- Email: [email protected]
Sarcoidosis: Role of non-tuberculosis mycobacteria and Mycobacterium tuberculosis
3 ( 2 0 1 4 ) 2 2 5 –2 2 9
International Journal of Mycobacteriology
H O S T E D BY
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/IJMYCO
Review
Sarcoidosis: Role of non-tuberculosis mycobacteria and Mycobacterium tuberculosis Esmaeil Mortaz
a,b,c
, Ian M. Adcock
c,* ,
Peter J. Barnes
c
a
Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences, Utrecht University, Utrecht, The Netherlands b Clinical Tuberculosis and Epidemiology Research Center, National Research and Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran c Cell and Molecular Biology Group, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
Sarcoidosis is a granulomatous inflammatory disease that is induced by unknown antigen(s)
Received 16 October 2014
in a genetically susceptible host. Although the direct link between Mycobacterium tuberculosis
Accepted 18 October 2014
(MTB) infection and sarcoidosis can be excluded on the basis of current knowledge, non-
Available online 30 October 2014
infectious mechanisms may explain the causative role of mycobacterial antigens. Ever since sarcoidosis was first described, its relationship with tuberculosis (TB) has been under-inves-
Keywords:
tigated. Whereas some researchers consider sarcoidosis and TB as two examples of the same
Sarcoidosis
disease process, others have rejected mycobacteria as playing any causative role in sarcoid-
Mycobacterium tuberculosis
osis. Whether they are linked causally or not, clinical evidence makes a differential diagnosis
Non-tuberculosis mycobacterium
between the two conditions very challenging, particularly in countries with high burden of
Lung
TB. The present study analyzes the relationship between sarcoidosis and TB and its implications in clinical practice. The coincidence of TB and sarcoidosis and the higher incidence of mycobacterial DNA in biological samples of sarcoid patients have been reported by many authors. In addition, new evidence of a similarity in MTB phenotype in sarcoidosis is provided. Overall, these observations suggest that TB and sarcoidosis may not only share the same etiology, but may even be different aspects of one disease. 2014 Asian-African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-tuberculosis and tuberculosis mycobacterium . . . . . . Does mycobacterium infection play a role in sarcoidosis?
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* Corresponding author. E-mail address: [email protected] (I.M. Adcock). http://dx.doi.org/10.1016/j.ijmyco.2014.10.008 2212-5531/ 2014 Asian-African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.
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International Journal of Mycobacteriology
3 ( 2 0 1 4 ) 2 2 5 –2 2 9
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
Introduction The incidence of non-tuberculous mycobacteria (NTM) infection has been increasingly reported both in immunocompromised and immunocompetent patients. Pulmonary infections due to NTM and Mycobacterium tuberculosis (MTB) are also increasing worldwide [1]. Fast-growing NTM mycobacteria are ubiquitous organisms in the environment and may cause diseases in both healthy and immunocompromised patients. As such, they are a recognized cause of environmentally acquired diseases, including post-traumatic skin, soft tissue, and bone infections, pulmonary disease [2–4], disseminated infection [5] and cervical lymphadenitis [6]. Information about the risk factors for NTM disease is unclear given that the data comes from case reports and retrospective studies. Many factors have been involved in the increased susceptibility of NTM, such as pre-existing lung disease, immune suppression or genetic defects of cell-mediated immunity that may be playing an important role [7]. Sarcoidosis is an idiopathic, multi-organ, inflammatory disease which is characterized by the presence of epithelioid cell, non-caseating granulomas in various organs [8–10]. The lungs, lymph nodes, skin and eyes are the most commonly affected organs [11]. Yet the potential involvement of any organ system contributes to its myriad of clinical manifestations not well understood. The etiology of sarcoidosis remains unknown; its development is complex, with genetic susceptibility and environmental factors that may be playing important roles in the pathogenesis of diseases [12–14]. Furthermore, certain occupations and environmental exposures have been linked
to the higher risk of sarcoidosis in some patients [15,16]. Since the lungs are the most commonly affected organ, the search for an etiologic agent has focused on airborne antigens and infectious or non-infectious bacteria [17,18]. The use of molecular tools and techniques demonstrating genomic or protein material of mycobacterial origin in sarcoidosis tissues, along with elevated humeral and cellular immune response to Mycobacterial antigens, may support the hypothesis that mycobacterial antigens may drive some cases of sarcoidosis. In addition, there is much clinical evidence supporting the similarity between tuberculosis (TB) and sarcoidosis [19–24]. The present study provides a brief overview on the possible role of mycobacterium in the pathogenesis of sarcoidosis with a focus on the role of NTM. Finding a causal link between the concomitant occurrence of TB and sarcoidosis will be a challenge for the future, but will lead to the use of new therapeutic drugs for suppressing lung inflammation in these patients.
