| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
Guest Access | Sign In via User Name/Password
|
|
|
|||||||
Guest Access | Sign In via User Name/Password |
|||||||||
Electronic Letters to:
|
|
Electronic letters published:
![[Read eLetter]](/icons/misc/sectionDOWN.gif){kind=icon}
Brown, et al, ACCESS Study finds Bacterial Pathogens in Sarcoidosis Patients
Brown et al, Cell Wall Deficient bacteria in the blood of sarcoidosis
Antibiotics Do Help Chronic Sarcoidosis Patients
Author's Reply:
Sarcoid Inflammation has a Primary, Homogeneous, Bacterial Pathogensis
|
|
|||
|
Trevor G Marshall, Research Director SarcInfo, Thousand Oaks, California 91360
Send letter to journal:
trevor.m{at}yarcrip.com Trevor G Marshall
|
I have to admit to more than my usual amount of confusion trying to understand the aim and conclusions of the study by Brown, et al, "Recovery of Cell Wall Deficient (CWD) Organisms From Blood Does Not Distinguish Between Patients With Sarcoidosis and Control Subjects."[1] I had thought that Sarcoidosis was a disease which leads to a patient being particularly sensitive to environmental pathogens and irritants. I had thought that a Sarcoidosis patient's immune system often reacted violently, by forming granulomatous inflammation [2], to immune challenges which were easily handled by Controls. Brown, et al, used a novel method for culturing bacterial organisms from blood (developed in 1996 by Lida Mattman [3] at Wayne State University) to "search for bacterium in the etiology of sarcoidosis." As I understand it, this technique uncovered a special type of bacteria, called CWD bacteria, in 38% to 61% of the Sarcodiosis patients. Yet they concluded that their result "call(s) into question the widespread applicability of these .. techniques."How can this be? It has been well documented that BALF from Sarcoidosis patients is hyper-reactive to the presence of bacteria. A recent study by Agerberth, et al, [4] extensively demonstrated the hyper-reactivity of BALF from Sarcodiosis patients to the biochemicals formed by bacteria (lipopolysaccharide and lipopeptides). For two decades, study after study has shown that bacterial lipopolysaccharide actively stimulates the production of more inflammatory Cytokines from the BALF of Sarcoidosis patients than it does from the BALF of Controls [4,5,6,7,8,9,10,11,12,13,14] Surely the conclusion should have been that such a high incidence of bacterial infection would seem to present a major challenge in the management of Sarcoidosis? Wouldn't these pathogens need to be eradicated as part of any therapy aimed at reducing or controlling sarcoid inflammation? In my opinion, this study has a flawed methodology. It purports to test the levels of CWD bacteria in Controls and Patients, and hence to draw some inference as to "bacterium in the etiology of sarcoidosis." The implicit assumption is that the CWD bacteria will have the same effect on the health of Controls as they will on the health of sarcoidosis patients. The study's results do not support this assumption.
