1: Zhonghua Nei Ke Za Zhi. 1992 Oct;30(10):631-3, 659. Related Articles, Links
[Borrelia burgdorferi may be the causal agent of sarcoidosis]
[Article in Chinese]
Hua B, Li QD, Wang FM.
Naval General Hospital of PLA, Beijing.
Serum antibody to Borrelia burgdorferi was measured in 33 patients with sarcoidosis who were confirmed clinically and pathologically. The results showed that 81.8% of the patients were positive. In addition, a strain of Borrelia burgdorferi was isolated from a patient's blood. Fourteen patients received ceftriaxone 2 g per day and/or penicillin 12 million per day and a patient received lincomycin 1.2 g per day. The antibody titer of the patients turned to normal level, their SACE turned to normal range, and chest X-ray findings were markedly improved in 3 cases after the treatment. According to the facts mentioned above, we consider that Borrelia burgdorferi may be the causal agent of sarcoidosis and sarcoidosis might be a special type of Lyme disease.
PMID: 1582344 [PubMed - indexed for MEDLINE]
1: Graefes Arch Clin Exp Ophthalmol. 1998 Apr;236(4):280-4. Related Articles, Links
Seroprevalence of anti-Borrelia antibodies among patients with confirmed sarcoidosis in a region of Japan where Lyme borreliosis is endemic.
Ishihara M, Ohno S, Ono H, Isogai E, Kimura K, Isogai H, Aoki K, Ishida T, Suzuki K, Kotake S, Hiraga Y.
Department of Ophthalmology, Yokohama City University School of Medicine, Japan.
BACKGROUND: Sarcoidosis is a multisystemic granulomatous disease of unknown etiology, while Lyme borreliosis is a multisystemic disorder caused by Borrelia burgdorferi. The purpose of this study is to evaluate the relationship between sarcoidosis and Lyme borreliosis in a region of Japan where Lyme borreliosis is endemic. METHODS: We determined the seroprevalence of anti-Borrelia burgdorferi antibodies as well as antibodies three Japanese Borrelia strains by enzyme-linked immunosorbent assay and dotblot assay using purified Borrelia-specific proteins in 46 patients with confirmed sarcoidosis and 150 controls (50 disease controls and 100 healthy controls) in Hokkaido, the affected region. RESULTS: Fifteen patients with sarcoidosis (32.6%) tested positive for Borrelia spirochete in both assays, compared with two disease controls (4.0%) and two healthy controls (2.0%). The seroprevalence of anti-Borrelia antibodies in patients with sarcoidosis was much higher in the affected region than in the region in our previous study were Lyme borreliosis is non-endemic. CONCLUSION: In a region where Lyme borreliosis is endemic, Borrelia infection may be partially associated with sarcoidosis.
PMID: 9561361 [PubMed - indexed for MEDLINE]
Sarcoidosis/Bacterial pathogens/Marshall protocol studies + articles
Recent Publications and Presentations
1. Marshall TG: OLMESARTAN OVERCOMES ANTIBIOTIC RESISTANCE, INDUCING RECOVERY FROM ADVANCED AUTOIMMUNE DISEASE. Session keynote, 6th International Congress on Autoimmunity, Ljubljana, May 2007
Video of presentation available from http://www.youtube.com/watch?v=z2yEwnZy8B8.
2. Marshall TG: AUTOIMMUNE DISEASES SUCCUMB TO A VDR NUCLEAR RECEPTOR AGONIST. Asian Congress on Autoimmunity, Singapore, September 2007
Video of presentation available from http://www.youtube.com/watch?v=hcAVeKobsxU.
3. Marshall TG: The VDR Nuclear Receptor is a Novel Proxy for MTSS1 and MTUS1 in Breast, Bladder and Colorectal Cancers. 4th Medical Biotech Forum, Dalian, China, Aug 7-10, 2009
Video of oral presentation is at http://www.vimeo.com/6110400.
Transcript available from URL http://autoimmunityresearch.org/transcr ... script.pdf
4. Proal AD, Albert PJ, Marshall TG: Autoimmune disease in the era of the Metagenome. Autoimmunity Reviews. 2009 Jul;8(8):639-44.
Preprint available from http://AutoimmunityResearch.org/transcr ... genome.pdf
5. Albert PJ, Proal AD, Marshall TG: Vitamin D: the alternative hypothesis. Autoimmunity Reviews. 2009 Jul;8(8):677-81.
Preprint available from http://AutoimmunityResearch.org/transcr ... t-VitD.pdf
6. Proal AD, Albert PJ, Marshall TG: Dysregulation of the Vitamin D Nuclear Receptor may contribute to the higher prevalence of some autoimmune diseases in women. Contemporary Challenges in Autoimmunity, Annals of the New York Academy of Sciences. 2009 Sep;1173.
Preprint available from http://AutoimmunityResearch.org/transcr ... eprint.pdf
7. Clinical Seminar at West China Hospital, Chengdu. Dec 2008.
Video of oral presentation is at http://www.vimeo.com/2599416.
Transcript available from URL http://AutoimmunityResearch.org/transcr ... script.pdf
8. Marshall TG: Understanding Human Disease Requires Study of a Metagenome, not just the Human Genome. Keynote: World Gene Congress 2008. Foshan, China, Dec 2008.
Video of oral presentation is at http://www.vimeo.com/2585394.
Transcript available from URL http://AutoimmunityResearch.org/transcr ... script.pdf
More info available from the Conference website
9. Marshall TG: The VDR Nuclear Receptor is Key to Understanding ?Diseases of the Aging?. Understanding Aging: Biomedical and Bioengineering Approaches. June 2008, UCLA.
Video of oral presentation is at http://www.vimeo.com/1270611.
