|Year : 2018 | Volume
| Issue : 4 | Page : 247-253
The prevalence of latent tuberculosis infection among Iranian sarcoidosis patients
Arda Kiani1, Fatemeh Razavi2, Esmaeil Mortaz3, Habib Emami4, Shima Ghazali2, Abbas Danesh Anbardan1, Hossein Mehravaran2, Atefeh Abedini2
1 Tracheal Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
3 Clinical Tuberculosis and Epidemiology Research Center, National Research Institute for Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
4 Tobacco Prevention and Control Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
|Date of Submission||01-Sep-2018|
|Date of Decision||15-Oct-2018|
|Date of Acceptance||04-Nov-2018|
|Date of Web Publication||11-Dec-2018|
Dr. Atefeh Abedini
Chronic Respiratory Diseases Research Center, National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, PO Box: 19569.44413, Tehran
Source of Support: None, Conflict of Interest: None
Background: Sarcoidosis is a multisystemic disorder with unknown causes. Mycobacterium tuberculosis has been implicated as one of the possible causes of sarcoidosis. Interferon-gamma release assays are in vitro diagnostic tests for detection of the latent tuberculosis infection (LTBI) which has been replaced by tuberculin skin test (TST) in some countries. The purpose of this study was to investigate the prevalence of LTBI in Iranian sarcoidosis patients. Methods: Ninety participants with the mean age of 42.22 ± 14.55 were enrolled in this study. They were divided into three equal groups consisted of patients with active TB, patients with sarcoidosis, and controls. TST and QuantiFERON®-TB Gold (QFT) were performed according to the manufacturer's instructions and the result interpreted. Results: The positive rates of TST were 76.66%, 3.3%, and 6.66% in TB, sarcoidosis, and control groups, respectively. However, QFT was positive in 24 (96.66%) of the TB group, 6 (20%) of sarcoidosis patients, and 5 (16.66%) of the control group. The agreement between the aforementioned tests was low (Cohen's kappa coefficient (κ) = 0.24). Conclusions: The current study suggests that in an intermediate-incidence TB population such as Iran, QFT is much more accurate than TST for the diagnosis of LTBI in patients with sarcoidosis. The present finding increases the possibility of this hypothesis which states that nontuberculous mycobacteria may play a role in the etiology of sarcoidosis.
Keywords: Latent tuberculosis (D055985), Mycobacterium tuberculosis (D009169), nontuberculous mycobacteria (D009170), QuantiFERON-tuberculosis gold, sarcoidosis (D012507), tuberculin skin test
|How to cite this article:|
Kiani A, Razavi F, Mortaz E, Emami H, Ghazali S, Anbardan AD, Mehravaran H, Abedini A. The prevalence of latent tuberculosis infection among Iranian sarcoidosis patients. Biomed Biotechnol Res J 2018;2:247-53
|How to cite this URL:|
Kiani A, Razavi F, Mortaz E, Emami H, Ghazali S, Anbardan AD, Mehravaran H, Abedini A. The prevalence of latent tuberculosis infection among Iranian sarcoidosis patients. Biomed Biotechnol Res J [serial online] 2018 [cited 2019 Mar 25];2:247-53. Available from: http://www.bmbtrj.org/text.asp?2018/2/4/247/247238
| Introduction|| |
Sarcoidosis is a multisystemic disorder of unknown causes which involves several organs approximately always the lungs and also the immune system activities. There are different theories for the development of sarcoidosis including exposure to environmental factors, genetic orientation, viral infection, overactivation of the immune system, or a combination of the mentioned factors. As shown in [Figure 1], several antigens by Mycobacterium species are suggested as the suspected potential initiator factors in developing sarcoidosis., Cough, fever, fatigue, and weight loss are some nonspecific symptoms of both sarcoidosis and tuberculosis (TB). The computed tomography (CT) finding in TB is “caseating”, however, in sarcoidosis is “noncaseating” granuloma.
The main treatment of sarcoidosis is immunosuppressive medicals generally including glucocorticosteroids (such as prednisolone and methotrexate), cyclophosphamide, and chloroquine.
There are two forms of TB including active TB and latent TB. The latent TB in patients undertaking immunosuppressive treatments (such as sarcoidosis patients) is more likely in the risk of conversion to the active TB. Sputum smear microscopy and culture have been known as the primary method to distinguish pulmonary TB. Since these two methods are time-consuming, tuberculin skin test (TST) has been considered as a customary method in distinguishing sarcoidosis and TB in low- and middle-income countries. The sensitivity of TST is low, however, the specificity of this test is extremely high. Many sarcoidosis patients show a negative TST result that is caused by anergy. Therefore, it is necessary to ensure that they do not interfere with latent TB as well.
