previously for causing anxiety, depression even psychosis.
* Depletion of melatonin noted above causes depletion of serotonin in the brain. Inadequate serotonin results in depression, as well as increased pain sensitivity.
* Cytokine depression- cytokines are clearly linked to causing depressive symptoms.[27]

Endocrine disturbance (thyroid, periods, etc.)

* Infection of endocrine gland cells: thyroid, pancreas islet cells, pituitary, pineal, etc.
* 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 these episodes of these hypoglycemic symptoms over the course of treatment.

Headaches

* Porphyrins- one of the neurotoxic effects of porphyrins is headaches.
* Vascular disturbance direct and indirect- Cpn infects the vascular system leading to high blood pressure^{i [225]} (from rigidified vascular walls), headaches, inflammation of blood vessels (including those in the brain), etc.
* Sympathetic nervous system over activation from chronic upregulated innate immune response caused by infection.[28]

"Sickness behavior"

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 it being one of the most life-impacting symptoms for the sufferer. Cpn infection explains this very wel.

* Secondary porphyria induced by it and the impact of porphyrins on brain functioning.
* Cerebral inflammation from circulating cytokines.
* Brain infection
* Endotoxins.

Fibromyalgia Symptoms[30]

All of the above plus...
Musculoskeletal pain and inflammation

* Soft tissue infection by Chlamydia pneumoniae and subsequent inflammation
* 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. http://www.cpnhelp.org/how_chlamydia_pneumoniae_ [13]
* Porphyrins blocking GABA receptors will also lowers pain tolerance.
* Generalized cytokine load causes broad based "feels lousy all over."

The case for Cpn in CFS does not prove that Cpn is always the causal element. As a syndrome, Chronic Fatigue 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^{i [1]}.

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!

[2] http://www.cdc.gov/cfs/cfsbasicfacts.htm#prevalence [226]
[3] CDC Diagnostic Symptoms-

1. 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.

2. 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 effect 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 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 [3] 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.

See http://www.meresearch.org.uk/research/reviews/cbt.html [227] for further discussion.

[6] Effective Treatment Of Chronic Fatigue Syndrome (CFIDS^{i [92]}) & Fibromyalgia (FMS) - A Randomized, Double-Blind, Placebo-Controlled, Intent To Treat Study

Teitelbaum J.*1, Bird B., Greenfield R.*1, Weiss A.*1, Muenz L.*2, Gould L.*3

[* Annapolis Research Center For Effective FMS/CFIDS Therapies; 466 Forelands Rd., Annapolis, MD 21401; 1) Anne Arundel Medical Center, Annapolis, MD; 2) Gaithersburg, MD; 3) USDA, Beltsville, MD]

Journal Of Chronic Fatigue Syndrome Volume 8, Issue 2 - 2001

Background: Hypothalamic dysfunction has been suggested in Fibromyalgia (FMS) and Chronic Fatigue Syndrome (CFS). This dysfunction may result in disordered sleep, subclinical hormonal deficiencies, and immunologic changes. Our previously published open trial showed that patients usually improve by using a protocol which treats all the above processes simultaneously. The current study examines this protocol using a randomized, double-blind design with an intent-to-treat analysis.

Methods: 72 FMS patients (38 active: 34 placebo; 69 also met CFS criteria) received all active or all placebo therapies as a unified intervention. Patients were treated, as indicated by symptoms and/or lab testing^{i [157]}, for: (1) subclinical thyroid, gonadal, and/or adrenal insufficiency, (2) disordered sleep, (3) suspected Neurally Mediated Hypotension (NMH), (4) opportunistic infections, and (5) suspected nutritional deficiencies.

Results: At the final visit, 16 active patients were “much better,” 14 “better,” 2 “same,” 0 “worse,” and 1 “much worse” vs. 3, 9,11, 6, and 4 in the placebo group (p < .0001, Cochran-Mantel-Haenszel trend test). Significant improvement in the FMS Impact Questionnaire (FIQ) scores (decreasing from 54.8 to 33.2 vs. 51.4 to 47.7) and Analog scores (improving from 176.1 to 310.3 vs. 177.1 to 211.9) (both with p < .0001 by random effects regression), and Tender Point Index (TPI) (31.7 to 15.5 vs. 35.0 to 32.3, p < .0001 by baseline adjusted linear model) were seen. Long term follow-up (mean 1.9 years) of the active group showed continuing and increasing improvement over time, despite patients being able to discontinue most treatments.

Conclusions: Significantly greater benefits were seen in the active group than in the placebo group for all primary outcomes. Using an integrated treatment approach, effective treatment is now available for FMS/CFS.

Article link here

[7] The immune system, atherosclerosis and persisting infection

http://www.cpnhelp.org/?q=node/129 [228]

[8]

Article link here

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.

Chronic Chlamydia pneumoniae infection: a treatable cause of chronic fatigue syndrome.

Chia JK, Chia LY.

Torrance Memorial Medical Center, California, USA.

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

BMC Infectious Diseases 2006, 6:23 doi:10.1186/1471-2334-6-23

Frances Cirino, Wilmore C. Webley, Nancy L. Croteau, Chester Andrzejewski Jr.,Elizabeth S. Stuart (esstuart@microbio.umass.edu [174])

Transfusion. 2004 Jul;44(7):1072-8.

Prevalence of viable Chlamydia pneumoniae in peripheral blood mononuclear cells of healthy blood donors.

