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ORIGINAL ARTICLE |
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| Year : 2022 | Volume
: 67
| Issue : 1 | Page : 19-25 |
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| Comparison of interferon gamma release assay and tuberculin skin test for diagnosis of latent tuberculosis in psoriasis patients planned for systemic therapy |
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Shekhar Neema1, Sunmeet Sandhu2, Sweta Mukherjee3, Deepak Vashisht1, Senkadir Vendhan1, Anwita Sinha1, Biju Vasudevan1
1 Department of Dermatology, AFMC, Pune, Maharashtra, India
2 Department of Dermatology, CH (AF), Bengaluru, Karnataka, India
3 Department of Pediatrics, CH (SC), Pune, Maharashtra, India
| Date of Web Publication | 19-Apr-2022 |
Correspondence Address:
Shekhar Neema
Department of Dermatology, AFMC, Pune - 411 040, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijd.ijd_681_21
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 Abstract | | |
Background: Latent tuberculosis infection (LTBI) is a common yet difficult problem to diagnose in tuberculosis endemic countries. Both tuberculin skin test (TST) and interferon-gamma release assay (IGRA) are used for the diagnosis of LTBI. Aims: The aim of the study is to compare TST and IGRA in patients planned for systemic treatment of psoriasis. Methods: It was a diagnostic study conducted in a tertiary care centre during the study period from January 20 to December 20. Patients more than 18 years of age with chronic plaque psoriasis planned for systemic therapy were included. Psoriasis area severity index (PASI), history of tuberculosis in past or family and BCG vaccination were recorded. Complete blood count, radiograph of the chest, tuberculin skin test and interferon-gamma release assay were performed in all patients. Statistical analysis was performed using statistical package for social sciences (SPSS version 20, Chicago). Results: A total of 75 patients, including 48 males and 27 females, were included in the study. The mean age and mean duration of disease were 46.08 (±12.16) and 4.59 (±3.8) years, respectively. Seventy-one (94.6%) patients had BCG scar, and two (2.6%) had a history of tuberculosis in a family member. The TST and IGRA were positive (>10 mm) in 23 (30.6%) and 16 (21.3%) patients, respectively. Either TST or IGRA was positive in 28 (37.3%) patients. Out of these 28 patients, concordance was seen in 11 (39.2%) and discordance in 17 (60.7%). Discordance was TST+/IGRA − in 12 (42.8%) and TST−/IGRA + in five (17.8%) patients. Abnormality in radiograph of the chest and computed tomography (CT) scan of the chest were seen in five (6.6%) and nine (12%) patients, respectively. The patients with either TST or IGRA + were more likely to have abnormal chest radiographs than those who were TST−/IGRA− (OR: 11.3, 95% CI: 1.24–102.3, P = 0.03). The TST and IGRA showed fair agreement ([INSIDE:1] = 0.364, P = 0.003). ROC curve was plotted for the absolute value of TST in mm considering IGRA as the gold standard. The area under the curve was 0.805 (95%CI: 0.655–0.954). For the TST positivity cut-off of 10 and 15 mm, specificity was 77.3% and 95.5%, respectively; the sensitivity was 68.8% irrespective of the cut-off value. Limitation: Small sample size and lack of follow-up are the biggest limitations of the study. The lack of a gold standard in the diagnosis of LTBI is an inherent yet unavoidable flaw in the study. Conclusion: Reactivation of LTBI is a concern in a patient planned for immunosuppressive therapy. We suggest the use of both TST and IGRA rather than two-step testing (TST followed by IGRA) or IGRA alone for the diagnosis of LTBI, especially in patients with a high risk of reactivation. The positivity on either test should prompt further evaluation and treatment decisions should be taken considering the risk-benefit ratio of treatment rather than test results alone.