Abstract available from URL http://www.methuselahfoundation.org/UAB ... /marshall/
10. Marshall TG: VDR Nuclear Receptor is key to Recovery from Cognitive Dysfunction. Abstract presentation, Days of Molecular Medicine, Karolinska Institute, Stockholm, April 2008.
Copy available from URL http://autoimmunityresearch.org/dmm2008 ... rshall.pdf
11. Marshall TG: Vitamin D discovery outpaces FDA decision making. BioEssays. 2008 Feb;30(2):173-82 Online ISSN: 1521-1878 Print ISSN: 0265-9247
Preprint of FullText available from URL http://TrevorMarshall.com/BioEssays-Feb ... eprint.pdf
Preprint of Associated Correspondence available from URL: http://AutoimmunityResearch.org/BioEssa ... etters.pdf
Preprint of Author's response available from URL: http://AutoimmunityResearch.org/Bioessa ... eprint.pdf
12. Marshall TG: Bacterial Capnine Blocks Transcription of Human Antimicrobial Peptides. Abstract presentation, Metagenomics 2007, San Diego, July 11-13, 2007. doi:10.1038/npre.2007.164.1
Copy available from URL http://autoimmunityresearch.org/transcr ... ics2007pdf
Available from Nature Precedings http://precedings.nature.com/documents/164/version/1
Available from University of California Metagenomics 2007 Program Guide.
13. Marshall TG: Molecular Static and Dynamic Analyses Reveal Flaw in Murine Model used by US FDA to Detect Drug Carcinogenicity. Abstract presentation, Days of Molecular Medicine, Cambridge MA, May 22-24, 2007. doi:10.1038/npre.2007.52.1
Copy available from URL http://autoimmunityresearch.org/dmm2007 ... andout.pdf
Copy available from 'Nature Precedings' http://precedings.nature.com/documents/52/version/1
14. Marshall TG: Molecular Mechanisms Driving the Current Epidemic of Chronic Disease. Seminar presentation, Bio21, University of Melbourne, Australia, 16 Nov 2006
Online Video available from URL: http://autoimmunityresearch.org/bio21.ram
Transcript available from URL http://autoimmunityresearch.org/transcr ... 1_2006.pdf
15. Marshall T: We have a lot to learn about 'diseases of the aging'. Correspondence to Giunta S: Is inflammaging an auto[innate]immunity subclinical syndrome? Immun Ageing. 2006 Dec 16;3(1):12.
Available from URL http://www.immunityageing.com/content/3/1/12/comments
16. Marshall TG: Are statins analogs of vitamin D?. Correspondence to Grimes, DS. The Lancet 2006; 368:1234 doi:10.1016/S0140-6736(06)69509-3
Copy available from URL http://www.thelancet.com/journals/lance ... 3/fulltext
17. Marshall TG: A New Approach to Treating Intraphagocytic CWD Bacterial Pathogens in Sarcoidosis, CFS, Lyme and other Inflammatory Diseases. American Academy of Environmental Medicine; 2006, Plenary Sessions Syllabus, 41st Annual Meeting
Low resolution copy of the DVD video available online at YouTube
Transcript available from URL http://autoimmunityresearch.org/transcr ... m_2006.pdf
18. Marshall TG: VDR Nuclear Receptor Competence is the Key to Recovery from Chronic Inflammatory and Autoimmune Disease. Abstract presentation, Days of Molecular Medicine, Karolinska Institutet, Stockholm, May 2006.
Copy available from URL http://autoimmunityresearch.org/karolinska-handout.pdf
19. Marshall TG: Molecular genomics offers new insight into the exact mechanism of action of common drugs - ARBs, Statins, and Corticosteroids. FDA CDER Visiting Professor presentation, FDA Biosciences Library, Accession QH447.M27 2006
Online Video available from URL http://www.youtube.com/watch?v=IsHWoRpkTw0
20. Marshall TG, Lee RE, Marshall FE: Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b. Theor Biol Med Model. 2006 Jan 10;3(1):1. Available from URL http://www.tbiomed.com/content/3/1/1
21. Waterhouse JC, Marshall TG, Fenter B, Mangin M, Blaney G: High levels of active 1,25-dihydroxyvitamin D despite low levels of the 25-hydroxyvitamin D precursor - Implications of dysregulated vitamin D for disgnosis and treatment of Chronic Disease. In Vitamin D: New Research. Volume 1. Edited by: Stoltz VD. New York: Nova Science Publishers; 2006. ISBN: 1-60021-000-7 Info from Publishers website
22. Marshall TG, Marshall FE: Sarcoidosis succumbs to antibiotics - implications for autoimmune disease.
4th International Conference on Autoimmunity, Budapest, Nov 2004
Available from: http://www.kenes.com/autoim2004/program ... Key=308065
23. Marshall TG: Bacterial Th1 Processes Seem Key to Chronic Lyme Remission.
ILADS Conference, Oct 2004, Rye Town, NY
24. Marshall TG, Mangin M, Marshall FE: Bacterial Th1 Processes Key to CFS/ME Remission.
AACFS Conference, Madison, WI, Oct 2004
25. Marshall TG, Fenter BJ, Marshall FE: Antibacterial Therapy Induces Remission in Sarcoidosis (in English). JOIMR 2005;3(1):2 Available from URL http://www.joimr.org/phorum/read.php?f=2&i=107&t=107
26. Marshall TG, Fenter B, Marshall FE: Antibacterial Therapy Induces Remission in Sarcoidosis. Herald MKDTS 2004g; Volume III: Release 1. (The Journal of the Interregional Clinical-Diagnostic Center, Kazan, Invited paper, Special issue on Sarcoidosis. Published in Russian translation). ISSN: 1726-6149
Available from URL http://www.icdc.ru/home.nsf/ae6ba61f237 ... enDocument
27. Marshall TG, Marshall FE: Sarcoidosis succumbs to antibiotics - implications for autoimmune disease. Autoimmunity Reviews,2004; 3(4):295-3001.