Interferon-gamma (IFN-γ) release assays (IGRAs) are in vitro diagnostic methods with high specificity for detecting M. tuberculosis infection in sarcoidosis that is available in two forms of QuantiFERON-TB Gold (QFT) and T-SPOT., IGRAs are based on the principle that T-cells from a complete blood sample coincubated with a specific antigen for M. tuberculosis complex (ESAT-6, CFP-10) produce IFN-γ. Since the aforementioned proteins do not exist in most of the non-TB mycobacteria neither in any of the Bacillus Calmette–Guérin (BCG) strains which are the routine vaccine in Iran, this test is specific for the detection of M. tuberculosis.
To the best of our knowledge, there has not been any large cohort conducted on the etiology of the Iranian sarcoidosis patients with latent TB infection (LTBI), yet. Hence, the purpose of the current survey was to study the prevalence of LTBI in Iranian sarcoidosis patients.
| Methods|| |
This diagnostic study was carried out between September 2017 and April 2018 on individuals referred to National Research Institute of TB and Lung Disease (NRITLD). On the other hand, information of registered sarcoidosis patients of our sarcoidosis clinic was extracted retrospectively to use in the current study. The study was approved by NRITLD Ethics Committee and the written informed consent was obtained from each participant The Ethical committee approval number was IR.SBMU.MSP.REC.1396.356 dated 2017-2018.
Ninety participants enrolled in the study were classified into three groups: the first group was consisted of 30 sarcoidosis patients who were diagnosed in accordance with ATS/ERS/WASOG statement. The inclusion criteria for Group 1 included (1) the clinical characteristics of lung involvement (sore throat, dry cough, chest pain, fever, fatigue, and wheezing); (2) lung involvement proven by X-ray and chest CT [Figure 2] and [Figure 3]; and (3) proof of noncaseating granulomas on lung biopsy samples. Patients with sarcoidosis who had received steroids or were under anti-inflammatory treatments were excluded from the study.
|Figure 2: Typical and atypical manifestations of lung involvement in sarcoidosis based on computed tomography|
Click here to view
Group 2 consisted of patients with active pulmonary TB. The inclusion criteria for Group B included (1) the presence of signs and symptoms and also radiological evidence for pulmonary TB and (2) proven acid-fast bacilli through positive smear and culture.
The control group was selected among individuals who referred to the hospital due to asthma or allergic reactions with no history and clinical signs or symptoms of TB with normal lung X-rays and also without the history of exposure to a known patient with active TB. The control group was entered in the study to determine the rate of LTBI among Iranian healthy population. Family members of patients and hospital staff were not included in this study as the control.
BCG vaccination status was checked by history or existence of BCG scar.
Tuberculin skin test
TST was either performed or extracted from clinical records of all individuals. To perform this test, a thin syringe was first filled with 0.1 ml solution of purified protein derivative (PPD) (RAZI Vaccine and Serum Research Institute, Karaj, Iran). After 48–72 h of inoculation, the transverse diameter of the TST indurations was measured by expert technician. The positive result was considered when the average TST diameter was >10 mm.
IGRA was performed using commercially available QFT In-Tube (QFT-IT) assay (QIAGEN, GmbH, Germany). Five milliliters of whole blood was collected from all 90 participants. Blood samples were delivered to the laboratory to determine IFN-γ levels (IU/mL). The measurement was performed according to the manufacturer's instructions. Blood samples were equally aliquots into all three QFT pipelines, which included a zero control tube, a TB antigen tube, and a mitogen tube. The contents of the tubes were shaken for 5–10 s and were incubated at 37 ± 1°C for 16–24 h. The plasma was isolated by high-speed centrifugation and stored before the test at 80°C. In the next step, the release of IFN-γ (IU/mL) was measured by ELISA according to the manufacturer's protocol (QIAGEN Company, GmbH, Germany). The QFT-IT analysis software was used to analyze the data and results. A positive result was considered when the difference in the IFN-γ levels between the test tube and negative control was ≥0.35 IU/mL.
Data were analyzed using SPSS version 22 software (IBM Corp. Released 2013. IBM SPSS Statistics for Windows, version 22.0. Armonk, NY: IBM Corp). Quantitative variables were compared between three groups using ANOVA test. Chi-square test was applied to compare the distribution of qualitative variables. A value of P < 0.05 was considered as statistical significance. The agreement between QFT and TST was measured using kappa statistics interpreted in accordance with Landis and Koch through which κ > 0.75 was considered as the excellent agreement, κ = 0.40–0.75 is known as fair to a good agreement, and κ < 0.40 is poor agreement.
| Results|| |
In this study, 30 sarcoidosis patients (female: 22 and male: 8), 30 TB patients (female: 13 and male: 17), and also 30 healthy controls (female: 15 and male: 15) were investigated.
