Dheeraj Gupta, Ritesh Agarwal, Ashutosh N. Aggarwal, and Surinder K. Jindal Curr Opin Pulm Med. (2012) September Sarcoidosis and tuberculosis: the same disease with different manifestations or similar manifestations of different disorders Journal club R4. Yoo, Jung-sun

The relationship between sarcoidosis and tuberculosis (TB) remains an enigma. Even the earliest description by Caesar Boeck of a case of ‘multiple benign sarkoid of the skin’ was thought to be allied in some way to tuberculosis Mycobacterium tuberculosis (MTB): as a putative cause of sarcoidosis has been extensively studied with conflicting reports Remarkable clinical similarities make the differential diagnosis of the two conditions difficult They review the available literature, and analyze the relationship between sarcoidosis and TB and its implications in clinical practice Introduction Eur Resp Mon 2005; 32:23–48 Am J Respir Cell Mol Biol 2011; 45:899–905.

Granulomatous inflammation in sarcoidosis : believed to be caused by some persistent poorly degradable antigen, and the resulting host response to it This antigenic stimulus can arise from noninfectious or infectious sources Various noninfective agents have been suspected primarily because of their epidemiologic association, but have not stood the test of time Similarly, a number of infective organisms have also been implicated in cause of sarcoidosis (MTB : One of the strongest contenders) Sarcoidosis–Tuberculosis Link Semin Respir Infect 2003; 18:23–32 Eur Respir Mon 2005; 32:13–22 J Intern Med 2003; 253:4–17 Eur Resp Mon 2005; 32:23–48

An epidemiological link was suggested by previous history of contact with tuberculosis in patients with sarcoidosis. (also noted that ethnic populations with a higher incidence of TB also had more sarcoidosis) More recently, in an elegant review of epidemiological link between sarcoidosis and TB, it was observed that sarcoidosis was detected only when TB decreased in the population (India) However, the increasing recognition of sarcoidosis may simply be due to increasing awareness and widespread availability of better diagnostic facilities, especially bronchoscopy (India) Epidemiological studies Br J Dis Chest 1972;66:45–52 Sarcoidosis Vasc Diffuse Lung Dis 2004; 21:85–93

A transmissible infectious cause of sarcoidosis was suggested by several studies that demonstrated: 1. Sarcoid tissue preparations to induce granulomatous reaction in mice 2. Close contact with a patient of sarcoidosis prior to diagnosis of disease 3. Development of sarcoidosis in patients following organ transplantation from donors having sarcoidosis A recent study (India): Documented coexistence of the two diseases. Several cases have been described after documented infection with non-tubercular mycobacteria or vaccination by BCG  Present an indirect link to a mycobacterial cause of sarcoidosis; (however, the Koch’s postulates have never been fulfilled) Microbiological studies Ann N Y Acad Sci 1976; 278:560–564 Lancet 1969; 2:81–84 Thorax 1987; 42:420–426

Molecular techniques such as the nucleic acid amplification tests (NAAT) : have invigorated researchers to establish a definitive link between sarcoidosis and MTB They hypothesized that the detection rates for mycobacterial DNA in sarcoid samples would be higher in countries with high prevalence of TB. Molecular studies J Infect 2010; 60:501–503

Further updating meta-analyses with a recent literature search (up to 15 March 2012) : NAAT in sarcoid tissues was higher in HBC [32.0%; 95% confidence interval (CI), 17.3–51.4] than others [22.4%; 95% CI, 14.9–32.4] The pooled odds for a positive mycobacterial NAAT in studies including a control arm : [7.32; 95% CI, 3.74–14.33] Molecular studies

Demonstration of mycobacterial antigens and immune responses to them in sarcoidosis : Additional evidence in favor of mycobacterial cause Mycobacterial proteins encoded by the genes located on the Region of Difference 1 (RD1) in the mycobacterial genome are not shared by BCG strains and most nontuberculous mycobacteria (Commonly studied RD1 antigens (ESAT-6 and CFP-10): specific indicators of MTB complex infection). Other mycobacterial antigens : catalase-peroxidase (katG), superoxide dismutase (sodA), mycolyl transferase (Ag85A) and heat-shock proteins (hsp) have also been reported Immunological studies Microbiology 1998; –3203 Respir Med 2006; 100:2098–2106