References:
|
|||
|
|
|||
|
Alan R Cantwell Jr., MD, physician, retired
Send letter to journal:
alanrcan{at}aol.com Alan R Cantwell Jr., MD
|
The study by Brown et al. concludes that cell wall deficient forms (CWDF) of mycobacteria can be cultured with the same frequency from the blood of sarcoid patients as from the blood of normal control subjects. This study seemingly negates the significance of previous investigators who identified acid-fast organisms and mycobacteria-like microbes from the blood of sarcoid patients. In 1981-1982, I reported in three separate publications the identification of pleomorphic CWD variably acid-fast bacteria, primarily in the coccoid form, in the histopathologic tissue specimens from sarcoidosis of the skin, lymph nodes, and lungs (1-3). Larger forms of the microbe were also observed in vivo and were morphologically similar to "large body" and "giant L-forms" previously described in vitro as valid CWD forms (4). The microbes I observed in vivo in sarcoid were similar to bacteria associated with certain forms of cancer and certain immunologic diseases of unknown etiology (5). This research has been reviewed in my book, The Cancer Microbe (Aries Rising Press, Los Angeles, CA, 1990). The possible role of CWD bacteria in sarcoidosis and other diseases has been viewed with widespread skepticism, and even disdain. Nevertheless, for the past three decades there have been increasing reports that pleomorphic, occasionally acid-fast bacteria, are a constituent of all human blood. This, of course, goes against the almost universal belief that normal, healthy blood is sterile. In 1978, G Tedeschi et al. detected pleomorphic bacteria as intracytoplasmic parasites in clinically healthy human subjects (6). A variety of microbes, such as micrococci, staphylococci, and corynebacteria-like bacteria were cultured. A very recent study in the Journal of Clinical Microbiology confirms the presence of a wide diversity of microorganisms within the blood of healthy people (7). One intensively studied microbe was identified as Pseudomonas maltophilia (later called Xanthomonas maltophilia); another as Stenotrophomonas maltophilia. It is apparent that the study of CWD bacteria in the blood is still in its infancy and that the possible role of these bacteria in human disease (and in health) needs further investigation. The ubiquitous presence of CWD acid-fast bacteria in human blood makes the proof of an etiologic bacterial agent in sarcoid blood more difficult, if not impossible. One wonders if the culture for bacteria in sarcoid tissue might be also rendered moot in view of the fact that tissue contains blood. It is my contention that the possible role of variably acid-fast bacteria as etiologic agents in sarcoid can be further strenghtened by an intensive search for CWD bacteria in vivo in sarcoid tissue sections. Such an evaluation must be made with a full understanding of the microscopic appearance (as well as the differential staining properties) of CWD "coccoid" bacteria and an awareness of larger forms consistent with "large bodies". In order to evaluate the contention that sarcoid bacteria can also be found in other diseases, it would be advantageous to search for CWD bacteria in other neoplastic and inflammatory diseases as well, and to compare any findings with a similar study of normal and disease-free tissue. Although the Brown paper might seem to discourage the search for a bacterial agent in sarcoid blood, it seems to me it is a call to further re-examine sarcoid tissue and to search diligently for CWD acid-fast bacteria, and using the highest magnification possible (oil-immersion lens, magnification x 1000) in order to demonstrate them more successfully. It is also useful to remember that pathologists and other researchers were remiss for months in failing to identify the bacteria that cause Legionnaire's disease, and to remember that bacteria in the form of Helicobacter pyloris were not identified in gastric ulcers for over a century. References: 1. Cantwell AR Jr. Variably acid-fast bacteria in a rare case of coexistent malignant lymphoma and cutaneous sarcoid-like granulomas. Int J Dermatol 1982 Mar;21(2):99-106 2. Cantwell AR Jr. Histologic observations of variably acid-fast pleomorphic bacteria in systemic sarcoidosis: a report of 3 cases. Growth 1982 Summer;46(2):113-25 3. Cantwell AR Jr. Variably acid-fast bacteria in a case of systemic sarcoidosis and hypodermitis sclerodermiformis. Dermatologica 1981;163(3):239-48 4. Cantwell AR Jr. Histologic forms resembling "large bodies" in scleroderma and "pseudoscleroderma". Am J Dermatopathol. 1980 Fall;2(3):273-6. 5. Livingston VW, Alexander-Jackson E. A specific type of organism cultivated from malignancy: bacteriology and proposed classification. Ann N Y Acad Sci. 1970 Oct 30;174(2):636-54. 6. Tedeschi GG, Bondi A, Paparelli M, Sprovieri G. Electron microscopical evidence of the evolution of corynebacteria-like microorganisms within human erythrocytes. Experientia 1978 Apr 15;34(4):458-60 7. McLaughlin RW, Vali H, Lau PC, Palfree RG, De Ciccio A, Sirois M, Ahmad D, Villemur R, Desrosiers M, Chan E. Are there naturally occurring pleomorphic bacteria in the blood of healthy |
|||
|
|
|||
|
Meg M. Mangin, R.N., Registered Nurse none, N.A.