Yamaguchi H, Yamada M, Uruma T, Kanamori M, Goto H, Yamamoto Y, Kamiya S.

Department of Infectious Disease, Division of Microbiology, Kyorin University School of Medicine, Tokyo, Japan. hiroyuki@sahs.med.osaka-u.ac.jp [229]

…”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 [3] 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] http://www.cpnhelp.org/?q=cell_death_and_inflammati [230]

[13] Article link here

: Am J Pathol. 2007 Jan;170(1):33-42.

Persistent Chlamydia pneumoniae infection of cardiomyocytes is correlated with fatal myocardial infarction.

* Spagnoli LG, Pucci S, Bonanno E, Cassone A, Sesti F, Ciervo A, Mauriello A.

Cattedra di Anatomia ed Istologia Patologica, Dipartimento di Biopatologia e Diagnostica per Immagini, Universita di Roma Tor Vergata, Via Montpellier 1, Rome, Italy. spagnoli@uniroma2.it [231]

Acute myocardial infarction (AMI) associated with unfavorable prognosis is likely to be the consequence of a diffuse active chronic inflammatory process that destabilizes the whole coronary tree and myocardium, suggesting a possible common causal agent underlying both conditions. The main objective of this study was to investigate whether Chlamydia pneumoniae (CP) infection occurred beyond the coronary plaques, namely in the myocardium of individuals who died of AMI. The presence of CP cell wall antigen (OMP-2) and CP-HSP60 was investigated in the myocardium and coronary plaques of 10 AMI and 10 age-matched control patients by immunohistochemistry, electron microscopy, and molecular biology. OMP-2 antigens were found in the unaffected myocardium of 9 of 10 AMI patients. Conversely, only 1 of 10 control patients exhibited a positive staining for CP. Moreover, OMP-2 and CP-HSP60 were detected in the whole coronary tree. CP presence was strongly associated with a T-cell inflammatory infiltrate. Our results suggest that CP may underlie both coronary and myocardial vulnerabilities in patients who died of AMI and corroborate the notion that CP may act by reducing cardiac reserves, thus worsening the ischemic burden of myocardium.

[14] Additional cardiac findings in CFS consistent with cardiac infection by Chlamydia pneumoniae—

From: Causes of death among patients with chronic fatigue syndrome.

Journal: Health Care Women Int. 2006 Aug;27(7):615-26.

Authors: Jason LA, Corradi K, Gress S, Williams S,

Torres-Harding S.

Affiliation: DePaul University, Chicago, Illinois, USA.

NLM Citation: 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] Annals of the New York Academy of Sciences 933:185-200 (2001)

© 2001 New York Academy of Sciences

Cytokines and Chronic Fatigue Syndrome

Roberto Patarcaa

E. M. Papper Laboratory of Clinical Immunology, Department of Medicine, University of Miami School of Medicine, Miami, Florida 33101, USA

Address for correspondence: E. M. Papper Laboratory of Clinical Immunology, Department of Medicine (R-42), University of Miami School of Medicine, P.O. Box 016960, Miami, FL 33101.

http://www.annalsonline.org/cgi/content/abstract/933/1/185 [232]

[16] Vestn Ross Akad Med Nauk. 2005;(2):17-22.

The immune system, atherosclerosis and persisting infection

Pigarevskii PV, Mal'tseva SV, Seliverstova VG.

Article Link here

[17] Eur Respir J. 2004 Apr;23(4):506-10.

Phagocytes transmit Chlamydia pneumoniae from the lungs to the vasculature.

Gieffers J, van Zandbergen G, Rupp J, Sayk F, Kruger S, Ehlers S, Solbach W, Maass M.

Institute for Medical Microbiology and Hygiene, University of Lubeck, Ratzeburger Allee 160, 23538 Lubeck, Germany. jens.gieffers@hygiene.ukl.mu-luebeck.de [233]

Chlamydia pneumoniae, a major cause of community-acquired pneumonia, primarily infects the respiratory tract. Chronic infection of nonrespiratory sites, such as the vascular wall, the brain or blood monocytes, requires evasion from the lungs and spreading via the bloodstream. The cell types involved in dissemination are insufficiently characterised. In this study, New Zealand White rabbits were infected intratracheally with C. pneumoniae, and lung manifestation and systemic dissemination were monitored by polymerase chain reaction and immunohistochemistry. Infection of the lungs was characterised by an early phase dominated by granulocytes and a late phase dominated by alveolar macrophages (AM). Granulocytes, AM and alveolar epithelial cells acted as host cells for chlamydiae, which remained detectable for up to 8 weeks. AM transported the pathogen to the peribronchiolar lymphatic tissue, and subsequently C. pneumoniae entered the spleen and the aorta via dissemination by peripheral blood monocytes. In conclusion, Chlamydia pneumoniae-infected alveolar macrophages transmigrate through the mucosal barrier, and give the pathogen access to the lymphatic system and the systemic circulation. Infected peripheral blood monocytes are the vector system within the bloodstream and transmit the infection to the vascular wall. This is the first description of granulocytes acting as a reservoir for Chlamydia pneumoniae early in infection.

Article link here

[18] From: Causes of death among patients with chronic fatigue syndrome.

Journal: Health Care Women Int. 2006 Aug;27(7):615-26.

Authors: Jason LA, Corradi K, Gress S, Williams S,

Torres-Harding S.