Sarcoidosis The immunopathology of sarcoidosis remains elusive despite years of research into this multi-organ disease [25]. However, recent studies have provided new insights into the genetics and immune components involved in the clinical manifestation of the disease. Granulomatous inflammation is believed to be the host immune response to a persistent poorly degradable unknown antigen [25]. Although direct evidence
Fig. 1 – The cartoon indicating simple pathogenesis of Sarcoidosis Exposure of body to unknown sarcoid antigen leads to activation of the T cells and APCs which leads to releasing of cytokines. CD4 activation can skew the immune system to Th1 and Th2 response which in turn induces the granuloma formation. Formation of granuloma in later phases can end up to resolution or chronic status of diseases with fibrosis condition. Mortaz et al., Iran J. Allergy Asthma Immunol. 2014;13(5):300–6
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227
lie at the edge of clinical pathogenicity. A combination of a high-infecting dose, long-standing colonization of bacteria, and host immune status decline may trigger an invasive disease whose clinical presentation may be misdiagnosed as a recurrence of the underlying disease [28,29]. An increase in the rate of NTM diseases in Western countries is associated with a decline in the prevalence of TB [30]. Rather than an increase in prevalence, it is most likely due to an increased number of immunocompromised patients following a longstanding disease and to the introduction of more accurate methods for NTM identification. NTM diseases, unlike MTB, are not reportable to public health authorities; therefore, best estimates of their incidence are often based on the progress in laboratory isolation of NTM. This has led to the recognition of several new species associated with human diseases, such as sarcoidosis [31]. It is believed that granulomatous diseases of lungs may be the result of the continued presentation of an unknown poorly degradable antigen [32,33]. With the increased ability to detect NTM presence in sarcoidosis, this raises the possibility that MTB and sarcoidosis may have a similar causal agent, namely NTM, and that these may even be different clinical manifestations of the same disease in the patient.
Does mycobacterium infection play a role in sarcoidosis?
Fig. 2 – (A) Photomicrograph showing cell wall deficient forms (CDWF) grown from the blood of a patient’s body as seen in the center, and small yellow fluorescing with active sarcoidosis using the Mycobacterium tuberculosis H37RV monoclonal antibody. A large yellow fluorescing L microcolonies (·400) are seen elsewhere. (Almenoff PL et al., Thorax 1996;51:530–3). (B) Atomic force microscopy shows the cell wall deficient forms of M. tuberculosis during a dormant phase of growth. (Farnia P et al. Int. J. Clin. Exp. Med. 2010; 3:320–326).
is limited, it is thought that M. tuberculosis (MTB) induces the sarcoid granuloma reaction [26]. The immune mechanisms that cause this disease start with the antigenic stimulus, followed by T-cell, macrophage and dendritic cell activation via a classic MHC II–mediated pathway (Fig. 1). The etiology of sarcoidosis is intriguing, since a part of its definition (i.e., unknown cause) makes it uniquely different from granulomatous disorders arising from exposure to a known chronically persisting antigen, such as TB, visceral leishmaniasis and chronic beryllium disease [20,27].
Non-tuberculosis and tuberculosis mycobacterium Much remains to be understood in the pathogenesis of NTM infections in humans as most of these organisms appear to
Mycobacteria are a class of bacteria which are very similar to other bacteria, but possess some unique characteristics and behaviors which induce many diverse diseases; for example, M. tuberculosis causes TB, and mycobacterium leprae causes leprosy [34]. Interestingly, both MTB and NTM have been isolated from a majority of sarcoidosis patients [35–41]. Thus, it has been suggested that sarcoidosis may be a clinical manifestation of this group of patients with infection by the mycobacteria who have a strong granulomatous response which diminishes upon elimination of the mycobacteria [42]. To date, both infective (MTB) and non-infective (NTM) mycobacteria have been implicated in sarcoidosis pathogenesis [43]. Despite this, the role of mycobacteria in sarcoidosis remains unclear and needs to be elucidated in the future. Non-infective agents have previously been implicated as causal agents in sarcoidosis because of their epidemiological association with disease [44], but this concept has not been well understood [45]. Currently, the focus is on infective agents, and the two strongest candidates are Propionibacterium and mycobacterium [46]. Since sarcoidosis was first described, there has always been a belief that the disease is in some way related to MTB [47]. However, the inability to identify mycobacteria by histological staining or culture from pathological tissues continues to be one of the strongest arguments against a potential role for mycobacteria. Some studies have suggested a promising association between mycobacteria (both MTB and NTM) and sarcoidosis [48]. In particular, slow-growing mycobacteria species with low pathogenic potential, but with the capability of eliciting a type IV immune response, may be important in sarcoidosis. In support of this, Almenoff et al. in 1997 and Farnia et al.
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recently were able to isolate and culture mycobacterium from sarcoidosis patients with a similar phenotype to that seen in TB, respectively (Fig. 2A and B), which provides further evidence for a similar causal agent [49–51]. Whether or not mycobacterium in this form induces antigenicity to mimic sarcoidosis pathogenesis is better left to a perspective study which needs to be elucidated in the future. In order to confirm this hypothesis, it will be necessary to perform large multi-center trials using a central laboratory for mycobacteria sample testing.
Conflict of interest We have no conflict of interest to declare.