Send letter to journal:
tmmangin{at}charter.net Meg M. Mangin, R.N., et al.
|
After reading Brown et al, [1], I am quite puzzled as to the purpose of the study's objectives. Was it the intent to discredit bacterial etiology theory of sarcoidosis and discourage further investigation of treatments based on this theory? Numerous studies have demonstrated that CWD bacteria act as an antigen in genetically predisposed individuals. And that their immune system forms granulomatous inflammatory tissue in which CWD bacteria have been found. How then does a study examining blood explore this relationship or dispute the bacterial pathogenesis theory? This report concludes that since there is little difference between CWDF mycobacteria found in the blood of sarcoidosis patients and that of normals, bacteria cannot be the etiology of sarcoidosis. Because this supposition does not take into account the biochemistry of sarcoidosis, I respectfully question the relevance of this inference. I have knowledge of numerous, chronic sarcoidosis patients who are currently receiving specialized antibiotic treatment and experiencing resolution of symptoms involving multiple body organs which cannot be explained by spontaneous remission . Many of these patients have been debilitated not only by the disease but by previous toxic, yet standard, sarcoidosis medications. It is my hope that future studies will explore the inflammatory pathways involved in sarcoidosis, the medications that interrupt those pathways (such as angiotensin receptor blockers) and the antibiotics (which eliminate the known bacterial antigens in order to effect a cure). Surely research time, energies and monies directed at these aims would provide more benefits to science, and ultimately those who are suffering, and make it possible for even more sarcoidosis patients to be prescribed the much-needed CWD antibiotics. 1. Brown ST, Brett I, Almenoff PL, Lesser M, Terrin M, Teirstein AS. Recovery of Cell Wall-Deficient Organisms From Blood Does Not Distinguish Between Patients With Sarcoidosis and Control Subjects. Chest. 2003;123: 413-417 |
|||
|
|
|||
|
Sheldon T. Brown, Chief, Infectious Disese Section Bronx VA Medical Center, Ian Brett, Peter L. Almenoff, Marvin Lesser, Michael Terrin, and Alvin S. Teirstein
Send letter to journal:
sheldon.brown{at}med.va.gov Sheldon T. Brown, et al.
|
We are grateful for the thoughtful comments submitted in response to our report. Marshall asserts that the role of bacteria in the pathogenesis of sarcoidosis results from an overexuberant host inflammatory response to bacterial antigens. Our study was not designed to test this hypothesis. The immunological constituents of the host response in sarcoidosis have been widely described and share similarities to host responses to antigens of both microbial and non-microbial origin 12 3. Many chronic bacterial infections including tuberculosis, nocardiosis, histoplasmosis and Whipple’s disease are associated with enhanced non-specific responses to other antigenic stimuli, but these epiphenomena generally subside when the primary infection is eradicated4. Without a clearer understanding of the primary pathogenesis of sarcoidosis, it remains difficult to characterize, as primary or secondary processes, the various elements of its associated immunological responses. The ACCESS study, of which our effort was a part, seeks to clarify this question using epidemiological methods; and other ACCESS sub-studies are evaluating specific immunological aspects of sarcoidosis5. Unfortunately, our sub-study contributes little to knowledge in this area 6. Marshall suggests that “the conclusion should have been that such a high incidence of bacterial infection would seem to present a major challenge in the management of Sarcoidosis”. We do not agree. Our investigation was based on acknowledgement of the plausibility of a role for bacterial infection in the pathogenesis of sarcoidosis. We did see microscopic entities in specially stained smears from cultures that fulfill criteria for the morphologic description of CWDF. However, these forms did not revert to cell wall intact wild type organisms on extended culture or subculture. Furthermore, exploratory attempts to amplify bacterial genetic material from these cultures led to inconsistent