Chlamydia Pneumoniae in Human Disease

Chlamydia Pneumoniae in Human Disease

These links present this topic best:

*The pdf of Charles Stratton's review of Cpn in Chronic Disease : http://www.cpnhelp.org/pdfs/ChronicDisease.pdfA detailed review of Cpn in chronic diseases at: http://www.chlamydiae.com/Chlamydophila_pneumoniae_introbk.asp Crossing the Barriers http://www.cpnhelp.org/?q=node/35 We will have separate pages eventually which discuss specific Cpn in diseases eventually. For now you can find these reference links as starter points.

Multiple Sclerosis-

David Wheldon't site http://www.davidwheldon.co.uk/ms-treatment.htmland the following links from Marie's excellent compilation on our Research page:  

CPn and Cardiovascular Issues

We have so many links to cardiovascular issues that these are now found on their own page here. Please do read this material even if you are here for something other than cardiovascular problems! While you may be on this site for MS, CFS or FMS, it is the cardiovascular research that has all the depth and impressive volume about CPn and how it causes human disease that makes the picture truly clear. Don't make the mistake of thinking this is some new idea or that it has only a few studies just because it is relatively unknown in one field. This is as significant to human disease as understanding staphylococcus, only we are talking in this case about chlamydia pneumoniae. Information about the germ applies and transfers from one field to the next: the important thing is to understand the pathogen.

CPn and Arthritis:

-Antibiotic treatment of arthritis Osteoarthritis when treated with doxycycline has significantly reduced joint space narrowing 40% better than controls. Persisitant CPn and Arthritis Great paper overviews the concept of CPn and C. trachomatis as causitive agents in arthritis.

CPn and Respiratory disease:

Mechanisms of chlamydiophilia mediated GM-CSF release in HUman Bronchial cellsHow does CPn tirgger inflammatoin in lung tissue? this attempts to pinpoint the answer Serum IgG and IgA antibodies to CPn in EmphysemaThis article indicates that serology is positive in emphysema and that clinical course and worsening is tied to CPn status Asthma and CPn. Explains interaction of patient immune system with the CPn. Technical. -Cpn in recurrent respiratory infections This work with children with recurrent respiratory infections indicates that treating for cryptic bacteria improves outcomes. Treatment was prolonged due to the nature of cryptic, or "atypical" bacteria. Chlamydia Pneumoniae and COPD This reserach indicates that acute exacerbations of COPD re associated with CPn. -Cpn in asthma This research indicates that cryptic bacteria play a role in asthma. Outcomes were improved by adding abx.

CPn and other diseases:

  Behcets may be CPn related. A disease traditionally thought to be autoimmune is found to have significant titers of CPn. -Cpn in prostate pathology This research found CPn in prostates with pathology. It even offers the theory that patholgy from hypertrophy to cancer represents different stages of infection. -Chlamydia Pneumoniae in Interstitial Cystitis Is IC a mystery disease or is it a bacteria? This paper outlines the results of research investigating this. Interstitial cystitis and CPn Link out to paper on this subject. -Chlamydia pneumoniae in the Alzheimer's brain varies with APOE genotype The APOE genotype apparently interacts with CPn in alzheimers patients carrying that genotype. This suggests an interesting theory: that a bacteria is not the same in every person in terms of effects but rather an interaction between genes and bugs results in the pathology an individual experiences. This is a whole new understanding of how we interact with our environment.  

Jim K Sat, 2006-02-04 11:44

How Chlamydia Pneumoniae Causes Such a Plethora of Diseases

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 Dr. Charles Stratton's Current Thinking on How Chlamydia Pneumoniae (Cpn) Infection Causes Specific Diseases   Dr. Stratton has been observing the emerging literature and research on Cpn, as well as the clinical trials of new anti-chlamydial agents (see footnotes at bottom of this page). His unique and expert microbiological perspective on Cpn helps to shed some light on how such a singular organism can engender such multiple and varied clinical diseases. These observations inform Dr. Stratton’s current thinking about the course and pattern of Cpn infection. I’ve attempted to diagram this below to give the reader a feel for the sequence and locus of Cpn in the body, as well as the resulting disease picture. WHile these should be termed theoretical speculations, his theoretical speculations are based on his considerable research, his expertise in microbiology, and his varied clinical experience in treating numerous Cpn infections in a variety of diseases. The picture he describes makes much clearer the multiple pathways and illnesses caused by Cpn, as well as the challenges in treating it.  Initial Infectious Entry- The initial entry into the body for Cpn infection is through the respiratory system. Studies have demonstrated that Cpn crosses from the lungs into the blood stream via infecting macrophages, the first response immune cells which are trying to combat the respiratory infection.   These circulating infected macrophages both produce EB’s, the infectious spores of Cpn, directly into the blood stream where they attach to and are carried by red blood cells throughout the body (see the picture on our home page), and are taken up by the natural filter organs of the body where they infect those organs with Cpn.   The Inflammatory Trigger: Stage is now set for focal diseases: any source of inflammation attracts infected macrophages and white cells as well as EB carrying red cells as part of the body’s natural repair process. Cpn then transfers from damaged macrophages via EB’s and sets up shop in inflamed areas.   At this point in the infection cycle, the type and locus of the Cpn infection then determines which disease will result and manifest symptomatically (the following is meant for example only, and is not intended to be a complete or exhaustive list):     Where specialists, and patients, tend to look at a particular disease as the problem, the microbiological perspective Dr. Stratton brings sees the problem as one of a systemically based infection.   Dr. Stratton now posits that the primary infection in Cpn is of the immune system: immune cells & bone marrow.

  • It is this which, in part, causes such difficulty in getting rid of Cpn.
  • It also causes continuous reinfection if the full spectrum of Cpn infection is untreated.
  • It also lowers the body’s ability to cope with other bacterial and viral infections.
  • This, in turn, fosters further sources of inflammation, and even has the potential (through immuno-incompetence) to compromise the body’s ability to fight cancer and other diseases.

  It also answers some common questions that arise in Cpn Combined Antibiotic Protocol (CAP) treatment.   Why do viruses and cold sores “surface” during CAP treatment? This could be due to apoptosis (cell death) of infected immune cells and resulting neutropenia which temporarily lowers your immune response until these cells are replaced. Hence latent but suppressed viruses and fungi emerge as immune cells, which previously held them in check, die.   Why is aggressive or rapid treatment of Cpn potentially dangerous? In addition to the misery of massive endotoxin release from killing Cpn, and related cytokine (inflammatory) responses of pain and brain fog, massive kill of Cpn infected cells in the body could potentially cause crashing white counts and potential organ dysfunction or even organ failure (E.G.. liver failure) as large scale apoptosis of infected immune and organ cells occurs. As there is no quantitative measure of infectious load, and no way other than symptoms to know which organs are significantly infected, it behooves physicians treating Cpn to start gradually until some measure of the patient’s response indicates how quickly one can “ramp up” to full treatment. This also suggests that highly potent anti-chlamydial agents such as Rifabutin are not the best first-line treatment, even though they appear to be more effective at killing Cpn more quickly. Once the load has been brought down through gradual introduction of the regular CAP, then a cautious trial of such other agents can be considered.   Dr. Stratton has been paying close attention to reports of drug trials of Rifabutin, a very potent new anti-chlamydial. Even healthy young volunteers showed lowered white cells and liver problems during the Pfizer trials.   Given that Dr. Lee Stewart’s findings that 20-25% of young, healthy blood donors were found to be  flow cytometry positive for Cpn, Dr. Stratton believes that these effects could be not so much side effects of Rifabutin, as it has been currently viewed, but rather a main effect of the drug, that of killing Cpn and resulting death of previously infected cells.   In other words, since Cpn infection is ubiquitous and often sub-clinical, and “side” effects from potent antichlamydial agents in so-called “healthy” volunteers are actually main effects--- the subjects were not healthy after all, just not clinically ill.   Multi-year treatment process- Treating Cpn is a multi-year treatment process because of it’s potential to be widespread throughout in body organs, the vascular system, and immune system, as well as it’s toxicity in treatment (from endotoxins, porphyrins, inflammatory and cellular apoptosis). The more body systems involved, the longer and more difficult it is to treat, both in terms of tolerance of treatment from endotoxins, porphyria and apoptosis, as well as being able to get to all the tissues involved, which have differentials in terms of how antibiotics may concentrate in them. Cpn cells also have active pumps which try to lower concentrations of noxious substances (like antibiotics) which also have to be overcome.   How long treatment will take depends, of course, on the degree of infection, amount of bacterial load, severity of infection and number of organs involved, and so on. We don’t have any quantitative measures of infection currently. A good clinician, knowledgeable about the conditions which Cpn can cause, may be able to make an educated guess as to how many organ systems are involved on the basis of history and symptoms. Dr. Stratton sees the degree of reaction to NAC as a useful rough indicator of EB load—the more you react to it the more EB’s you have built up. He also sees the length of time one has been infected (when symptoms may have started) as a rough indicator of the length of treatment (note: one can only guess at this, as we may have initiated Cpn infection from what seemed a mild respiratory infection many years ago, and did not demonstrate serious problems such as MS until years later).   Dr. Stratton’s rule is “Go as fast as you can but no faster,” i.e. as rapidly as your own particular condition can tolerate given the above factors.   He sees that towards the latter phase of treatment, when one is no longer responding with significant reactions to metronidazole pulses, doing a course of 2 weeks on Flagyl and 2 weeks off while continuing with dual antibiotics, is a useful process to clear remaining tissues. When this is tolerated without significant side effects, a cautious trial of Zithromax and Rifabutin as a final test of Cpn clearance could be tried under careful supervision (watching for plummeting white cells and liver toxicity). At this point one should have cleared organs sufficiently that any apoptosis from the potency of Rifabutin would likely be easily tolerated.  

