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Tuberculosis or sarcoidosis: Opposite ends of the same disease spectrum?
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Tuberculosis xxx (2016) 1e6
Contents lists available at ScienceDirect
Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube
REVIEW
Q10 Q9
Tuberculosis or sarcoidosis: Opposite ends of the same disease spectrum? Rupesh Agrawal a, Ae Ra Kee b, Leslie Ang a, Yeo Tun Hang a, Vishali Gupta c, Onn Min Kon d, Donald Mitchell e, Manfred Zierhut f, Carlos Pavesio g, * a
Tan Tock Seng Hospital, National Healthcare Group Eye Institute, Singapore Yong Loo Lin School of Medicine, National University of Singapore, Singapore Advanced Eye Centre, Post Graduate Institute of Ophthalmology, Chandigarh, India d St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK e St Mary's NHS Foundation Trust, London, UK f Centre for Ophthalmology, University of Tuebingen, Germany g Moorfields Eye Hospital, London, United Kingdom b c
a r t i c l e i n f o Article history: Received 28 December 2015 Accepted 9 January 2016
1. Introduction Tuberculosis (TB) and sarcoidosis are chronic, multi-systemic, granulomatous diseases that have similar pulmonary and extrapulmonary manifestations. TB, caused by Mycobacterium tuberculosis (MTB) infection, is a global phenomenon affecting approximately one in three people worldwide [1], with a high mortality of 2 million across the world [1]. TB can manifest as primary or secondary (reactivation or reinfection) disease. Formation of granuloma with characteristic caseous necrosis is the pathologic hallmark of TB. Sarcoidosis has a varied incidence around the world, with highest yearly incidence reported in northern Europe (5e40 cases per 100,000) [2]. Its aetiology is unknown and manifests as a multisystem granulomatous inflammation with formation of noncaseating epithelioid granulomas [3]. Often, granulomatous
* Corresponding author. Moorfields Eye Hospital, NHS Foundation Trust, London EC1V 2PD, UK. Tel.: þ44 0207 253 3411 (switchboard), þ44 020 7566 2016 (direct Q1,2 line); fax: þ44 20 7566 2019. Q3 E-mail addresses: [email protected] (R. Agrawal), [email protected]. edu (A.R. Kee), [email protected] (L. Ang), [email protected] (Y. Tun Hang), [email protected] (V. Gupta), [email protected] (O.M. Kon), [email protected] (D. Mitchell), Manfred.Zierhut@med. uni-tuebingen.de (M. Zierhut), carlos.pavesio@moorfields.nhs.uk (C. Pavesio).
inflammation is associated with infectious diseases like tuberculosis, leprosy and schistosomiasis, and it raises the possibility that sarcoidosis could also be induced by an infectious agent until now not identified Thus far, sarcoidosis as a syndrome has been postulated to be due to persistent presentation of poorly-degradable antigens and the subsequent host response to it [4]. Though the exact agent remains unclear, it can be divided mainly into noninfectious and infectious causes. Non-infective antigens have been speculated due to their epidemiologic association [5]. Infective agents associated with sarcoidosis are many, but Propionibacterium and Mycobacterium [6,7] seem to have the strongest associations. It is notable that the Kveim test had the ability to potentially offer a diagnosis in a significant proportion of cases with clinical sarcoidosis but this is no longer a widely available test given concerns about validated supply and also the potential for transferring infection [8]. In addition to the pulmonary presentations of both diseases, the extrapulmonary manifestations of TB and sarcoidosis, which includes the ocular presentations, are often much harder to distinguish from one another. In addition, the two disease entities share radiological and histological similarities. Moreover, the possibility of mycobacteria being an etiological factor for sarcoidosis, and the limitations in the use of molecular and serological tests to differentiate sarcoidosis from TB, makes the distinction between them, a clinical challenge [9]. The aim of this report is to critically evaluate the relationship between TB and sarcoidosis and expand further on the current debate as to whether these two clinical entities are truly unique, or whether they are simply two ends of the same disease spectrum [10]. While it is difficult to say with certainty that they are part of the same disease process, there are many features which support the hypothesis that sarcoidosis is a syndrome with MTB as a common aetiology.
http://dx.doi.org/10.1016/j.tube.2016.01.003 1472-9792/© 2016 Published by Elsevier Ltd.