Affiliation: DePaul University, Chicago, Illinois, USA.

NLM Citation: PMID: 16844674

People with CFS appear to have two basic problems with immune function: immune activitation as demonstrated by elevations of activated T lymphocytes, including cytotoxic T cells and elevations of circulating cytokines; and poor cellular function, with low natural killer cell cytotoxicity and frequent immunoglobulin deficiencies (most often IgG1 and IgG3; Patarca-Montero, Mark, Fletcher, & Klimas, 2000).

For example, Antoni, Fletcher, Weiss, Maher, Siegel, and Klimas, (2003) found that patients with low natural killer cell activity (NKCA) and a state of overactivation of lymphocyte subsets (e.g., CD2+CD26+% activation markers) had the greatest fatigue intensity and greatest fatigue-related impairments in emotional and mental functioning. It seems that the Th2 cytokines are dominant over the Th1 cytokines.

In addition, Suhadolnik and colleagues (1997) found a novel low-molecular-weight (37 kDa) binding protein in a subset of individuals with CFS who are severely disabled by their disease. A European team (De Meirleir et al., 2000) has also found increased levels of 80 kDa and 37 kDa RNase L in patients with CFS. The ratio of this 37 kDa protein to the normal 80 kDa protein was high in 72% of patients with CFS but only in 1% of the healthy controls and in none of the depression and fibromyalgia control patients.

[19] Eur J Haematol. 2005 Jan;74(1):77-83.

Detection of Chlamydophila pneumoniae in the bone marrow of two patients with unexplained chronic anaemia.

Nebe CT, Rother M, Brechtel I, Costina V, Neumaier M, Zentgraf H, Bocker U, Meyer TF, Szczepek AJ.

Central Laboratory, University Hospital Mannheim, Mannheim, Germany. thomas.nebe@ikc.ma.uni-heidelberg.de [185]

Anaemia of chronic disease (ACD) is a common finding involving iron deficiency and signs of inflammation. Here, we report on two patients with ACD where a persistent infection with Chlamydophila (Chlamydia) pneumoniae (CP) was detected in bone marrow (BM) biopsies. Infection was suspected by routine cytology and confirmed by immunofluorescence, electron microscopy, polymerase chain reaction (PCR) including different primer sets and laboratories and sequencing of the PCR product. This is a first report of chlamydial presence in the BM of anaemic patients. The cases are presented because persistent chlamydial infection may contribute more frequently to chronic refractory anaemia than previously suspected.

[20] Am J Med Sci. 2003 Aug;326(2):55-60.Click here to read Links

Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome.

Peckerman A, LaManca JJ, Dahl KA, Chemitiganti R, Qureishi B, Natelson BH.

Department of Neurosciences, CFS Cooperative Research Center, University of Medicine and Dentistry of New Jersey, Newark, NJ, USA. apeckerm@njneuromed.org [234]

BACKGROUND: Findings indicative of a problem with circulation have been reported in patients with chronic fatigue syndrome (CFS). We examined this possibility by measuring the patient's cardiac output and assessing its relation to presenting symptoms. METHODS: Impedance cardiography and symptom data were collected from 38 patients with CFS grouped into cases with severe (n = 18) and less severe (n = 20) illness and compared with those from 27 matched, sedentary control subjects. RESULTS: The patients with severe CFS had significantly lower stroke volume and cardiac output than the controls and less ill patients. Postexertional fatigue and flu-like symptoms of infection differentiated the patients with severe CFS from those with less severe CFS (88.5% concordance) and were predictive (R2 = 0.46, P < 0.0002) of lower cardiac output. In contrast, neuropsychiatric symptoms showed no specific association with cardiac output. CONCLUSIONS: These results provide a preliminary indication of reduced circulation in patients with severe CFS. Further research is needed to confirm this finding and to define its clinical implications and pathogenetic mechanisms.

Article Link Here

[21] http://www.cfids-cab.org/MESA/Lerner.html [235]

[22] http://www.cpnhelp.org/cpn_in_gi_tract_tissue_1 [236]

http://www.cpnhelp.org/cpn_in_gi_tract_tissue_2 [237]

http://www.cpnhelp.org/cpn_in_gi_tract_tissue_3 [238]

[23] Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2007, 1, 63-82 63

Melatonin as Antioxidant Under Pathological Processes

Cristina Tomás-Zapico*, Ana Coto-Montes1

Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spain

http://www.bentham.org/emi/samples/emi1-1/Tom%E1s-Zapico.pdf [239]

[24] Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents

endotoxemia in lipopolysaccharide^{i [144]}-induced multiple organ dysfunction syndrome in rats

ELENA CRESPO,* MANUEL MACI´AS,* DAVID POZO,† GERMAINE ESCAMES,*

MIGUEL MARTI´N,* FRANCISCO VIVES,* JUAN M. GUERRERO,† AND

DARI´O ACUN˜ A-CASTROVIEJO*,1

www.fasebj.org/cgi/reprint/13/12/1537.pdf

[25] J Immunol. 1994 Sep 15;153(6):2671-80.

Activation of human monocytes by the pineal hormone melatonin.

Morrey KM, McLachlan JA, Serkin CD, Bakouche O.

Department of Molecular Pharmacology and Biologic Chemistry, Northwestern University Medical School, Chicago, IL 60611.