Footnotes: Specific observations

  Dr. Stratton has paid particular attention to findings by Dr. Stewart that supposedly young, healthy blood donors are showing positive cultures and flow cytometry for Cpn. Her study showed a number of very important findings with implications for our understanding of Cpn transmission and proliferation in the body.   The first is that approximately 25% of buffy coat samples (a buffy coat is the WBC— white blood cell— portion of spun blood) were culture positive for Cpn. This is not an antigen test, but means that Cpn could actually be cultured or grown in the lab from 25% of white blood cell samples. This means infectious Elementary Bodies are circulating in the blood stream.   The second significant finding in Dr. Stewart’s study, was that approximately 25% of WBC’s were seen by Flow Cytometry to have intracellular Cpn. The work of Yamaguchi, demonstrating messenger RNA from peripheral blood mononuclear cells, suggests that these intracellular Cpn found by Stewart are viable. Thus, we know that viable Cpn in WBCs and infectious Cpn elementary bodies circulate in the blood stream and can go anywhere blood goes and can infect any tissue. I will go into why Dr. Stratton sees this finding as so important in a bit.   Dr. Stratton also notes that, in her study, this 25% of donors infected with viable Cpn, both intracellular and free EB’s, occurred in so-called “young healthy blood donors.” That is, while they were culture-positive for Cpn, they have no disease symptoms and were considered to be a “normal” control sample. Dr. Stratton links this finding to reports from the Pfizer drug trials for Rifabutin, a highly potent anti-chlamydial. In the drug trials for Rifabutin there were some cases of liver failure and also of plummeting white blood cell counts in “healthy” volunteer subjects. This has been interpreted in some places as a potential side effect of the medication.   From Dr. Stratton’s perspective on the biology of Cpn, and utilizing the evidence from Stewart, Yamaguchi and others, if 25% of “healthy” volunteers are in fact infected with Cpn, including potentially liver and immune system (white cells) cells as important sites of infection (see explanation below), then a highly potent anti-chlamydial agent will kill many Cpn in parasitized cells. This could initiate large-scale apoptosis (natural cell death) of those body cells that have been inhibited from apoptosis by the Cpn which previously infected them.   Let me say that again, a little differently. We know that Cpn inhibits apoptosis of its host cell so that the host cell stays alive and the infecting Cpn survives. If you kill the Cpn invader, the host cell is no longer being prevented from it’s natural death and replacement cycle. And If you kill a bunch of Cpn all at once, you have a bunch of your body or organ cells dying all at once, and it takes time for them to be cleared by the immune system and then replaced by the natural cell replacement process. It is this, on a more gradual scale, which David Wheldon has noted makes for continuing die-off like symptoms after a Flagyl pulse has been completed.   So, if a whole bunch of liver cells undergo apoptosis at once then liver failure or liver problems could occur. Similarly, if a whole bunch of immune cells undergo apoptosis then, then macrophages and white cells die and severe neutropenia (lowered white count) could occur. From Dr. Stratton’s perspective, these reports may not be a side effect of the Rifabutin, i.e. an unintended effect of a medication, but rather could be due to it’s main effect—killing Cpn.     Jim K   Related References-     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. Transfusion. 2004 Jul;44(7):1072-8.    Department of Infectious Disease, Division of Microbiology, and the Department of 1st Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan.   BACKGROUND: Demonstration of viable Chlamydia (Chlamydophila) pneumoniae in peripheral blood mononuclear cells (PBMNCs) is essential to understand the involvement of C. pneumoniae in atherosclerosis. Nevertheless, the prevalence of viable C. pneumoniae in the blood of healthy donors has not yet been studied. STUDY DESIGN AND METHODS: The presence of C. pneumoniae transcript in PBMNCs from blood of healthy human donors was assessed by real-time reverse transcription-polymerase chain reaction (RT-PCR) with primers for C. pneumoniae 16S rRNA, which is more sensitive than genomic-DNA-based analysis, and by the use of staining with fluorescein isothiocyanate-conjugated chlamydia monoclonal antibody (MoAb). RESULTS: Thirteen of 70 donors (18.5%) showed the presence of bacterial transcript in cultured PBMNCs. The prevalence of bacterial detection and bacterial numbers was significantly increased in PBMNC cultures incubated with cycloheximide. Immunostaining of PBMNCs with antichlamydial MoAb also revealed the presence of bacterial antigen in the PBMNCs judged as positive. Nevertheless, cultivation of C. pneumoniae from all PCR-positive donors was unsuccessful. There was no signifi-cant correlation between the presence of chlamydia and either sex or current smoking habits. A possible age variation, however, in the presence of chlamydia in blood of healthy donors was suggested by the results obtained. 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.   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 (fcirino@microbio.umass.edu) Wilmore C. Webley Nancy L. Croteau (Nancy.Croteau@umassmed.edu) Chester Andrzejewski Jr. (chester.andrzejewski@bhs.org) Elizabeth S. Stuart (esstuart@microbio.umass.edu)   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 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.   Tolerance and Pharmacokinetic Interactions of Rifabutin ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 0066-4804/01/$04.000 DOI: 10.1128/AAC.45.5.1572–1577.2001May 2001, p. 1572–1577 Vol. 45, No. 5 Copyright © 2001, American Society for Microbiology. All Rights Reserved. and Azithromycin RICHARD HAFNER,1* JAMES BETHEL,2 HAROLD C. STANDIFORD,3 STEPHEN FOLLANSBEE,4 DAVID L. COHN,5 RONALD E. POLK,6 LARRY MOLE,7 RALPH RAASCH,8 PRINCY KUMAR,9 DAVID MUSHATT,10 AND GEORGE DRUSANO11 FOR THE DATRI 001B STUDY GROUP† This multicenter study evaluated the tolerance and potential pharmacokinetic interactions between azithromycin and rifabutin in volunteers with or without human immunodeficiency virus infection. Daily dosing with the combination of azithromycin and rifabutin was poorly tolerated, primarily because of gastrointestinal symptoms and neutropenia. No significant pharmacokinetic interactions were found between these drugs.   Severe neutropenia among healthy volunteers given rifabutin in clinical trials CLINICAL PHARMACOLOGY & THERAPEUTICS DECEMBER 2003 591 Glen Apseloff, MD The Ohio State University College of Medicine and Public Health Columbus, Ohio CLINICAL PHARMACOLOGY & THERAPEUTICS Letters to the Editor DECEMBER 2003, p. 592     Comparison of azithromycin and clarithromycin in their interactions with rifabutin in healthy volunteers. J Clin Pharmacol. 1998 Sep;38(9):830-5 Apseloff G, Foulds G, LaBoy-Goral L, Willavize S, Vincent J.   Department of Pharmacology, The Ohio State University College of Medicine, Columbus 43210-1239, USA.   A 14-day, randomized, open, phase I clinical trial was designed to examine possible pharmacokinetic interactions between rifabutin and two other antibiotics, azithromycin and clarithromycin, used in the treatment of Mycobacterium avium complex infections. Thirty healthy male and female volunteers were divided into five groups of six participants each: 18 received 300 mg/day of rifabutin, 12 in combination with therapeutic doses of either azithromycin or clarithromycin; the remaining 12 received azithromycin or clarithromycin alone. On day 10 the study was terminated because of adverse events, including severe neutropenia. Fourteen participants who received rifabutin developed neutropenia, including all 12 participants who received azithromycin or clarithromycin concomitantly. Analyses of serum revealed no apparent pharmacokinetic interaction between azithromycin and rifabutin. However, the mean concentrations of rifabutin and 25-O-desacetyl-rifabutin (an active metabolite) in participants who received clarithromycin and rifabutin concomitantly were more than 400% and 3,700%, respectively, of concentrations in those who received rifabutin alone. Physicians should be aware that recommended prophylactic doses of rifabutin may be associated with severe neutropenia within 2 weeks after initiation of therapy, and all patients receiving rifabutin, especially with clarithromycin, should be monitored carefully for neutropenia.  

Jim K Sun, 2006-12-24 23:31

Chlamydia Pneumoniae in CFS/ME & Fibromyalgia

Chlamydia Pneumoniae in CFS/ME & Fibromyalgia

Chronic Fatigue Syndrome, 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), or called Myalgic Encephalomyelitis (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).[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.e. those organisms that are either typically overlooked, difficult to test for, or tend to evade the immune system[7]. Within this causal possibility are infectious organisms such as Chlamydia pneumoniae.My purpose here will be to present the information that argues for the involvement of Chlamydia pneumoniae in at least a sub-set of Chronic Fatigue Syndrome and Fibromyalgia Syndrome patients. I will outline how Chlamydia pneumoniae's known biology and impact on the body could explain some of the characteristic symptoms and signs of Chronic Fatigue Syndrome.At the outset it should be said that Chlamydia pneumoniae is not the only infectious agent that has implicated in Chronic Fatigue Syndrome/Fibromyalgia Syndrome. We certainly don't know if it is involved in all, a subset or merely a co-condition of such cases. But there is good reason to look further at this particular organism's involvement. Most of the argument discounting Cpn's involvement in CFS/FMS has been based on ignorance and poor understanding about the organism itself and the difficulties of testing and treatment for it. This is an attempt at trying to correct this ignorance, and place Chlamydia pneumoniae more clearly in the realm of possible sources for these devastating conditions.The Early Vanderbilt Work: Chlamydia pneumoniae in Chronic Fatigue Syndrome-The Incomplete Research-There is some published work linking Chlamydia pneumoniae to Chronic Fatigue Syndrome/Fibromyalgia Syndrome in medical research journals.[8] But perhaps the most important research in this regard never reached publication. This article is the first thorough description in a public information setting.The original initial work at Vanderbilt by Dr. Charles Stratton 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 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 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 known to be antichlamydial and see if reduction of PCR signal for Cpn correlated with reduction in CFS symptoms. This was done by the by Dr.'s Cheney, Peterson & Bell with a sample of their patients. It turned out that no single antibiotic agent eradicated the Chlamydia pneumoniae PCR signal. So, Dr. Stratton's lab, having laboriously developed the PCR susceptibility tests (described quite elegantly in the patent materials which can be found linked elsewhere in this website) now had to use them to discover which agents or combinations of agents were required to eradicate Cpn completely, such that no PCR signal was evident in blood samples. This is called "sensitivity testing."This was a greater challenge than most of us would think. Along the way to infecting mice and cell cultures with Cpn and looking for effective combinations of antibiotics, they discovered that the available laboratory mice and commercial cell cultures widely assumed by scientists to be "clean," and thus proper starting points for introducing new variables, were themselves often infected with Chlamydia pneumoniae. This could seriously skew the interpretation of their tests. So Dr. Stratton's lab had to first develop methods to clear the cell cultures of Chlamydia pneumoniae and prove such clearance using their sensitive PCR testing. This is a remarkable bit of science here. Their finding that common biological laboratory materials are contaminated with Cpn appears also to be relatively unknown.From all of this they managed to find that only certain combinations of antibiotic agents (described elsewhere in this website) would completely eradicate Chlamydia pneumoniae from tissue cultures and laboratory mice, as indicated by clearance of Cpn PCR signal. No single antibiotic treatment, nor any series of antibiotics one at a time, was able to eradicate Cpn. Now that they had the combination antibiotic protocol (CAP) protocol, they could test the impact of eradicating Cpn on the resulting CFS symptoms, and then confirm whether patients were actually clear of Cpn from the blood testing.And another thing…As in all research, there is always another problem ahead. This time the problem was with the reactions to the clinical treatment itself being tried by Dr.'s Cheney, Peterson & Bell, as well as by Dr. Stratton with his own Chronic Fatigue Syndrome patients. The treatment was indeed working to kill Cpn, but the toxicity of the Cpn kill was causing existing symptoms to worsen significantly. The dropout rate using the combination antibiotic protocol (CAP) for Chronic Fatigue Syndrome was very high. Many patients were unable to see it through to the endpoint of the whole of the treatment process—where PCR signal was absent for Cpn. As Dr. Stratton put it to me in an interview, "The cure appeared worse than the disease." It was difficult for the treating physicians to keep patients on the protocol long enough to begin to see significant symptomatic improvement. This was due to two major difficulties. Die-off reactions- When combinations were used the die-off reactions from this potent mix could be as bad, or worse, than the Chronic Fatigue Syndrome itself. Little was yet known about how to support patients through these reactions, or what exactly their nature was. Length of treatment- Moreover, the length of treatment of Cpn with these combination antibiotic protocols 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 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, 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 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 and amoxicillin 2. Once the EB invades a host cell it converts to the replicating Reticulate Body (RB)- only antibiotics that interfere with replication, such as protein synthase inhibitors doxycycline or azithromycin, affect it. 3. Finally, Cpn can survive those drugs by converting to the low metabolizing "cryptic" form, which Dr. Stratton's research found is only killed by metronidazole family drugs.Thus two weeks, or even two years of a single antibiotic may improve symptoms by suppressing one form of Chlamydia pneumoniae, but symptoms recur as soon as the antibiotic is withdrawn. * Worsening- Killing Chlamydia pneumoniae liberates significant amounts of bacterial endotoxins which cause widespread cytokine reactions, including inflammation, pain, depression, low energy and so on. These are precisely the symptoms of Chronic Fatigue Syndrome/Fibromyalgia Syndrome itself. In addition, Stratton's work found that Chlamydia pneumoniae causes a condition of secondary porphyria[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 pneumoniaeWhen 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 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, 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 and HSP-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 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 nodesOne 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 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 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 (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_ * 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.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[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 nodesOther Commonly Observed Symptoms in CFSThe 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 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 for further discussion.[6] Effective Treatment Of Chronic Fatigue Syndrome (CFIDS) & Fibromyalgia (FMS) - A Randomized, Double-Blind, Placebo-Controlled, Intent To Treat StudyTeitelbaum 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 - 2001Background: 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, 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 infectionhttp://www.cpnhelp.org/?q=node/129[8]Article link hereMultiple 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 techniquesBMC Infectious Diseases 2006, 6:23 doi:10.1186/1471-2334-6-23Frances Cirino, Wilmore C. Webley, Nancy L. Croteau, Chester Andrzejewski Jr.,Elizabeth S. Stuart (esstuart@microbio.umass.edu)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…”Thirteen of 70 donors (18.5%) showed the presence of bacterial transcript in cultured PBMNCs. …CONCLUSION: The bacterial transcripts in PBMNCs obtained from healthy donors were detected by the RT-PCR method. Viable C. pneumoniae may be present in healthy human PBMNCs…”[10] Note- One of the things Dr. Stratton said to me shortly after I started www.cpnhelp.org was that this kind of thing was one of the missing elements in the treatment process: some kind of on-going support community that could help patients through the challenges and confusions of being on a difficult protocol.[11] As far as I know Dr. Stratton’s group are the only ones to have found the link between Chlamydia pneumoniae infection and secondary porphyria. It remains unpublished in the scientific literature and so virtually unknown to most medical practitioners.[12] http://www.cpnhelp.org/?q=cell_death_and_inflammati[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.itAcute 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 SciencesCytokines and Chronic Fatigue SyndromeRoberto PatarcaaE. M. Papper Laboratory of Clinical Immunology, Department of Medicine, University of Miami School of Medicine, Miami, Florida 33101, USAAddress 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[16] Vestn Ross Akad Med Nauk. 2005;(2):17-22.The immune system, atherosclerosis and persisting infectionPigarevskii 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.deChlamydia 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: 16844674People 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.deAnaemia 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 LinksAbnormal 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.orgBACKGROUND: 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[22] http://www.cpnhelp.org/cpn_in_gi_tract_tissue_1http://www.cpnhelp.org/c…] Recent Patents on Endocrine, Metabolic & Immune Drug Discovery 2007, 1, 63-82 63Melatonin as Antioxidant Under Pathological ProcessesCristina Tomás-Zapico*, Ana Coto-Montes1Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, 33006 Oviedo, Spainhttp://www.bentham.org/emi/samples/emi1-1/Tom%E1s-Zapico.pdf[24] Melatonin inhibits expression of the inducible NO synthase II in liver and lung and preventsendotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in ratsELENA CRESPO,* MANUEL MACI´AS,* DAVID POZO,† GERMAINE ESCAMES,*MIGUEL MARTI´N,* FRANCISCO VIVES,* JUAN M. GUERRERO,† ANDDARI´O ACUN˜ A-CASTROVIEJO*,1www.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 hereAnnals of the New York Academy of SciencesVolume 933 THE ROLE OF NEURAL PLASTICITY IN CHEMICAL INTOLERANCE Page 211 - March 2001Annals of the New York Academy of Sciences 933 (1), 211–221.The Role of Cytokines in Physiological Sleep Regulation* James M. Kruegera et alArticle 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…] Migraine: A Chronic Sympathetic Nervous System DisorderStephen J. Peroutkahttp://www.medscape.com/viewarticle/466937_1[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.ilVarious 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, 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 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 monthsPain in at least 11 of 18 tender-point sites.http://www.arthritis.org/conditions/DiseaseCenter/Fibromyalgia/fibromya… 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_…;