Keywords: IGRA, latent tuberculosis, LTBI, psoriasis, TST
How to cite this article:
Neema S, Sandhu S, Mukherjee S, Vashisht D, Vendhan S, Sinha A, Vasudevan B. Comparison of interferon gamma release assay and tuberculin skin test for diagnosis of latent tuberculosis in psoriasis patients planned for systemic therapy. Indian J Dermatol 2022;67:19-25 |
How to cite this URL:
Neema S, Sandhu S, Mukherjee S, Vashisht D, Vendhan S, Sinha A, Vasudevan B. Comparison of interferon gamma release assay and tuberculin skin test for diagnosis of latent tuberculosis in psoriasis patients planned for systemic therapy. Indian J Dermatol [serial online] 2022 [cited 2023 May 29];67:19-25. Available from: https://www.e-ijd.org/text.asp?2022/67/1/19/343281 |
| Introduction | |  |
Tuberculosis (TB) is a major health problem in endemic countries like India. Latent tuberculosis (LTBI) is defined as persistent immune response to stimulation by Mycobacterium tuberculosis antigens with no evidence of clinically manifest active TB. This immune response occurs due to the presence of viable (latent) bacilli that may reactivate later. The lifetime risk of reactivation is 5%–10% with the risk being maximum in the first 5 years of acquiring infection. The risk is higher in patients on immunosuppressive treatment and on tumour necrosis factor-alpha (TNF-α) inhibitors.[1] The global prevalence of LTBI based on interferon-gamma release assay (IGRA) and 10-mm tuberculin skin test (TST) cut-off is 24.8% and 21.2%, respectively; however, the prevalence varies from 8% to 10% in low-burden countries to 40%–45% in high-burden countries. The prevalence may be higher in specific groups such as health care workers and families of tuberculosis patients.[2],[3],[4] The goal of testing is to identify individuals at higher risk of development of active tuberculosis. TST or IGRA both can be used for diagnosis as there is no gold standard for diagnosis. Psoriasis is a common skin disorder affecting 0.4%–2.8% of the Indian population. Systemic treatments such as methotrexate, cyclosporine and TNF inhibitors are used in the management of moderate to severe psoriasis.[5] These immunosuppressive treatments increase the risk of reactivation of LTBI.[6] We performed a diagnostic study to compare TST and IGRA for diagnosis of LTBI in psoriasis patients planned for systemic therapy.
| Methodology | | |
It was a diagnostic study conducted in a tertiary care centre during the study period from January 20 to December 20. Institutional ethical committee clearance was obtained. Patients more than 18 years of age with chronic plaque psoriasis planned for systemic therapy and willing to be part of the study were included. Erythrodermic psoriasis, patients with HIV infection, previously treated tuberculosis, features of active tuberculosis on history and clinical examination, recent history (12 weeks) of live vaccination and patients already on immunosuppressant treatment were excluded from the study.
Baseline clinical data, severity assessment using psoriasis area severity index (PASI), history of tuberculosis in past or family and BCG vaccination were recorded. History of active tuberculosis (cough, fever, night sweats and weight loss) was noted. Investigations performed were complete blood count, radiograph of the chest, tuberculin skin test and interferon-gamma release assay. Computed tomography (CT) scan of the chest and sputum microscopy were performed in patients with either TST or IGRA positivity.
TST was performed using the Mantoux test method with 0.1 mL (5 units) of purified protein derivative- Tween 80 (PPD-T), intradermally in the volar aspect of left forearm with the help of tuberculin syringe to produce a wheal of 6–10 mm in diameter. The reaction was measured in mm of induration, across the forearm (perpendicular to the long axis) after 48–72 h. A measurement of 10 mm or more was considered positive.
Interferon-gamma release assay (IGRA) was performed using TB platinum test, which is an in-tube test and determines interferon-gamma concentration in antigen and nil tube by using an enzyme immunoassay. Further, 3 mL of whole blood was collected in a heparin tube and transported immediately to the laboratory. The sample for IGRA was collected before TST was administered to prevent any false-positive test. The interpretation of IGRA was as follows:
- >400 pg in nil tube – Indeterminate
- Nil tube ≤400 pg/mL and antigen tube minus nil tube in pg/mL
- <14: Negative
- ≥14 and <25% of nil tube: Negative
- ≥14 and ≥25% of nil tube: Positive
Sample size and data analysis
All patients who reported to dermatology OPD and met the inclusion criteria during the study duration were offered to be part of the study. Statistical analysis was performed using statistical package for social sciences (SPSS version 20, Chicago). Categorical data are presented as numbers with percentages and continuous data as mean with standard deviation. Kappa coefficient was calculated to find the agreement between the tests. There is no gold standard for diagnosis of LTBI and because IGRA has higher specificity, a receiver operating characteristic curve was plotted considering IGRA as the gold standard. All statistical tests were two-sided and were performed at a significance level of α = 0.05.
| Results | | |
A total of 81 patients were assessed for inclusion during the study period. Six patients were excluded (two unwilling, two with a history of treated tuberculosis, one active tuberculosis and one with erythrodermic psoriasis) and 75 patients were included in the study. The study included 48 males and 27 females with a mean age of 46.08 (±12.16) years and a mean duration of disease of 4.59 (±3.8) years. The mean PASI was 16.85 (±9.290). Twenty (26.7%) patients were alcohol consumer, 14 (18.6%) patients were current smokers, 28 (37.3%) patient had concomitant arthritis, 8 (10.6%) had type 2 diabetes and 14 (18.6%) had hypertension. Seventy-one (94.6%) patients had BCG scar and two (2.6%) had a history of tuberculosis in a family member. The baseline data and comorbidities are tabulated in [Table 1].