R E F E R E N C E S
[1] Diagnosis and treatment of disease caused by nontuberculous mycobacteria. This official statement of the American Thoracic Society was approved by the Board of Directors, Medical Section of the American Lung Association, Am. J. Respir. Crit. Care Med. 156 (1997) S1–25. [2] M.M. Johnson, E.A. Waller, J.P. Leventhal, Nontuberculous mycobacterial pulmonary disease, Curr. Opin. Pulm. Med. 14 (2008) 203–210. [3] D.E. Griffith, T. Aksamit, B.A. Brown-Elliott, et al, An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases, Am. J. Respir. Crit. Care Med. 175 (2007) 367–416. [4] S.K. Field, R.L. Cowie, Lung disease due to the more common nontuberculous mycobacteria, Chest 129 (2006) 1653–1672. [5] C. Bennett, J. Vardiman, H. Golomb, Disseminated atypical mycobacterial infection in patients with hairy cell leukemia, Am. J. Med. 80 (1986) 891–896. [6] C. Berger, G.E. Pfyffer, D. Nadal, Treatment of nontuberculous mycobacterial lymphadenitis with clarithromycin plus rifabutin, J. Pediatr. 128 (1996) 383–386. [7] P. Sexton, A.C. Harrison, Susceptibility to nontuberculous mycobacterial lung disease, Eur. Respir. J. 31 (2008) 1322–1333. [8] J. Hutchinson, Illustrations of Clinical Surgery, J and A Churchill, London, 1875. [9] D.G. James, O.P. Sharma, From Hutchinson to now: a historical glimpse, Curr. Opin. Pulm. Med. 8 (2002) 416–423. [10] J.G. Scadding, Mycobacterium tuberculosis in the aetiology of sarcoidosis, BMJ 2 (1960) 1617–1623. [11] Statement on sarcoidosis. Joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999, Am. J. Respir. Crit. Care Med. 160 (1999) 736– 755. [12] G. Smith, I. Brownell, M. Sanchez, S. Prystowsky, Advances in the genetics of sarcoidosis, Clin. Genet. 73 (2008) 401–412. [13] J. Grunewald, Genetics of sarcoidosis, Curr. Opin. Pulm. Med. 14 (2008) 434–439. [14] J. Muller-Quernheim, M. Schurmann, S. Hofmann, K.I. Gaede, A. Fischer, A. Prasse, et al, Genetics of sarcoidosis, Clin. Chest Med. 29 (2008) 391–414. [15] Access research group, Design of a case control etiologic study of sarcoidosis (access), J. Clin. Epidemiol. 52 (1999) 1173–1186.
3 ( 2 0 1 4 ) 2 2 5 –2 2 9
[16] M.D. Rossman, M.E. Kreider, Lesson learned from access (a case controlled etiologic study of sarcoidosis), Proc. Am. Thorac. Soc. 4 (2007) 453–456. [17] E.S. Chen, D.R. Moller, Etiology of sarcoidosis, Clin. Chest Med. 29 (2008) 365–377. [18] D.R. Moller, Etiology of sarcoidosis, Clin. Chest Med. 18 (1997) 695–706. [19] D. Gupta, R. Agarwal, A.N. Aggarwal, S.K. Jindal, Sarcoidosis and tuberculosis: the same disease with different manifestations or similar manifestations of different disorders, Curr. Opin. Pulm. Med. 18 (2012) 506–516. [20] W.J. Piotrowski, P. Go´rski, J. Duda-Szyman´ska, S. Kwiatkowska, Mycobacterium tuberculosis as a sarcoid factor? A case report of family sarcoidosis, Am. J. Case Rep. 15 (2014) 216–220. [21] I. Litinsky, O. Elkayam, G. Flusser, R. Segal, M. Yaron, D. Caspi, Sarcoidosis: TB or not TB?, Ann Rheum. Dis. 61 (2002) 385– 386. [22] K. Babu, Sarcoidosis in tuberculosis-endemic regions: India, J. Ophthalmic Inflamm. Infect. 3 (2013) 53. [23] Y. Zhou, H.P. Li, Q.H. Li, H. Zheng, R.X. Zhang, G. Chen, et al, Differentiation of sarcoidosis from tuberculosis using realtime PCR assay for the detection and quantification of Mycobacterium tuberculosis, Sarcoidosis Vasc. Diffuse Lung Dis. 25 (2008) 93–99. [24] F. Badar, S.F. Azfar, I. Ahmad, Y. Shagufta, S. Kirmani, Diagnostic difficulties in differentiating sarcoidosis from tuberculosis, Oman Med. J. 26 (3) (2011) 210–211. [25] J.W.T. van Enschot, R.H.H. van Balkom, Sarcoidosis following Mycobacterium tuberculosis infection: Coincidence or consequence, Respir. Med. Case Rep. 9 (2013) 11e14. [26] E. Mortaz, M.R. Masjedi, P. Tabarsi, M. Pourabdollah, I.M. Adcock, Immunopathology of sarcoidosis, Iran J. Allergy Asthma Immunol. 13 (5) (2014) 300–306. [27] E. Guirado, L.S. Schlesinger, Modeling the Mycobacterium tuberculosis granuloma-the critical battlefield in host immunity and disease, Front. Immunol. 4 (2013) 98, http:// dx.doi.org/10.3389/fimmu.2013.00098. [28] J.W.J. Moore, D. Moyo, L. Beattie, P.S. Andrews, J. Timmis, P.M. Kaye, Functional complexity of the Leishmania granuloma and the potential of in silico modeling, Front. Immunol. 4 (2013) 98, http://dx.doi.org/10.3389/fimmu.2013.00035. [29] J.O. Falkinham 3rd, Surrounded by mycobacteria: nontuberculous mycobacteria in the human environment, J. Appl. Microbiol. 107 (2) (2009) 356–367. [30] M.J. van der Werf, C. Ko¨dmo¨n, V. Katalinic´-Jankovic´, T. Kummik, H. Soini, E. Richter, et al, Inventory study of nontuberculous mycobacteria in the European Union, BMC Infect. Dis. 14 (2014) 62. [31] Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999, Am. J. Respir. Crit. Care Med. 160 (1999) 736–755. [32] C.E. Broos, M. van Nimwegen, H.C. Hoogsteden, R.W. Hendriks, M. Kool, B. van den Blink, Granuloma formation in pulmonary sarcoidosis, Front. Immunol. 4 (2013) 437, http:// dx.doi.org/10.3389/fimmu.2013.00437. [33] T. Kawai, N. Watanabe, M. Yokoyama, Y. Nakazawa, F. Goto, T. Uchiyama, et al, Interstitial lung disease with multiple microgranulomas in chronic granulomatous disease, J. Clin. Immunol. (2014). PMID: 25186973. [34] A.A. Velayati, P. Farnia, S. Khalizadeh, A.M. Farahbod, M. Hasanzadh, M.F. Sheikolslam, Interferon-gamma receptor-1 gene promoter polymorphisms and susceptibility to leprosy in children of a single family, Am. J. Trop. Med. Hyg. 84 (4) (2011) 627–629.