Jim K Sat, 2007-12-29 18:53

Chlamydia pneumoniae and Rosacea: A potential link?

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 is a chronic disorder of still unknown cause that affects an estimated 14 million Americans.1 Rosacea 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) 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), 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, Asthma, 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 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, 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'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. Rosacea.org.

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

3. Bikowski, Joseph. Examining Inflammation as a Common Factor in Theories of Rosacea Pathophysiology. 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. Br J Ophthalmol. 2007 Feb;91(2):226-9.

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

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

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

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

9. Stratton, Charles W. Association of Chlamydia pneumoniae with Chronic Human Diseases. 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. 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. 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. Medical News Today. 13 Nov 2005.

13. Blasi F, Centanni S, Allegra L. Chlamydia pneumoniae: crossing the barriers? 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. Infection and Immunity, April 2004, p. 1843-1855, Vol. 72, No. 4.

15. National Rosacea Society. Is Rosacea Like an Allergy?, 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. J Clin Invest. 2003 June 1; 111(11): 1665–1672.

17. Nizet Victor, Gallo Richard L. Cathelicidins and Innate Defense Against Invasive Bacterial Infection. 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. 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. 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. Antimicrobial Agents and Chemotherapy, March 2005, 49(3), 1201-1202.

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

 

 

Red Thu, 2007-03-01 08:45

Chlamydia pneumoniae in Chronic Fatigue Syndrome and Fibromyalgia

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 Chronic Fatigue Syndrome, Fibromyalgia & Chlamydia Pneumoniae[1]

Introduction

Chronic Fatigue Syndrome (CFS), also called Chronic Fatigue Immunodeficiency Disorder (CFIDS), or called Myalgic Encephalomyelitis (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).[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.e. those organisms that are either typically overlooked, difficult to test for, or tend to evade the immune system[7]. Within this causal possibility are infectious organisms such as Chlamydia pneumoniae. My purpose here will be to present the information that argues for the involvement of Chlamydia pneumoniae in at least a sub-set of Chronic Fatigue Syndrome and Fibromyalgia Syndrome patients. I will outline how Chlamydia pneumoniae's known biology and impact on the body could explain some of the characteristic symptoms and signs of Chronic Fatigue Syndrome. At the outset it should be said that Chlamydia pneumoniae is not the only infectious agent that has implicated in Chronic Fatigue Syndrome/Fibromyalgia Syndrome. We certainly don't know if it is involved in all, a subset or merely a co-condition of such cases. But there is good reason to look further at this particular organism's involvement. Most of the argument discounting Cpn's involvement in CFS/FMS has been based on ignorance and poor understanding about the organism itself and the difficulties of testing and treatment for it. This is an attempt at trying to correct this ignorance, and place Chlamydia pneumoniae more clearly in the realm of possible sources for these devastating conditions.

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

The Incomplete Research-

There is some published work linking Chlamydia pneumoniae to Chronic Fatigue Syndrome/Fibromyalgia Syndrome in medical research journals.[8] But perhaps the most important research in this regard never reached publication. This article is the first thorough description in a public information setting. The original initial work at Vanderbilt by Dr. Charles Stratton 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 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 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 known to be antichlamydial and see if reduction of PCR signal for Cpn correlated with reduction in CFS symptoms. This was done by the by Dr.'s Cheney, Peterson & Bell with a sample of their patients. It turned out that no single antibiotic agent eradicated the Chlamydia pneumoniae PCR signal. So, Dr. Stratton's lab, having laboriously developed the PCR susceptibility tests (described quite elegantly in the patent materials which can be found linked elsewhere in this website) now had to use them to discover which agents or combinations of agents were required to eradicate Cpn completely, such that no PCR signal was evident in blood samples. This is called "sensitivity testing." This was a greater challenge than most of us would think. Along the way to infecting mice and cell cultures with Cpn and looking for effective combinations of antibiotics, they discovered that the available laboratory mice and commercial cell cultures widely assumed by scientists to be "clean," and thus proper starting points for introducing new variables, were themselves often infected with Chlamydia pneumoniae. This could seriously skew the interpretation of their tests. So Dr. Stratton's lab had to first develop methods to clear the cell cultures of Chlamydia pneumoniae and prove such clearance using their sensitive PCR testing. This is a remarkable bit of science here. Their finding that common biological laboratory materials are contaminated with Cpn appears also to be relatively unknown. From all of this they managed to find that only certain combinations of antibiotic agents (described elsewhere in this website) would completely eradicate Chlamydia pneumoniae from tissue cultures and laboratory mice, as indicated by clearance of Cpn PCR signal. No single antibiotic treatment, nor any series of antibiotics one at a time, was able to eradicate Cpn. Now that they had the combination antibiotic protocol (CAP) protocol, they could test the impact of eradicating Cpn on the resulting CFS symptoms, and then confirm whether patients were actually clear of Cpn from the blood testing.

And another thing…

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

  • Die-off reactions- When combinations were used the die-off reactions from this potent mix could be as bad, or worse, than the Chronic Fatigue Syndrome itself. Little was yet known about how to support patients through these reactions, or what exactly their nature was.
  • Length of treatment- Moreover, the length of treatment of Cpn with these combination antibiotic protocols 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 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, 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 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 and amoxicillin
  2. Once the EB invades a host cell it converts to the replicating Reticulate Body (RB)- only antibiotics that interfere with replication, such as protein synthase inhibitors doxycycline or azithromycin, affect it.
  3. Finally, Cpn can survive those drugs by converting to the low metabolizing "cryptic" form, which Dr. Stratton's research found is only killed by metronidazole family drugs.

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

  • Worsening- Killing Chlamydia pneumoniae liberates significant amounts of bacterial endotoxins which cause widespread cytokine reactions, including inflammation, pain, depression, low energy and so on. These are precisely the symptoms of Chronic Fatigue Syndrome/Fibromyalgia Syndrome itself. In addition, Stratton's work found that Chlamydia pneumoniae causes a condition of secondary porphyria[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 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, 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 and HSP-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 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 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 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 (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_
  • 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. 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 [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 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 for further discussion. [6] Effective Treatment Of Chronic Fatigue Syndrome (CFIDS) & 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, 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 [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) 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 …”Thirteen of 70 donors (18.5%) showed the presence of bacterial transcript in cultured PBMNCs. …CONCLUSION: The bacterial transcripts in PBMNCs obtained from healthy donors were detected by the RT-PCR method. Viable C. pneumoniae may be present in healthy human PBMNCs…” [10] Note- One of the things Dr. Stratton said to me shortly after I started www.cpnhelp.org was that this kind of thing was one of the missing elements in the treatment process: some kind of on-going support community that could help patients through the challenges and confusions of being on a difficult protocol. [11] As far as I know Dr. Stratton’s group are the only ones to have found the link between Chlamydia pneumoniae infection and secondary porphyria. It remains unpublished in the scientific literature and so virtually unknown to most medical practitioners. [12] http://www.cpnhelp.org/?q=cell_death_and_inflammati [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 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 [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 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 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 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 [22] http://www.cpnhelp.org/cpn_in_gi_tract_tissue_1 http://www.cpnhelp.org/cpn_in_gi_tract_tissue_2 http://www.cpnhelp.org/cpn_in_gi_tract_tissue_3 [23] 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 [24] Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats 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 [28] Migraine: A Chronic Sympathetic Nervous System Disorder Stephen J. Peroutka http://www.medscape.com/viewarticle/466937_1 [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 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, 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 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/fibromyalgia.asp 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_id/135.html

Jim K Wed, 2007-03-14 14:57

Diseases associated with Cpn: the exhaustive list

Diseases associated with Cpn: the exhaustive list

I have culled from Mitchell & Stratton patent #6,884,784 an exhaustive list of diseases where Cpn 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. Multiple Sclerosis (MS) Rheumatoid Arthritis (RA) Inflammatory Bowel Disease (IBD) Interstitial Cystitis (IC) Fibromyalgia (FM) Autonomic nervous dysfunction (AND neural-mediated hypotension); Pyoderma Gangrenosum (PG) Chronic Fatigue (CF) and Chronic Fatigue Syndrome (CFS).