Please cite this article in press as: Agrawal R, et al., Tuberculosis or sarcoidosis: Opposite ends of the same disease spectrum?, Tuberculosis (2016), http://dx.doi.org/10.1016/j.tube.2016.01.003
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2. Systemic manifestations The majority of patients with TB or sarcoidosis present with non-specific constitutional symptoms e malaise, generalised fatigue, loss of weight and non-specific fever. Classic pulmonary symptoms like exertional dyspnoea, cough and pleuritic chest pain seen in pulmonary TB are similarly seen in patients with sarcoidosis. Patients with Lofgren's syndrome, a type of acute sarcoidosis, may present with fever, bilateral hilar lymphadenopathy and polyarthralgia, which can also be seen as symptoms of TB. Clinically, the features are often confused with each other and many cases of TB are misdiagnosed initially as sarcoidosis and vice versa. Moreover, there has been a number of case reports of concomitant TB and sarcoidosis in the same patients [11e14]. Intraocular TB is sometimes referred to as a “great imitator” of many uveitic conditions including sarcoidosis. Any of the seven classical signs, as determined by Papadia et al. during the first International Workshop on Ocular Sarcoidosis (IWOS) [15], can be described in patients with intraocular sarcoidosis. These include mutton-fat keratic precipitates, iris nodules, trabecular meshwork nodules, tent-shaped peripheral anterior synechiae, string of pearls vitreous opacities, chorioretinal peripheral lesions, periphlebitis, macroaneurism, choroidal nodule, optic disc nodule or granuloma. In a recent work, we evaluated the sensitivity and specificity of seven clinical signs of ocular sarcoidosis (in press) [16] and its correlation with the suggestions of the IWOS. While there is a strong correlation of those clinical signs with IWOS criteria, there are similar overlapping clinical signs suggestive of ocular tuberculosis and the final diagnosis usually pivots on ancillary laboratory investigations and biopsy. It also should be noted that though both diseases can present with a wide variety of clinical signs, certain signs are more specific for one of the disease entities. For instance, occlusive vasculitis with perivascular choroiditis patches is more suggestive of ocular TB, as compared to nodular, segmental vasculitis which is in favour of sarcoidosis. Similarly, serpiginouslike choroiditis and single choroidal granulomas are more likely due to TB. 3. Link between TB and sarcoidosis An epidemiological association between TB and sarcoidosis has been found in many studies, where previous contact history with TB [17] and populations with higher prevalence of TB [18] were associated with sarcoidosis. Similarly, there is also a molecular and immunological link between TB and sarcoidosis. 3.1. Epidemiology The yearly incidence of uveitis ranges from 17 to 52 per 100,000 across the world, with herpes, toxoplasmosis, Behcet's disease, HLA-B27-isolated anterior uveitis, ankylosing spondylitis, TB, birdshot chorioretinopathy and sarcoidosis being the most common etiologies [19]. In a Western urban population, TB and sarcoidosis accounted for 5% and 3% of uveitis respectively [19]. In this study, we have made further comparison between the incidence (per 100,000) of sarcoidosis and tuberculosis. Though data on incidence of tuberculosis is abundant, demographic studies on sarcoidosis are rare. The incidence of sarcoidosis is the highest in India, ranging from 61 to 150 out of 100,000 in Delhi and Kolkata respectively. Similarly, there was a high incidence rate of tuberculosis, with 171 new tuberculosis cases out of 100,000, in India. Sarcoidosis is prevalent amongst Scandinavian, Northern Europeans and African Americans, while being rare in countries like Japan and Singapore. Moreover, studies conducted in United States, United Kingdom and South Africa showed that sarcoidosis is more
common amongst those of African American descent. The corresponding incidences of tuberculosis in these countries are also stated in this paper (Figure 1A, B, and Table 1) but there was no obvious correlation between the incidences of the two diseases. 3.2. Molecular Multi-targeted polymerase chain reaction (PCR), specific for IS6110, MPB64 and protein b found in MTB, has sensitivity of 77$77% and specificity of 100% [20]. Likewise, molecular profiling of sarcoidosis, such as overexpression of IL-17RC, can also be evaluated using PCR [21]. Gupta et al. have done extensive research on the molecular and cellular aspect of TB and sarcoidosis. Their metaanalysis showed a 30% overall positivity of mycobacterial nucleic acids in sarcoid samples [22] and mycobacterial DNA in 48% of samples from newly diagnosed patients with sarcoidosis [23]. This may suggest the possibility of MTB being a common pathophysiologic mechanism for both TB and sarcoidosis, though this is disputed by several studies, such as the one conducted by Svendsen et al. [24]. Furthermore, given the difference in MTB genomes found in TB and sarcoidosis patients, Zhou et al. [25] suggested the use of PCR as an investigative modality to differentiate the two entities where 1$14 103 copies/ml of MTB genomes can be used as a cutoff value. 3.3. Immunological Dubaniewicz and his team have done studies into both humoural and cell-mediated immune responses of sarcoid patients to MTB antigens. MTB-heat shock protein (mtb-hsp) stimulated Tcell subsets and Th1/Th2 cytokine patterns in the peripheral blood mononuclear cell cultures from 22 sarcoidosis patients, 20 TB patients and 20 healthy controls [26]. Their results showed that mtbhsp stimulation lead to increased levels of pro-inflammatory cytokines, TNF-alpha, and IL-6 in sera from sarcoidosis and TB patients in comparison with healthy controls. Moreover, sarcoidosis patients demonstrated the lowest levels of IL-4 and the highest levels of IL-10. The close association in immunological response of sarcoidosis and TB patients indicate the possibility of the two diseases arising from similar aetiology. They also evaluated the presence of several anti-mtb-hsp antibodies by ELISA in patients with sarcoidosis, TB and normal individuals, and found significantly higher levels of anti-mtb-hsp70 in sarcoid and TB individuals compared to controls. Thus, indicating that this protein in particular may play a potential role in the pathogenesis of sarcoidosis [27]. Gupta et al. also studied the antibodies against RD1 (ESAT-6 and CFP-10) antigens in the serum of patients with sarcoidosis and showed a high prevalence of antibodies against the region of difference 1 (RD1) antigens with an overall reactivity of 44$4%, and with none of the Tuberculin PPD positive cases positive for the RD1 antibodies by the PPD negative cut-off. Several genes have been identified in the RD1 location of the MTB genome, coding for several specific proteins, such as ESAT-6 and CFP-10. Several studies identified Th1 immune responses to ESAT-6 in 20/56 versus 2/50 purified protein derivative (PPD) negative controls in patients with sarcoidosis [28,29]. These studies led to the conclusion that the sarcoidosis-induced immune response may be directed against mycobacterial virulence factors. The proteins of the Antigen 85 complex, composed of Ag 85A, 85B and 85C are amongst the most common proteins in M. tuberculosis culture fluids and are strongly immunogenic. Another study found a 60% reactivity from peripheral blood mononuclear cells to Ag85A in sarcoidosis patients, as opposed to just 2 of 22 PPD negative controls [30].
Please cite this article in press as: Agrawal R, et al., Tuberculosis or sarcoidosis: Opposite ends of the same disease spectrum?, Tuberculosis (2016), http://dx.doi.org/10.1016/j.tube.2016.01.003
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Figure 1. Epidemiologic distribution of sarcoidosis and tuberculosis on world map (1A) and country specific comparative distribution of tuberculosis and sarcoidosis (1B).
Please cite this article in press as: Agrawal R, et al., Tuberculosis or sarcoidosis: Opposite ends of the same disease spectrum?, Tuberculosis (2016), http://dx.doi.org/10.1016/j.tube.2016.01.003
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Table 1 Epidemiologic distribution of sarcoidosis and tuberculosis across the world (Incidence; per 100,000).