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[35] R.L. Perez, C.A. Rivera-Marrero, J. Roman, Pulmonary granulomatous inflammation: from sarcoidosis to tuberculosis, Semin. Respir. Infect. 18 (2003) 23–32. [36] R.E. Epps, R.A. El-Azhary, W.C. Hellinger, R.K. Winkelmann, R.E. Van Scoy, Disseminated cutaneous Mycobacterium avium-intracellulare resembling sarcoidosis, J. Am. Acad. Dermatol. 33 (3) (1995) 528–531. [37] F.A. El-Zaatari, S.A. Naser, D.C. Markesich, D.C. Kalter, L. Engstand, D.Y. Graham, Identification of Mycobacterium avium complex in sarcoidosis, J. Clin. Microbiol. 34 (9) (1996) 2240–2245. [38] J.A. Ikonomopoulos, V.G. Gorgoulis, N.G. Kastrinakis, P.V. Zacharatos, S.N. Kokotas, K. Evangelou, et al, Sensitive differential detection of genetically related mycobacterial pathogens in archival material, Am. J. Clin. Pathol. 114 (6) (2000) 940–950. [39] N. Girard, V. Cottin, A. Hot, B. Etienne-Mastroianni, C. Chidiac, J.F. Cordier, Opportunistic infections and sarcoidosis, Rev. Mal. Respir. 21 (6 Pt 1) (2004) 1083–1090. [40] Y. Eishi, M. Suga, I. Ishige, D. Kobayashi, T. Yamada, T. Takemura, et al, Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis, J. Clin. Microbiol. 40 (1) (2002) 198–204. [41] N. Li, A. Bajoghli, A. Kubba, J. Bhawan, Identification of mycobacterial DNA in cutaneous lesions of sarcoidosis, J. Cutan. Pathol. 26 (6) (1999) 271–278. [42] H. Klemen, A.N. Husain, P.T. Cagle, E.R. Garrity, H.H. Popper, Mycobacterial DNA in recurrent sarcoidosis in the transplanted lung – A PCR-based study on four cases, Virchows Arch. 436 (4) (2000) 365–369.
3 ( 2 0 1 4 ) 2 2 5 –2 2 9
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[43] G. Mangiapan, A.J. Hance, Mycobacteria and sarcoidosis: an overview and summary of recent molecular biological data. Sarcoidosis, in: G.J. Domingue (Ed.), Cell wall deficient, 12, 1995, pp. 20–37. [44] L.S. Newman, Aetiologies of sarcoidosis, in: M. Dent, U. Costabel (Eds.), Sarcoidosis, Eur Respir Mon, 32, 2005, pp. 23– 48. [45] M. Thomeer, M. Demedts, W. Wuyts, Epidemiology of sarcoidosis, in: M. Dent, U. Costabel (Eds.), Sarcoidosis, Eur Respir Mon, 32, 2005, pp. 13–22. [46] R.M. du Bois, N. Goh, D. McGrath, P. Cullinan, Is there a role for microorganisms in the pathogenesis of sarcoidosis?, J Intern. Med. 253 (2003) 4–17. [47] W.P. Drake, L.S. Newman, Mycobacterial antigens may be important in sarcoidosis pathogenesis, Curr. Opin. Pulm. Med. 12 (2006) 359–363. [48] O.P. Sharma, Murray Kornfeld, American College of Chest Physician, and sarcoidosis: a historical footnote: 2004 Murray Kornfeld Memorial Founders Lecture, Chest 128 (2005) 1830– 1835. [49] P.L. Almenoff, A. Johnson, M. Lesser, L.H. Mattman, Growth of acid fast L forms from the blood of patients with sarcoidosis, Thorax 51 (5) (1996) 530–533. [50] P. Farnia, M.R. Masjedi, et al, Growth and cell-division in extensive (XDR) and extremely drug resistant (XXDR) tuberculosis strains: transmission and atomic force observation, Int. J. Clin. Exp. Med. 3 (2010) 320–326. [51] A.A. Velayati, P. Farnia, M.R. Masjedi, G.K. Zhavnerko, J. Ghanavi, N.N. Poleschuyk, Morphological modification by tubercle bacilli: no time for denial, J. Infect. Dev. Countries 6 (1) (2012) 97–99.