Available from URL http://dx.doi.org/10.1016/j.autrev.2003.10.001
PMID: 15246025 or access FullText at author website
28. La thérapie antibactérienne induit une rémission de la sarcoïode. Réseau Internationnal de Soutien des Malades de la Sarcoïdose.
Available from URL http://tinyurl.com/6al6g, Last Accessed April 2, 2005.
29. Marshall TG, Fenter B, Marshall FE: Putative Antibacterial Mechanisms for Angiotensin Receptor Blockers. JOIMR 2004;2(2):1.
Available from URL http://www.joimr.org/phorum/read.php?f=2&i=53&t=53
30. Marshall TG, Marshall FE: Sarcoidosis succumbs to antibiotics - implications for autoimmune disease. Autoimmunity Reviews,2004; Suppl 2:55 (Abstracts of 4th International Congress on Autoimmunity)
31. Marshall TG, Marshall FE: Antibiotics in Sarcoidosis - Reflections on the First Year. JOIMR 2003;1(3):2
Available from URL http://www.joimr.org/phorum/read.php?f=2&i=38&t=38
32. Marshall TG: Puzzling vitamin D results. CMAJ 2002 Oct 15;167(8):849. PMID: 12406940 or access FullText at CMAJ site
33. Marshall TG, Mekhiel N, Jackman WS, Perlman K, Albisser AM.
New microprocessor-based insulin controller. IEEE Trans Biomed Eng. 1983 Nov;30(11):689-95. PMID: 6662523
34. Keogh EJ, MacKellar A, Mallal SA, Dunn AG, McColm SC, Somerville CP, Glatthaar C, Marshall T, Attikiouzel J.
Treatment of cryptorchidism with pulsatile luteinizing hormone-releasing hormone (LH-RH). J Pediatr Surg. 1983 Jun;18(3):282-3. PMID: 6135766
Assorted 'Letters to the Editor' and NetPrints
# Marshall TG: Brown, et al, ACCESS Study finds Bacterial Pathogens in Sarcoidosis Patients.
[Review] JOIMR 2003;1(2):2
[eLetter] CHEST 2003 Feb 23.
# Marshall TG, Marshall FE: The Science points to Angiotensin II and 1,25-dihydroxyvitamin D.
[Review] JOIMR 2003;1(2):3
[eLetter] CHEST 2003 Feb 6.
# Marshall TG, Marshall FE: New Treatments Emerge as Sarcoidosis Yields Up Its Secrets clinmed 2003 Jan 27;2003010001
# Marshall TG, Marshall FE: Remission in Sarcoidosis. clinmed 2002 Aug 22;2002080004
# Marshall TG, Marshall FE: Valsartan Dosing Regime Modulates Psychotic Events in Two Sarcoidosis Patients. clinmed 2002 Aug 29; 2002080006
# Marshall TG, Marshall FE: A Mechanism to Explain the T lymphopenia (in SARS)
BMJ [Rapid Response] 20 June 2003; 33479
# Marshall TG: A Potential Blood Test for SARS Triage
BMJ [Rapid Response] 5 May 2003: 31939
# Marshall TG, Marshall FE: Vitamin D may be Harmful in Rheumatic Disease. BMJ [Rapid Response] Jan 13 2003: 28700
Author: TG and FE Marshall (---.vnnyca.adelphia.net)
Date: 08-03-03 10:22
Antibiotics in Sarcoidosis - Reflections on the First Year
Authors: Trevor G Marshall, PhD1, and Frances E Marshall, GradDipPharm, RPh2
1AutoimmunityResearch.org, Thousand Oaks, California
2Los Robles Regional Medical Center, Thousand Oaks, California 91360
email corresponding author: Trevor. email@example.com
telephone contact: (805)492-3693
Date Received: 2 Aug 2003
Date Published: 2 Aug 2003
Article Type: Review
Cite this paper as:
Marshall TG, Marshall FE: Antibiotics in Sarcoidosis - Reflections on the First Year. JOIMR 2003;1(3):2
Two 'Comments' have been published for this paper:
1. Cantwell AR Jr: Bacteria in Sarcoidosis and a Rationale for Antibiotic Therapy in this Disease. JOIMR 2003;1(5):1
2. Mangin M: Observations of Jarisch-Herxheimer Reaction in Sarcoidosis Patients. JOIMR 2004;2(1):1
A year has passed since our paper "Remission in Sarcoidosis", and, in that year, over 50 sarcoidosis patients have been early adopters of minocycline antibiotic therapy. Almost without exception, they have flourished. Additionally, a much better picture of the occult bacteria has emerged, and the mechanisms by which they assert their toxicity upon the immune system is taking form. Clinical experience has significantly clarified the precepts underpinning the use of tetracycline antibiotics to induce remission in sarcoidosis.
Prior Arguments Supporting the Bacterial Pathogenesis
Similarities between Tuberculosis and Sarcoidosis have caused researchers to suspect a mycobacterial pathogenesis since, at least, Guy Scadding's Bradshaw Lecture in 1949 . Attempts at using anti-tuberculosis medications however, have been largely unsuccessful (for reasons that will be explained below). Du Bois, et al., [2,3] have postulated an etiology where "microbes are a likely trigger (but not as an infection) in a genetically predisposed individual" while Eishi, et al., have suggested that "sarcoidosis may arise from a Th1 immune response to one or more antigens of propionibacteria in an individual with a hereditary or acquired abnormality of the immune system".