To determine the effects of the pineal hormone melatonin on human monocytes, human monocytes were activated by different concentrations of melatonin. Above the activation threshold of 5 x 10(-11) M, melatonin was able to induce the cytotoxicity of human monocytes, the secretion of IL-1, and the production of reactive oxygen intermediates. Melatonin and LPS seemed to have a synergistic effect on human monocyte activation. Indeed, below their respective monocyte activation threshold (5 x 10(-11) M and 0.625 ng/ml), melatonin (10(-12) M) in association with LPS (0.2 ng/ml) was able to induce cytotoxicity, IL-1 secretion, and reactive oxygen intermediates production. Melatonin alone at 10(-12) M or LPS alone at 0.2 ng/ml did not activate monocytes. Furthermore, melatonin was able to prime the monocytes for a subsequent activation by LPS. When monocytes were activated by LPS (0.25 ng/ml) at the time that they were plated and then activated by melatonin (10(-12) M) 8 h later, no IL-1 secretion and no cytotoxicity were detected. However, when the cells were first activated by melatonin (10(-12) M), and then 8 h later by LPS (0.25 ng/ml), IL-1 secretion and monocyte cytotoxicity were observed. Above its monocyte activation threshold, melatonin induces both cell-associated IL-1 alpha and IL-1 beta activities. Below this activation threshold, i.e., at 10(-12) M, melatonin does not induce the cell-associated IL-1 alpha and IL-1 beta activities, but does induce the mRNA for both IL-1 (alpha and beta). It seems that melatonin activates monocytes through protein kinase C. These data suggest that melatonin activates monocytes and induces their cytotoxic properties, along with the IL-1 secretion.
Article link here

Annals of the New York Academy of Sciences

Volume 933 THE ROLE OF NEURAL PLASTICITY IN CHEMICAL INTOLERANCE Page 211 - March 2001

Annals of the New York Academy of Sciences 933 (1), 211–221.

The Role of Cytokines in Physiological Sleep Regulation

* James M. Kruegera et al

Article link here

[27] “…cytokine treatment causes serotonin depletion. They hypothesized that cytokines suppress serotonin by activating the enzyme indoleamine-2,3-dioxygenase (IDO) that catabolizes tryptophan. Dr. Dantzer explained that in the brain, IDO prevents tryptophan from being turned into serotonin, which causes decreased levels of serotonin and leads to the symptoms of depression.”

Dr. Dantzer pointed out that his current research is built on a concept that he had ignored a few years ago, which is the fact that the brain is representing what is going on in the body—“what we already knew for quite a long time, but in terms of inflammation, and it is doing that with the same molecules as the ones that are promoting inflammation at the periphery. If you have an inflammatory response in your body, it will be represented in the brain with exactly the same molecules that in your body are responsible for inflammation. This normally is responsible for what we call sickness behavior—why you feel sick and behave in a sick way when you are ill.”

http://www.neuropsychiatryreviews.com/sep04/sep04_npr_inflammatory.html [240]

[28] Migraine: A Chronic Sympathetic Nervous System Disorder

Stephen J. Peroutka

http://www.medscape.com/viewarticle/466937_1 [241]

[29]Illness, cytokines, and depression.

Ann N Y Acad Sci. 2000;917:478-87.

Yirmiya R, Pollak Y, Morag M, Reichenberg A, Barak O, Avitsur R, Shavit Y, Ovadia H, Weidenfeld J, Morag A, Newman ME, Pollmacher T.

Department of Psychology, Hebrew University, Hadassah Hospital, Jerusalem, Israel. msrazy@mscc.huji.ac.il [242]

Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double-blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus-induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPS-induced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS-induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive-like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS-induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF-alpha mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness-associated depression.

Neuroimmunomodulation. 2005;12(5):255-69.

Cytokine dysregulation, inflammation and well-being.

* Elenkov IJ, Iezzoni DG, Daly A, Harris AG, Chrousos GP.

Division of Rheumatology, Immunology and Allergy, Georgetown University Medical Center, Washington, D.C., USA.

Cytokines mediate and control immune and inflammatory responses. Complex interactions exist between cytokines, inflammation and the adaptive responses in maintaining homeostasis, health, and well-being. Like the stress response, the inflammatory reaction is crucial for survival and is meant to be tailored to the stimulus and time. A full-fledged systemic inflammatory reaction results in stimulation of four major programs: the acute-phase reaction, the sickness syndrome, the pain program, and the stress response, mediated by the hypothalamic-pituitary-adrenal axis and the sympathetic nervous system. Common human diseases such as atopy/allergy, autoimmunity^{i [115]}, chronic infections and sepsis are characterized by a dysregulation of the pro- versus anti-inflammatory and T helper (Th)1 versus Th2 cytokine balance. Recent evidence also indicates the involvement of pro-inflammatory cytokines in the pathogenesis of atherosclerosis and major depression, and conditions such as visceral-type obesity, metabolic syndrome and sleep disturbances. During inflammation, the activation of the stress system, through induction of a Th2 shift, protects the organism from systemic 'overshooting' with Th1/pro-inflammatory cytokines. Under certain conditions, however, stress hormones may actually facilitate inflammation through induction of interleukin (IL)-1, IL-6, IL-8, IL-18, tumor necrosis^{i [243]} factor-alpha and C-reactive protein production and through activation of the corticotropin-releasing hormone/substance P-histamine axis. Thus, a dysfunctional neuroendocrine-immune interface associated with abnormalities of the 'systemic anti-inflammatory feedback' and/or 'hyperactivity' of the local pro-inflammatory factors may play a role in the pathogenesis of atopic/allergic and autoimmune diseases, obesity, depression, and atherosclerosis. These abnormalities and the failure of the adaptive systems to resolve inflammation affect the well-being of the individual, including behavioral parameters, quality of life and sleep, as well as indices of metabolic and cardiovascular health. These hypotheses require further investigation, but the answers should provide critical insights into mechanisms underlying a variety of common human immune-related diseases. Copyright (c) 2005 S. Karger AG, Basel