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  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 complex and infections) 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 Stroke Asthma 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 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, 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 signals for C. pneumoniae. They can be used as appropriate animal models for treatment using specific combination antibiotics 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.

Jim K Sun, 2006-01-22 08:41

Multiple Sclerosis and the CPn model

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 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

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 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.

A recent work by Dr Sriram of Vanderbilt University published in the Annals of Neurology and referenced HERE indicates that MS is utterly different on a cellular level than EAE which is a pure autoimmune disease. There are different cytokine 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
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 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 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. 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 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 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. 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 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 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 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) is not selectively restricted to MS, but is shared by several inflammatory neurological conditions. In addition, our results suggest that an intrathecal 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's site. There is a greater number and a more in depth evaluation of studies there. HERE. The question "how do we evaluate these controversial findings?" is tackled on the Great Debate page.

mrhodes40 Thu, 2006-03-02 12:32

Cpn in MS: Over Easy

Cpn in MS: Over Easy

Why could Cpn affect MS sufferers so much? There may be more than one explanation… The answer could lie in a person’s genes.   Amongst our genetic code we all have instructions for T-cells.   These are a group of white blood cells, part of the body's immune system, that defend against infection.    Whilst these T cells are necessary for us to fight infection if they run unchecked they can cause damage to the Central Nervous System (CNS) by damaging the nerve fibres.   In MS patients it is possible that the cells  that stop some T cells from being over efficient are not working properly. For a more comprehensive explanation please visit http://www.msneighborhood.com/content/in_the_news/archive_2248.aspx   Or in the Blood-Brain Barrier The brain is an especially sensitive area of the body which is protected by the Blood Brain Barrier (BBB) basically a very fine meshed sieve.   Unlike the kitchen variety it is selective of what can go through.   It will only allow what it needs to pass through the BBB but some infections get in under cover of other cells, a bit like a Trojan horse.   The idea here is that Cpn has infected the brain and the BBB opens up enough to allow the body’s immune system to come and fight the infection and remove the debris.   In the process the very sensitive brain could be damaged by the clean up operation. For a more comprehensive explanation please visit www.cpnhelp.org/?q=the_brain_and_pathogenic_   Or it could be a combination of factors, such as a BBB which does not work quite as it should and an immune systems that over-reacts.   There are many other possibilities, including infection by viruses or bacteria and many others are unknown.   How Cpn could affect MS patients Cpn is a common organism (a bacterium) which can affect many parts of the body without causing too many problems if it decides to settle in areas that are not particularly sensitive.   Many people will have sinusitis, or a dry cough, or dry skin, or what feels like an upset tummy and carry on regardless of these small discomforts.   But if the bacteria infect the brain then, over a period of years, the symptoms recognised as MS may surface.   Often this first shows up as eye problems, maybe some numbness which goes away after a couple of weeks, but gradually the symptoms can become more severe and end up disabling the sufferer. One possible reason for this is that Cpn is a slow growing organism and it could be many years before the infection is bad enough to cause the immune system to react to it so severely as to result in disablement.   For a more comprehensive explanation please visit http://www.cpnhelp.org/?q=multiple_sclerosis_and_th www.cpnhelp.org/pdfs/Cp-MSAssoc.pdf    

Michèle Tue, 2006-04-25 06:53

Limitations of the Model

Limitations of the Model

Hello, if you have come to this page you are probably investigating this protocol and you are looking for as much information as possible. This page is not here to discourage people but to be honest in offering a more balanced picture, though I am stating up front that I am biased towards this model.

Every approach has limitations. In the field of MS, even the traditional approaches have one: the autoimmune model remains unproven. Even so many pharmaceutical companies and doctors treat based on this model anyway. In a situation where something must be done for the patient or you may watch them slip away, this may be fine. But one of the biggest complaints I have against the traditional approach is the lack of honesty about this limitation and the unwillingness to discuss it with you, the person who needs treatment.

We want you to understand that the CPn/MS model has limitations as well in the interests of full disclosure and healthy scientific self-examination. These arguments may be mostly of interest to the scientifically minded and should not discourage anyone from considering this approach. But we believe you should know the scientific realities as part of your considerations. It is not a sure bet, partly because it has not been done with hundreds of MS patients so that statistics and clarity about who should be treated this way and who should not are not known. It appears clear from cases reporting here that some people experience changes dramatic enough to change EDSS scores and cause some reversal of lost function. The limitations on this page also apply generally to treatment with CAP for other diseases as well.

If you have read all the other pages in this section of the handbook on MS; Multiple Sclerosis and the CPn Model, Smoking Guns, Cellular Similarities between CPn and MS, The Great Debate and The Brain on Pathogenic treatment, you are well versed in the model we use here as a guide for treatment. It is a very good model with many reasons to think CPn is possibly the cause of MS. The question then becomes is it possible that there are any limitations to this model? Is it possible that it could be incorrect?

It is possible and this is where the limitations are.

1. It is not known if all people with MS have this kind of MS or not.

Pneumonia can be caused by a virus, a bacteria, a chemical, or even smoke inhalation. Obviously, if someone had viral pneumonia, antibiotics, which treat bacteria, would only play a supportive role in healing by preventing any bacteria from taking advantage of the already inflamed tissue and becoming a secondary issue. The actual cause of the pneumonia in that case would need to heal on its own, or possibly be treated by using antivirals.

In the same way, more than one trigger might be cause MS. If this is true, there will be some people for whom treatment works perfectly and others for whom it does not and there is no way to know ahead of time which group you would be in.

2. There is no standard lab test and no standard primer used in the MS/CPn research.

This means that many researchers use in house tests-- tests that they developed themselves. Obviously every standard test at one time was someone's in house test so this is not a criticism in and of itself, but it does mean that the research from one worker to another is not necessarily looking at the same thing. It also means that other acknowledged CPn experts in the field do not necessarily agree that "x" researcher using his in house test and who says CPn is there actually was testing for CPn.

Margaret Hammerschlag MD who is a CPn researcher says the VU work was looking at and amplifying human genetic material not CPn. VU says the supposed "clean" primers MH used to make that determination from the lab supply were themselves infected with CPn, so it was CPn they were finding not human. Other labs in other places using OTHER tests also said CPn was present in MS patients, and still others said no CPn in MS. The fact the VU team has been working on this specific issue (rather than CPn in general) for over 10 years gives them added credibility in my mind, but the fact remains that this is unresolved and there is no agreement as to how to detect cryptic CPn.

In regards to MS and the possibility that CPn is the root cause, this means that the research looking at that issue is not necessarily authoritative and the findings must be considered "preliminary". This is true for BOTH sides of the debate, those who find it AND those who do not.

This ties in to the first issue as well since it means that we can't know who to treat and who not to treat. If we had a generally accepted lab test for cryptic CPn that issue would be solved. Another route for proving that CPn causes MS is if researchers use autopsied MS brain tissue and look directly and specifically for CPn in lesions.

Until there is a test that is universally considered reliable for cryptic CPn infection, we are in a place of assessing the model for its circumstantial support. There is a large body of research on how CPn behaves in the body and about the difficulties finding it in cryptic states, which seem to fit nicely with MS. The model makes sense on many levels, but it remains unproven at this time.

3. It is possible that CPn is a bystander, a secondary infection that moves in to the MS brain potentially making the "real" cause of MS more complicated than simply a bacterial cause.

This might be compared to a person with cystic fibrosis, who has very thick secretions in the lungs due to this genetic defect, getting a bacterial pneumonia in addition to the primary disease process. The bacterial process has sinister implications for the person compromised in that way. Treating the bacteria will allow them to return to being relatively stable, but the underlying disease process is still there. It should be noted though that it is always best to treat secondary infections; one does not ignore them and they can be more problematic than the original disease process.

4. It is also possible that the real cause is a combination of infective organisms, such as viral and bacterial. If such were true, it is possible that antivirals might be needed. It is also possible that these co pathogens would not be an issue in most patients and as their immune system recovers they would be completely cleared of such secondary infections, while some other patients with more advanced secondary infections might need antivirals as well to get a complete cure. These copathogens are known to be present in CPn infection but it is not known for certain when they might need to be addressed and when they can be ignored.

5. In the lab it is possible for CPn infected mice to develop secondary autoimmune disease through epitope spreading. In other words, the body attacks the CPn but in its effort to clear the infection it also accidentally makes antibodies that are self-reactive. It is possible that CPn causes MS but that a secondary autoimmune process is also in play. If such were true, it is possible ridding the person of the infection and addressing the autoimmunity as well would best facilitate treatment. On the other hand, rheumatic fever, which is an autoimmune disease secondary to a germ (strep), is self-limiting once the germ is gone so even if CPn autoimmunity were an issue it may not be something that needs treatment.

I have been told by my neurologist that only about 10% of people with MS actually have myelin active antibodies in their blood that can be treated with the new treatment in development in which they filter your blood and extract the myelin active antibodies, radiate them, and reinject them as a vaccine so your body destroys those antibodies (this treatment is called "Tovaxin"). Is it possible that 10% of people infected with CPn develop autoimmunity? Such things are unknown, but certainly could complicate the picture and the eventual "best" treatment.

The actual facts of how MS develops and what co factors are in play is unknown. The theory that CPn causes MS is plausible and very compelling, but it is possible some of these other co factors will be understood as more people are treated this way or as more research comes out.

Treating Empirically has some limitations also.

1. There is no reliable test for cryptic infection. However, empirical treatment is problematic because it may be hard to know when you have enough objective improvement to know it is working for you. In terms of MS, some of your symptoms may be caused by axonal degeneration and permanent scarring which may not go away without regeneration of some kind; it is hard to know what "I still have a weak leg" means in relation to CAPs treatment. It may be that some people with disease of shorter duration recover function with EDSS scores lowering, while others with more longstanding disability may "only" stop progressing. However it should be noted that the brain is much more plastic than used to be thought and it is likely some level of regeneration is possible if the disease process is stopped (just as people who've had strokes can recover more function with aggressive rehabilitation than anyone ever thought before recent research proved it was possible). If you do not have noticeable or dramatic exacerbations it might also be some time before you know you have stopped progressing, or if you have stopped. This can be devilishly frustrating.

2. It is possible that reactions to the antibiotics do not mean that a CPn brain infection is present. There could be other bugs, even normal intestinal bacteria, causing some systemic reaction to antibiotics. It is also possible that you are reacting to CPn in your body, but none of it has passed through the blood brain barrier and thus none is in your brain. If this were so, one could "react" to antibiotic treatment but the real MS process would go on unhindered.

3. It is also possible that the antibiotics themselves ameliorate the disease process in a way not related to their antibiotic activity. There is a fair amount of reserch on minocin, a tetracycline antibiotic closely related to doxycycline, which suggests it helps MS by altering the immune system and dampening it a little thus reducing lesion loads and exacerbations. If you are a person who believes the CPn model, you might see that relief as an antibiotic effect instead of any immune system modulation. However, one cannot determine cause by results so such positive outcomes do not prove either theory.