Bachelez et al  administered long-term minocycline and/or doxycycline in a cohort of twelve sarcoidosis patients, achieving remissions both of cutaneous lesions and pulmonary manifestations of the disease.
Finally, Moller and Chen presented persuasive arguments  based, in part, on communication of sarcoidosis during transplant surgery, both from a sarcoidosis patient to one previously without the disease, and upon infection spreading into 'clean' tissues implanted into a sarcoidosis patient.
What does the pathology of Sarcoid Granuloma tell us?
It is commonly believed "the immunologic process that leads to sarcoidosis begins when an antigen is presented to a macrophage via HLA class II molecules to a T Lymphocyte. This induces a Th1 T-lymphocyte response whereby cytokines are released that result in granuloma formation".
However, a century of research has failed to definitively identify how the antigen-processes thus described could ever result in the characteristic pathology of the sarcoid granuloma. Further, while this description implies that the Th1 cytokine cascade should be associated with high levels of T-lymphocytes, the opposite is true:- advanced cases of sarcoid inflammation present with T-lymphopenia .
This conventional description is based on an understanding of the immune system of healthy individuals, and it fails to describe the immune system of patients with sarcoidosis because the factors at work in immune disease are different from those at work in a healthy individual.
The presence of cell-dwelling pathogens creates an entirely different immune environment, one where it is the pathogens 'calling the tune', and where the conventional sequence of antigen-to-T-lymphocyte activation is no longer the driving force.
Cell-dwelling pathogens cause Th1 immune disease by utilizing an ability to mimic the T-cell Receptor alpha-beta V protein . They are thus capable of directly activating the 'host' monocytes, macrophages and giant-cells which they have parasitized. A cascade of cytokines and chemokines is then continuously released, directly by the parasitized 'host' cells, without the need for any activated T-lymphocytes to be present.
The SARS Coronavirus is a pathogen with the apparent ability to virulently hyper-activate the immune system in this manner [9,10,11,12]. While the granuloma of sarcoidosis are formed by an accumulation of considerably less virulent pathogens than SARS, the anomalous T-cell Receptor alpha-beta V protein is similarly present .
The granuloma of sarcoidosis are formed within inflamed tissue when sufficient lymphopenia-inducing parasites have colonized the monocytes, macrophages and giant-cells in order to sustain a self-activated and non-necrotic inflammatory core . The un-needed T-lymphocytes are down-regulated and expelled to the granuloma's periphery, forming the characteristic non-caseating granulomatous pathology of Sarcoidosis.
What Species of Microbes Have Been Found in Sarcoid Granuloma?
In 1982 Cantwell  described a special type of bacteria, called 'Cell Wall Deficient' (CWD) bacteria (synonyms: L-form, pleomorphic, mollicutes, mycoplasma, cysts), which were minute granules in the inflamed tissue, appearing as 'coccoid' or 'cyst' semi-spherical forms. He found this bacteria in a variety of tissue samples from sarcoidosis patients. Cantwell recently published some colored micrographs of this CWD pathology .
Mattman, et al., in 1996,  performed a careful study of blood samples from 20 sarcoidosis patients and 20 controls using an oil-immersion lens and the Intensified Kinyoun stain. Mattman also developed specialized media which were capable of culturing the CWD organisms she isolated from the CWD specimens.
Cantwell reported that the CWD forms were extremely difficult to culture, even with special media, and that the cultures sometimes took several months to produce visible results. CWD bacteria grow and propagate very much more slowly than spirochetes and other walled forms. Recognizing this extremely slow growth is crucial when choosing an optimal antibiotic therapy.
In 1989 Wirostko, Wirostko and Johnson  published transmission electron microscopy photographs of CWD bacteria living inside each type of immune cell:- lymphocytes, monocytes, macrophages and giant-cells. They used cells taken from the eyes of sarcoidosis patients.
Finally, in 2002, Nilsson et al., published stunning electron microscopy of a bacterial organism replicating within the cells of a granuloma. Here was definitive evidence that not only could bacteria live within the phagocytic cells of the immune system, but also that the bacteria remained healthy, and they were able to flourish inside the hostile environment of the granuloma.
Lessons from Lyme Disease
Until the widespread availability of PCR DNA assays there was a general reluctance to even recognize that CWD bacteria exist, and, if they did, that they might induce disease. The Lyme parasite, Borrelia burgdorferi, is one of the few bacteria that have been actively studied in both the spirochetal and mycoplasmal states. Borrelia studies can give us valuable information about the characteristics of the bacteria we are facing when treating the CWD bacteria of sarcoidosis.
Dr. Willy Burgdorfer (who first discovered Borrelia burgdorferi) observed  "It's probably the answer for the difficulties we have in diagnosing Lyme and other spirochetal diseases, in that we can demonstrate these cysts by microscopy, but once they are in the tissues of the patient, we can no longer detect them. It is quite possible that this material that we cannot see by microscopy is responsible for producing prolonged and chronic disease." Further, Burgdorfer notes that when "the antibiotic or immune pressure is gone, and then when the conditions are right for their further development, they develop into typical spirochetes again."
Borrelia spirochetes have been observed to revert to the CWD form when confronted with the immune components of spinal-fluid in-vitro, and then to transform back to mobile spirochetes in a less hostile environment .
There have also been reports that patients whose immune systems have been suppressed with Remicade (and other TNF-α agonists) often present with Tuberculosis . Total elimination of the TNF-α cytokine apparently creates a less hostile immune environment, allowing the tissue-bound CWD mycobacterial organisms to transform into the mobile walled form, a form capable of propagating an active Tuberculosis infection.
Although 'Chronic-lyme' is a lymphopenic disease, chronic-lyme patients do not usually form sarcoid granuloma. Borrelia burgdorferi appears to be a pathogen with insufficient lymphopenic activity to proliferate sarcoid granulomas on its own. However, together with other pathogens, it is frequently found as a component of sarcoid inflammation.