[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 the you display the following symptoms:

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

Pain in at least 11 of 18 tender-point sites.

http://www.arthritis.org/conditions/DiseaseCenter/Fibromyalgia/fibromyal... [244]

An excellent review of infectious issues in Fibromyalgia can be found at:

Fibromyalgia- is there an infectious connection?

http://www.roadback.org/index.cfm/fuseaction/education.display/display_i... [245]

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CAP^{i [4]} for Cpn^{i [90]} 11/04. Dx^{i [91]i [91]}: 25yrs CFS^{i [92]} & FMS^{i [93]}. Currently: 250 aithromycin mwf, doxycycline 100mg BID^{i [94]i [94]}, Tini^{i [95]i [95]} 1000mg/day pulses; Vit D2000 units, T4 & T3, 12mg Iodoral

Chlamydia pneumoniae in Chronic Fatigue Syndrome and Fibromyalgia

This page is broken. The article can be found here: http://www.cpnhelp.org/chlamydia_pneumoniae_in_0 [15]

Diseases associated with Cpn: the exhaustive list

I have culled from Mitchell & Stratton patent #6,884,784 an exhaustive list of diseases^{i [1]} where Cpn^{i [90]} has been implicated as a possible cause or co-factor (reference: Mitchell & Stratton patent #6,884,784):

Diseases where an association has been discovered between chronic Chlamydia infection of body fluids and/or tissues with several disease syndromes of previously unknown etiology in humans which respond to unique antichlamydial regimens include:

Editorial comment: Strong findings from their research. If you have any of these it suggests to me that at least an empirical course of the combination antibiotic therapy is strongly indicated, with or without serology^{i [157]}.

Multiple Sclerosis (MS^{i [113]})
Rheumatoid Arthritis (RA)
Inflammatory Bowel Disease^{i [106]} (IBD)
Interstitial Cystitis^{i [339]} (IC)
Fibromyalgia (FM)
Autonomic nervous dysfunction (AND neural-mediated hypotension);
Pyoderma Gangrenosum (PG)
Chronic Fatigue (CF) and Chronic Fatigue Syndrome^{i [134]} (CFS^{i [92]}).

Diseases where Cpn load has been associated where measured, and where treatment can create improvement in the primary condition:

Chronic hepatitis
Systemic lupus erythematosus
Arthritis
Thyroidosis
Scleroderma
Diabetes mellitus
Graves' disease
Beschet's disease and
Graft versus host disease (graft rejection).

Diseases where Cpn may be associated as a secondary or primary factor:

Editorial Comment: The diseases from here on have been associated with Cpn. At minimum it seems to suggest that at least serology^{i [340]}  for Cpn should be explored, or where there are other diagnostic indicators of Cpn an empirical course of the combination protocol should be looked at.

Sepsis syndrome
Cachexia
Circulatory collapse and shock resulting from acute or chronic bacterial infection
Acute and chronic parasitic and/or infectious diseases from bacterial
Viral or fungal sources such as a HIV, AIDS (including symptoms of cachexia, autoimmune disorders, AIDS dementia^{i [341]} complex and infections^{i [129]}) can be treated as well as Wegners Granulomatosis.

Various inflammatory diseases, there are certain features of the inflammatory process that are generally agreed to be characteristic. These include fenestration of the microvasculature, leakage of the elements of blood into the interstitial spaces, and migration of leukocytes into the inflamed tissue. On a macroscopic level, this is usually accompanied by the familiar clinical signs of erythema, edema, tenderness (hyperalgesia), and pain. Inflammatory diseases, such as chronic inflammatory pathologies and vascular inflammatory pathologies, including:
Chronic inflammatory pathologies such as aneurysms
Hemorrhoids
Sarcoidosis
Chronic inflammatory bowel disease
Ulcerative colitis
Crohn's disease and vascular inflammatory pathologies
Disseminated intravascular coagulation
Atherosclerosis
Kawasaki's pathology
Coronary artery disease
Hypertension^{i [225]}
Stroke
Asthma^{i [146]}
Chronic hepatitis
Multiple sclerosis
Peripheral neuropathy
Chronic or recurrent sore throat
Laryngitis
Tracheobronchitis
Chronic vascular headaches (including migraines
Cluster headaches and tension headaches) and pneumonia when demonstrated to be pathogenically related to Chlamydia infection.