International Journal of Mycobacteriology
H O S T E D BY
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/IJMYCO
Review
Sarcoidosis: Role of non-tuberculosis mycobacteria and Mycobacterium tuberculosis Esmaeil Mortaz
a,b,c
, Ian M. Adcock
c,* ,
Peter J. Barnes
c
a
Division of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences, Utrecht University, Utrecht, The Netherlands b Clinical Tuberculosis and Epidemiology Research Center, National Research and Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran c Cell and Molecular Biology Group, Airways Disease Section, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London, UK
A R T I C L E I N F O
A B S T R A C T
Article history:
Sarcoidosis is a granulomatous inflammatory disease that is induced by unknown antigen(s)
Received 16 October 2014
in a genetically susceptible host. Although the direct link between Mycobacterium tuberculosis
Accepted 18 October 2014
(MTB) infection and sarcoidosis can be excluded on the basis of current knowledge, non-
Available online 30 October 2014
infectious mechanisms may explain the causative role of mycobacterial antigens. Ever since sarcoidosis was first described, its relationship with tuberculosis (TB) has been under-inves-
Keywords:
tigated. Whereas some researchers consider sarcoidosis and TB as two examples of the same
Sarcoidosis
disease process, others have rejected mycobacteria as playing any causative role in sarcoid-
Mycobacterium tuberculosis
osis. Whether they are linked causally or not, clinical evidence makes a differential diagnosis
Non-tuberculosis mycobacterium
between the two conditions very challenging, particularly in countries with high burden of
Lung
TB. The present study analyzes the relationship between sarcoidosis and TB and its implications in clinical practice. The coincidence of TB and sarcoidosis and the higher incidence of mycobacterial DNA in biological samples of sarcoid patients have been reported by many authors. In addition, new evidence of a similarity in MTB phenotype in sarcoidosis is provided. Overall, these observations suggest that TB and sarcoidosis may not only share the same etiology, but may even be different aspects of one disease. 2014 Asian-African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.
Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sarcoidosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Non-tuberculosis and tuberculosis mycobacterium . . . . . . Does mycobacterium infection play a role in sarcoidosis?
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* Corresponding author. E-mail address: [email protected] (I.M. Adcock). http://dx.doi.org/10.1016/j.ijmyco.2014.10.008 2212-5531/ 2014 Asian-African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.
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Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228
Introduction The incidence of non-tuberculous mycobacteria (NTM) infection has been increasingly reported both in immunocompromised and immunocompetent patients. Pulmonary infections due to NTM and Mycobacterium tuberculosis (MTB) are also increasing worldwide [1]. Fast-growing NTM mycobacteria are ubiquitous organisms in the environment and may cause diseases in both healthy and immunocompromised patients. As such, they are a recognized cause of environmentally acquired diseases, including post-traumatic skin, soft tissue, and bone infections, pulmonary disease [2–4], disseminated infection [5] and cervical lymphadenitis [6]. Information about the risk factors for NTM disease is unclear given that the data comes from case reports and retrospective studies. Many factors have been involved in the increased susceptibility of NTM, such as pre-existing lung disease, immune suppression or genetic defects of cell-mediated immunity that may be playing an important role [7]. Sarcoidosis is an idiopathic, multi-organ, inflammatory disease which is characterized by the presence of epithelioid cell, non-caseating granulomas in various organs [8–10]. The lungs, lymph nodes, skin and eyes are the most commonly affected organs [11]. Yet the potential involvement of any organ system contributes to its myriad of clinical manifestations not well understood. The etiology of sarcoidosis remains unknown; its development is complex, with genetic susceptibility and environmental factors that may be playing important roles in the pathogenesis of diseases [12–14]. Furthermore, certain occupations and environmental exposures have been linked
to the higher risk of sarcoidosis in some patients [15,16]. Since the lungs are the most commonly affected organ, the search for an etiologic agent has focused on airborne antigens and infectious or non-infectious bacteria [17,18]. The use of molecular tools and techniques demonstrating genomic or protein material of mycobacterial origin in sarcoidosis tissues, along with elevated humeral and cellular immune response to Mycobacterial antigens, may support the hypothesis that mycobacterial antigens may drive some cases of sarcoidosis. In addition, there is much clinical evidence supporting the similarity between tuberculosis (TB) and sarcoidosis [19–24]. The present study provides a brief overview on the possible role of mycobacterium in the pathogenesis of sarcoidosis with a focus on the role of NTM. Finding a causal link between the concomitant occurrence of TB and sarcoidosis will be a challenge for the future, but will lead to the use of new therapeutic drugs for suppressing lung inflammation in these patients.