The TST was positive (>10 mm) in 23 (30.6%) patients, and results were concordant with IGRA in 11 (47.8%) patients. IGRA was positive in 16 (21.3%) patients and results were concordant with TST in 11 (68.7%) patients. Either TST or IGRA was positive in 28 (37.3%) patients. Out of these 28 patients, concordance was seen in 11 (39.2%) and discordance in 17 (60.7%). Discordance was TST+/IGRA − in 12 (42.8%) and TST−/IGRA + in five (17.8%) patients. Radiograph of the chest was performed in all patients and showed evidence of previous infection in five (6.6%) patients. Out of these five patients, four had discordant test results (two: TST+/IGRA−; two: TST−/IGRA+). Computed tomography (CT) scan of the chest was done in 26 patients and sputum microscopy in 28 patients. CT scan showed evidence of old healed infection in nine (34.61%) patients. No evidence of active tuberculosis was seen. Out of these nine patients, five (55.5%) patients had abnormal chest radiograph and either TST or IGRA was positive in all the patients; TST+/IGRA + was seen in four (44.4%), TST+/IGRA − in three (33.3%) and TST − IGRA + in two (22.2%) patients. This data has been tabulated in [Table 2]. The flow chart of the study is demonstrated in [Chart 1].
The agreement between TST and IGRA was calculated using Cohen's kappa and found to have a fair agreement ( = 0.364, P = 0.003). ROC curve was plotted for the absolute value of TST considering IGRA as the gold standard. The area under the curve was 0.805 (95%CI: 0.655–0.954) [Table 3]. For the TST positivity cut-off as 10 mm, sensitivity and specificity were 68.8% and 77.3%, respectively, and for 15 mm, the sensitivity and specificity were 68.8% and 95.5%, respectively [Table 3]. The patients with either TST or IGRA + were more likely to have abnormal chest radiographs than those who were TST−/IGRA− (OR: 11.3, 95% CI: 1.24–102.3, P = 0.03).
| Discussion | | |
Latent tuberculosis (LTBI) is a complex health problem. It is difficult to diagnose as there is no gold standard and the treatment in an asymptomatic patient requires careful consideration. The reactivation of LTBI leads to active tuberculosis and forms a pool for the development of new cases. WHO guidelines for the diagnosis of LTBI suggest the use of TST or IGRA for diagnosis of LTBI; however, these tests should only be performed in patients at high risk of reactivation and not in the general population as it can lead to ethical issues.[1] These tests should not be used for the diagnosis of active tuberculosis as they are not validated for this indication. In psoriasis patients planned for immunosuppressive systemic therapy, tuberculosis needs consideration. Pulmonary tuberculosis is diagnosed with detailed history and examination, chest radiograph and sputum microscopy, while LTBI is diagnosed by positive TST or IGRA in absence of any signs and symptoms suggestive of tuberculosis.[7]
TST is an in-vivo test performed using purified protein derivative injected intradermally. It is simple, easy to perform and cheap; however, both false-negative and false-positive tests can occur due to wrong administration or reading, poor cold chain maintenance, previous BCG vaccination and infection with non-tuberculous mycobacteria (NTM). However, a study suggests that BCG vaccination during infancy has no effect on initial TST reading after 5 years. The increased TST reading on repeated testing can be due to boosting (immunological recall), conversion (new infection) or random variability and leads to dilemmas. Boosting effect is maximum when the test is repeated between 1–5 weeks and is much less after 60 days, though it can occur years later. This phenomenon makes the interpretation of repeated TST difficult and makes it an unreliable test for the diagnosis of LTBI during follow-up.[8] Exposure to NTM is common and may result in cross-reactivity with purified protein derivative (PPD); however, the false positive reading of more than 10 mm due to cross-reactivity is uncommon and seen in only 2%–5% of individuals. It also requires two visits to the healthcare set-up, thus increasing the indirect cost.[9]