Borrelia burgdorferi is also found as an inflammatory component of Lofgren's syndrome  and Lupus Erythematosus , presumably in combination with a different set of pathogens.
Indeed [4,24,25,26,27] it seems that sarcoid granuloma hardly ever form in response to a single species of parasitic lymphopenia-inducing pathogen. Prudent therapeutic intervention must assume the presence of multiple species of CWD pathogen.
Satisfying Koch's Postulates
It is important to note that bacteria can cause the Th1 immune reaction without morphing to the walled form, as we have previously detailed in a response to the Brown, et al., ACCESS study . This walled-CWD pleomorphism is key to understanding why a bacterial pathogenesis for Sarcoidosis has not been proven to the satisfaction of Koch's Postulates. However, it is instructive to note that Leprosy has never satisfied Koch's postulates, yet it is accepted that Leprosy indisputably has a bacterial pathogenesis.
Jarisch-Herxheimer - Indisputable Evidence of Bacterial Pathogenesis - And a Therapeutic Problem
We have been following the progress of a heterogeneous mix of over 50 neurosarcoidosis, cutaneous sarcoidosis, and pulmonary sarcoidosis patients, some chronic (wheelchair-bound), and some newly diagnosed. Of these 'early adopters', all except two have reported a lifestyle-limiting Jarisch-Herxheimer Reaction [40,42]. Many of these reactions have been severe, some with (fortunately benign) cardiac involvement . Several required supplemental oxygen due to tightening of muscles in the trachea (oxygen had been unnecessary before the Herxheimer).
We found the only way to minimize the risk of cardiac and respiratory complications is to start therapy with an extremely low dose of antibiotic and let the patient increase that dose, month by month, as the degree of Herxheimer allows.
The Herxheimer reaction most commonly reported was an exacerbation of previous symptomology. Patients reported that it was just as though their sarcoidosis had become "much worse". Herxheimer usually disappears 24-48 hours after dosing, and reducing the dose also reduced the degree of discomfort experienced. Several patients reported that skin lesions became more prominent during the first few weeks of antibiotic treatment.
Most of the 'early adopter' patients report that the Herxheimer has lasted for 3 months or more, and in several cases it has not totally disappeared after 9 months of continuous therapy.
The Biochemistry of the Th1 Immune Reaction
The secosteroid hormone 1,25-dihydroxyvitamin-D is responsible for differentiation of hematopoetic cells into monocytes, and then for catalyzing monocyte differentiation into macrophages and giant-cells. It is an excellent marker of the presence of sarcoid inflammation, even when the serum ACE is masked by steroids or ACE Inhibitors [29,30].
The Angiotensin II Receptor blocker, Benicar (Olmesartan Medoxomil), administered as 40mg q6h or q8h, has been very effective at reducing the suffering of patients experiencing Herxheimer. Some 'early adopters' have called it a 'miracle drug'.
ARBs suppress the release of TNF-α, apparently without disabling the immune system. When Angiotensin II binds at Type 1 receptors in the granulomas it signals the release of cytokines (including TNF-α) and chemokines via the NuclearFactor-kappaB pathway. We have previously published the detailed Th1 biochemistry [29,30] explaining why ARB therapy is so effective, and will avoid repetition in this review.
Rifampin is an antimicrobial commonly used in Tuberculosis and Leprosy. This antimicrobial does not kill CWD organisms effectively. In fact, one study showed Mycobacteria changing into a Rifampin-resistant CWD form under the action of a triple therapy of rifampin, isoniazid and ethambutol . This drug is thus a poor choice for sarcoid therapy. Our aim should be to kill the CWD bacteria, not to create more of them.
Hydroxychloroquine Sulfate (HCQ) (Plaquenil) is an anti-microbial which has been partially successful in a small group of sarcoidosis patients. But like Rifampin, it does not kill CWD organisms very effectively. In fact, "HCQ alone may be sufficient in the treatment of intracellular cystic forms .. at concentrations which are achievable in-vivo .. however, when the infection is located at the dermis .. the MBC (minimum bactericidal concentration) of HCQ is not achievable." Considering the widespread tissue distribution of CWD organisms reported by Cantwell , HCQ monotherapy is therefore not an optimal choice. Further, its use as a component of multiple-antibiotic therapies must also be questioned in view of the risk of serious ophthalmologic complications
The Flouroquinolones have been reported with some activity against intra-cellular pathogens, albeit at one tenth the efficacy of doxycycline . One of the 'early adopter' patients was experiencing Herxheimer at only 50mg of minocycline, q48h. Minocycline was stopped, and he was placed on Ciproflaxin for 2 weeks to treat a kidney infection. There was no Herxheimer while using Cipro. As soon as the 50mg q48h minocycline was resumed, so did the Herxheimer. Neither the study nor this clinical observation bode well for the potential efficacy of Flouroquinolones against the CWD bacteria of Sarcoidosis.
Minocycline has recently been recommended for the treatment of Rheumatoid Arthritis (RA). A University of Nebraska study found minocycline an effective treatment for RA, with remissions cumulative during all four years of the study . With a tissue penetration twice that of doxycycline , and a low incidence of side-effects, low-dose minocycline would seem to be the ideal antibiotic for treatment of sarcoid CWD bacteria.