Sarcoidosis The immunopathology of sarcoidosis remains elusive despite years of research into this multi-organ disease [25]. However, recent studies have provided new insights into the genetics and immune components involved in the clinical manifestation of the disease. Granulomatous inflammation is believed to be the host immune response to a persistent poorly degradable unknown antigen [25]. Although direct evidence
Fig. 1 – The cartoon indicating simple pathogenesis of Sarcoidosis Exposure of body to unknown sarcoid antigen leads to activation of the T cells and APCs which leads to releasing of cytokines. CD4 activation can skew the immune system to Th1 and Th2 response which in turn induces the granuloma formation. Formation of granuloma in later phases can end up to resolution or chronic status of diseases with fibrosis condition. Mortaz et al., Iran J. Allergy Asthma Immunol. 2014;13(5):300–6
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lie at the edge of clinical pathogenicity. A combination of a high-infecting dose, long-standing colonization of bacteria, and host immune status decline may trigger an invasive disease whose clinical presentation may be misdiagnosed as a recurrence of the underlying disease [28,29]. An increase in the rate of NTM diseases in Western countries is associated with a decline in the prevalence of TB [30]. Rather than an increase in prevalence, it is most likely due to an increased number of immunocompromised patients following a longstanding disease and to the introduction of more accurate methods for NTM identification. NTM diseases, unlike MTB, are not reportable to public health authorities; therefore, best estimates of their incidence are often based on the progress in laboratory isolation of NTM. This has led to the recognition of several new species associated with human diseases, such as sarcoidosis [31]. It is believed that granulomatous diseases of lungs may be the result of the continued presentation of an unknown poorly degradable antigen [32,33]. With the increased ability to detect NTM presence in sarcoidosis, this raises the possibility that MTB and sarcoidosis may have a similar causal agent, namely NTM, and that these may even be different clinical manifestations of the same disease in the patient.
Does mycobacterium infection play a role in sarcoidosis?
Fig. 2 – (A) Photomicrograph showing cell wall deficient forms (CDWF) grown from the blood of a patient’s body as seen in the center, and small yellow fluorescing with active sarcoidosis using the Mycobacterium tuberculosis H37RV monoclonal antibody. A large yellow fluorescing L microcolonies (·400) are seen elsewhere. (Almenoff PL et al., Thorax 1996;51:530–3). (B) Atomic force microscopy shows the cell wall deficient forms of M. tuberculosis during a dormant phase of growth. (Farnia P et al. Int. J. Clin. Exp. Med. 2010; 3:320–326).
is limited, it is thought that M. tuberculosis (MTB) induces the sarcoid granuloma reaction [26]. The immune mechanisms that cause this disease start with the antigenic stimulus, followed by T-cell, macrophage and dendritic cell activation via a classic MHC II–mediated pathway (Fig. 1). The etiology of sarcoidosis is intriguing, since a part of its definition (i.e., unknown cause) makes it uniquely different from granulomatous disorders arising from exposure to a known chronically persisting antigen, such as TB, visceral leishmaniasis and chronic beryllium disease [20,27].
Non-tuberculosis and tuberculosis mycobacterium Much remains to be understood in the pathogenesis of NTM infections in humans as most of these organisms appear to
Mycobacteria are a class of bacteria which are very similar to other bacteria, but possess some unique characteristics and behaviors which induce many diverse diseases; for example, M. tuberculosis causes TB, and mycobacterium leprae causes leprosy [34]. Interestingly, both MTB and NTM have been isolated from a majority of sarcoidosis patients [35–41]. Thus, it has been suggested that sarcoidosis may be a clinical manifestation of this group of patients with infection by the mycobacteria who have a strong granulomatous response which diminishes upon elimination of the mycobacteria [42]. To date, both infective (MTB) and non-infective (NTM) mycobacteria have been implicated in sarcoidosis pathogenesis [43]. Despite this, the role of mycobacteria in sarcoidosis remains unclear and needs to be elucidated in the future. Non-infective agents have previously been implicated as causal agents in sarcoidosis because of their epidemiological association with disease [44], but this concept has not been well understood [45]. Currently, the focus is on infective agents, and the two strongest candidates are Propionibacterium and mycobacterium [46]. Since sarcoidosis was first described, there has always been a belief that the disease is in some way related to MTB [47]. However, the inability to identify mycobacteria by histological staining or culture from pathological tissues continues to be one of the strongest arguments against a potential role for mycobacteria. Some studies have suggested a promising association between mycobacteria (both MTB and NTM) and sarcoidosis [48]. In particular, slow-growing mycobacteria species with low pathogenic potential, but with the capability of eliciting a type IV immune response, may be important in sarcoidosis. In support of this, Almenoff et al. in 1997 and Farnia et al.
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recently were able to isolate and culture mycobacterium from sarcoidosis patients with a similar phenotype to that seen in TB, respectively (Fig. 2A and B), which provides further evidence for a similar causal agent [49–51]. Whether or not mycobacterium in this form induces antigenicity to mimic sarcoidosis pathogenesis is better left to a perspective study which needs to be elucidated in the future. In order to confirm this hypothesis, it will be necessary to perform large multi-center trials using a central laboratory for mycobacteria sample testing.
Conflict of interest We have no conflict of interest to declare.