4. It is possible the adjuncts to treatment, the supplements, have an ameliorating effect on symptoms all by themselves. Many people who start the adjuncts first report that they already feel better before they have begun taking antibiotics. It is possible that a combination of supplements and amelioration of symptoms by the anti-inflammatory effects of antibiotics combine to create some apparent improvement independent of any antibacterial activity.

5. The protocols here are based on current research and are still evolving as new material comes out. Even if the MS/CPn model is proven it is possible the eventual protocol will include elements not now known, or that co factors will be understood and addressed in a way not now imagined.

What IS a "proven" approach?

If a person is given a pill filled with sugar, a placebo, and believes it will help, about 35% of the time it will actually help them. Their belief activates their healing in some way we do not thoroughly understand. It is more than just "thinking" they are doing better-- they really do better.

The CRAB drugs are all considered "proven" meaning that they have been given in blinded trials to larger groups of MS patients and shown to be marginally better than placebo. For more on this and why I used the word "marginal", please look at the objective Cochrane reviews of these drugs on Pubmed.

MS is a disease of unknown origin. It is often stated as being autoimmune, but that is actually an unproven theory. For autoimmiunity to be proven, it would need to be shown that a specific part of the immune system is different consistently in MS patients and that inducing this precise difference in other animals, preferably primates, results in a relapsing remitting neurodegenerative disease that eventually becomes progressive identical to MS. After decades of looking, no such trigger has been uncovered.

In light of the unknown trigger for MS what drug manufacturers can do for us now is to treat based on the generally accepted "best" theory for MS, do a trial, and see if they actually get any positive results with their drug. These trials result in "proven" therapies even though the cause of MS is still unknown: they do not prove the theory that MS is autoimmune, they only show that the approach used helps in some unknown way. These are relatively expensive trials and are undertaken for promising therapies likely to recover the cost of the trial. This is just a simple business reality, not a conspiracy.

It is extremely unlikely that CAPs will be trialed in the way described above to see if it helps patients with MS. The drugs are long off patent so they cannot generate the profits necessary to make it possible to recoup the expense.

Our best hope is for someone in academic research to look for and find CPn in MS lesions by preserving a donated MS brain properly and staining the samples near lesions correctly to see inclusions. This would result in a proven association with MS. However, even if such were discovered tomorrow it would likely be a long time before there was a universally accepted and proven antibiotic regimen for patients (although IMHO the VU protocol is the most likely due to the extensive research they have done).

As an illustrative example, it has been known for years that atherosclerotic lesions have CPn in them, yet the medical literature continues to debate whether or not it is a secondary infection or causative, whether or not intermittent mono therapy antibiotics reduce second heart attacks, whether it has triggered a secondary autoimmune attack on the blood vessels, and whether it is even possible to get rid of cryptic CPn infections. I have not yet seen anything remotely resembling a CAPs protocol being tested on atherosclerosis patients. During these years of debate on the issue, dozens of patent medicines to treat cholesterol have come out and patients needing some kind of treatment today are offered these new drugs because nothing related to CPn and atherosclerosis is proven. During these years also heart disease remains the leading cause of death. Once again we see drugs go to trials based on the most generally accepted theory, in this case that cholesterol causes atherosclerosis. This offers proprietary targets (cholesterol is a viable target for drugs) and when the created patented drug works better than placebo in reducing cholesterol, the drug is approved for use in patients. However, if CPn causes atherosclerosis, there will never be a cure by reducing cholesterol.

With a few exceptions, science moves very slowly with a lot of back and forth research before final conclusions are drawn and everyone agrees on one fact as a generally accepted principle to guide treatment. This process is greatly enhanced when a commercially viable product is the agent in question, and there is not one for CPn.

No one can or should make any promises to you about how you will do on CAPs, there are unknowns as described in this page. What I can tell you is that some people, though not all, have had verified reductions in EDSS scores using this approach and that if CPn causes MS then this is the best hope you have for a cure.

With all these limitations duly noted, there are good reasons to initiate a CAP for Cpn despite these scientific uncertainties. In many cases there are really no good approved treatments for the individual person. Additionally, CAP protocols do not conflict with other approved treatments so it is certainly possible to do both. CAPs are also low risk and low cost, and if you are a person who engaged in Empirical treatment and reacted to the NAC, the antibiotics, or the protocol in general you know you are dealing with some kind of bacterial load, the eradication of which cannot help but improve your system.

Addendum: In a thread started to discuss this Limitations page found HERE Dr aWheldon made a comment on this page that lends adds more food for thought and I have pasted it below. The link to the thread is worthwhile reading also.

Dr Wheldons's comment on this page:
I always look forward to Marie's posts; this one is an analysis of the limitations in the viewpoint that C. pneumoniae has a role in Multiple Sclerosis. It is impartial and thorough. I read it carefully and with great interest, and recommend others to read it also.

As I read it I found myself pondering the manner in which medicine is practised. It is often not very rational. I recall, as a medical student, standing in a women's ward in a big mental hospital which had been built in the 30's in beautiful countryside. It was a consultant ward round; we had almost finished. We came to one very perplexing woman who was behaving very bizarrely. Her symptoms fitted no psychiatric stereotype. The consultant clearly didn't know what to do. Two psychiatric social workers were having a private but rather loud discussion about tatting in the background. The sister was keeping her thoughts to herself. The registrar was quietly doing isometric exercises. 'Tell you what,' said the registrar, suddenly, and rather impertinently. The consultant looked at him. 'Have you a suggestion?' he asked. 'Yes,' said the registrar, smilingly. 'Let's give ECT[1] a whirl.'

I've never forgotten that phrase: 'let's give ECT a whirl.' Give it a whirl! What an odd way to recommend a much-argued treatment, and yet how refreshingly honest! There is a deadly comicality about it. The main thing about recommending something on a hunch is never to forget that it is on a hunch. When Sarah was falling through the EDSS numbers, the diagnosis made, the Internet searched, the original Vanderbilt paper discovered, the objections by Hammerschlag discovered also, I must confess that I didn't weigh all the evidence scientifically. I did a brief risk analysis (aggressive SPMS: deadly - doxycycline: one of the most harmless antibiotics available) and started. It was a hunch that maybe the Vanderbilt workers were right and that the entire neurological Home Fleet was wrong. (This was in 2003.) I remember reading an interview with Hammerschlag in which she said ". . . this study shows that it's much too soon to put MS patients on antibiotics for Chlamydia pneumoniae." And as I read these uninspired words that risk analysis went through my head. Other people's risk analyses came to mind, too: the risk that if MS has an infective input (as seems likely from the epidemiological data, even if one does not stipulate a pathogen) the administration of a T-cell immobilizing antibody may be clinically rather unwise. Hippocrates was surely right when he said: 'first, do no harm.' Many times, as a doctor, I have to make recommendations on poor or inadequate information. One has to admit to making assumptions. Often one can only say, 'If I were in your place I would take this road.'

So Marie is quite right: there is a weight of evidence on either side of the equation, and it's wise that we admit this, even if positive evidence carries more weight than negative evidence. We are still in the opening pages of the story. But I have a hunch that in 20 years' time the idea that C. pneumoniae infection is a key factor in the multifactorial illness MS will be mainstream.

[1]ECT - Electro-convulsive Therapy.

-D W

mrhodes40 Tue, 2007-05-15 15:58

Smoking Guns, Cellular similarities between CPn cellular reactions and MS

Smoking Guns, Cellular similarities between CPn cellular reactions and MS

MS has been well studied for the last several decades. As a result there are volumes of knowledge about what happens inside the brain of an MS patient, though we are still very unclear on the cause. Any potential "cause" of MS has to fit with the known body of evidence for MS. Interestingly enough there are some similarities between MS on the cellular level and CPn infection and this page will explore that.

As we begin I'd like you to understand that CPn is relatively newly discovered (the 1980's) and new findings are coming out every week in this field. It is also a very different germ in that it behaves in ways that seem "wrong" based on what is "known" about germs. For example, we tend to think of resistence as occuring when a bacteria is exposed to an antibiotic then finds a way to still replicate in the presence of that antibiotic, thus remaining an active infection that we can culture. We do not recognize the kind of resistence that CPn is now proven to be capable of: exposed to an antibiotic it can become persistent, essentially going into hibernation and thus invisible and unaffected by the antibiotic, only to reactivate as soon as the threat of the antibiotic is gone. See THIS PAGE ON PERSISTENCE. Though technical this paper is a wonderful review of the available research on the subject. CPn is an evolutionary coup de gras.

As backgroud for this page, bear with me as I do a quick overview of the CPn lifecycle because it is pertinent to our discussion. CPn is an obligate (it has to) intracellular ( lives inside of another cell) organsim of eukaryotic cells (cells with a nucleus). It is parasitic in nature meaning it converts the cell's energy mechanisms (mitochondria)for its own uses and leaves the host cell essentially nonfunctional for its original purpose. The elementary body (EB), a tiny hard cell with barbs on it which allow it hook on to potential host cells, is the infective form of CPn. Once contacted, EB's are carried in the blood floating around looking for a cell to hook into and parasitize. As a CPn EB sticks itself to a cell, it is included, or pulled in, to the cell in a sort of tiny bubble. There, it converts to a reticulate body (RB) which does several things. First, it grows larger by about 2 times and takes over the mitochondria. All the energy the cell can now produce is used to feed the RB which now begins metabolizing and replicating, making new EBs which will look for another new cell to infect. In order to escape detection and death, the CPn covers it's inclusion a lipid bilayer. It also turns off apoptosis in order to increase the life of the cell so its home is safe. At the same time, having an infection in the cell makes it vulnerable to death as the toxic by products of the CPn lifecycle are pushed out of the CPn inclusion and into the cytoplasm of the host cell.

Please also note that CPn was first thought to be a virus because it behaves like one: it floats around and invades your cells themselves, living off of the host cell and unable to metabolize and replicate on its own. Further research showed that it has almost all the usual cellular machinery that bacteria
have. With its own machinery, and a bacterial-size genome (not the tiny gene sequences that viruses have), it can play more tricks than viruses can play. For example, it can convert freely back and forth between these different forms, it can detect "threats" to its survival like antibiotics or gamma interferon, and then go persistent or hibernate in a non metabolic state wherein it is immune to the abx. The article on persistnce above is very good on this subject.

So let's begin noticing the cellular similarities with a well known concern in MS: The fact that nitric oxide (NO) is high. An example of MS research on this can be found HERE This particular abstract was chosen for two reasons. First it shows that researchers believe that NO is part of the problem in MS, and this fact is so well established that I can't find a reference that establishes it.

So in MS the upregulation of NO is an accepted problem. Frequently we see research focused on potential strategies to reduce the NO and thus spare the nerves. But might that high NO indicate that CPn is present? In this abstract HERE we have the authors showing that the body upregulates NO on purpose to defeat CPn. The organism cannot multiply in the presence of NO. This is the way the body kills unwanted villains like bacteria and viruses, with oxidative metabolites that are harmful to them, then the other immune cells like phagocytes can come in and clean up the debris. Interestingly enough, it is gamma interferon that is responsible for signalling this upregulation(and gamma interferon will come up again later). HERE we have second paper in which cells that can make NO and cells that could not were compared. The NO sufficient cells were regulatory for CPn as we might expect. This is just two of the studies on this subject.