Treatable disorders when associated with Chlamydia infection also include but are not limited to Neurodegenerative diseases including
Demyelinating diseasessuch as multiple sclerosis and acute transverse myelitis;
Extrapyramidal and cerebellar disorders such as lesions of the corticospinal system;
Disorders of the basal ganglia or cerebellar disorders;
Hyperkinetic movement disorders such as Huntington's Chorea and senile chorea;
Drug-induced movement disorders such as those induced by drugs which block CNS^{i [342]} dopamine receptors;
Hypokinetic movement disorders
such as Parkinson's disease;
Progressive supranucleo palsy;
Cerebellar and Spinocerebellar Disorders such as astructural lesions of the cerebellum;
Spinocerebellar degenerations (spinal ataxia)
Friedreich's ataxia
Cerebellar cortical degenerations
Multiple systems degenerations (MencelDejerine-Thomas
Shi-Drager and Machado Joseph)); and systemic disorders (Refsum's disease
Abetalipoprotemia, ataxia telangiectasia and mitochondrial multi-system disorder);
Demyelinating core disorders such as:
Multiple sclerosis
Acute transverse myelitis;
Disorders of the motor unit such as neurogenic muscular atrophies (anterior horn cell degeneration) such as
Amyotrophic lateral sclerosis
Infantile spinal muscular atrophy and juvenile spinal muscular atrophy);
Alzheimer's disease;
Down's Syndrome in middle age;
Diffuse Lewy body disease; Senile Dementia of Lewy body type;
Wernicke-Korsakoff syndrome;
Chronic alcoholism;
Creutzfeldt-Jakob disease;
Subacute sclerosing panencephalitis
Hallerrorden-Spatz disease; and
Dementia pugilistica

Malignant pathologies involving tumors or other malignancies such as:
Leukemias (acute chronic myelocytic
chronic lymphocytic and/or myelodyspastic syndrome);
Lymphomas (Hodgkin's and non-Hodgkin's lymphomas such as malignant lymphomas (Burkitt's lymphoma or Mycosis fungoides));
Carcinomas (such as colon carcinoma) and metastases thereof;
Cancer-related angiogenesis;
Infantile hemangiomas;
Alcohol-induced hepatitis.
Ocular neovascularization
Psoriasis
Duodenal ulcers
Angiogenesis of the female reproductive tract
can also be treated when demonstrated by the diagnostic procedures described herein to be associated with Chlamydial infection.

An immunocompromised individual is generally defined as a person who exhibits an attenuated or reduced ability to mount a normal cellular or humoral defense to challenge by infectious agents
e.g., viruses, bacterial, fungi and protozoa. Persons considered immunocompromised include malnourished patients, patients undergoing surgery and bone narrow transplants, patients undergoing chemotherapy or radiotherapy, neutropenic patients, HIV-infected patients, trauma patients, burn patients, patients with chronic or resistant infections such as those resulting from myeloodysplastic syndrome, and the elderly, all of who may have weakened immune systems. A protein malnourished individual is generally defined as a person who has a serum albumin level of less than about 3.2 grams per deciliter (g/dl) and/or unintentional weight loss greater than 10% of usual body weight.

The course of therapy, serological results and clinical improvements from compassionate antichlamydial therapy in patients diagnosed with the diseases indicated were observed and are reported in Example 5. The data provides evidence to establish that treatment of Chlamydia infection results in the serological and physical improvement of a disease state in the patient undergoing combination therapy. These observations were consistent among a variety of different diseases which fall within a generalized disease class.

Other Diseases of Unknown Etiology with New Evidence for a Chlamydia pneumoniae Etiology

Both C. trachomatis and C. psittaci exhibit a protean disease complex dependent on different serovars. One known basis for this diversity to date is the amino acid sequence of the MOMP. FIG. 1 shows a sequence alignment of various Chlamydia MOMPs. Note that the size and sequence are relatively homologous except for the four variable regions that are responsible for the serovar (serotype) basis of classification. Further, it has been discovered that C. pneumoniae infects blood vessel endothelial cells from which EBs are released in the blood stream. In addition, macrophages are known targets for C. pneumoniae and may serve as reservoirs and provide an additional mechanism of transmission. C. pneumoniae is thus able to spread throughout the human body, establishing infection in multiple sites and in multiple organ systems. Infected sites may exist for an extended period without inducing symptoms that are noticed by the patient or by an examining physician. Sequence variability of MOMPs or other chlamydial antigens may provide a basis for organ specificity while other chlamydial proteins, such as the 60K and 70K heat shock proteins or LPS^{i [143]}, may influence immune response.

C. psittaci and C. pecorum are known to cause a host of infections in economically significant animals. Thus, the teachings of this invention are relevant to animals. Throughout this application and for purposes of this invention, "patient" is intended to embrace both humans and animals. Virtually all rabbits and mice tested to date have PCR^{i [140]} signals for C. pneumoniae. They can be used as appropriate animal models for treatment using specific combination antibiotics^{i [111]} to improve therapy. (Banks et al., Ameri. J. of Obstetrics and Gynecology 138(7Pt2):952-956 (1980)); (Moazed et al., Am. J. Pathol. 148(2):667-676 (1996)); (Masson et al., Antimicrob. Agents Chemother. 39(9):1959-1964 (1995)); (Patton et al., Antimicrob. Agents Chemother. 37(1):8-13 (1993)); (Stephens et al., Infect. Immun. 35(2):680-684 (1982)); and (Fong et al., J. Clin. Microbiol. 35(1):48-52 (1997)).

Coupled with these developments are the recently developed rabbit models of coronary artery disease, where rabbits exposed to C. pneumoniae subsequently develop arterial plaques similar to humans (Fong et al., J. Clin. Microbiol. 35:48-52 (1997)). Most recently, a study at St. George's Hospital in London found that roughly 3⁄4 of 213 heart attach victims have significant levels of antibodies to C. pneumoniae antibody and that those that have such antibodies achieve significantly lower rates of further adverse cardiac events when treated with antibiotics (Gupta et al., Circulation 95:404-407 (1997)). Taken together, these three pieces of evidence (the bacteria found in diseased tissue, inoculation with the bacteria causes diseases, and treating for the bacteria mitigates disease) make a case for a causal connection.