The common presenting signs and symptoms of sarcoidosis patients, course of the disease, involved organs, and history of smoking and stage of the disease are presented in [Table 1].
The most common presenting symptoms of sarcoidosis patients were dyspnea and fatigue. More than 50% of sarcoidosis patients were in the acute phase of the disease. The extrapulmonary involvements of these patients were skin lesions and cartilage involvements. There was not any correlation between the positive result of PPD/QFT and stage of the disease, course of the disease and organ involvement with the positive results of QFT neither PPD in sarcoidosis group [Table 2].
|Table 2: The correlations between two tests of QuantiFERON-tuberculosis Gold and tuberculin skin test and stage of sarcoidosis, course of the disease and involved organ|
Click here to view
Baseline characteristics of participants, as well as TST and QFT results, are presented in [Table 3]. More than 95% of all individuals had been vaccinated. As it is obvious in [Table 3], TST was positive in 76.66% of TB patients, while the QFT was positive in 96.66%. In the sarcoidosis group, positive TST was seen in 3.3% of patients. However, 20% of sarcoidosis patients had latent TB based on the QFT. Positive TST and QFT were 6.66% and 16.66%, respectively, in the control group. The positive results of QFT and TST are significantly diffrente [Figure 4]. By relying on TST-positive results, 16.6% of sarcoidosis patients, 20% of TB patients, and also 10% of controls who had LTBI would have been missed.
|Figure 4: The positive rate of tuberculin skin test and QuantiFERON®-TB Gold compared between three groups of sarcoidosis, tuberculosis and control. *Statistical significance was established at P < 0.05 tuberculosis: Tuberculosis; tuberculin skin test +: Positive result of Tuberculin skin test; QuantiFERON®-TB Gold +: Positive result of Quantiferon-gold test|
Click here to view
Of the six QFT-plus patients in the sarcoidosis group, two cases belonged to each stage of I, II, and IV, respectively.
The positive results for latent TB based on QFT and TST were compared between three groups [Figure 4]. Significantly, the positive results of QFT were higher than the TST results (Chi-square = 4.73, degrees of freedom = 2, and P < 0.05).
To evaluate TST and QFT agreement in the sarcoidosis group, a statistical analysis was applied using Cohen's kappa coefficient (κ), resulting in a low agreement in 0.24 (95% confidence interval 0.19–0.21).
The diagnostic yield of TST was compared with QFT, and the results are presented in [Table 4]. Based on the results, TST had the highest sensitivity in the TB group. However, the sensitivity and specificity of the test were low for sarcoidosis cases. To avoid the effect of prevalence on the results, the likelihood ratio was calculated as well. The negative likelihood ratio (LR−) of TST in sarcoidosis patients was considerable (4.97).
|Table 4: Predictive value of tuberculin skin test in three groups of sarcoidosis, tuberculosis, and control|
Click here to view
| Discussion|| |
On the one hand, nontuberculous mycobacteria (NTM) are widely seen as pathogens for respiratory organ in immunocompromised people. On the other hand, the immunosuppressive treatments are customarily prescribed in sarcoidosis patients. The major concern for increasing the incidence of TB in several countries is TB reactivity after taking corticosteroids or tumor necrosis factor-alpha inhibitors., Hence, here is a real need for considering LTBI among these cases. Accordingly, the current diagnostic study aimed to elucidate the prevalence of LTBI in Iranian sarcoidosis patients. In this regard, QFT test is preferred to TST because the presence of PPD causes anergy in populations who are vaccinated with the BCG or exposed to NTM.
The current study results revealed that among six LTBI sarcoidosis patients, only one of them had been confirmed by TST test. Based on QFT, 29 of 30 TB patients were positive; however, 23 of them were recognized by the TST test. Furthermore, of five QFT-positive results for LTBI in the control group, two of them were positive based on TST result. Therefore, as previously had revealed, it should be acknowledged that only based on TST measurement, it seems to be difficult to detect LTBI certainly.
Our results are in accordance with a study by Vyas et al. in which 62 sarcoidosis patients were investigated. Sixteen of them had a positive result based on QFT, while all TST results were negative. The existence of LTBI was recognized in 25% of sarcoidosis cases with negative TST results through the QFT.