Q8
India [18]
United States [2,19]
Sweden [20]
South Africa [21]
United Kingdom [22,23]
Brazil [24]
Australia [25]
Japan [26]
Sarcoidosis
61e150
19
20 (1.5 amongst Whites; 19.8 amongst Blacks) 13
4.4e6.3
1.01
171
3.7 amongst Whites; 23.2 amongst Blacks 880
<10
TB
6.1 (10.9 amongst Whites; 35.5 amongst Blacks) 3.3
7.2
Another specific mycobacterial protein, mycobacterial catalseperoxidase (mKatG) reactive, had been previously identified in 55% of sarcoidosis tissues [31], and IgG antibodies to recombinant mKatG was detected in 48% of sarcoidosis individuals compared to 0% of PPD negative controls. More recently, studies have shown a preferential immune response of mKatG-reactive CD4þ Th1 cells in the lungs of patients with sarcoidosis, by analysing bronchoalveolar lavage fluids. Furthermore, these mKatG-specific T cell responses appear to have a correlation with disease activity, with circulating mKatG-reactive T cells found in patients with chronic active sarcoidosis but not in those with inactive disease [32], similar to that seen in tuberculosis infections [33]. The presence of T-cell responses against the various studied mycobacterial-specific proteins indicates that these patients with sarcoidosis were likely exposed at some time to Mycobacteria. Many of these proteins, like ESAT-6 and Ag85 complex are typically released during times of growth and mycobacterial proliferation, rather than during dormancy [34]. This suggests that MTB is a possible trigger to the development of sarcoidosis. Alternatively, patients diagnosed with sarcoidosis could in fact have tuberculosis, but in the form of a more benign, less infectious and aggressive phenotype of the same disease process. Sarcoidosis patients possibly have more stronger immune response controlling the infection triggered by the MTB. As such, other investigations, be it molecular, radiological or other aspects not discussed here, should be adopted to determine whether there is an overlap between sarcoidosis and tuberculosis. 4. Diagnostic challenges As TB and sarcoidosis are closely linked in terms of pathogenesis and clinical manifestation, and may even coexist in the same patient, the diagnosis linking the systemic manifestation to the specific condition may be very difficult. Apart from closely observing the clinical presentation of the disease, further laboratory and radiological investigations need to be undertaken in an attempt to reach the correct diagnosis. A positive culture from the body fluids or tissues is the gold standard for the diagnosis of TB, but may not be possible in particular target organs because of the difficulties of access non-invasively or due to the risks of accessing such compartments - particularly in the setting of extrapulmonary TB. In this setting the diagnosis of TB can be supported by a positive tuberculin skin test (TST), interferon gamma release assays (IGRA) (T-SPOT.TB or QuantiFERON gold in tube), radiology, (mainly based on CT scan images) or detection of mycobacterial DNA via PCR of body fluids or tissue [35]. On the other hand, a diagnosis of sarcoidosis can be supported by a negative TST or IGRA with elevated serum angiotensin-converting enzyme (ACE), and bilateral hilar lymphadenopathy on chest X-ray/CT [36]. The not infrequent lack of definitive microbiology clearly shows the diagnostic challenge and the consequent difficulties in managing these patients. Newer diagnostic methods are still being explored, such as high CD4/CD8 ratios of vitreous T-lymphocytes in sarcoidosis [37], to make an accurate diagnosis of a clinical entity. In the diagnosis of TB, Lenzini et al. proposed that TB is a spectrum of immune reactions with two polar forms, reactive (RR)
46
6.2
18
Singapore [27] 0.56 47
and unreactive (UU) tuberculosis, where RR has active cellmediated immunological response with little or no antibody production and UU has poor cell-mediated immunological response with high antibody production. Intermediate forms also exist, where they display characteristics of adjacent polar form [38]. Likewise, leprosy, another infectious disease caused by Mycobacterium leprae, is also considered to be a spectrum of immune reactions, classified into two major forms, tuberculoid and lepromatous leprosy, which are associated with different human leukocyte antigen alleles (HLA) respectively [39e41]. This has been further sub-grouped into a five-group Ridley-Joplin classification system: Polar tuberculoid, borderline tuberculoid, borderline, borderline lepromatous and polar lepromatous [42]. Such a classification arose after studies were undertaken to evaluate the host's immunological responses in both disease entities, lepromatous and tuberculoid, upon which, disease spectrum with strong T cell mediated response to M. leprae was classified as “tuberculoid leprosy” and that with minimal cellular response as “lepromatous leprosy”. Subsequently, a therapeutic regime, differing according to mycobacterial load, was developed [43]. In view of the above, we postulate that TB and sarcoidosis may represent a spectrum of the same disease. While sarcoidosis can be caused by non-infectious agents, it can also be a result of MTB infection in a host with strong cellular immunological response. The difference in the immune response of the host may lead to varying degree of presentations. Such a hypothesis has already been suggested previously by Saltini et al. [10] and Shah [44]. We would like to propose the development of a subdivision classification system for TB and sarcoidosis (Figure 2): Sarcoidosis (S); Sarcoid-Tuberculous (ST); Tuberculous Sarcoid (TS) and Tuberculosis (TB). S and TB will comprise of pure forms of sarcoidosis and tuberculosis respectively, whereas ST and TS will represent mixed features of both diseases, with ST being predominantly sarcoid with tuberculous features and TS being predominantly tuberculous with sarcoid features. In fact, the term “tuberculous sarcoidosis” was first coined by Scadding [45] in 1960 so as to distinguish patients who had features of both TB and sarcoidosis as a separate entity. This viewpoint was subsequently taken up by Shah who further defined “tuberculous sarcoidosis” as a “gray zone” entity which includes (1) prior TB patients who developed sarcoidosis (2) patients with concomitant TB and sarcoidosis and (3) prior sarcoidosis patients who developed tuberculosis, and eventually formulated a diagnostic criterion [46] for this particular group of patients. However, in our classification system, we aim to take into account molecular, immunological and histopathological aspects of each disease entityto supplement the clinical phenotypes as previously discussed by Shah. Further studies not relying on these traditional parameters are needed to be carried out to explore if there is a clear distinction amongst our four proposed subdivisions. Based on current available tests, we suggest a possible clinicopathological definition with categories to delineate between S, ST, TS and TB (Table 2). Such a classification system may be pertinent and useful in the management of patients. In pure S and TB, current management guidelines, i.e. immunosuppressants for sarcoidosis and anti-TB medications for TB, should continue to be undertaken. It has been
Please cite this article in press as: Agrawal R, et al., Tuberculosis or sarcoidosis: Opposite ends of the same disease spectrum?, Tuberculosis (2016), http://dx.doi.org/10.1016/j.tube.2016.01.003
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Figure 2. Diagrammatic representation of proposed classification for tuberculosis and sarcoidosis.