IGRA is an in-vitro test and is based on the release of interferons by lymphocytes exposed to mycobacterial antigens. The patient's blood is incubated with the antigens and interferon-gamma (IFNγ) released by sensitised leukocyte is measured. They use specific peptides such as early secreted antigenic target (ESAT6), culture filtrate protein (CFP10) and TB7.7 as antigens. These antigens are absent in BCG vaccine strain and many NTM, making it more specific. The test has good reproducibility, is observer-independent and is more specific, especially in BCG vaccinated population; however, the test is more expensive, needs equipped laboratory and requires sample processing within 12 h; moreover, any errors in the collection, transportation or running the assay can affect the results.[10],[11]
The sensitivity of TST in the BCG-vaccinated population was found to vary from 80% to 98% and specificity between 15% and 92% in various studies. The sensitivity of IGRA was found to vary between 76% and 95% and specificity between 95% and 100% in various studies. The specificity is based on the exposure history of the patient; however, superior specificity of IGRA may be due to the higher sensitivity of TST to pick up remote exposure.[12] In our study, 23 (30.6%) patients had positive TST and 16 (21.3%) had positive IGRA, while either of the tests was positive in 28 (37.3%) patients. Most of our patients (71/75) were vaccinated with BCG in infancy and only two had a history of recent exposure to a case of tuberculosis. In absence of a gold standard, it is difficult to ascertain whether the higher positivity rate to TST is due to higher sensitivity or false-positive reaction. Unlike in low-prevalence countries, the history of exposure may not be relevant in the diagnosis of LTBI in our country. The comparison of TST and IGRA has been tabulated in [Table 3].
Macahdo et al. analysed the factors associated with discordance in TST and IGRA among household contacts of pulmonary tuberculosis patients in a cross-sectional study. They found discordance in 61 (24%) cases with 44 (72%) with TST+/IGRA − result and 17 (28%) with TST−/IGRA + result. They also found that TST+/IGRA − and TST+/IGRA + groups were more likely to show abnormal chest radiographs as compared to the TST−/IGRA − group. They concluded that TST appears to be more suitable for the diagnosis of LTBI in tuberculosis endemic settings.[13],[14] In our study, we found discordance between TST and IGRA in 17 (60.7%) patients, which is much higher as compared to previous studies; however, TST+/IGRA− (12/28) is more common as compared to TST − IGRA+ (5/28), which is like previous studies. In our study, we also found that patient with either TST or IGRA positivity is more likely to have abnormal chest radiograph (OR: 11.3, 95% CI: 1.24–102.3, P = 0.03). Twenty-six of our patients (TST or IGRA positive) underwent a CT scan of the chest and found abnormal results in nine (32%) patients; four (44.4%) had normal radiographs, but all the patients were either TST or IGRA positive. In our study, high TST positive results and higher rates of discordance may be due to higher sensitivity of TST, BCG vaccination (as part of the national immunisation programme), likely higher exposure to NTM (farmers and daily wage labourers) and use of 5-TU PPD instead of 2-TU PPD used in western studies.
In a follow-up contact tracing study in Germany, only IGRA+ individuals progressed towards active tuberculosis and not those who were TST+/IGRA−. It appears from this study that IGRA is more specific for the diagnosis of LTBI.[15] We found five (31%) patients to be TST negative out of 16 cases who were IGRA+. We also found abnormal radiographs in 16.6% (2/12) patients who were TST+/IGRA−. A previous study suggested that the sensitivity of TST reduces with age; however, we could not find a significant age difference in TST+/IGRA+ patients and TST−/IGRA+ patients. This may be due to the small sample size in our study. With our data, we have shown that discordance between TST and IGRA is more in our population due to various reasons as discussed. IGRA is considered more specific for the diagnosis of LTBI, but we noted abnormal radiographs in IGRA− patients and TST+/IGRA− results cannot be overlooked. We also showed that a cut-off of 15 mm on TST improves the specificity of TST, though the clinical relevance of this is not clear. It appears that TST and IGRA complement each other and detect even those patients who have normal radiograph and abnormality on CT scan. In the absence of follow-up studies, we feel that both TST and IGRA should be done together for detection of LTBI and cognisance should be given to even discordant results (TST+/IGRA−), especially in endemic areas and in patients with a high risk of reactivation.