Gupta et al. in 2003 conducted a study on an Indian population. Through their results, 50 sarcoidosis patients (92%) in one group and 62 cases in another group (88.7%) had negative results by the TST, which are in accordance with the 96% TST-negative results in the sarcoidosis group in our study (cutoff >10 mm). Based on these studies, it can be concluded that in an intermediate-TB prevalence countries such as Iran, the TST-negative results may play a role in detecting LTBI among sarcoidosis patients. On the other hand, several studies declared the advantages of IGRAs over the TST in healthy groups. The mentioned results are in line with our study in which the QFT was significantly more accurate than TST to distinguish LTBI among healthy individuals.,,
In our study, the kappa (κ) coefficient revealed a poor agreement between QFT and TST. This finding is in accordance with Kempisty et al. study in which TST ≥10 mm was considered positive as well. Through their result and compared with the TST, the QFT was further reliable in the diagnosis of LTBI in sarcoidosis patients. In another study conducted by Triverio et al., hemodialysis patients were investigated for the LTBI. Similar to our study, their findings showed that there was a poor agreement between TST and IGRAs (QFT) methods (κ = 0.16). Through a research on the United States Navy recruits in 2004, we observed a poor agreement between TST and IGRAs (QFT), with κ ranging from 0.16 to 0.25 among the United States Navy recruits.
Besides the small sample size that can be taken as the limitation of the research, it should be mentioned that this study was conducted in a country with intermediate prevalence of TB; therefore, results are not necessarily generalizable to areas with low or high TB incidence. On the other hand, it would be better to classify TB patients as pulmonary and extrapulmonary types. Future study can be conducted with a larger sample size to investigate the efficacy of Mycobacterium antigens as the etiology of sarcoidosis.
| Conclusions|| |
Based on our results, it was revealed that a significant number of patients with LTBI exist among sarcoidosis population which was not recognized by TST due to the anergy. This finding increases the possibility of this hypothesis which states that NTMmay play a role in the etiology of sarcoidosis.
We appreciate National Research Institute of Tuberculosis and Lung Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran, for their support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Delaney P. Neurologic manifestations in sarcoidosis: Review of the literature, with a report of 23 cases. Ann Intern Med 1977;87:336-45.
Chen ES, Moller DR. Etiology of sarcoidosis. Clin Chest Med 2008;29:365-77, vii.
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;201:755-67.
Shamaei M, Pourabdollah M, Mousaei H, Mirsaeidi M, Masjedi MR. The presence of mycobacterial antigens in sarcoidosis associated granulomas. Sarcoidosis Vasc Diffuse Lung Dis 2018;34:236-41.
Mortaz E, Masjedi MR, Abedini A, Matroodi S, Kiani A, Soroush D, et al.
Common features of tuberculosis and sarcoidosis. Int J Mycobacteriol 2016;5 Suppl 1:S240-1.
Müller NL, Kullnig P, Miller RR. The CT findings of pulmonary sarcoidosis: Analysis of 25 patients. AJR Am J Roentgenol 1989;152:1179-82.
Selroos O. Treatment of sarcoidosis. Sarcoidosis 1994;11:80-3.
Kempisty A, Białas-Chromiec B, Borkowska D, Kuś J. Interferon gamma release assays based on M. tuberculosis
-specific antigens in sarcoidosis patients. Adv Respir Med 2015;83:126-34.
Dye C, Watt CJ, Bleed DM, Hosseini SM, Raviglione MC. Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence, and deaths globally. JAMA 2005;293:2767-75.
Smith-Rohrberg D, Sharma SK. Tuberculin skin test among pulmonary sarcoidosis patients with and without tuberculosis: Its utility for the screening of the two conditions in tuberculosis-endemic regions. Sarcoidosis Vasc Diffuse Lung Dis 2006;23:130-4.
Mukai S, Shigemura K, Yamamichi F, Kitagawa K, Takami N, Nomi M, et al.
Comparison of cost-effectiveness between the quantiFERON-TB gold-in-tube and T-spot tests for screening health-care workers for latent tuberculosis infection. Int J Mycobacteriol 2017;6:83-6.
] [Full text]
Ndzi EN, Nkenfou CN, Gwom LC, Fainguem N, Fokam J, Pefura Y, et al.
The pros and cons of the quantiFERON test for the diagnosis of tuberculosis, prediction of disease progression, and treatment monitoring. Int J Mycobacteriol 2016;5:177-84. [Full text]
Cirak AK, Komurcuoglu B, Tekgul S, Bilaceroglu S, Tasdogen N, Gunduz A, et al.