Table 2 Clinicopathologic definition for proposed classification for tuberculosis and sarcoidosis.
Tuberculosis Sarcoid-like tuberculosis Tuberculous-sarcoidosis Sarcoidosis
TST
IGRA
SACE
Histology
Radiology
Micro
þ þ e e
þ þ e e
e e þ þ
Caseating granulomas Non caseating granulomas Focal necrosis in granulomas Non caseating granulomas
Cavitation with tree in bud change Primarily lymphadenopathy Primarily lymphadenopathy Bilateral symmetrical mediastinal nodes with bronchovascular beading, subpleural nodules and fissural change
þ þ/ e e
postulated that the management of sarcoidosis with steroids and immunosuppressants may reactivate tuberculosis in the absence of concurrent anti-TB medications [47]. In a similar vein, those with features of both TB and sarcoidosis, i.e. TS and ST, should be treated with a combination therapy, with both immunosuppressants and anti-TB medications so as to avoid reactivation or under treatment of one or another. In refractory TB or sarcoidosis, one should consider the “gray zone” entities like TS and ST to allow treatment of the underlying alternative disease adequately. 5. Conclusion The current sparse evidence suggests that sarcoidosis and TB may potentially be two opposing manifestations of the same disease with overlapping spectrum. Clinically, they share many similar features and immunologically, they incite similar responses from the body. However it is important to make an accurate diagnosis, distinguishing between the four proposed subdivisions, as this will affect the management of the patient. In current practice although we suggest that this is the same disease with varying presentations, it is important to note that anti-TB treatment in sarcoidosis has no effect and similarly the definitive treatment of tuberculosis is that of quadruple therapy antibiotics and not steroids for most forms of TB. More research and clinical trials need to be done to refute or confirm this potential link. Various aspects may be explored for future research. Mycobacterial DNA, antigens and immune responses in sarcoid patients can be further evaluated. Just as leprosy having HLA correlations with TB, HLA of sarcoidosis can be studied to determine if different HLA is associated with a different spectrum of the disease. Moreover, future clinical trials can include performing current available diagnostic investigations for TB and sarcoidosis on sarcoid and TB
patients respectively, so as to determine if these modalities can truly distinguish between the two entities and whether there are any associations between the two. Moreover, response to antituberculous therapy amongst patients in “gray zone” or with sarcoidosis can also be examined. In the meantime, differentiating between the two conditions will continue to be challenging especially in cases where extrapulmonary manifestations like ocular involvement occur with few or no systemic manifestations. Thus, on top of looking at the clinical picture for characteristic symptoms and signs as well as chest x-ray for systemic manifestations, further investigations such as TST and IGRA can be considered for the diagnosis of TB uveitis while serum ACE or lysozyme and liver enzyme tests can be used to aid in the diagnosis of sarcoid uveitis. However, if TB and sarcoidosis are proven to be connected as it has been proposed and a patient develops a disease that falls in between the spectrum, then the subsequent management would not differ. Funding:
None.
Competing interests: Ethical approval:
None declared. Not required.
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Please cite this article in press as: Agrawal R, et al., Tuberculosis or sarcoidosis: Opposite ends of the same disease spectrum?, Tuberculosis (2016), http://dx.doi.org/10.1016/j.tube.2016.01.003
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[26] Dubaniewicz A, Trzonkowski P, Dubaniewicz-Wybieralska M, Dubaniewicz A, Singh M, Mysliwski A. Mycobacterial heat shock protein-induced blood T lymphocytes subsets and cytokine pattern: comparison of sarcoidosis with tuberculosis and healthy controls. Respirology 2007;12:346e54. http:// dx.doi.org/10.1111/j.1440-1843.2007.01076.x. [27] Dubaniewicz A, K€ ampfer S, Singh M. Serum anti-mycobacterial heat shock proteins antibodies in sarcoidosis and tuberculosis. Tuberculosis 2006;86: 60e7. http://dx.doi.org/10.1016/j.tube.2005.09.004. [28] Drake WP, Dhason MS, Nadaf M, Shepherd BE, Vadivelu S, Hajizadeh R, et al. Cellular recognition of Mycobacterium tuberculosis ESAT-6 and KatG peptides in systemic sarcoidosis. Infect Immun 2007;75:527e30. http://dx.doi.org/ 10.1128/IAI.00732-06. [29] Carlisle J, Evans W, Hajizadeh R, Nadaf M, Shepherd B, Ott RD, et al. Multiple Mycobacterium antigens induce interferon-?? production from sarcoidosis peripheral blood mononuclear cells. Clin Exp Immunol 2007;150:460e8. http://dx.doi.org/10.1111/j.1365-2249.2007.03510.x. [30] Hajizadeh R, Sato H, Carlisle J, Nadaf MT, Evans W, Shepherd BE, et al. Mycobacterium tuberculosis antigen 85A induces Th-1 immune responses in systemic sarcoidosis. J Clin Immunol 2007;27:445e54. http://dx.doi.org/ 10.1007/s10875-007-9080-4. [31] Song Z, Marzilli L, Greenlee BM, Chen ES, Silver RF, Askin FB, et al. Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis. J Exp Med 2005;201:755e67. http://dx.doi.org/10.1084/jem.20040429. €m J, Song Z, Willett MH, Wike n M, Yung RC, et al. T cell [32] Chen ES, Wahlstro responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis. J Immunol 2008;181:8784e96. http://dx.doi.org/ 10.4049/jimmunol.181.12.8784. [33] Pathan A, Wilkinson K, Klenerman P, McShane H, Davidson R, Pasvol G, et al. Direct ex vivo analysis of antigen-specific IFN-gamma-secreting CD4 T cells in Mycobacterium tuberculosis-infected individuals: associations with clinical disease state and effect of treatment. J Immunol 2001;167:5217e25. [34] Anderson P. The T cell response to secreted antigens of Mycobacterium tuberculosis. Immunobiology 1994;191:537e47. [35] Yeh S, Sen HN, Colyer M, Zapor M, Wroblewski K. Update on ocular tuberculosis. Curr Opin Ophthalmol 2012;23:551e6. http://dx.doi.org/10.1097/ ICU.0b013e328358ba01. [36] Wakefield D, Zierhut M. Controversy: ocular sarcoidosis. Ocul Immunol Inflamm 2010;18:5e9. http://dx.doi.org/10.3109/09273941003597276. [37] Kojima K, Maruyama K, Inaba T, Nagata K, Yasuhara T, Yoneda K, et al. The CD4/CD8 ratio in vitreous fluid is of high diagnostic value in sarcoidosis. Ophthalmology 2012;119:2386e92. http://dx.doi.org/10.1016/j.ophtha. 2012.05.033. [38] Lenzini L, Rottoli P, Rottoli L. The spectrum of human tuberculosis. Clin Exp Immunol 1977;27:230e7. [39] Soebono H, Giphart MJ, Schreuder GM, Klatser PR, de Vries RR. Associations between HLA-DRB1 alleles and leprosy in an Indonesian population. Int J Lepr Other Mycobact Dis 1997;65:190e6. [40] Visentainer JEL, Tsuneto LT, Serra MF, Peixoto PRF, Petzl-Erler ML. Association of leprosy with HLA-DR2 in a Southern Brazilian population. Braz J Med Biol Res 1997;30:51e9. http://dx.doi.org/10.1590/S0100-879X199 7000100008. [41] De Vries RRP. An immunogenetic view of delayed type hypersensitivity. Tubercle 1991;72:161e7. http://dx.doi.org/10.1016/0041-3879(91)90001-9. [42] Ridley D, Jopling W. Classification of leprosy according to immunity. A fivegroup system. Int J Lepr Other Mycobact Dis 1966;34:255e73. [43] WHO. WHO multidrug therapy regimens, leprosy elimination. World Heal Organ; 2015 (accessed April 5, 2015), http://www.who.int/lep/mdt/en/. [44] Shah JR. Tuberculous sarcoidosis. Lung India 2007;26:83e6. [45] Scadding J. Tuberculosis in the etiology of sarcoidosis. Brompt Hosp Case Rep 1961;30:121e43. [46] Shah JR, Hede J, Mathur RS. Diagnostic criteria of tuberculous sarcoidosis. Lung India 2009;26:86e8. http://dx.doi.org/10.4103/0970-2113.53232. [47] Petousi N, Mathew J, Thomas EC. A patient presenting with generalised lympadenopathy - sarcoidosis, lymphoma or tuberculosis? Case Rep 2012;2012. http://dx.doi.org/10.1136/bcr.11.2011.5150. bcr1120115150.
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Contents lists available at ScienceDirect
Tuberculosis journal homepage: http://intl.elsevierhealth.com/journals/tube
REVIEW
Q10 Q9
Tuberculosis or sarcoidosis: Opposite ends of the same disease spectrum? Rupesh Agrawal a, Ae Ra Kee b, Leslie Ang a, Yeo Tun Hang a, Vishali Gupta c, Onn Min Kon d, Donald Mitchell e, Manfred Zierhut f, Carlos Pavesio g, * a
Tan Tock Seng Hospital, National Healthcare Group Eye Institute, Singapore Yong Loo Lin School of Medicine, National University of Singapore, Singapore Advanced Eye Centre, Post Graduate Institute of Ophthalmology, Chandigarh, India d St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK e St Mary's NHS Foundation Trust, London, UK f Centre for Ophthalmology, University of Tuebingen, Germany g Moorfields Eye Hospital, London, United Kingdom b c
a r t i c l e i n f o Article history: Received 28 December 2015 Accepted 9 January 2016
1. Introduction Tuberculosis (TB) and sarcoidosis are chronic, multi-systemic, granulomatous diseases that have similar pulmonary and extrapulmonary manifestations. TB, caused by Mycobacterium tuberculosis (MTB) infection, is a global phenomenon affecting approximately one in three people worldwide [1], with a high mortality of 2 million across the world [1]. TB can manifest as primary or secondary (reactivation or reinfection) disease. Formation of granuloma with characteristic caseous necrosis is the pathologic hallmark of TB. Sarcoidosis has a varied incidence around the world, with highest yearly incidence reported in northern Europe (5e40 cases per 100,000) [2]. Its aetiology is unknown and manifests as a multisystem granulomatous inflammation with formation of noncaseating epithelioid granulomas [3]. Often, granulomatous
* Corresponding author. Moorfields Eye Hospital, NHS Foundation Trust, London EC1V 2PD, UK. Tel.: þ44 0207 253 3411 (switchboard), þ44 020 7566 2016 (direct Q1,2 line); fax: þ44 20 7566 2019. Q3 E-mail addresses: [email protected] (R. Agrawal), [email protected]. edu (A.R. Kee), [email protected] (L. Ang), [email protected] (Y. Tun Hang), [email protected] (V. Gupta), [email protected] (O.M. Kon), [email protected] (D. Mitchell), Manfred.Zierhut@med. uni-tuebingen.de (M. Zierhut), carlos.pavesio@moorfields.nhs.uk (C. Pavesio).