R E F E R E N C E S
[1] Diagnosis and treatment of disease caused by nontuberculous mycobacteria. This official statement of the American Thoracic Society was approved by the Board of Directors, Medical Section of the American Lung Association, Am. J. Respir. Crit. Care Med. 156 (1997) S1–25. [2] M.M. Johnson, E.A. Waller, J.P. Leventhal, Nontuberculous mycobacterial pulmonary disease, Curr. Opin. Pulm. Med. 14 (2008) 203–210. [3] D.E. Griffith, T. Aksamit, B.A. Brown-Elliott, et al, An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases, Am. J. Respir. Crit. Care Med. 175 (2007) 367–416. [4] S.K. Field, R.L. Cowie, Lung disease due to the more common nontuberculous mycobacteria, Chest 129 (2006) 1653–1672. [5] C. Bennett, J. Vardiman, H. Golomb, Disseminated atypical mycobacterial infection in patients with hairy cell leukemia, Am. J. Med. 80 (1986) 891–896. [6] C. Berger, G.E. Pfyffer, D. Nadal, Treatment of nontuberculous mycobacterial lymphadenitis with clarithromycin plus rifabutin, J. Pediatr. 128 (1996) 383–386. [7] P. Sexton, A.C. Harrison, Susceptibility to nontuberculous mycobacterial lung disease, Eur. Respir. J. 31 (2008) 1322–1333. [8] J. Hutchinson, Illustrations of Clinical Surgery, J and A Churchill, London, 1875. [9] D.G. James, O.P. Sharma, From Hutchinson to now: a historical glimpse, Curr. Opin. Pulm. Med. 8 (2002) 416–423. [10] J.G. Scadding, Mycobacterium tuberculosis in the aetiology of sarcoidosis, BMJ 2 (1960) 1617–1623. [11] Statement on sarcoidosis. Joint statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999, Am. J. Respir. Crit. Care Med. 160 (1999) 736– 755. [12] G. Smith, I. Brownell, M. Sanchez, S. Prystowsky, Advances in the genetics of sarcoidosis, Clin. Genet. 73 (2008) 401–412. [13] J. Grunewald, Genetics of sarcoidosis, Curr. Opin. Pulm. Med. 14 (2008) 434–439. [14] J. Muller-Quernheim, M. Schurmann, S. Hofmann, K.I. Gaede, A. Fischer, A. Prasse, et al, Genetics of sarcoidosis, Clin. Chest Med. 29 (2008) 391–414. [15] Access research group, Design of a case control etiologic study of sarcoidosis (access), J. Clin. Epidemiol. 52 (1999) 1173–1186.
3 ( 2 0 1 4 ) 2 2 5 –2 2 9
[16] M.D. Rossman, M.E. Kreider, Lesson learned from access (a case controlled etiologic study of sarcoidosis), Proc. Am. Thorac. Soc. 4 (2007) 453–456. [17] E.S. Chen, D.R. Moller, Etiology of sarcoidosis, Clin. Chest Med. 29 (2008) 365–377. [18] D.R. Moller, Etiology of sarcoidosis, Clin. Chest Med. 18 (1997) 695–706. [19] D. Gupta, R. Agarwal, A.N. Aggarwal, S.K. Jindal, Sarcoidosis and tuberculosis: the same disease with different manifestations or similar manifestations of different disorders, Curr. Opin. Pulm. Med. 18 (2012) 506–516. [20] W.J. Piotrowski, P. Go´rski, J. Duda-Szyman´ska, S. Kwiatkowska, Mycobacterium tuberculosis as a sarcoid factor? A case report of family sarcoidosis, Am. J. Case Rep. 15 (2014) 216–220. [21] I. Litinsky, O. Elkayam, G. Flusser, R. Segal, M. Yaron, D. Caspi, Sarcoidosis: TB or not TB?, Ann Rheum. Dis. 61 (2002) 385– 386. [22] K. Babu, Sarcoidosis in tuberculosis-endemic regions: India, J. Ophthalmic Inflamm. Infect. 3 (2013) 53. [23] Y. Zhou, H.P. Li, Q.H. Li, H. Zheng, R.X. Zhang, G. Chen, et al, Differentiation of sarcoidosis from tuberculosis using realtime PCR assay for the detection and quantification of Mycobacterium tuberculosis, Sarcoidosis Vasc. Diffuse Lung Dis. 25 (2008) 93–99. [24] F. Badar, S.F. Azfar, I. Ahmad, Y. Shagufta, S. Kirmani, Diagnostic difficulties in differentiating sarcoidosis from tuberculosis, Oman Med. J. 26 (3) (2011) 210–211. [25] J.W.T. van Enschot, R.H.H. van Balkom, Sarcoidosis following Mycobacterium tuberculosis infection: Coincidence or consequence, Respir. Med. Case Rep. 9 (2013) 11e14. [26] E. Mortaz, M.R. Masjedi, P. Tabarsi, M. Pourabdollah, I.M. Adcock, Immunopathology of sarcoidosis, Iran J. Allergy Asthma Immunol. 13 (5) (2014) 300–306. [27] E. Guirado, L.S. Schlesinger, Modeling the Mycobacterium tuberculosis granuloma-the critical battlefield in host immunity and disease, Front. Immunol. 4 (2013) 98, http:// dx.doi.org/10.3389/fimmu.2013.00098. [28] J.W.J. Moore, D. Moyo, L. Beattie, P.S. Andrews, J. Timmis, P.M. Kaye, Functional complexity of the Leishmania granuloma and the potential of in silico modeling, Front. Immunol. 4 (2013) 98, http://dx.doi.org/10.3389/fimmu.2013.00035. [29] J.O. Falkinham 3rd, Surrounded by mycobacteria: nontuberculous mycobacteria in the human environment, J. Appl. Microbiol. 107 (2) (2009) 356–367. [30] M.J. van der Werf, C. Ko¨dmo¨n, V. Katalinic´-Jankovic´, T. Kummik, H. Soini, E. Richter, et al, Inventory study of nontuberculous mycobacteria in the European Union, BMC Infect. Dis. 14 (2014) 62. [31] Statement on sarcoidosis. Joint Statement of the American Thoracic Society (ATS), the European Respiratory Society (ERS) and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of Directors and by the ERS Executive Committee, February 1999, Am. J. Respir. Crit. Care Med. 160 (1999) 736–755. [32] C.E. Broos, M. van Nimwegen, H.C. Hoogsteden, R.W. Hendriks, M. Kool, B. van den Blink, Granuloma formation in pulmonary sarcoidosis, Front. Immunol. 4 (2013) 437, http:// dx.doi.org/10.3389/fimmu.2013.00437. [33] T. Kawai, N. Watanabe, M. Yokoyama, Y. Nakazawa, F. Goto, T. Uchiyama, et al, Interstitial lung disease with multiple microgranulomas in chronic granulomatous disease, J. Clin. Immunol. (2014). PMID: 25186973. [34] A.A. Velayati, P. Farnia, S. Khalizadeh, A.M. Farahbod, M. Hasanzadh, M.F. Sheikolslam, Interferon-gamma receptor-1 gene promoter polymorphisms and susceptibility to leprosy in children of a single family, Am. J. Trop. Med. Hyg. 84 (4) (2011) 627–629.