The diagnostic efficiency of quantiFERONTB®-gold test in the diagnosis of tuberculous pleurisy. Int J Mycobacteriol 2012;1:180-4. [Full text]
Diel R, Nienhaus A, Loddenkemper R. Cost-effectiveness of interferon-gamma release assay screening for latent tuberculosis infection treatment in Germany. Chest 2007;131:1424-34.
Beydon N, Davis SD, Lombardi E, Allen JL, Arets HG, Aurora P, et al.
An official American Thoracic Society/European Respiratory Society statement: Pulmonary function testing in preschool children. Am J Respir Crit Care Med 2007;175:1304-45.
World Health Organization. Recommendations for Investigating Contacts of Persons with Infectious Tuberculosis in Low-and Middle-Income Countries. Switzerland: World Health Organization; 2012.
Velayati AA, Masjedi MR, Farnia P, Tabarsi P, Ghanavi J, ZiaZarifi AH, et al.
Emergence of new forms of totally drug-resistant tuberculosis bacilli: Super extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. Chest 2009;136:420-5.
Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159-74.
Olivier KN, Weber DJ, Wallace RJ Jr., Faiz AR, Lee JH, Zhang Y, et al.
Nontuberculous mycobacteria. I: Multicenter prevalence study in cystic fibrosis. Am J Respir Crit Care Med 2003;167:828-34.
Pal D, Behera D, Gupta D, Aggarwal A. Tuberculosis in patients receiving prolonged treatment with oral corticosteroids for respiratory disorders. Indian J Tuberc 2002;49:83-6.
Baughman RP, Iannuzzi M. Tumour necrosis factor in sarcoidosis and its potential for targeted therapy. BioDrugs 2003;17:425-31.
Inui N, Suda T, Chida K. Use of the quantiFERON-TB gold test in Japanese patients with sarcoidosis. Respir Med 2008;102:313-5.
Kruczak K, Mastalerz L, Sładek K. Interferon-gamma release assays and tuberculin skin testing for diagnosing latent Mycobacterium tuberculosis
infection in at-risk groups in poland. Int J Mycobacteriol 2016;5:27-33. [Full text]
Vyas S, Thangakunam B, Gupta R, Michael JS, Christopher DJ. Interferon gamma release assay and tuberculin skin test positivity in sarcoidosis. Lung India 2015;32:91-2. [Full text]
Gupta D, Chetty M, Kumar N, Aggarwal AN, Jindal SK. Anergy to tuberculin in sarcoidosis is not influenced by high prevalence of tuberculin sensitivity in the population. Sarcoidosis Vasc Diffuse Lung Dis 2003;20:40-5.
Hoffner S, Hadadi M, Rajaei E, Farnia P, Ahmadi M, Jaberansari Z, et al
. Geographic characterization of the tuberculosis epidemiology in Iran using a geographical information system. Biomed Biotechnol Res J 2018;2:213. [Full text]
Hardy AB, Varma R, Collyns T, Moffitt SJ, Mullarkey C, Watson JP, et al.
Cost-effectiveness of the NICE guidelines for screening for latent tuberculosis infection: The quantiFERON-TB gold IGRA alone is more cost-effective for immigrants from high burden countries. Thorax 2010;65:178-80.
Winje BA, Oftung F, Korsvold GE, Mannsåker T, Ly IN, Harstad I, et al.
School based screening for tuberculosis infection in Norway: Comparison of positive tuberculin skin test with interferon-gamma release assay. BMC Infect Dis 2008;8:140.
Lee SS, Liu YC, Huang TS, Chen YS, Tsai HC, Wann SR, et al.
Comparison of the interferon – Gamma release assay and the tuberculin skin test for contact investigation of tuberculosis in BCG-vaccinated health care workers. Scand J Infect Dis 2008;40:373-80.
Kempisty A, Bialas-Chromiec B, Kus J. Tuberculin skin test or interferon gamma release assay-How to detect latent tuberculosis infection in sarcoidosis patients? Eur Respir Soc 2015;PA833.
Triverio PA, Bridevaux PO, Roux-Lombard P, Niksic L, Rochat T, Martin PY, et al.
Interferon-gamma release assays versus tuberculin skin testing for detection of latent tuberculosis in chronic haemodialysis patients. Nephrol Dial Transplant 2009;24:1952-6.
Lempp JM, Zajdowicz MJ, Hankinson AL, Toney SR, Keep LW, Mancuso JD, et al.
Assessment of the quantiFERON-TB gold in-tube test for the detection of Mycobacterium tuberculosis
infection in United States navy recruits. PLoS One 2017;12:e0177752.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]