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 Strattoni's Current Thinking on How Chlamydia Pneumoniae (Cpni) Infection Causes Specific Diseasesi

 

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 infectionsi 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 immunei 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 inflammationi 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 (CAPi) treatment.

 

Why do viruses and cold sores “surface” during CAP treatment?

This could be due to apoptosis (cell deathi) 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 endotoxini release from killing Cpn, and related cytokinei (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 endotoxinsi, 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, porphyriai and apoptosis, as well as being able to get to all the tissues involved, which have differentials in terms of how antibioticsi 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 loadi, 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 NACi 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 metronidazolei 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.

 

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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 intracellulari 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 Wheldoni 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-PCRi) 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.

 

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

Rosaceai is a chronic disorder of still unknown cause that affects an estimated 14 million Americans.¹ Rosaceai 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 (ROSi) 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 (LPSi), 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 Sclerosisi, Asthmai, 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, intracellulari 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 Strattoni, 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 (EBi'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.

Chlamydia Pneumoniae in CFS/ME & Fibromyalgia

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

The first research problem:

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

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

The next problem- treatment:

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

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

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

And another thing…

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

Die-off reactions- When combinations were used the die-off reactions from this potent mix could be as bad, or worse, than the Chronic Fatigue Syndrome itself. Little was yet known about how to support patients through these reactions, or what exactly their nature was.
Length of treatment- Moreover, the length of treatment of Cpn with these combination antibiotic protocolsi for Chronic Fatigue Syndrome was very long. It was difficult to get patients to "stay the course" without extraordinary support, or dedication on the part of both the patient and the physician.

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

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

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

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

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

Implied in this also is...

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

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

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

Research is halted-

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

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

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

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

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

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

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

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

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

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

Chlamydial persistencei and antibiotic response-

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

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

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

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

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

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

There are three known phases or forms of Cpn:

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

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

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

Chronic Fatigue Syndrome/Fibromyalgia Syndrome Symptoms & Chlamydia pneumoniae

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

Features of Chlamydia pneumoniae (Cpn) and Cpn infection:

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

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

Secondary porphyria- Depletion of host cell ATP by Chlamydia pneumoniae means that your cells don't have enough energy to complete their normal biochemical reactions. One of these, the production of hemei, 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 LPSi and HSPi-60. These endotoxins cause widespread inflammation (cytokine cascades) and a host of other metabolic disturbances. These are released chronically in small amounts in 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 cytokinesi 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.
* Melatonini 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 antioxidanti 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 pressurei (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 diseasesi.

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 (CFIDSi) & 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 testingi, 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 lipopolysaccharidei-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