International Journal of Mycobacteriology
[35] R.L. Perez, C.A. Rivera-Marrero, J. Roman, Pulmonary granulomatous inflammation: from sarcoidosis to tuberculosis, Semin. Respir. Infect. 18 (2003) 23–32. [36] R.E. Epps, R.A. El-Azhary, W.C. Hellinger, R.K. Winkelmann, R.E. Van Scoy, Disseminated cutaneous Mycobacterium avium-intracellulare resembling sarcoidosis, J. Am. Acad. Dermatol. 33 (3) (1995) 528–531. [37] F.A. El-Zaatari, S.A. Naser, D.C. Markesich, D.C. Kalter, L. Engstand, D.Y. Graham, Identification of Mycobacterium avium complex in sarcoidosis, J. Clin. Microbiol. 34 (9) (1996) 2240–2245. [38] J.A. Ikonomopoulos, V.G. Gorgoulis, N.G. Kastrinakis, P.V. Zacharatos, S.N. Kokotas, K. Evangelou, et al, Sensitive differential detection of genetically related mycobacterial pathogens in archival material, Am. J. Clin. Pathol. 114 (6) (2000) 940–950. [39] N. Girard, V. Cottin, A. Hot, B. Etienne-Mastroianni, C. Chidiac, J.F. Cordier, Opportunistic infections and sarcoidosis, Rev. Mal. Respir. 21 (6 Pt 1) (2004) 1083–1090. [40] Y. Eishi, M. Suga, I. Ishige, D. Kobayashi, T. Yamada, T. Takemura, et al, Quantitative analysis of mycobacterial and propionibacterial DNA in lymph nodes of Japanese and European patients with sarcoidosis, J. Clin. Microbiol. 40 (1) (2002) 198–204. [41] N. Li, A. Bajoghli, A. Kubba, J. Bhawan, Identification of mycobacterial DNA in cutaneous lesions of sarcoidosis, J. Cutan. Pathol. 26 (6) (1999) 271–278. [42] H. Klemen, A.N. Husain, P.T. Cagle, E.R. Garrity, H.H. Popper, Mycobacterial DNA in recurrent sarcoidosis in the transplanted lung – A PCR-based study on four cases, Virchows Arch. 436 (4) (2000) 365–369.
3 ( 2 0 1 4 ) 2 2 5 –2 2 9
229
[43] G. Mangiapan, A.J. Hance, Mycobacteria and sarcoidosis: an overview and summary of recent molecular biological data. Sarcoidosis, in: G.J. Domingue (Ed.), Cell wall deficient, 12, 1995, pp. 20–37. [44] L.S. Newman, Aetiologies of sarcoidosis, in: M. Dent, U. Costabel (Eds.), Sarcoidosis, Eur Respir Mon, 32, 2005, pp. 23– 48. [45] M. Thomeer, M. Demedts, W. Wuyts, Epidemiology of sarcoidosis, in: M. Dent, U. Costabel (Eds.), Sarcoidosis, Eur Respir Mon, 32, 2005, pp. 13–22. [46] R.M. du Bois, N. Goh, D. McGrath, P. Cullinan, Is there a role for microorganisms in the pathogenesis of sarcoidosis?, J Intern. Med. 253 (2003) 4–17. [47] W.P. Drake, L.S. Newman, Mycobacterial antigens may be important in sarcoidosis pathogenesis, Curr. Opin. Pulm. Med. 12 (2006) 359–363. [48] O.P. Sharma, Murray Kornfeld, American College of Chest Physician, and sarcoidosis: a historical footnote: 2004 Murray Kornfeld Memorial Founders Lecture, Chest 128 (2005) 1830– 1835. [49] P.L. Almenoff, A. Johnson, M. Lesser, L.H. Mattman, Growth of acid fast L forms from the blood of patients with sarcoidosis, Thorax 51 (5) (1996) 530–533. [50] P. Farnia, M.R. Masjedi, et al, Growth and cell-division in extensive (XDR) and extremely drug resistant (XXDR) tuberculosis strains: transmission and atomic force observation, Int. J. Clin. Exp. Med. 3 (2010) 320–326. [51] A.A. Velayati, P. Farnia, M.R. Masjedi, G.K. Zhavnerko, J. Ghanavi, N.N. Poleschuyk, Morphological modification by tubercle bacilli: no time for denial, J. Infect. Dev. Countries 6 (1) (2012) 97–99.