inflammation is associated with infectious diseases like tuberculosis, leprosy and schistosomiasis, and it raises the possibility that sarcoidosis could also be induced by an infectious agent until now not identified Thus far, sarcoidosis as a syndrome has been postulated to be due to persistent presentation of poorly-degradable antigens and the subsequent host response to it [4]. Though the exact agent remains unclear, it can be divided mainly into noninfectious and infectious causes. Non-infective antigens have been speculated due to their epidemiologic association [5]. Infective agents associated with sarcoidosis are many, but Propionibacterium and Mycobacterium [6,7] seem to have the strongest associations. It is notable that the Kveim test had the ability to potentially offer a diagnosis in a significant proportion of cases with clinical sarcoidosis but this is no longer a widely available test given concerns about validated supply and also the potential for transferring infection [8]. In addition to the pulmonary presentations of both diseases, the extrapulmonary manifestations of TB and sarcoidosis, which includes the ocular presentations, are often much harder to distinguish from one another. In addition, the two disease entities share radiological and histological similarities. Moreover, the possibility of mycobacteria being an etiological factor for sarcoidosis, and the limitations in the use of molecular and serological tests to differentiate sarcoidosis from TB, makes the distinction between them, a clinical challenge [9]. The aim of this report is to critically evaluate the relationship between TB and sarcoidosis and expand further on the current debate as to whether these two clinical entities are truly unique, or whether they are simply two ends of the same disease spectrum [10]. While it is difficult to say with certainty that they are part of the same disease process, there are many features which support the hypothesis that sarcoidosis is a syndrome with MTB as a common aetiology.
http://dx.doi.org/10.1016/j.tube.2016.01.003 1472-9792/© 2016 Published by Elsevier Ltd.
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2. Systemic manifestations The majority of patients with TB or sarcoidosis present with non-specific constitutional symptoms e malaise, generalised fatigue, loss of weight and non-specific fever. Classic pulmonary symptoms like exertional dyspnoea, cough and pleuritic chest pain seen in pulmonary TB are similarly seen in patients with sarcoidosis. Patients with Lofgren's syndrome, a type of acute sarcoidosis, may present with fever, bilateral hilar lymphadenopathy and polyarthralgia, which can also be seen as symptoms of TB. Clinically, the features are often confused with each other and many cases of TB are misdiagnosed initially as sarcoidosis and vice versa. Moreover, there has been a number of case reports of concomitant TB and sarcoidosis in the same patients [11e14]. Intraocular TB is sometimes referred to as a “great imitator” of many uveitic conditions including sarcoidosis. Any of the seven classical signs, as determined by Papadia et al. during the first International Workshop on Ocular Sarcoidosis (IWOS) [15], can be described in patients with intraocular sarcoidosis. These include mutton-fat keratic precipitates, iris nodules, trabecular meshwork nodules, tent-shaped peripheral anterior synechiae, string of pearls vitreous opacities, chorioretinal peripheral lesions, periphlebitis, macroaneurism, choroidal nodule, optic disc nodule or granuloma. In a recent work, we evaluated the sensitivity and specificity of seven clinical signs of ocular sarcoidosis (in press) [16] and its correlation with the suggestions of the IWOS. While there is a strong correlation of those clinical signs with IWOS criteria, there are similar overlapping clinical signs suggestive of ocular tuberculosis and the final diagnosis usually pivots on ancillary laboratory investigations and biopsy. It also should be noted that though both diseases can present with a wide variety of clinical signs, certain signs are more specific for one of the disease entities. For instance, occlusive vasculitis with perivascular choroiditis patches is more suggestive of ocular TB, as compared to nodular, segmental vasculitis which is in favour of sarcoidosis. Similarly, serpiginouslike choroiditis and single choroidal granulomas are more likely due to TB. 3. Link between TB and sarcoidosis An epidemiological association between TB and sarcoidosis has been found in many studies, where previous contact history with TB [17] and populations with higher prevalence of TB [18] were associated with sarcoidosis. Similarly, there is also a molecular and immunological link between TB and sarcoidosis. 3.1. Epidemiology The yearly incidence of uveitis ranges from 17 to 52 per 100,000 across the world, with herpes, toxoplasmosis, Behcet's disease, HLA-B27-isolated anterior uveitis, ankylosing spondylitis, TB, birdshot chorioretinopathy and sarcoidosis being the most common etiologies [19]. In a Western urban population, TB and sarcoidosis accounted for 5% and 3% of uveitis respectively [19]. In this study, we have made further comparison between the incidence (per 100,000) of sarcoidosis and tuberculosis. Though data on incidence of tuberculosis is abundant, demographic studies on sarcoidosis are rare. The incidence of sarcoidosis is the highest in India, ranging from 61 to 150 out of 100,000 in Delhi and Kolkata respectively. Similarly, there was a high incidence rate of tuberculosis, with 171 new tuberculosis cases out of 100,000, in India. Sarcoidosis is prevalent amongst Scandinavian, Northern Europeans and African Americans, while being rare in countries like Japan and Singapore. Moreover, studies conducted in United States, United Kingdom and South Africa showed that sarcoidosis is more
common amongst those of African American descent. The corresponding incidences of tuberculosis in these countries are also stated in this paper (Figure 1A, B, and Table 1) but there was no obvious correlation between the incidences of the two diseases. 3.2. Molecular Multi-targeted polymerase chain reaction (PCR), specific for IS6110, MPB64 and protein b found in MTB, has sensitivity of 77$77% and specificity of 100% [20]. Likewise, molecular profiling of sarcoidosis, such as overexpression of IL-17RC, can also be evaluated using PCR [21]. Gupta et al. have done extensive research on the molecular and cellular aspect of TB and sarcoidosis. Their metaanalysis showed a 30% overall positivity of mycobacterial nucleic acids in sarcoid samples [22] and mycobacterial DNA in 48% of samples from newly diagnosed patients with sarcoidosis [23]. This may suggest the possibility of MTB being a common pathophysiologic mechanism for both TB and sarcoidosis, though this is disputed by several studies, such as the one conducted by Svendsen et al. [24]. Furthermore, given the difference in MTB genomes found in TB and sarcoidosis patients, Zhou et al. [25] suggested the use of PCR as an investigative modality to differentiate the two entities where 1$14 103 copies/ml of MTB genomes can be used as a cutoff value. 