Point two from the abstract on NO in MS above was that LPS was the agent that the researchers used to damage the oligodendrocytes so that they could study the effect of NO in the MS brain. What is LPS? Lipopolysaccharide is the fragment of the outer cell of a gram negative bacteria. LPS is very toxic to cells in general, and very immunogenic causing a brisk reaction of the immune system, and here we see it is used to induce damage typical of MS damage to oligodendrocytes. LPS comes from a gram negative bacteria like CPn when it dies. This is a very important bit of circumstantial evidence for CPn causing MS. Clearly if CPn, which is a gram negative bacteria, was in the brain and died there would be oligodendrocyte damage similar to MS due to the presence of the LPS fragments released.

Lets go deeper into this subject with THIS paper which discusses the microglial activation in the CNS by LPS. This paper shows that it is the microglia specifically that must respond to LPS damage of the nerves, and it also says plainly that LPS causes " injury to oligodendrocytes and myelin as occurs in periventricular leukomalacia and multiple sclerosis", a direct replication of the information above. This work also says the oligodendrocyte precursor cells were damaged by the LPS. Since OPC's are another known concern in MS, LPS damage to brain tissue is a good match for MS damage. Also, note that microglial activation opens the BBB and allows peripheral immune cells like B-cells and T-cells in to the area to aid in cleanup.

HERE is an abstract and link to an older paper that discusses the activation of microglia in the CNS in MS and EAE. This supports both the idea that microglial activation is normal in infection, as well as presenting the notion that microglial activation is the damaging feature of MS. These authors suggest that if we could turn off the microglial activation, the MS brain could be spared. But obviously if the brain is responding to pathogen by turning on microglia to fight the germ, ridding the brain of that pathogen "turns off" microglial activation, and it does this without leaving the brain open to opportunistic infections like PML. It leaves your brain's pathogen surveillance system intact.

Another well known fact in MS is that there is upregulation of cox 2 prostaglandins which are inflammatory.HERE is one paper showing that this is true in MS. HERE is another, this one also tying it in to the oligodendrocytes, which when injured send out the Cox 2 signal which results in caspase 3 activation and death. The speculated conclusion of this paper is that it is the cox 2 that causes MS oligodendrocyte damage. It supposedly does this by cox 2 upregulating by itself (autoimmune theory) and thus starting the cascade we call MS.

HERE is a paper that shows that cox 2 is upregulated by the body on purpose in CPn infection. Actually, cox 2 upregulation can be inferred from the previous discussion on the LPS damage because it is stated that damaged oligodendrocytes will send out this chemical signal. Once again we see natural, expected immune reactions to infection occuring that mirror the known cellular/chemical profile in MS.

I mentioned gamma interferon above. In early studies (the 1970's) of the interferon drugs, pwMS got rapidly worse when taking gamma interferon. Yet we just showed that gamma interferon regulates CPn growth by being responsible for upregulating NO. Isn't this opposing the CPn theory? In fact in those early trials the patients given gamma interferon had myalgia, fevers, and arthralgia, and while gamma interferon itself may have caused this directly, this triad of symptoms is also common to endotoxin reaction. No patient of the seven who had worsening had residual symptoms and every patient had a flare up of symptoms already known to them, suggesting pseudoflare (common in fevers, and familiar to people using the CPn protocols here as an endotoxin reaction)not a true exacerbation which would be involvement of a new area of the brain. The reference for this information is HERE titled "Experimental allergic encephalomyelitis: a misleading model of multiple sclerosis." by Sriram S and Steiner I in the Annals of Neurology Dec 2005. You have to get the whole citation to read the material about the gamma interferon I mention as it is not discussed in the abstract. Might it be true these people had transient worsening due to endotoxin as the gamma interferon via nitric oxide and tryptophan depletion killed some of the CPn load? It is unusual for people to have worsening with no residual deficits. This author also mentions that gamma globulin results in an upregulation of gamma interferon without exacerbation in MS ptients. Circumstantial but possibly important information supporting the idea that gamma interferon may not be the profoundly negative influence it was thought to be.

Tryptophan is of interest in MS also and has a role in CPn regulation. In the Eur J Neurol. 2005 Aug;12(8):625-31 there was a paper titled "Interferon-beta affects the tryptophan metabolism in multiple sclerosis patients" authored by Amirkhani A, et al found HERE In this work it is clear that the tryptophan pathway is altered in MS and that beta interferon plays a role in mediating this. But in CPn the body, again via the gamma interferon pathway, catabolizes tryptophan in order to deny this amino acid to the CPn which needs it to replicate. See this HERE from our own archives. So tryptophan is altered in MS, but it is altered by the body in response to CPn also. Tryptophan is important because it is necessarly for making melatonin and serotonin in the brain, two important neurotransmitters associated with mood and immune function. Without adequate amounts a person is prone to depression and poor sleep, both known problems in MS.

Speaking of beta interferon, it also hampers CPn apparently. HERE is a citation titled "Role of Interferon-Stimulated Gene Factor 3 and Beta Interferon in HLA Class I Enhancement in Synovial Fibroblasts upon Infection with Chlamydia trachomatis " by Jürgen Rödel, et al. Perhaps the modest improvement seen with beta interferon use in people with MS could be related to this mechanism.

Many features of MS are actually known features of EAE with the authors ASSUMING that MS has this same feature. For example, caspase 3 is a regulator of apoptosis (organized cell death) and is seen to be upregulated in EAE. There has been speculation that caspase 3 itself may be at fault in MS, the logic being that if there was extra caspase 3 floating around it would mistakenly kill off perfectly good nerves and thus cause MS. While we do see CNS cells dying, they also would die from being infected and as discussed above, this will result in caspase 3 activation secondary to cox 2 activation caused by LPS. And all of this would cause the body to respond to the area with inflammation and immune cells to clean up the dead tissue. So it is not necessarily true that caspase 3 activation is secondary to anything other than natural response to pathogen. The Prineas and Barnett paper cited earlier also looked at caspase3 in the areas of apoptotic nerve cells. They found very little.

And here we have this PDF file which is a review of the pathology of the MS lesion found HERE Note that the author of the review of the pathology of an MS lesion draws a very clear parallel between the MS brain and viral infection, saying the cellular immunopathology is the same while also noting that EAE is not the same as MS. This again supports and repeats the information offered on the page "MS and the CPn Model" which establishes that there is significant research showing MS is not autoimmune. Additionally, remember that CPn is very similar to viruses because it is an intracellular organism. Once again we have support for the notion that MS is not autoimmune and a clue that the cytokine profile we see in MS is indistinguishable from a natural reaction to a pathogen, and here on this page we are showing research that directly ties the same cytokines to CPn.

Another angle to MS which is considered an autoimmune clue which people frequently point out is that MS has been shown to have various upregulated genes. Doesn't that prove that pwMS have a problem gene that causes this abherrent reaction? Well, no it does not. The average person thinks a gene is like your eye color- it is what it is and it cannot be different. But genes turn on and off all the time and this is called upregulation and down regulation, and they do this in reaction to the environment. HERE is an abstract that outlines a couple of kinds of gene upregulation in response to CPn infection. In this case the macrophages (an immune system cell) have upregulated some genes and down regulated others.

In another example of genetic changes, HERE is a paper that shows how CPn itself changes and upregulates a whole bunch of its genes in persistent states vs acute infection, this giving it the flexibility to do the many things it is capable of doing and making it so difficult a pathogen to eliminate.

In order to be fair it is obvious that some genes such as your HLA type impacts the way your body responds to germs. It is possible that some people with some genetic profiles respond to CPn in such a way that persistence is more likely in that individual. It would be narrow to assume that a genetic type could cause autoimmunity, but not that it could cause an atypical reaction to a bacteria.

So this page is focused on the fact that many known features of MS are also known physiological reactions to CPn infection, remembering that infections of many kinds likely have a similar if not identical profile. This is not unexpected as it has been amply pointed out by many authors that MS resembles, on a cellular level, a reaction to an infective process. The fly in the ointment has been the inability to culture anything consistently, though the known fact that CPn is possibly unculturable in the persistent state might easily account for the "we found it" and the "we tried to replicate their work and did not find it" back and forth nature of the MS/CPn research to date.

It is interesting to note that while CPn is known to live in human cells, is known to cause cellular inflammatory reactions to that cellular infection, is known to cause immune reactions and cellular death and that it is very hard (and some say impossible)to culture and complicated to kill in persistent state, we still have people who debate whether or not it is a "problem" suggesting perhaps CPn's presence is innocuous for human beings. And we also have people seeing cell death, immune response and inflammation, and who are unable culture any germs at the site continue to insist that this immune response has to be the body attacking itself for no good reason (autoimmunity)seemingly oblivious to the possibility of an intracellular infection like CPn and ignoring the limitations of current ability to find these bacteria.

At this point in time it is not proven one way or the other. We really need a test every competant researcher can do which shows the presence of CPn in MS brains to get to that level of understanding. This is all circumstantial evidence for the presence of CPn in MS brains. But also note there is nothing that is excludes the possibility of it either and the evidence indicates that if CPn WERE in a brain it would: upregulate NO, cause oligodendrocyte damage via LPS identical to MS damage, cause the cox 2 prostaglandin to be made which would signal caspase 3 and apoptosis, would damage the nerves and cause death, would cause microglial activation, would catabolize tryptophan. Since this profile of changes mirrors MS, we have a smoking gun in CPn for being involved in MS.

This is speculative and based on currently available research which may not be all inclusive, or which may not apply to you directly. It is posted here for informational and purposes. This page may be added to or revised as new material comes up......

mrhodes40 Fri, 2006-03-03 12:28

The Brain and Pathogenic Treatment

The Brain and Pathogenic Treatment

The brain. For many the final frontier of medicine, it's fragile tissues the seat of the mind and in many ways, the very heart of personality and who we are.

What is known about this privileged area of the body is that healing is limited and things that on other parts of the body would be minor issues in the brain become devastating and life altering. A simple extavasation of blood, which in an arm is a mere bruise or hematoma, in the brain becomes a hemmorhagic stroke, the person forever altered and changed by this mere physical accident.

Why is that? Why is a minor issue on the periphery a major life changing event in the brain? Why does it not heal as does the arm? The answer lies in how the brain is set up.

The brain is a privileged area of the body. It separated from the rest of the body by the blood brain barrier which is a special different kind of endotheluim than is present in the rest of the vascular system. The BBB has very, very tight bonds between the cells and thus is very selective and allows only very specific things that the brain needs in, and keeps out other things that flow freely through the rest of the body, out. Among the things not permitted in are the immune cells of the peripheral system, like t cells, b cells, macrophages etc.

Because of this protection from the rest of the body, the brain has its own immune cells called microglia. Microglia are essentially very similar to monocytes and macrophages in other peripheral areas of the body, except that they have very specialized abilities. The microgia can send a chemical signal to the BBB to open up and allow t-cells, b-cells, monocytes and macrophages to enter if they need help cleaning up a problem inside the brain. This makes sense! How else can the "garbage" be taken out of the brain! There are well known situations that allow BBB to be opened by the microglia, for example infections, particularly any that involve the microglial cells themselves such as HIV, cytomegalovirus, the herpes viruses, and any situation in which cells inside the BBB died or were injured. It is known in vitro that CPn can invade microglia, so we might make an assumption that should that happen the BBB would be opened to clean up the area.