A few studies have identified mycobacterial antigens from blood or broncho- alveolar lavage fluid (BALF), and reported humoral responses to them. IgG antibodies against recombinant mKatG antigen were identified in nearly half of sarcoidosis patients Humoral response to RD1 (ESAT-6 and CFP10) antigens of MTB in sarcoidosis. B-cell responses Proc Am Thorac Soc 2007; 4:465–468 Indian J Med Res 2012; 135

Sarcoidosis: a unique ‘immunological paradox’ (1.Depressed delayed hypersensitivity manifesting as cutaneous anergy, 2.Diffuse granulomatous inflammation in the tissues characterized by polarized CD4+ T cells with Th-1) Sarcoidosis patients : immune responses against ESAT-6, katG, hsp and sodA  It is possible that presence of mycobacterial infection or BCG vaccination in a genetically predisposed host may contribute to the development of an immune response leading to sarcoidosis T-cell responses Immunobiology 1994; 191:537–547 Autoimmun Rev 2010; 9:419–424

Both tuberculosis and sarcoidosis show granulomatous inflammation in tissue biopsies. (Sarcoidosis: presence of noncaseating, compact, ‘naked’ granulomas  TB: more intense with plenty of ‘caseous’ necrosis in the center of granulomas) Histological similarities

Both tuberculosis and sarcoidosis : share remarkable similarities in their clinicoradiological presentation Both present with constitutional symptoms of fever, malaise, fatigue, anorexia and weight loss. Expectoration and/or hemoptysis(Respiratory symptoms) are distinctly more frequent in fibrocavitary tuberculosis, Untreated tuberculosis: more signs and symptoms Both hilar lymphadenopathy, the commonest clinical presentation of sarcoidosis. Clinical similarities

Differentiating sarcoidosis from TB poses a challenge, particularly in countries with high prevalence of TB Supported by a constellation of clinical, radiological and laboratory evidence, to make a confident diagnosis of sarcoidosis Two investigations : tuberculin skin test (TST) and the interferon gamma release assays (IGRAs) Differential diagnosis

Depression of delayed type hypersensitivity, manifesting in cutaneous anergy to tuberculin, is a clinically important phenomenon occurring in sarcoidosis A negative test at a cut-off of 10mm reaction to 5TU PPD has virtually 100% sensitivity for sarcoidosis  A negative tuberculin test excludes TB, except in seriously sick or otherwise immunosuppressed individuals Tuberculin skin test Sarcoidosis Vasc Diffuse Lung Dis 2003; 20:40–45

IGRAs : higher sensitivity and specificity for detecting MTB infection than the conventional TST, as they utilize antigens specific for MTB complex IGRA: a more sensitive test than TST in healthy individuals and, unlike the depressed TST, it continues to remain positive in patients with sarcoidosis IGRA: better than TST in detecting latent TB infection (sarcoidosis) In high prevalence countries, a positive IGRA should not be a deterrent for making a diagnosis of sarcoidosis Interferon-gamma release assays Scand J Infect Dis 2008; 40:373–380 Sarcoidosis Vasc Diffuse Lung Dis 2011; 28:95–101

Conclusion The role of mycobacteria in sarcoidosis has been extensively studied and debated. Whereas some consider sarcoidosis and tuberculosis as two extremes of the same disease process, other researchers have negated the role of mycobacteria in causation of sarcoidosis On the other hand there are several counter arguments to these unifying hypotheses. The balance of evidence favors mycobacteria or its products as a trigger for inciting immune responses leading to sarcoidosis in a proportion of patients, which is likely to be higher in countries with high tuberculosis burden. This evidence also highlights the limitations of molecular or serological studies to discriminate between the two conditions