BMJ 2015;350:h1060 doi: 10.1136/bmj.h1060 (Published 5 March 2015)
Page 1 of 5
Practice
PRACTICE RATIONAL TESTING
Screening tests for tuberculosis before starting biological therapy 1
1
Richard J Hewitt core medical trainee , Marie Francis clinical respiratory research nurse , Aran 1 Singanayagam academic clinical lecturer , Onn Min Kon consultant respiratory physician adjunct 12 professor and reader in respiratory medicine Chest and Allergy Department, St Mary’s Hospital, Imperial College NHS Trust, London W2 1NY, UK; 2Imperial College London, St Mary’s Campus, London, UK 1
This series of occasional articles provides an update on the best use of key diagnostic tests in the initial investigation of common or important clinical presentations. The series advisers are Steve Atkin, professor of medicine, Weill Cornell Medical College Qatar; and Eric Kilpatrick, honorary professor, department of clinical biochemistry, Hull Royal Infirmary, Hull York Medical School. To suggest a topic for this series, please email us at [email protected].
A 27 year old white woman born in the United Kingdom presented with diarrhoea and rectal bleeding. A diagnosis of Crohn’s disease was made after urgent flexible sigmoidoscopy and she was treated with high dose intravenous corticosteroid. She relapsed on conversion to oral drugs and was start on infliximab, a tumour necrosis factor α (TNF-α) inhibitor.
Introduction
Biological drugs that target components of the immune system, such as TNF-α antagonists, interleukin 1 receptor antagonists, and interleukin 6 receptor antagonists, are licensed for the treatment of immune mediated inflammatory conditions such as rheumatoid arthritis and Crohn’s disease. These agents suppress the host immune response, so are associated with increased risk of opportunistic infections including viral infections (odds ratio 1.91, 95% confidence interval 1.02 to 3.58), such as herpes simplex virus and varicella zoster virus, and mycobacterial infections (3.73, 1.72 to 8.13), although risk varies with different agents.1
In about 95% of people infected with Mycobacterium tuberculosis the infection is controlled by the immune system. This results in a state of “latent tuberculosis infection,” with no features of active disease.2 However 5% of those with latent tuberculosis later develop reactivation of tuberculosis and active disease.2 TNF-α antagonists can cause such reactivation of latent infection and active disease.3 People with reactivation have a significantly higher risk of disseminated tuberculosis, and deaths have been recorded.3 Crucially, screening for latent tuberculosis
before starting biological drugs and chemoprophylaxis reduced the risk of reactivation by 78%, from a tuberculosis incidence of 522 (95% confidence interval 369 to 738) to 117 (29 to 470) per 100 000 patient years.2
Initial clinical assessment to exclude active tuberculosis Before starting biological drugs, undertake a full clinical history and examination. This should focus on symptoms of active tuberculosis infection including cough, fever, weight loss, and night sweats; history of exposure to tuberculosis infected contacts; and history of tuberculosis. Perform chest radiography in all patients to look for signs of previous or active tuberculosis. Refer patients with symptoms of active tuberculosis, a history of tuberculosis, or an abnormal chest radiograph to a specialist for further assessment.
What is the next investigation? If clinical evidence of active tuberculosis is excluded by the methods described above, the next step is to assess the patient for evidence of latent tuberculosis infection. This can be identified by: • The tuberculin skin test—intradermal injection of purified protein derivative and measurement of skin erythema and induration, which corresponds to a delayed type hypersensitivity reaction in patients with previous exposure to tuberculosis (including latent tuberculosis). Previous vaccination with BCG will also cause a skin reaction but of lower magnitude than after exposure to tuberculosis
• Interferon γ release assays (two commercially available: QuantiFERON-TB Gold In-Tube assay (QFT) and T-SPOT.TB), which measure interferon γ release by T cells
Correspondence to: O M Kon [email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2015;350:h1060 doi: 10.1136/bmj.h1060 (Published 5 March 2015)
Page 2 of 5
PRACTICE
The bottom line • Biological drugs are associated with an increased risk of progression from latent to active tuberculosis • Before starting treatment, exclude active tuberculosis by asking about symptoms (such as cough, fever, weight loss, and night sweats) and possible exposure to or history of tuberculosis, and with a chest radiograph • Check for latent tuberculosis with the tuberculin skin test or an interferon γ release assay; a combination of both tests may be the most sensitive approach
in blood samples mixed with M tuberculosis antigens.4 QFT measures the interferon γ concentration (IU/mL) using ELISA (enzyme linked immunosorbent assay) technology, whereas T-SPOT.TB reports the number of T cells producing interferon γ (spot forming cells). Table 1⇓ summarises the benefits and limitations of the tuberculin skin test and interferon γ release assays.