Microglia live in a quiet resting state termed "ramified" Ramified microglia are not activated and are easy to see in a microscope as different from the activated form which is "amoeboid", and so it is the ameboid form we see in activated microglia and it is ameboid activated microglia we see in MS lesions. It has been this fact that has led researchers to believe that the microglia are to blame for MS damage, assuming that the microglia activated mistakenly and "attacked" the nerves causing them to die. This has been presumed to be the initial event in MS and a considerable amount of research has been focused on how we can turn off the microglia in MS patients. Activated microglia express many immune factors such as interleukins and toll like receptors, many of which are also targets for therapeutic intervention by novel pharmaceuticals. However, it was the detection of ramified (not activated)microglia and no peripheral immune cells in the presence of apoptotic, dying oligodendrocytes in Prineas and Barnett's paper that indicated the nerves had died THEN the microglia and finally the peripheral immune system were recruited to the area. This stunning finding proposes a completely new idea as to why the microglia are activated and ameboid in MS: given how microglia react to cell death it would have been their normal healthy job to open the BBB and allow t-cells b-cells and whatever else in to clean up the apoptotic mess.

Interestingly enough any activation of the immune system, either inside the brain via microglia or outside in the body by other macrophages, monocytes etc, results in profound changes in the area being repaired by the immune cells themselves. The chemical environment of the area is altered and many different genes are upregulated, cytokines respond, fluid filled with these immune factors rushes to the area and oxidative damage results secondary to all this activity. Much of this in the body outside of the CNS is no big deal, it repairs as "good as new", but this is not true of the brain. The brain, in the presence of these oxidative and otherwise toxic but necessary factors in response to pathogens, is damaged by all this immune activity. The brain literally can't tolerate normal immune responses.

Thus it is true that in the case of an infection of the brain part of the damage comes from the act of the body responding to the pathogen itself rather than any damage directly caused by that pathogen.

Why is this important to understand for us here? For several reasons which fall into the arena of my humble opinion based on my understanding of the brain. In terms of using the CAPs there is good justification for going slowly on treatment and not inspiring too large a response at one time. Your brain can only heal so much at once, and it must do that with it's limited resources. It is easy to overwhelm the brain's capacity to supply antioxidants and nutrients needed to repair. Therefore it's probably true that a pulse of flagyl that is small as outlined in the protocols is better than large ongoing doses for long periods of time unrelieved by healing time. It may be fine for CFS patients whose infection is not in the brain to take flagyl continuously as muscle heals in ways the delicate brain can not, but the MS patient is likely to need time to repair in between.

Another reason it is important to understand is that it offers a good reason for the apparent improvements in MS patients taking immunesuppressive therapies if you accept the model of CPn as causitive for MS. CPn is a slow infection, it invades slowly and does not harm it's host very much. What's a cell here and there being used by CPn? Well if it's a brain cell you DO miss it, and more as more are invaded and lost. But if the cell with CPn in it dies, either because you were taking a flagyl pulse or because it simply died from being infected as it will in the MS patient unaware of CPn, you get acute reaction and response by the immune system as described above, resulting in even more damage to an area. Therefore, if you knock out the immune system you will seemingly get better, at least for a while, because the cytokines and other immune factors are shut off.

We can understand this if we look at it this way. If you have a cold how do you know you are invaded by a virus? Your nose is plugged up, mucous runs and you feel tired. Every one of those symptoms is caused by your immune activity NOT by the virus. If you take a steroid, thus knocking out the immune system, you will feel better immediately. But the virus then without being "checked" by immunity will get the upper hand leaving you sicker than ever in a day or so. People with HIV who have their immune systems knocked out by HIV will have this happen. They get very serious infections we do not get...and they do not have the symptoms normal people do, all because the immune system is not active. A cold virus is a quick pathogen so we can understand how it reacts to steroids and immune suppression because we see the connection clearly, in a slow virus or bacteria however the connection is not so clear.

Persistent CPn however is a slow pathogen, so the timeline for all this is years not days when we are talking about possible CPn and the brain. But the cold virus example plainly shows how a patient can seem better simply because of immune suppression. What if an MS patient is given steroids, for example during an exacerbation of MS, and MS is actually an infection, exacerbations being another time when immune activity is clearly causing symptoms? I have often heard people say that MS cannot be an infection because immunosuppression works. Really? Do steroids cure people of MS?

The long term studies on steroid use for MS are disappointing. Though people given steroids seem better than those given placebo when evaluated within a week or two of treatment, at 6 months the "gain" is gone and there is no statistical difference between treated and untreated people. Steroids do not impact the disease although in the short term they impact the symptoms.

Other immunosuppressive therapies have not had great success to date either. Most seem to help a little bit for a while, then the gains drop off with time often eventually leaving the person at a few years time functionally equal to the untreated person, in some cases in spite of the fact they remain profoundly impacted by the treatment drug. The newest drugs have no long term time frames to discuss, but read the available research carefully for yourself. If they have gains right away does it remain just as good or get even better after a couple of years? or do the gains drop off so people seem to be much better than placebo in early comparisons but in later comparisons the treated group is maybe only slightly better than the placebo group? These are important questions for the MS patient to know the answers to.

If the problem is autoimmunity then aggressively knocking out the immune system ought to result in an improvement that gets better and better as time goes on should it not? Now that the brain is relieved of this relentless attack from the immune system, should it not get better and stay better and improve even more with time? Yet time and time again the most promising therapies which prove profound decreases in lesion activity (inflammation is actually what is seen on MRI) do not result in stopped disability. In my mind, it is a concern if people have profoundly impacted immunity but after a few years are nearly in the same boat as the placebo treated persons. This suggests to me the "cause of MS" whatever it is was not stopped but that the immune system was prevented from causing secondary damage in it's efforts to heal. If there were a slow bacteria in the brain this is exactly what would be seen with immunosuppression because the bacteria would continue to slowly invade the cells but the immune system is held at bay, reducing any secondary damage from immune sustem activity yet allowing the slow infection to invade more cells to the point that impairment results anyway. This is exactly like giving steroids to a person with a cold to me, only in slow infections timelines are years long compared to the "cold" model.

Who knows what the patient thus treated will be like at later years. Will the thing that causes MS, maybe CPn, get the upper hand and will the patient go downhill faster than ever later? People with immunosuppression are at risk for cancer and infection since immunity is grossly impaired, will they succomb to such issues? And if the treated people are much better than the placebo treated group in early comparisons but in later comparisons the treated and the placebo group are only a little different did the treated patient gain anything? Since most of us will live for decades, is this temporary gain worthwhile considering the cost? These things must be evaluated carefully by the patient. Ask questions about this of your doctor and get all the answers you can. You have a right to know what is known about the treatment you are considering. You have a right to know the limitations of the treatment you are being offered including what is not known about it. In the end it is you who lives with the decision and it's results.

There may be good reasons to take abx even if CPn is NOT at fault in MS. Minocin, a tetracycline drug similar to doxycycline, has been shown to have neuroprotective and antiinflammatory aspects to it. It is being tested in conjunction with a traditional medication as an "add on" combination therapy. They will compare the combination of traditional/minocin in this test to the traditional alone, but unfortunately there is not a treatment arm with just the minocin. This is sad. Perhaps the minocin with it's antiinflammatory properties all by itself would be as effective as the combined drugs, who could know without testing this? But this obviously not in the interest of the company who is running the trial, that company being the traditional medicine. They have no interest in abx as a stand alone therapy and it would bode poorly for their drug if the minocin won out as the best therapy since it is off patent. At any rate, there is no way of knowing or guessing how much of an effect this neuroprotection and antiinflammatory action is as such quantification of this property of the minocin has not been undertaken. It might be large or insignificant, but what I can tell you is that when people like S. Sriram at Vanderbilt University Neurology Center tested people using abx and published positive results, others who did not believe this could possibly work immediately said it was these "immune modulating properties" of the drug that caused the improvement, not the antibiotic aspects of it. Interestingly enough I bet that no one ever said to you "Well, we know that abx have these protective properties how about before we give you these immunosuppressives we try that to see if it helps..."?

It makes you wonder why there is objection to anyone trying antibiotics.

Cpn as the cause of MS is theoretical at this point and not proven. Most of the traditional medical communnity thinks MS is autoimmune. There is evidence that points the other way though and these pages explore these possibilities for informational puposes.

Deciding to use an experimental and unproven protocol is a decision you must make under guidance and advice of your doctor, based on your particular situation. Some people with very benign disease may want to use traditionals and wait for science to find a more certain answer. Some with more advanced disease may be at a point that for some reason they do not want or are not a candidate for the drugs available (heart disease runs in my family, I have made a personal decision not to use Novantrone, though I know some who think it was helpful for them). Some may even have tried the traditional medicines for MS and found them ineffective and they are thus without good options. These people may be interested in investigating this experimental approach. The VU released the information about the protocol they were using experimentally for just such compassionate purposes, and our pages here are for support of people doing just that. If you are in one of these situations and you decide with your doctor it makes sense for you in this site you will find others trying this approach as well as others who have had success with this approach already.

mrhodes40 Sat, 2006-03-11 19:30

The great MS debate Do we find CPn?

The great MS debate Do we find CPn?

One of the biggest issues in the question of whether or not CPn is present in MS brains is the publication of work that finds no CPn in MS. It puts us in the uncomfortable position of saying that we choose to think that this researcher is correct and that one is incorrect. Since few of us are lab experts, such discernment may be based on bias and not facts. Yet there may be some very good reasons to find the work that says CPn is not in MS brains is biased itself.

To look at this chronologically we start with the Vanderbilt University (VU) work found here. This paper is the whole citation. In that original work the team at VU found that pwMS (people with MS)were more likely to have CPn detected by PCR in the brain.

A top chlamydia expert, Margaret Hammerschlag MD, found the theory intriguing and conducted her own experiments in her labs. They found no CPn in any sample. The abstract may be found HERE

Following that work, Dr Sriram came out and said it is very difficult to find in the brain and that it was not surprising htey did not find it. What follows is taken from HERE (note: this paper was overall negative about the MS/CPn connection. It is an older paper talking about what was known at that time)

Quote from that paper:" Sriram responded by saying, "The fact that they can't find it in the brain is not surprising at all" because of difficulties his group had finding C. pneumoniae after injecting it into the brains of mice. "We know we put the bug there," he said. "But we're having difficulty finding out exactly what the conditions are to extract it from brain tissue. I don't know why."

To help settle the dispute, Sriram agreed to participate in a blinded study with three other teams. All received spinal fluid from patients with MS and controls, sent by Michael Kaufman, MD, of the MS Center of the Carolinas Medical Center in Charlotte, NC. The results, presented at the 2000 meeting of the American Neurology Association, further isolate the Vanderbilt team, who found C. pneumoniae DNA in 22 (73%) of 30 MS cases and in 5 (23%) of 22 controls. The other teams, at Johns Hopkins, the Centers for Disease Control and Prevention, and Umeå University, detected no traces of the organism.

Hammerschlag said the mass of evidence points to contamination or a lack of experience with delicate screening tests on the part of Sriram and his colleagues. "All of his work is being published in neurology journals, and they just kind of accept the methods. None of it would get published in microbiology journals," she said" end quote

This is very important. Please do note that in the teams other than VU they found no CPn. None. There have been many published papers since then by many experts all over the world finding CPn in brain samples of MS and other neurological diseases. It is peculiar that in this particular test they found absolutely none at all. But this was a long time ago as science goes and techniques have advanced since then, so the various researchers finding CPn since then may well be using much better techniques.

Let's note the VU findings in this interesting contest between labs. VU found CPn in 22 of 30 of the MS patients and in only 5 of 22 of controls. If Sriram contaminated his samples how did he manage, in a blinded sample, to contaminate primarily his MS samples? Why not contaminate most samples if his work is sloppy? Or even finding it in all of them?