Many studies refer to a biochemical immunospressive property of minocycline. Each cites a previous paper, yet none cite a definitive source which might describe a specific biochemical activity to which this property is due, or exactly how minocycline might actually act to ?suppress? 'the immune system'. The problem of dealing with barely-detectable mollicutes within tissue is that one is tempted to ignore that they might exist. "Caution should therefore be exercised when interpreting Ang II-related data obtained from cells that have not been checked for mollicute contamination" is the admonition from Whitebread, et al. Yet we have sifted through dozens of papers citing this ill-defined immunosuppressive property for Minocycline. Not one of them has considered the liklihood of 'mollicute contamination'. We formed the opinion that the experimental outcomes of the studies invoking such a property can all be explained solely by consideration of minocycline's antimicrobial actions against mollicute-like bacterial organisms. We do not believe Minocycline has ever been proven to possess a chemically-based immunosuppressive ability, and this belief was reinforced by numerous clinical observations during our study. We note particularly that antibiotics other than the tetracyclines have been effective at inducing remission.
Our 'early adopters' are primarily using Minocycline, with a dose determined solely by the level of Herxheimer they can tolerate (from 25mg q48h up to a maximum dose of 200mg q48h). A few used Doxycycline initially, then changed to Minocycline. Even though the tetracyclines are bacteriostatic, they produce intense and lengthy Herxheimer reactions in sarcoid patients, further highlighting the difference between fighting CWD microbes and blood-borne bacteria.
We also found that Azithromycin, Clarithromycin and Sulfa/Trimeth were effective at treating neuro, eye, and sinus manifestations when they were used at a low dosage in combination with low-dose minocycline.
We have previously demonstrated [36,37] how intermittent dosing of a drug can radically change its properties in Cryptorchidism and Diabetes. We were thus intrigued by Thomas McPherson Brown's book "The Road Back", where he chronicles half a century of antibiotic treatment in a disease that he was convinced was due to CWD bacteria (RA). Albert Sabin and he had simultaneously isolated mycoplasmas while they were both at Rockefeller Institute in the late 1930s.
Brown was convinced that the body had to be given time to clear away dead cells in between antibiotic doses, if the therapy was to be optimally effective against CWD bacteria. The 'early adopters' have proven him correct. Most are using a q48h dosing interval, slipping to q72h, or even longer, during significant Herxheimer events.
Herxheimer has, at times, made antibiotic therapy become somewhat onerous for many of the 'early adopters', and intermittent dosing has been a significant factor in in improving patient tolerance and ensuring compliance.
Limitations in Study Methodology
Ours is a Phase II observational study. Many of the patients in this cohort are Health Care workers (Physicians, Nurses and ex-Nurses), and thus are not necessarily representative of the patient population as a whole. Therapy was prescribed and monitored by the patients? personal physicians. Since the recruitment and ongoing support was provided over the Internet, all patients needed to have a level of education sufficient to operate Internet-capable Computers.
These factors are all capable of introducing bias into the study results. Further bias could be introduced by the lack of a standardized results questionnaire (it was adjudged impractical to produce a standardized questionnaire which could meaningfully evaluate a heterogeneous cohort of Cutaneous, Cardiac, Pulmonary and Neuro-sarcoidosis patients).
To compensate for these biases, extreme care was taken to document adverse events, especially adverse outcomes, and correspondence was publicly logged and reviewed by both investigators.
Despite these reservations, the remission induced by this Antibiotic/ARB protocol was dramatic, and it is unlikely that any of these methodological limitations were sufficient to have skewed the study?s conclusions.
The >50 'early adopters' are a heterogeneous mix of neurosarcoidosis, cutaneous sarcoidosis, cardiac and pulmonary sarcoidosis patients. Some cases are chronic (wheelchair-bound) and some are newly diagnosed. All but three patients report progress induced by minocycline alone, or by the combination of olmesartan medoxomil (40mg q6-8h) and minocycline (<200mg q48h). Sarcoid inflammation is proving to have a primary, homogeneous, bacterial pathogenesis [28,45].
The authors are indebted to Belinda Fenter and Meg Mangin for their invaluable assistance and encouragement, Alan Cantwell, Jr., for critical insights into CWD bacterial pathology and Tetracycline efficacy, and Prof. Robert E. Lee for providing the breakthrough which finally allowed all the pieces of the puzzle to fit together. Finally, thanks are due to Barry Marshall (aka "Mr. Helicobacter Pylori") from Trevor's alma mater (The University of Western Australia) who first showed that, with dedication and persistence, a kid from Perth really could make a difference...
1. Scadding JG: Sarcoidosis, with special reference to lung changes. BMJ 1950, 1: 745-753
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COMPETING INTERESTS: Trevor Marshall is the Managing Editor of JOIMR. The authors funded this research without any third party assistance
Minocycline, Adverse effects
Minocycline, Adverse effects
Azithromycin, Adverse Effects
Atypical Bacterial Forms
(C)2003 Trevor G Marshall
Jorge Romero, M.D;, Ulrich Jorde, MD;, Juan Carlos Diaz, MD;, Anthony Cioci, MD;, Mark I. Travin, MD;, Luigi Di Biase, MD-PhD'Correspondence information about the author MD-PhD Luigi Di BiaseEmail the author MD-PhD Luigi Di Biase
Cardiac sarcoidosis, Lyme disease, ventricular tachycardia, radiofrequency ablation, premature ventricular contraction, AV block
Cardiovascular involvement in Lyme disease is a rarely occurring manifestation. Following infection with Borrelia burgdorferi, Lyme carditis typically presents as atrioventricular (AV) block during the early disseminated stage of the disease, ranging from PR interval prolongation to complete heart block, typically resolving after proper antibiotic treatment. Interestingly, AV block is also common in patients with cardiac sarcoidosis (CS), and CS has been linked to Lyme disease. We report a patient who was diagnosed with Lyme carditis and ultimately developed cardiac sarcoidosis.