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CAP^{i [4]i [4]} for Cpn^{i [90]} 11/04. Dx^{i [91]i [91]}: 25yrs CFS^{i [92]} & FMS^{i [93]i [93]}. Currently: 250 aithromycin mwf, doxycycline 100mg BID^{i [94]i [94]}, Tini^{i [95]i [95]} 1000mg/day pulses; Vit D2000 units, T4 & T3, 12mg Iodoral

Multiple Sclerosis and the CPn model

Multiple sclerosis is a disease of the central nervous system thought by most to be autoimmune because it is clear that the nervous tissue is being damaged and that also the immune system is present at the actual lesion location. Efforts to find a germ that the immune system is attacking have fallen flat with conflicting and inconclusive results. We propose here that MS^{i [113]} may be caused by chlamydia pneumoniae (CPn). In this book page I will outline the various findings in research on MS and also findings on CPn highlighting similarites.

While it is very interesting material, the reader must understand that this is a theoretical model and I am coming at it with this point of view, "If CPn causes MS what does this research mean?" I do have a bias as I begin. But I offer this to you, the reader: Everyone has a bias, I am just stating mine up front. The pharmaceutical company that is making a drug to suppress your immune system comes at the issue from a bias that MS is autoimmune, even though this is not proven but a model. So, we will start there.....

MS:Is it autoimmune?

Most of the medical community thinks MS is autoimmune because every damaged area in the MS brain has immune system cells present. Or do they? In 2004, Prineas and Barnett rocked the MS world with their paper "Relapsing and remitting multiple sclerosis: pathology of a newly forming lesion" found HERE [343]

As you can see in that paper, and I was lucky enough to read the whole citation, the notion that the immune system comes in and damages the nerves is seriously questioned. Essentially these authors found that in autopsied brain tissue, the brain had the lesions that they expected with immune system cells present, but these tissue samples ALSO had NEW lesions in which the nerve had died, but the immune system had not yet gotten there to clean the area up and remove the dead tissue. How can the immune system have caused the injury if the injury occurs before it arrived? If we understand that immunity includes cleaning up dead cells and unwanted tissue, we see there is a very good reason for the immune system to be present in the brain if a nerve has died from some other cause.
In fact this is a very logical reason for the immune system to be present because we already know that the immune system works this way naturally, this is what it is designed to do. All other theories from molecular mimicry to autoimmunity require that the body made a mistake and began attacking itself.

This work is supported by review of the issue written by Chaudhuri and referenced on pubmed HERE [344] I have been fortunate enough read this paper (the link I provide here has a "blank", you'd have to subscribe to read it) and this author is adament that MS is not autoimmune,. In an earlier paper he said;

"Multiple sclerosis (MS) is a common, disabling neurological condition whose pathogenesis is not clearly understood. Although current treatment recommendations assume an immunopathogenic disease mechanism, MS may not be an autoimmune disorder. Long-term immunological therapy for MS is in our view an untested approach, guided by uncritical acceptance of data from drug trials. We do not believe that there is convincing evidence that any of these immune-based treatments prevents long-term disease progression, or has much effect on common disabilities such as fatigue, pain, depression and cognitive impairment. The recent recommendations of the National Institute of Clinical Excellence did not address important issues regarding disease modification, management of paroxysmal symptoms and the likely therapeutic candidates for future treatment trials. We discuss treatment options for MS beyond the NICE guidelines" (Chaudhuri 2005) reference HERE [345].

A recent work by Dr Sriram of Vanderbilt University published in the Annals of Neurology and referenced HERE [346] indicates that MS is utterly different on a cellular level than EAE which is a pure autoimmune disease. There are different cytokine^{i [128]} upregulations and a cellular immune different profile altogether, which is a critical issue because the therapies generated by looking at what impacts EAE are geared to alter these cytokines. He contends that the constant reliance on this model as a "good model" of MS and through which all treatments are brought to us limits research understandings about what MS really is. In essence we are treating EAE not MS when we bring new protocols and strategies to market via this method. It is interesting to note that EAE is curable and it has been so for decades via the same medications that do not actually help people with MS.

HERE [347]
is yet another abstract indicating that anti-inflammatory approaches may be misdirected in MS. Importantly, these authors say that even the newer immune suppressing approaches, while they do result in a large decreases in MRI activity, do not result in an improvement in disabiilty long term. Quote;

"Suppressing relapses by disease-modifying agents does not dramatically influence the progression of irreversible disability. Interferons beta reduce the relapse rate by 30% and conventional MRI activity by more than 50%. In spite of this effect on inflammation, the effect on disability is only marginal and possibly relapse-reduction-dependent. Administration of Campath-1H to patients with very active disease in terms of frequency of relapses, accumulation of disability and MRI activity, results in a profound, prolonged lymphopenia and the suppression of clinical and MRI activity, but in spite of this, clinical disability and cerebral atrophy still progress. The same experience has been reported with cladribine and autologous haematopoietic stem cell transplantation..." copied verbatim
The paper suggests that neuro regeneration and protection should be the main focus of MS strategies, not simply reducing inflammation. It also raises an important question for medicine in general in regards to currently available therapies, namely exactly what does reduction in inflammation accomplish for the MS patient and at what cost?