3.3. Immunological Dubaniewicz and his team have done studies into both humoural and cell-mediated immune responses of sarcoid patients to MTB antigens. MTB-heat shock protein (mtb-hsp) stimulated Tcell subsets and Th1/Th2 cytokine patterns in the peripheral blood mononuclear cell cultures from 22 sarcoidosis patients, 20 TB patients and 20 healthy controls [26]. Their results showed that mtbhsp stimulation lead to increased levels of pro-inflammatory cytokines, TNF-alpha, and IL-6 in sera from sarcoidosis and TB patients in comparison with healthy controls. Moreover, sarcoidosis patients demonstrated the lowest levels of IL-4 and the highest levels of IL-10. The close association in immunological response of sarcoidosis and TB patients indicate the possibility of the two diseases arising from similar aetiology. They also evaluated the presence of several anti-mtb-hsp antibodies by ELISA in patients with sarcoidosis, TB and normal individuals, and found significantly higher levels of anti-mtb-hsp70 in sarcoid and TB individuals compared to controls. Thus, indicating that this protein in particular may play a potential role in the pathogenesis of sarcoidosis [27]. Gupta et al. also studied the antibodies against RD1 (ESAT-6 and CFP-10) antigens in the serum of patients with sarcoidosis and showed a high prevalence of antibodies against the region of difference 1 (RD1) antigens with an overall reactivity of 44$4%, and with none of the Tuberculin PPD positive cases positive for the RD1 antibodies by the PPD negative cut-off. Several genes have been identified in the RD1 location of the MTB genome, coding for several specific proteins, such as ESAT-6 and CFP-10. Several studies identified Th1 immune responses to ESAT-6 in 20/56 versus 2/50 purified protein derivative (PPD) negative controls in patients with sarcoidosis [28,29]. These studies led to the conclusion that the sarcoidosis-induced immune response may be directed against mycobacterial virulence factors. The proteins of the Antigen 85 complex, composed of Ag 85A, 85B and 85C are amongst the most common proteins in M. tuberculosis culture fluids and are strongly immunogenic. Another study found a 60% reactivity from peripheral blood mononuclear cells to Ag85A in sarcoidosis patients, as opposed to just 2 of 22 PPD negative controls [30].
Please cite this article in press as: Agrawal R, et al., Tuberculosis or sarcoidosis: Opposite ends of the same disease spectrum?, Tuberculosis (2016), http://dx.doi.org/10.1016/j.tube.2016.01.003
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Figure 1. Epidemiologic distribution of sarcoidosis and tuberculosis on world map (1A) and country specific comparative distribution of tuberculosis and sarcoidosis (1B).
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3
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Table 1 Epidemiologic distribution of sarcoidosis and tuberculosis across the world (Incidence; per 100,000).
Q8
India [18]
United States [2,19]
Sweden [20]
South Africa [21]
United Kingdom [22,23]
Brazil [24]
Australia [25]
Japan [26]
Sarcoidosis
61e150
19
20 (1.5 amongst Whites; 19.8 amongst Blacks) 13
4.4e6.3
1.01
171
3.7 amongst Whites; 23.2 amongst Blacks 880
<10
TB
6.1 (10.9 amongst Whites; 35.5 amongst Blacks) 3.3
7.2
Another specific mycobacterial protein, mycobacterial catalseperoxidase (mKatG) reactive, had been previously identified in 55% of sarcoidosis tissues [31], and IgG antibodies to recombinant mKatG was detected in 48% of sarcoidosis individuals compared to 0% of PPD negative controls. More recently, studies have shown a preferential immune response of mKatG-reactive CD4þ Th1 cells in the lungs of patients with sarcoidosis, by analysing bronchoalveolar lavage fluids. Furthermore, these mKatG-specific T cell responses appear to have a correlation with disease activity, with circulating mKatG-reactive T cells found in patients with chronic active sarcoidosis but not in those with inactive disease [32], similar to that seen in tuberculosis infections [33]. The presence of T-cell responses against the various studied mycobacterial-specific proteins indicates that these patients with sarcoidosis were likely exposed at some time to Mycobacteria. Many of these proteins, like ESAT-6 and Ag85 complex are typically released during times of growth and mycobacterial proliferation, rather than during dormancy [34]. This suggests that MTB is a possible trigger to the development of sarcoidosis. Alternatively, patients diagnosed with sarcoidosis could in fact have tuberculosis, but in the form of a more benign, less infectious and aggressive phenotype of the same disease process. Sarcoidosis patients possibly have more stronger immune response controlling the infection triggered by the MTB. As such, other investigations, be it molecular, radiological or other aspects not discussed here, should be adopted to determine whether there is an overlap between sarcoidosis and tuberculosis. 4. Diagnostic challenges As TB and sarcoidosis are closely linked in terms of pathogenesis and clinical manifestation, and may even coexist in the same patient, the diagnosis linking the systemic manifestation to the specific condition may be very difficult. Apart from closely observing the clinical presentation of the disease, further laboratory and radiological investigations need to be undertaken in an attempt to reach the correct diagnosis. A positive culture from the body fluids or tissues is the gold standard for the diagnosis of TB, but may not be possible in particular target organs because of the difficulties of access non-invasively or due to the risks of accessing such compartments - particularly in the setting of extrapulmonary TB. In this setting the diagnosis of TB can be supported by a positive tuberculin skin test (TST), interferon gamma release assays (IGRA) (T-SPOT.TB or QuantiFERON gold in tube), radiology, (mainly based on CT scan images) or detection of mycobacterial DNA via PCR of body fluids or tissue [35]. On the other hand, a diagnosis of sarcoidosis can be supported by a negative TST or IGRA with elevated serum angiotensin-converting enzyme (ACE), and bilateral hilar lymphadenopathy on chest X-ray/CT [36]. The not infrequent lack of definitive microbiology clearly shows the diagnostic challenge and the consequent difficulties in managing these patients. Newer diagnostic methods are still being explored, such as high CD4/CD8 ratios of vitreous T-lymphocytes in sarcoidosis [37], to make an accurate diagnosis of a clinical entity. In the diagnosis of TB, Lenzini et al. proposed that TB is a spectrum of immune reactions with two polar forms, reactive (RR)
46
6.2
18
Singapore [27] 0.56 47