Small sample size and lack of follow-up are the biggest limitations of the study. Lack of a gold standard in the diagnosis of LTBI is an unavoidable yet inherent flaw in the conduct of this study.
| Conclusion | | |
There is no gold standard for diagnosis of LTBI, and WHO guidelines suggest the use of either TST or IGRA for diagnosis. Many centres use two-step testing (TST followed by IGRA) due to cost constraints or use only IGRA (more specific) for the diagnosis of LTBI. We suggest that TST and IGRA should be conducted simultaneously in patients with a high risk of reactivation. The positivity on either test should prompt further evaluation and treatment decisions should be taken considering the risk-benefit ratio of treatment rather than the test results alone.
| Acknowledgements | | |
The authors acknowledge the help of Dr Seema Patrikar, Lecturer in Biostatistics, Department of Community Medicine for her support during data analysis. The authors also acknowledge the help of office bearers of IADVl, Maharashtra for the support provided during the conduct of the study.
Financial support and sponsorship
The study was funded by IADVL, Maharashtra as a part of an annual research grant.
Conflicts of interest
There are no conflicts of interest.
| References | | |
| 1. | |
| 2. | Cohen A, Mathiasen VD, Schön T, Wejse C. The global prevalence of latent tuberculosis: A systematic review and meta-analysis. Eur Respir J 2019;54:1900655.  |
| 3. | Kashyap RS, Nayak AR, Gaherwar HM, Husain AA, Shekhawat SD, Jain RK, et al. Latent TB infection diagnosis in population exposed to TB subjects in close and poor ventilated high TB endemic zone in India. PLoS One 2014;9:e89524. doi: 10.1371/journal.pone. 0089524. |
| 4. | Kinikar A, Chandanwale A, Kadam D, Joshi S, Basavaraj A, Pardeshi G, et al. High risk for latent tuberculosis infection among medical residents and nursing students in India. PLoS One 2019;14:e0219131. doi: 10.1371/journal.pone. 0219131. |
| 5. | Dogra S, Yadav S. Psoriasis in India: Prevalence and pattern. Indian J Dermatol Venereol Leprol 2010;76:595-601. [ PUBMED] [Full text] |
| 6. | Doherty SD, Van Voorhees A, Lebwohl MG, Korman NJ, Young MS, Hsu S, et al. National psoriasis Foundation consensus statement on screening for latent tuberculosis infection in patients with psoriasis treated with systemic and biologic agents. J Am Acad Dermatol 2008;59:209-17. |
| 7. | Zellweger JP, Sotgiu G, Corradi M, Durando P. The diagnosis of latent tuberculosis infection (LTBI): Currently available tests, future developments, and perspectives to eliminate tuberculosis (TB). Med Lav 2020;111:170-83. |
| 8. | Menzies D. Interpretation of repeated tuberculin tests. Am J Respir Crit Care Med 1999;159:15-21. |
| 9. | |
| 10. | Detjen AK, Loebenberg L, Grewal HMS, Stanley K, Gutschmidt A, Kruger C, et al. Short-term reproducibility of a commercial interferon gamma release assay. Clin Vaccine Immunol 2009;16:1170-5. |
| 11. | Machingaidze S, Wiysonge CS, Gonzalez-Angulo Y, Hatherill M, Moyo S, Hanekom W, et al. The utility of an interferon gamma release assay for diagnosis of latent tuberculosis infection and disease in children: A systematic review and meta-analysis. Pediatr Infect Dis J 2011;30:694-700. |
| 12. | Oxlade O, Pinto M, Trajman A, Menzies D. How methodologic differences affect results of economic analyses: A systematic review of interferon gamma release assays for the diagnosis of LTBI. PLoS One 2013;8:e56044. doi: 10.1371/journal.pone.0056044. |
| 13. | Machado AJ, Emodi K, Takenami I, Finkmoore BC, Barbosa T, Carvalho J, et al. Analysis of discordance between the tuberculin skin test and the interferon-gamma release assay. Int J Tuberc Lung Dis 2009;13:446-53. |
| 14. | Alvarez GG, Dyk DDV, Davies N, Aaron SD, Cameron DW, Desjardins M, et al. The feasibility of the interferon gamma release assay and predictors of discordance with the tuberculin skin test for the diagnosis of latent tuberculosis infection in a remote aboriginal community. PLoS One 2014;9:e111986. doi:10.1371/journal.pone. 0111986. |
| 15. | Diel R, Loddenkemper R, Meywald-Walter K, Niemann S, Nienhaus A. Predictive value of a whole blood IFN-gamma assay for the development of active tuberculosis disease after recent infection with Mycobacterium tuberculosis. Am J Respir Crit Care Med 2008;177:1164-70. |
[Table 1], [Table 2], [Table 3] |
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