So here I have presented the idea that MS is not autoimmune and offered research that caused me to form that opinion. So, If MS is not autoimmune but instead a disease in which the nerves die for some reason then the immune system comes in to clean up the debris just as it is supposed to, what bacteria or virus is to blame?

The infective model of MS

The infective model of MS is the notion that MS is caused by a virus or bacteria. While numerous attempts have been made to isolate the infective organism, unfortunately no one organism has been consistently tied to MS. Several of the possibiities are human herpes 6 (roseola), epstein barr virus (mono or glandular fever), and pleomorphic bacteria like chlamydia pneumoniae, borrelia, and mycoplasma. While there are articles outlining some people finding and isolating each of these things in the MS brain, others do not find the same organism. Here in these pages we are presenting the idea of CPn as the possible infective organism but it may be that the kinds of changes we see in CPn could be common to changes seen in other bacterial infections like persistant borreliosis and potentially even viral causes. The body often uses the same strategies to do multiple things as in, for example, creating a fever in both viral and bacterial infections of many kinds. We are investigating CPn specifically here as the theoretical cause of MS because Vanderbilt University research finds CPn in higher numbers in the CFS^{i [92]} of people with MS. Additionally, there is a lot of general research on CPn indicating it is causing a variety of chronic illnesses because it has the ability to change forms and invade the cells themselves including especially immune cells, nerve cells, vessel walls, lung tissue, and blood cells. For example, CPn is considered an emerging pathogen in atherosclerosis. See the CDC link HERE [348] It is also implicated in asthma, and some authorities such as Margaret Hammerschlag MD of the CDC are now saying that asthma, long thought to be a chronic illness of unknown pathology which has decades of research looking at genetics and other putative factors as causal, is in fact probably a chronic infection with CPn. When discussing MS specifically, it is less clear at this point although there is a lot of circumstantial evidence for CPn possibly playing a role as well as the research done at VU finding it directly.

The first people to produce work that shows CPn in the MS brain were at Vanderbilt University Sriram, Stratton and Mitchell. The first paper is here [349]. This paper is the whole citation, and it is an incredible privilege to have this paper available to us. This was reprinted on CPnhelp.org with permission. In essence, the upshot of this article is that using their techniques, the team at VU found evidence of CPn in the vast majority of MS patients. It is important to note that the team used PCR^{i [140]} analysis, CSF immunoglobin IgG reactivity with CPn antigens and culture to evaluate the presence of CPn in these MS brains. People who produce work counter to this frequently offer a single test ie "we cultured the CSF for CPn and found none." Such "opposing" research simply does not have the authority that the original work did due to the lack of diligence. We will investigate this specific issue in depth in the next page about the debate.

Other researchers all over the world have also found CPn in MS brains. A list of some of these follows:

HERE [350] is a paper by Contini C, et al titled "Cerebrospinal fluid molecular demonstration of Chlamydia pneumoniae DNA is associated to clinical and brain magnetic resonance imaging activity in a subset of patients with relapsing-remitting multiple sclerosis". This paper found that CPn was associated with MS more often if the disease was active on MRI and if RRMS^{i [351]}. Again this author used several detection methods. But in this paper they also found CPn in people with other neurological diseases as well, suggesting it may be able to cause several problems. This might be compared to e.coli causing a bladder infection, urethritis, or nephritis. All are urinary tract infections with slightly different locations and problems.

HERE [352] is a link to an abstract by Dong-Si T, et al titled "Increased prevalence of and gene transcription by Chlamydia pneumoniae in cerebrospinal fluid of patients with relapsing-remitting multiple sclerosis". This author again found that other neurological diseases also had increased CPn, but that in MS patinets there was increased gene trascription of CPn indicating it may be more active for them.

HERE [353] is a link to an abstract by Sotgiu s, et al titled "Chlamydia pneumoniae in the cerebrospinal fluid of patients with multiple sclerosis and neurological controls.". This author found CPn in the MS patients only, as different from others.

HERE [354] is a paper by Fainardi E, Et al titled "Intrathecal production of Chlamydia pneumoniae-specific high-affinity antibodies is significantly associated to a subset of multiple sclerosis patients with progressive forms" in which an association between CPn and MS was found. The conclusion was "These findings confirm that the presence of a humoral immune response to C. pneumoniae within the central nervous system (CNS^{i [342]}) is not selectively restricted to MS, but is shared by several inflammatory neurological conditions. In addition, our results suggest that an intrathecal^{i [355]} production of C. pneumoniae-specific high-affinity IgG can occur in a subset of patients with MS progressive forms in which a C. pneumoniae brain chronic persistent infection may play an important pathogenetic role."

This is a sample of the work that found CPn in MS. To read more simply click one of the links and enter "multiple sclerosis chlamaydia pneumoniae" in the search box on pubmed. You'll get a whole list. Of interest note that this work is done all over the world and a considerable amount of it is done by infectious disease specialists and pathologists, not necessarily neurologists. There is other work, of course, that did not find it since this is how science works to advance understanding. For the best review of the debate on the potential for CPn to be the causitive organism in MS is found in David Wheldon^{i [118]}'s site. There is a greater number and a more in depth evaluation of studies there. HERE [98]. The question "how do we evaluate these controversial findings?" is tackled on the Great Debate page.