and unreactive (UU) tuberculosis, where RR has active cellmediated immunological response with little or no antibody production and UU has poor cell-mediated immunological response with high antibody production. Intermediate forms also exist, where they display characteristics of adjacent polar form [38]. Likewise, leprosy, another infectious disease caused by Mycobacterium leprae, is also considered to be a spectrum of immune reactions, classified into two major forms, tuberculoid and lepromatous leprosy, which are associated with different human leukocyte antigen alleles (HLA) respectively [39e41]. This has been further sub-grouped into a five-group Ridley-Joplin classification system: Polar tuberculoid, borderline tuberculoid, borderline, borderline lepromatous and polar lepromatous [42]. Such a classification arose after studies were undertaken to evaluate the host's immunological responses in both disease entities, lepromatous and tuberculoid, upon which, disease spectrum with strong T cell mediated response to M. leprae was classified as “tuberculoid leprosy” and that with minimal cellular response as “lepromatous leprosy”. Subsequently, a therapeutic regime, differing according to mycobacterial load, was developed [43]. In view of the above, we postulate that TB and sarcoidosis may represent a spectrum of the same disease. While sarcoidosis can be caused by non-infectious agents, it can also be a result of MTB infection in a host with strong cellular immunological response. The difference in the immune response of the host may lead to varying degree of presentations. Such a hypothesis has already been suggested previously by Saltini et al. [10] and Shah [44]. We would like to propose the development of a subdivision classification system for TB and sarcoidosis (Figure 2): Sarcoidosis (S); Sarcoid-Tuberculous (ST); Tuberculous Sarcoid (TS) and Tuberculosis (TB). S and TB will comprise of pure forms of sarcoidosis and tuberculosis respectively, whereas ST and TS will represent mixed features of both diseases, with ST being predominantly sarcoid with tuberculous features and TS being predominantly tuberculous with sarcoid features. In fact, the term “tuberculous sarcoidosis” was first coined by Scadding [45] in 1960 so as to distinguish patients who had features of both TB and sarcoidosis as a separate entity. This viewpoint was subsequently taken up by Shah who further defined “tuberculous sarcoidosis” as a “gray zone” entity which includes (1) prior TB patients who developed sarcoidosis (2) patients with concomitant TB and sarcoidosis and (3) prior sarcoidosis patients who developed tuberculosis, and eventually formulated a diagnostic criterion [46] for this particular group of patients. However, in our classification system, we aim to take into account molecular, immunological and histopathological aspects of each disease entityto supplement the clinical phenotypes as previously discussed by Shah. Further studies not relying on these traditional parameters are needed to be carried out to explore if there is a clear distinction amongst our four proposed subdivisions. Based on current available tests, we suggest a possible clinicopathological definition with categories to delineate between S, ST, TS and TB (Table 2). Such a classification system may be pertinent and useful in the management of patients. In pure S and TB, current management guidelines, i.e. immunosuppressants for sarcoidosis and anti-TB medications for TB, should continue to be undertaken. It has been
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Figure 2. Diagrammatic representation of proposed classification for tuberculosis and sarcoidosis.
Table 2 Clinicopathologic definition for proposed classification for tuberculosis and sarcoidosis.
Tuberculosis Sarcoid-like tuberculosis Tuberculous-sarcoidosis Sarcoidosis
TST
IGRA
SACE
Histology
Radiology
Micro
þ þ e e
þ þ e e
e e þ þ
Caseating granulomas Non caseating granulomas Focal necrosis in granulomas Non caseating granulomas
Cavitation with tree in bud change Primarily lymphadenopathy Primarily lymphadenopathy Bilateral symmetrical mediastinal nodes with bronchovascular beading, subpleural nodules and fissural change
þ þ/ e e
postulated that the management of sarcoidosis with steroids and immunosuppressants may reactivate tuberculosis in the absence of concurrent anti-TB medications [47]. In a similar vein, those with features of both TB and sarcoidosis, i.e. TS and ST, should be treated with a combination therapy, with both immunosuppressants and anti-TB medications so as to avoid reactivation or under treatment of one or another. In refractory TB or sarcoidosis, one should consider the “gray zone” entities like TS and ST to allow treatment of the underlying alternative disease adequately. 5. Conclusion The current sparse evidence suggests that sarcoidosis and TB may potentially be two opposing manifestations of the same disease with overlapping spectrum. Clinically, they share many similar features and immunologically, they incite similar responses from the body. However it is important to make an accurate diagnosis, distinguishing between the four proposed subdivisions, as this will affect the management of the patient. In current practice although we suggest that this is the same disease with varying presentations, it is important to note that anti-TB treatment in sarcoidosis has no effect and similarly the definitive treatment of tuberculosis is that of quadruple therapy antibiotics and not steroids for most forms of TB. More research and clinical trials need to be done to refute or confirm this potential link. Various aspects may be explored for future research. Mycobacterial DNA, antigens and immune responses in sarcoid patients can be further evaluated. Just as leprosy having HLA correlations with TB, HLA of sarcoidosis can be studied to determine if different HLA is associated with a different spectrum of the disease. Moreover, future clinical trials can include performing current available diagnostic investigations for TB and sarcoidosis on sarcoid and TB
patients respectively, so as to determine if these modalities can truly distinguish between the two entities and whether there are any associations between the two. Moreover, response to antituberculous therapy amongst patients in “gray zone” or with sarcoidosis can also be examined. In the meantime, differentiating between the two conditions will continue to be challenging especially in cases where extrapulmonary manifestations like ocular involvement occur with few or no systemic manifestations. Thus, on top of looking at the clinical picture for characteristic symptoms and signs as well as chest x-ray for systemic manifestations, further investigations such as TST and IGRA can be considered for the diagnosis of TB uveitis while serum ACE or lysozyme and liver enzyme tests can be used to aid in the diagnosis of sarcoid uveitis. However, if TB and sarcoidosis are proven to be connected as it has been proposed and a patient develops a disease that falls in between the spectrum, then the subsequent management would not differ. Funding:
None.
Competing interests: Ethical approval:
None declared. Not required.
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