It seems to me personally it would be very difficult, and statistically improbable to contaminate mainly the MS samples in a blinded study of that nature. Adding to the evidence that the VU laboratory test for CPn in CFS is finding real CPn in MS is the fact that the numbers of positive samples discovered were very similar to his previously stated numbers of positive MS samples. The VU team seems to find CPn in about 60-95% of MS CSF (multiple sclerosis cerebrospinal fluid).

Another comment in that article which points out the human side of research is in the final line of the quoted piece as it shows the opinion of one researcher stated as if it were fact. It is not exactly "scientific" but opinion, and peevish at that, to state that the neurology journals are somehow naive in what they accept and that the VU protocol "would never be published in microbiology journals". In fact, the VU lab protocol was published in a laboratory journal two years later HERE

And in another paper HERE we have the VU team and a team of researchers at the University of South Florida using split samples to compare results with one another. "Split samples", which were also used in the first lab contest above, means they send half any given sample to lab A and half to lab B and see if they get similar results. (Some few samples were too small to split, and VU got all of those samples resulting in the odd numbers)

In this comparison between USF and VU they both found positive samples of CPn in the MS brains using different CPn tests, confirming that it is possible to culture CPn in MS brains. The conclusion of the paper was quote "In clinically definite MS patients, the VUMC and USF detection rates were 72 and 61%, respectively, and in patients with monosymptomatic MS, the VUMC and USF detection rates were 41 and 54%, respectively. The PCR signal was positive for 7% of the OND controls at VUMC and for 16% at USF. These studies confirm our previous reports concerning the high prevalence of C. pneumoniae in the CSF of MS patients. The presence of C. pneumoniae in patients with monosymptomatic MS would also suggest that infection with the organism occurs early in the course of the disease." end quote

What we have here is a batch of evidence that indicates the VU approach is fairly effective at finding CPn in MS CSF, that at USF they also have the ability to find this, and the fact that these labs used split samples indicates that there is some concordance. In comment Sriram has been quoted as saying that the problem with the other contests where others found no CPn is that the other labs use formalin preserved brain samples, which ruins the possibility of detecting CPn. According to VU, the lab must use frozen tissue to find the CPn in these samples. USF also uses frozen samples, though they use their own unique test. This is the kind of technical detail that makes the difference, but takes time to prove the value of conclusively so everyone "knows" we must use frozen samples. Clearly in the Hammerschlag lab it is not considered important to use frozen samples.

Dr Hammerschlag is still convinced that MS has nothing to do with CPn though. As recently as 2005 she was asked to comment on some work being published by VU connecting CPn to MS and once again she talked about the 2000 lab contest in which her labs found no CPn. This comment was titled "The role of chlamydia pneumoniae in multiple sclerosis:real or fictitious? She remains adamant that the original work in which no CPn was found remains unchallenged, apparently rejecting the work of so many in the interveneing years in spite of the fact that various researchers all over the world have found at least some CPn in brain samples of many kinds. She seems very confident of her test results in which she found on CPn in MS CSF samples.

Interestingly enough though, Dr Hammerschlag herself has since authored a paper which in and of itself may offer support for the CPn theoretical model of MS causation. In this most recent work she states that we cannot culture persistent infection as it is undetectable. Now this is interesting, if a persistent infection is undetectable using currently available lab techniques, then what does it mean if you do a CPn test and it's negative? We know that CPn even in it's persistent state can cause inflammation (see smoking guns next page) so if that is true and you have an inflammatory disease of unknown etiology how can you say conclusively it is not CPn simply because you had a negative test if your own research says that persistent infections produce negative tests? It might be more accurate for her to say I do not agree with the VU methods, but I do not know if MS is related to CPn. The opinion paper indicating that we cannot culture persistent infections that she wrote is found HERE

If you read it carefully, you will see she is saying that while CPn might cause chronic illness like atherosclerosis and asthma, we can't design good studies since we can't test to know if eradication of CPn occurred. She suggests that without lab work to tell you if the patient got better from eradication of the germ, you can't know why the patient got better and your study is meaningless. From a purely scientific standpoint this is correct. But we are not lab experiments as individuals, and should this be applied to patients in general, it denies that the physician is a diagnostician who has been trained to evaluate people and their physical status based on a variety of findings, not just lab work. It would be naive to imagine labwork is flawless and perfect or the the MD is helpless without it to make clinical decisions. Good grief, if this were so why see an MD at all? Why not just see the lab tech, they're the ones who do the tests!

I would again like to mention the human side of science. Science has a certain inertia. People at this level and of this stature begin to get locked in to certain points of view for a variety of reasons. Not least is that once you publish a notable finding, you may be granted funding by interested organizations to do more of the same research. This leads you to work again along the same lines and after some time goes by you have a considerable paper trail clearly placing you on one side of the scientific debate. And you really believe your point of view, witness the absolute tanacity of the autoimmune model of MS in light of the research indicating it appears that autoimmunity does not explain the facts. It is difficult for someone who has done a lot of work on an issue to go back and say, "Oh, by the way, all this work I did before was wrong the other guy was right". You could be forced into that eventually, but it will not happen without a lot of weight on the other side to pull you over. Furthermore, the sheer numbers of people on that autoimmune side of the debate means there is a real sense that "most of us are over here and of course we are right, everybody thinks so...." It might help to recognize that Freud and Jung had a lifelong debate as did Einstein and several of his compatriots. Eventually some other finding may clarify a key issue making it possible to finally see what was missed before so everything falls into place. In this debate about CPn nd MS that would be something like a conclusive photo that shows CPn in the key structures of the MS brain. For example, if someone develops a way to see CPn inclusions in oligodendrocytes and we have an unmistakeable picture of such in an MS brain, maybe in a client that also cultured negative for CPn using traditional methods, we'd have extremely persuasive material wouldn't we? We do not have anything like that now however.

At this point in time there is still considerable debate over this issue. If we had Dr Hammerschlag here she would undoubtedly discuss the technical details of this work in ways I cannot. I am not a chlamydial lab expert. But then again, Dr. Sriram is a neurologist and the director for VU's Multiple sclerosis center. He is teamed up with Dr. Stratton a microbiologist (like MH), and Dr Mitchell an MD PhD pathologist, and they have studied this material and they have made it their business to say this IS happpening in MS and have published extensively on the subject. I am not swayed to believe that Dr Hammerschlag is correct and that the VU team is off base.

So what about other researchers beyond MH and VU? Well, if you go on pubmed and put "multiple sclerosis chlamydia pneumoniae" in the search box you will get a whole list of this kind of work done all over the world by othe people. Some will support the idea, some will not. This is the way science goes, it is a back and forth process until eventually something conclusive and reproducible is put forth. As you read the research, these are the questions to keep in mind;

If a study suggests that there were no people with CPn in the brain, what tests did they use to establish that? Often we see something like the VU study which utilized several highly technical and detailed methods on CSF samples to establish that CPn was there being "countered" with a study that used a single test, sometimes even a blood test.

Or sometimes the author finds not one single case of CPn in the tissue, and you wonder, considering how often other people find it even in seemingly healthy people, how does this author find none at all?

Or sometimes we lay people cannot judge without a tip from someone inside the study, as in the case where the formalin fixed samples were used. To find that out you might need to read comments or editorials in later issues of the publishing journal.

And finally, we have the notion that persistent CPn cannot be cultured at all. If you accept this might be a possibility then testing and it's positivity becomes a somewhat moot point, the germaine issue then being who will develop a test that will find persistent CPn, and importantly, has VU done it already?

So now we come full circle to where I began this page, we are in the uncomfortable position of saying I believe this researcher and not that one, and this question becomes vitally important to us if we are in the unenviable position of suffering from MS and having no results from traditional treatment. Dare we try this treatment in spite of it's not being fully proven and in light of the fact there are some people vehemently stating it is incorrect?

I offer this and this is entirely my personal opinion: The talented and highly qualified team at VU who have published several peer reviewed papers on the subject claiming that CPn is present in at least a subset of MS patients has been focused on this specific issue now for 9 years. That's 9 years of refining their PCR techniques, 9 years of making the tests more robust and redoing tests to remove doubt, 9 years of watching the few people they've treated experimentally with antibiotics get some level of improvement (which is documented) and 9 years of focus. From this multifaceted effort they say it appears to be there in at least a subset of patients. 9 years is long enough for an MD to become a specialist in a couple of disciplines. In my book I find it impossible to imagine the VU team is not utterly expert at this by now, and more expert than any other researcher because of their focus. Add to that the fact that USF gets similar results using a different test, and that some others all over the world are also weighing in on this side of the debate and we have a good weight of evidence agreeing that CPn appears to be there in MS in at least a subset of patients.

Considering the fact that this would be treated with currently available antibiotics and it is clear that these drugs are not patent drugs and therefore not going to make anyone anywhere any money, there is no commercial interest here in manipulating the data at all, which is always a concern with commercial patent drug research. I can find no reason for the people at VU to be anything but honest in their work; it appears legitimate even if still not widely accepted yet. We will hope for some large blinded studies down the road that will make it clear to every one the exact extent of CPn incidence in MS and or some interesting other data that clarifies the issue. Another important point related to the fact CPn is treated with antibiotics is that there is no interest on the part of any drug firm to rush to VU with a large grant to further the research either. This is the reality of our commercial research system. It might be worth noting that the year before Barry Marshall proved beyond a shadow of a doubt that h.pylori caused almost all ulcers, he was still correct, even though few agreed with him. A physician I know of made the comment that "CPn could be neurology's h. pylori". The original resistence to the idea on the part of doctors who treated ulcers with surgery and bland diets and who mocked the idea of h pylori causing ulcers are not unlike the neurolosits who reject Cpn/MS idea.

So that is the debate as it pertains to multiple sclerosis. I did not talk about PCR specifically or other issues about the labwork. For that please consult the other book pages.

So if we accept that labwork is not in 100% consensus about how to culture CPn in the CSF of the MS patient, nor is it even clear that persistent infection CAN be cultured, is there other circumstantial evidence that supports the theoretical model that CPn plays a role in MS? The next page is smoking guns and it talks about this issue...and I'd like to say for the person who has been into MS research for a long time, it is there that the correlations uncannily begin to fall into place, although once again we are talking about an idea, not a scientifically proven fact at this point.

mrhodes40 Fri, 2006-03-03 11:58

The Remarkable Effects of a CAP for Chlamydia Pneumoniae on High Blood Pressure

The Remarkable Effects of a CAP for Chlamydia Pneumoniae on High Blood Pressure

One of the remarkable things we have been finding from users of a Combined Antibiotic Protocol is a distinct lowering of blood pressure, even normalizing serious hypertension without other blood pressure medications. This was first noted and observed by David Wheldon in reporting his own treatment of Cpn for cardiovascular issues. As blood pressure readings are easy to gather as hard data, and pre-CAP pressures can be collected from one's own doctor's records, one of our members has been gathering this data into an ongoing survey. See for yourself at the link below. The charts are quite something to see, especially as high blood pressure is often very difficult to treat and stabilize.Ron's Blood Pressure Survey Link 

Jim K Sun, 2006-05-21 16:55

Viruses as cause or co-factors: Viral Henchmen in disease

Viruses as cause or co-factors: Viral Henchmen in disease

The question of viral causes or co-factors comes up often, as most of the diseases for which one might use the CAP to treat for Chlamydia pneumoniae have research which has found viral components as well. David Wheldon tackles this question on his web site, with his usual clarity of discussion and so well founded in his ready grasp of the scientific literature. Click the link below for his web page:David Wheldon on "Viral Henchmen"   

Jim K Mon, 2006-08-07 07:18