and irreproducible results. We therefore do not have evidence that what we observed were, in fact, bacteria. We suspect that they were not. Mangin misstates our conclusion as “bacteria cannot be the etiology of sarcoidosis”. Our report neither confirms nor denies this possibility. The observation of clinical responses to empiric antimicrobial treatment of sarcoidosis that Mangin alludes to may be of importance but should be interpreted with caution. The heterogeneity of sarcoidosis and its highly variable clinical course make it essential to validate such observations with carefully controlled clinical trials. As Cantwell points out, there are examples of diseases whose potential infectious etiology was dismissed until evidence proved otherwise. Alternatively, prion diseases are examples of non-infectious, transmissible maladies whose underlying mechanism was a cause for derision not long ago 7. For these conditions, cumulative evidence was required to overcome dogmatic assertions. This evidence did not come easily. We have sought to investigate a controversial but plausible hypothesis in a rigorous manner and felt it important to report our negative and, for us, disappointing results. We agree with Cantwell that we should keep an open mind and that studies directed at affected tissues may lead to a more rewarding outcome. Meanwhile, we think that efforts to elucidate a microbial etiology for sarcoidosis by culturing blood for CWDF are unlikely to be rewarding. 1 Newman LS. Immunologic mechanisms in granulomatous lung disease. Immunopharmacology 2000; 48(3):329-331. 2 Nathan C, Sporn M. Cytokines in context. J Cell Biol 1991; 113:981-986. 3 Somer T, Finegold SM. Vasculitides associated with infections, immunization, and antimicrobial drugs. Clin Infect Dis 1995; 20(4):1010- 1036. 4 Jappe U. Superantigens and their association with dermatological inflammatory diseases: facts and hypotheses. Acta Derm Venereol 2000; 80(5):321-328. 5 ACCESS Research Group. Design of a case control etiologic study of sarcoidosis (ACCESS). J Clin Epidemiol 1999; 52(12):1173-1186. 6 Brown ST, Brett I, Almenoff PL et al. Recovery of cell wall-deficient organisms from blood does not distinguish between patients with sarcoidosis and control subjects. Chest 2003; 123(2):413-417. 7 Hetz C, Soto C. Protein misfolding and disease: the case of prion disorders. Cell Mol Life Sci 2003; 60(1):133-143. |
|||
|
|
|||
|
Trevor G Marshall, PhD, Research Director Sarcinfo, Thousand Oaks, California 91360
Send letter to journal:
trevor.m{at}yarcrip.com Trevor G Marshall, PhD
|
There is no requirement for Cell Wall Deficient (CWD) bacterial forms to "revert to cell wall intact wild type organisms" before they can cause Th1 Sarcoid inflammation. Mühlradt et al [2] describe how CWD bacteria induce the Th1 inflammatory response, even in their mycoplasmal state. Brown calls for more "carefully controlled clinical trials", yet a century of such trials have failed to expose the etiology of Sarcoisosis, or to find a cure. What it took to reveal the etiology of Sarcoidosis [3] [4] was a "Eureka Moment", followed by two decades of hard work. Jarisch-Herxheimer Shock is now being consistently induced by our hormonal/antibiotic therapy, placing the bacterial pathogenesis beyond dispute. Sarcoidosis should no longer viewed as a "heterogenous" disease. Sarcoid inflammation is proving to have a primary, homogeneous, bacterial pathogenesis. 1. Brown ST, Brett I, Almenoff PL, Lesser M, Terrin M, Teirstein AS: Author's Reply. [Electronic Letter] Chest 2003; 4 April. Available from URL www.chestjournal.org/cgi/eletters/123/2/413#103 2. Mühlradt PF, Kiess M, Meyer H,Süssmuth R, Jung G. Structure and Specific Activity of Macrophage-Stimulating Lipopeptides from Mycoplasma hyorhinis. Infect Immun 1998 Oct; 6(10): 804-10 [Full Text] 3. Marshall TG, Marshall FE: The Science Points to Angiotensin II and 1,25-Dihydroxyvitamin D. [Electronic Letter] Chest 2003; 6 Feb. Available from URL www.chestjournal.org/cgi/eletters/123/1/18#95 4. Marshall TG, Marshall FE: New Treatments Emerge as Sarcoidosis Yields Up its Secrets. Clinmed 2003 Jan 27; 2003010001. Avalable from URL clinmed.netprints.org/cgi/content/full/2003010001 [Full Text] |
|||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
eLetters: