Author: Trevor G Marshall (---.vnnyca.adelphia.net)
Date: 07-10-03 03:20
Brown, et al, ACCESS Study finds Bacterial Pathogens in Sarcoidosis Patients
Author: Trevor G Marshall, PhD
Author's affiliation: Research Director, Sarcinfo, Thousand Oaks, California
Author's email: Trevor. m@yarcrip.com
Article Type: Review
Comment Upon: 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 [PubMed Abstract]
Abstract
The study of Brown, et al, has a flawed methodology. It purports to test the levels of CWD bacteria in Controls and Patients, and hence to draw 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 failed to consider that Sarcoid Inflammation results from an overexuberant host inflammatory response to Pathogens. The study report is thus incomplete and lacks utility. Additionally, the authors' statement that their result "call(s) into question the widespread applicability of" .. Lida Mattman's .. "techniques" not only maligns the work of an outstanding scientist, the statement is unsupported by their evidence.
Discussion
It is generally accepted that Sarcoid Inflammation results from an overexuberant host inflammatory response to Pathogens. At this point there is also an emerging concensus that (yet to be identified) Bacterial Pathogen(s) fuel the Th1 inflammation of Sarcoidosis. Brown, et al, were entrusted with analysis of the data resulting from the multicenter ACCESS study to "search for bacterium in the etiology of sarcoidosis."
Sarcoidosis is a disease which leads to a patient being particularly sensitive to environmental pathogens and irritants. A Sarcoidosis patient's immune system often reacts violently, by forming granulomatous inflammation [2], to immune challenges which are easily neutralized by the immune system of 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).
The authors state [15] "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."
But 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 [13] describe (in detail) how CWD bacteria induce the Th1 inflammatory response, even in their mycoplasmal state.
Further, Mattman[3] and Cantwell[16,17] both have been able to successfully culture CWD bacteria. Why were they not consulted? Why were the study's PCR efforts left at "exploratory attempts" and why did the authors then feel they could base conclusions on such "exploratory attempts"?
It is incomprehensible that while Mattman's staining technique uncovered a special type of bacteria, called CWD bacteria, in 38% to 61% of the ACCESS study's Sarcodiosis patients, the authors felt compelled to state that their result "call(s) into question the widespread applicability of these .. techniques."
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 authors' 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?
Our own antibiotic therapy is consistently inducing Jarisch-Herxheimer shock, placing the bacterial pathogenesis of sarcoidosis beyond dispute. In our studies, sarcoid inflammation is proving to have a primary, homogeneous, bacterial pathogenesis. This study had the funding and evidence to identify that pathogenesis. How could they have failed to do so?
Conclusion
This study has a fundamentally 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. This is incorrect. It is incomprehensible how the authors could have failed to seek assistance from Mattman[3] or Cantwell[16,17] when they had difficulty culturing the CWD bacterial forms which the study had identified. It is incomprehensible that the study's authors stoicly refused to revisit their conclusions after the study's failings had been identified.
References:
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 [Abstract]
2. Sugiyama Y, Oshikawa K. Mechanism of sarcoid granuloma formation--participation of cytokines and chemokines. Nippon Rinsho 2002 Sep;60(9):1728-33 [PubMed Abstract]
3. Almenoff PL, Johnson A, Lesser M, Mattman LH. Growth of acid fast L-forms from the blood of patients with sarcoidosis. Thorax 1996 May;51(5):530-3 [PubMed Abstract]
4. Agerberth B, Grunewald J, Castanos-Velez E, Olsson B, Jornvall H, Wigzell H, Eklund A, Gudmundsson GH. Antibacterial components in bronchoalveolar lavage fluid from healthy individuals and sarcoidosis patients. Am J Respir Crit Care Med 1999 Jul;160(1):283-90 [PubMed Abstract] [Full Text]
5. Ho LP, Davis M, Denison A, Wood FT, Greening AP. Reduced interleukin-18 levels in BAL specimens from patients with asthma compared to patients with sarcoidosis and healthy control subjects. Chest 2002 May;121(5):1421-6 [PubMed Abstract]
6. Yamaguchi E, Kawakami Y. Alveolar macrophages and granuloma formation. Nihon Kyobu Shikkan Gakkai Zasshi 1992 Dec;30 Suppl:219-24 [PubMed Abstract]
7. Eden E, Turino GM. Interleukin 1 secretion from human alveolar macrophages in lung disease. J Clin Immunol 1986 Jul;6(4):326-33 [PubMed Abstract]
8. Reichel H, Koeffler HP, Barbers R, Norman AW. Regulation of 1,25-dihydroxyvitamin D3 production by cultured alveolar macrophages from normal human donors and from patients with pulmonary sarcoidosis. J Clin Endocrinol Metab 1987 Dec;65(6):1201-9 [PubMed Abstract]
9. Terao I, Hashimoto S, Horie T. Effect of GM-CSF on TNF-alpha and IL-1-beta production by alveolar macrophages and peripheral blood monocytes from patients with sarcoidosis. Int Arch Allergy Immunol 1993;102(3):242-8 [PubMed Abstract]
10. Homolka J, Muller-Quernheim J. Increased interleukin 6 production by bronchoalveolar lavage cells in patients with active sarcoidosis. Lung 1993;171(3):173-83 [PubMed Abstract]
11. Steffen M, Petersen J, Oldigs M, Karmeier A, Magnussen H, Thiele HG, Raedler A. Increased secretion of tumor necrosis factor-alpha, interleukin-1-beta, and interleukin-6 by alveolar macrophages from patients with sarcoidosis. J Allergy Clin Immunol 1993 Apr;91(4):939-49 [PubMed Abstract]
12. Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U. Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages. Am J Respir Crit Care Med 1999 Feb;159(2):508-11 [PubMed Abstract]
13. 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]
14. Hudspith BN, Brostoff J, McNicol MW, Johnson NM. Anergy in sarcoidosis: the role of interleukin-1 and prostaglandins in the depressed in vitro lymphocyte response. Clin Exp Immunol 1984 Aug;57(2):324-30 [PubMed Abstract]
15. Brown ST, Brett I, Almenoff PL, Lesser M, Terrin M, Teirstein AS: Author's Reply.Electronic Letter, CHEST 4 April 2003 [Full Text]
16. 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 [PubMed Abstract]
17. Cantwell AR: The Eccrine Sweat Gland as a possible Focus of Infection with Acid-Fast Cell Wall Deficient Bacteria. JOIMR 2003;1(1):1 [Full Text]
FOOTNOTES
No agency funded this research
Competing Interests: None Declared
KEYWORDS
Sarcoidosis
acid-fast bacteria
cell-wall-deficient bacteria
lupus erythematosus, cutaneous
MeSH CLASSIFICATIONS
Sarcoidosis
Atypical Bacterial Forms
Transformation, Bacterial
Lupus Erythematosus, Cutaneous
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