A 42-year-old female from Cooperstown, New York presented to our institution after being treated in three other tertiary medical centers for an interesting course of heart disease beginning in 2013. A prior marathon runner, the patient first noted symptoms of fatigue, hair-loss, paresthesia, and light sensitivity; she was treated for depression and anxiety with Prozac and Xanax, respectively, for almost 4 weeks. Due to worsening symptoms, she consulted at another institution where a 12-lead electrocardiogram (ECG) revealed complete heart block with a junctional escape rhythm. An Elisa immunofluorescent assay and subsequent confirmatory Western Blot analysis for IgG and IgM antibodies against B. Burgdorferi were positive, and a diagnosis of Lyme disease with carditis was made. Following several cycles of antibiotic treatment, the heart block persisted and the patient underwent placement of a dual chamber pacemaker. Cardiac magnetic resonance imaging (MRI) performed in 2013 was unremarkable. In 2015, the patient developed progressive heart failure symptoms associated with pacemaker syndrome requiring upgrade to a cardiac resynchronization therapy pacemaker (CRT-P) with His-bundle lead placement. In the following months she was noted to have rising His-bundle lead pacing thresholds. Subsequently, the patient manifested palpitations, and in 2015 underwent an electrophysiology study (EPS) during which typical cavotricuspid isthmus (CTI) dependent atrial flutter was induced; a CTI ablation was performed successfully.
The patient first presented at our institution early in 2017 with a chief complaint of one year of palpitations on exertion and a rapid decline in exercise tolerance. A 12-lead ECG revealed frequent premature ventricular contractions (PVCs) suggesting an origin in the basal portion of the RV (Figure 1A). She subsequently underwent a stress test during which she developed sustained monomorphic VT (figure 1B). A transesophageal echocardiogram (TEE) revealed a moderately dilated RV with moderate hypokinesis; mild left ventricular (LV) dilation with normal left ventricular ejection fraction (LVEF) of 55%. The patient did not respond to beta-blockers (PVC burden 33%) and was referred for catheter ablation (CA), during which two distinct PVC/VT morphologies were demonstrated. Using the CartoSound system, an electroanatomical endocardial activation map (approximately 400 points for each map) of PVC 1 was created, which was observed in the anterior wall of the RVOT (-37 ms pre QRS). Radiofrequency (RF) energy (power 25 W, temperature <42 degrees) was delivered at the RVOT at these sites. Following successful ablation of PVC 1, PVC 2 was no longer seen. Due to the observed dilation of the RV on TEE, an electroanatomical map of the RV was also created revealing extensive fibrosis in the anterolateral and inferolateral RV wall; unipolar voltage map suggested a larger epicardial substrate (Figure 1C).
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A) 12-lead ECG showing a PVC with LBBB morphology inferior axis and transition in V6 suggesting RVOT origin. B) sustained monomorphic VT with LBBB morphology, left superior axis probably originating in the basal portion of the RV free wall. C) Electroanatomical map of the RV revealing extensive fibrosis in the anterolateral and inferolateral RV wall with areas of low voltage extending from the base to the apex of the RV. Unipolar voltage map suggested a larger epicardial substrate (right column).
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The patient was referred for a positron emission tomographic (PET) scan with 18F-fluorodeoxyglucose (PET-CT 18FDG) and nitrogen-13 ammonia (13NH3) to assess for potential active cardiac sarcoidosis (Figure 2A). Discrete perfusion defects suggestive of scar/fibrosis of the basal anterior wall, the septum, and the basal inferoseptal and distal inferior walls were seen, with areas of inflamation involving the anterior, septal and inferior walls consistent with active CS. Additionally, focal FDG uptake also seen in bilateral hilar and subcarinal regions. Genetic testing was negative for any known mutation for arrhythmogenic right ventricular cardiomyopathy (ARVC) and endomyocardial biopsy (EMB) (Figure 2B) confirmed CS. The patient was started on a 12-week course of high dose prednisone (i.e., 50 mg). A follow up PET-CT 18FDG showed a decrease in myocardial 18F-FDG uptake (Figure 2C). For the septum, maximum standard uptake value (SUV max) decreased from 6.85 to 4.56, and SUV mean decreased from 2.71 to 2.47. The right ventricular SUV max decreased from 5.99 to 2.71, and the SUV mean decreased from 2.36 to 1.56. The patient was treated for another three months with high dose prednisone, and PET-CT was repeated. There was minimal to no RV FDG uptake, but septal uptake was visually increased (max SUV increased from 4.56-7.55).
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A) 13NH3 perfusion (top rows) and 18F-FDG metabolic (bottom rows) PET slices. 13NH3 perfusion defect (s) are present in the basal anterior (white arrows), septal (red arrows), and basal and distal inferior (bright green arrows) walls, consistent with scarred regions. Focal 18F-FDG uptake, indicative of inflammation, is present in the anterior wall (turquoise arrows), inferior wall (gold arrows), septum (orange arrows) as well, as the right ventricle (yellow arrows) (note: only selected perfusion defects and focal uptake regions are highlighted). Inflammation in areas of scar, i.e., metabolic/perfusion mismatch, are present in the basal anterior (turquoise/white) and septal walls (orange/red arrows). B) Endomyocardial biopsy demonstrating granulomas consistent with cardiac sarcoidosis. C) Transverse PET18F-FDG metabolic /CT fusion images shows focal tracer uptake in the septum and the right ventricle indicative of inflammation, consistent with active cardiac sarcoidosis (left panel). At 3 months (mid panel) after immunosuppressive therapy shows lessening of septal 18FDG PET-CT uptake and near total resolution of right ventricular uptake, but at 6 months (right panel) shows increased septal tracer uptake and total resolution of right ventricular uptake.
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The patient continued to have frequent symptomatic PVC (burden: 21%) with daily episodes of sustained and non-sustained VT and was referred for a repeat CA. Frequent PVC was observed spontaneously every 3 sinus beats; an endocardial activation map of the RV was created, revealing an earliest activation site in the distal inferolateral wall of the RV (Figure 3A) and ablation delivered at this site (35W). Voltage mapping of the RV revealed a less extensive area of fibrosis/scar tissue in the anterolateral and inferolateral wall when compared to the previous voltage map. This area of low voltage extended from the base to the apex of the RV. The unipolar voltage map of the RV suggested a slightly larger area of fibrosis in the epicardial surface, which also improved from prior voltage maps (Figure 3B).
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A) PVC observed spontaneously at the beginning of the second procedure (LBBB pattern, left superior axis and transition in V6). Epicardial features were not present (MDI<55%, IDT 85 ms and pseudo delta wave < 34 ms). B) Voltage bipolar and unipolar maps of the right ventricle before (pre) and after (post) steroid therapy demonstrating a reduction in the area of fibrosis/scar tissue in the anterolateral and inferolateral RV wall.
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After ablation and during continued steroid use, the patient has had significant symptomatic improvement, with a decrease in His bundle pacing thresholds from 5 to 3 mV and a decrease on PVC burden to 2% and no more episodes of VT seen on device interrogation. Finally, the patient underwent RV lead extraction and upgrade to a Boston Scientific Dynagen CRT-D (His bundle lead) for secondary prevention of sudden cardiac death due to previously demonstrated sustained VT despite initial ablation.
Cardiac involvement is estimated to occur in 20-30% of individuals with sarcoidosis, yet as few as 5% of total patients present with clinical cardiac manifestations. Complete heart block is the most common finding, occurring in up to 30% of these patients, with ventricular arrhythmias accounting for 23% of cases1. When clinical manifestations are limited to conduction system disease, as was the case for our patient at initial diagnosis, age-related conduction diseases such as Lyme disease, Brugada syndrome, myocarditis, and sarcoidosis should be considered 2. The etiology remains poorly: current knowledge suggests an aberrant immune response in genetically predisposed individuals. Interestingly, multiple pathogens including Borrelia, Mycobacteria, and Herpes virus have been linked to sarcoidosis 3 .
Diagnostic criteria for CS have relied on evidence of extracardiac sarcoidosis or positive EMB, even though EMB has demonstrated low sensitivity making the diagnosis of CS often difficult 1, 4, 5. Importantly, 18F-FDG PET has emerged as a useful quantitative tool in the diagnosis of CS given its ability to diagnose active inflammation and monitor response to treatment 1, 6
In our case, following a negative cardiac MRI Lyme carditis was diagnosed based on complete heart block in a young patient, residence in an endemic region, and serological analysis. Following the diagnosis of Lyme myocarditis, our patient was started on IV antibiotics with a very favorable prognosis. Among treated patients, heart block is typically resolved, with only a few rare cases describing persistent conduction disturbances 7, 8. The persistence of heart block in our patient and subsequent development of RV dilation and hypokinesis mandated ruling out sarcoidosis and ARVC. Cardiomyopathy has only seldom been described in European Lyme patients and has never been observed in the United States. In contrast, cases of predominant right ventricular dilation have been described in sarcoidosis, helping our team reach our final diagnosis 9. Interestingly, only a small reduction in PVC burden with steroid therapy and initial ablation was observed, probably reflecting a reduced effect in patients with more advanced disease.
Several possible explanations can be found regarding the association of previous Lyme disease and sarcoidosis: 1. a “two-hit” scenario, in which the patient developed cardiac sarcoidosis (either preceding or following Lyme disease) and Lyme carditis without any relation between them, 2. increased susceptibility to the development of Lyme disease due to the immune response of underlying sarcoidosis, or 3. Lyme disease triggering an immune response which lead to the development of sarcoidosis. Although initial MRI ruled out sarcoidosis, it is possible that further evaluation with 18F-FDG-PET could have demonstrated the presence of active inflammation, as both tests are complementary in the diagnosis of sarcoidosis. Sarcoidosis has been demonstrated to occur in areas of intense inflammatory activity, including scars, tattoos and cutaneous infections. As such, it is possible that intense inflammatory activity during Lyme carditis could have resulted in the patient developing cardiac sarcoidosis. Indeed, B. burgdorferi has been hypothesized as a possible etiological trigger in sarcoidosis, demonstrated by increased seroprevelance of antibodies to B. burgdorferi in patients with a confirmed diagnosis of sarcoidosis 1, 3, 10, 11. In fact, serum angiotensin converting enzyme levels (which have been described to be elevated in patients with sarcoidosis) have been reported to return to normal levels after initiation of antibiotic treatment in patients with biopsy confirmed sarcoidosis and B. burgdorferi infection 12. As such, it is possible that an early diagnosis and initiation of appropriate antibiotic therapy could have changed the disease course, without development of cardiac sarcoidosis. Additionally, “Borrelia-like” organisms have been described within biopsy specimens in patients with cutaneous sarcoidosis13. Nonetheless, other studies using specific immunologic analysis have not found similar results14 and as such a definitive connection between sarcoidosis and Lyme disease has not been established.
Regardless of whether or not an association between Lyme disease and sarcoidosis exists, this case demonstrates the need to include cardiac sarcoidosis in the differential diagnosis of heart block, even in the presence other confirmed etiological entities such as Lyme disease.
Key teaching points
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Dr. Di Biase is a consultant for Biosense Webster, Boston Scientific and St Jude Medical.
Dr. Di Biase has received speaker honoraria/travel from Medtronic, Atricure, EPiEP and Biotronik.
Dr Romero has no disclosures.
Division of Cardiology at Montefiore-Einstein Center for Heart and Vascular Care, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY.
© 2018 Published by Elsevier Inc. on behalf of Heart Rhythm Society.
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