A major problem with identifying latent tuberculosis in patients due to start biological drugs is that the tuberculin skin test and, to a lesser extent, interferon γ release assays are thought to be less reliable in immunosuppressed patients.10 11
A recent meta-analysis of the performance of interferon γ release assays versus tuberculin skin tests patients with rheumatic disease before starting biological drugs reported pooled concordances between the QFT assay and tuberculin skin test of 72% (65% to 78%) and between T-SPOT.TB and tuberculin skin test of 75% (67% to 83%). It also showed that, compared with the tuberculin skin test, interferon γ release assays have a lower rate of false negative and false positive results in patients treated with corticosteroids and those with a history of BCG vaccination.5 It is not currently possible to determine the true sensitivity or specificity of the tuberculin skin test or interferon γ release assays because a gold standard test for presence of latent tuberculosis infection is lacking. However, a closer correlation has been found between interferon γ release assays and risk factors for latent tuberculosis infection, including personal history, tuberculosis contact history, and a suggestive chest radiograph.12 13
Some studies have suggested using only an interferon γ release assay when screening for latent tuberculosis because, in the context of immunosuppression, it is more specific than the tuberculin skin test and may therefore reduce the proportion of patients needing antibiotic chemoprophylaxis.9 14 However, observational studies suggest that, given the discordance between these two types of test, use of only one test may miss some patients with latent tuberculosis who would be identified by the alternative test.12 15 16 A longitudinal cohort study reported reduced detection of latent tuberculosis infection when only a tuberculin skin test or interferon γ release assay was used, compared with the use of both tests.17 Observational studies further support combination testing. 8 10 18
What do guidelines recommend? Current international guidelines clearly support screening all patients for latent tuberculosis before starting anti-TNF drugs.19 However, given the evidence above, the optimum screening strategy is not clear, with disagreement on whether to use an interferon γ release assay or tuberculin skin test, or both (table 2⇓). There is considerable heterogeneity in the studies on which these guidelines are based, with many appraised studies having a small sample size and differing rates of BCG vaccination. In the UK, 2011 guidance from the National Institute for Health and Care Excellence (NICE) recommends testing all immunocompromised patients for latent tuberculosis with an For personal use only: See rights and reprints http://www.bmj.com/permissions
interferon γ release assay alone or together with a tuberculin skin test—a positive result in either test should prompt consideration of chemoprophylaxis.20 However the World Health Organization recommends using either test,19 whereas the European Centre for Disease Prevention and Control recommends both (table 2).21 In a BCG vaccinated or immunosuppressed population, there are some advantages to considering the interferon γ release assays as a single test if available. But in the absence of conclusive data, current evidence suggests that a combination of the tuberculin skin test and an interferon γ release assay, with preventive treatment if either test is positive, is the safest and most pragmatic approach.
Difficulties arise when a patient with risk factors for latent tuberculosis tests negative with both the tuberculin skin test and an interferon γ release assay. Two large cohort studies noted patients who developed active tuberculosis despite having had a negative tuberculin skin test and interferon γ release assay result.7 17 WHO guidelines recommend that people with a negative tuberculin skin test or interferon γ release result should be given information about the symptoms of tuberculosis and the importance of seeking medical care if such symptoms develop.19
Outcome In this patient, active tuberculosis was excluded clinically. Before starting anti-TNF therapy she was screened for latent tuberculosis infection with both an interferon γ release assay and the tuberculin skin test, according to NICE guidelines.20 Despite being born in the UK, a low incidence country, the interferon γ release assay was positive, indicating latent tuberculosis infection. She was treated with six months of isoniazid and did not develop active tuberculosis when started on infliximab. In summary, current evidence suggests that decisions about chemoprophylaxis should be based on the results of the tuberculin skin test and an interferon γ release assay. If either test is positive, it would be appropriate to treat with chemoprophylaxis while monitoring carefully for treatment related side effects.20
Melissa Wickremasinghe, Heather Milburn, and Suranjith Seneviratne reviewed the article and provided advice on its content. Contributors: AS and OMK were responsible for the idea and conception of the article. RJH and MF did the literature review and analysis. RJH and MF drafted the article. AS and OMK revised the article critically for important intellectual content. All authors reviewed and approved the final version to be published. OMK is guarantor. Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: OMK has chaired an advisory board for Janssen and spoken on postgraduate educational sessions for Janssen and Otsuka Pharmaceuticals at the European Respiratory Society. Provenance and peer review: Not commissioned; externally peer reviewed. Subscribe: http://www.bmj.com/subscribe
BMJ 2015;350:h1060 doi: 10.1136/bmj.h1060 (Published 5 March 2015)
Page 3 of 5
PRACTICE
Patient consent not required (patient anonymised, dead, or hypothetical).
12
1
13
2
3
4 5 6
7
8
9
10 11
Kourbeti IS, Ziakas PD, Mylonakis E. Biologic therapies in rheumatoid arthritis and the risk of opportunistic infections: a meta-analysis. Clin Infect Dis 2014;58:1649-57. Carmona L, Gómez-Reino JJ, Rodríguez-Valverde V, Montero D, Pascual-Gómez E, Mola EM, et al. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum 2005;52:1766-72. Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A, BSRBR Control Centre Consortium, Symmons DP; BSR Biologics Register. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis 2010;69:522-8. Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4:761-76. Ruan Q, Zhang S, Ai J, Shao L, Zhang W. Screening of latent tuberculosis infection by interferon-γ release assays in rheumatic patients: a systemic review and meta-analysis. Clin Rheumatol 2014; published online 7 Nov. Cattamanchi A, Smith R, Steingart KR, Metcalfe JZ, Date A, Coleman C, et al. Interferon-gamma release assays for the diagnosis of latent tuberculosis infection in HIV-infected individuals: a systematic review and meta-analysis. J Acquir Immune Defic Syndr 2011;56:230-8. Hsia EC, Schluger N, Cush JJ, Chaisson RE, Matteson EL, Xu S, et al. Interferon-γ release assay versus tuberculin skin test prior to treatment with golimumab, a human anti-tumor necrosis factor antibody, in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. Arthritis Rheum 2012;64:2068-77. Costantino F, de Carvalho Bittencourt M, Rat A, Loeuille D, Dintinger H, Béné MC, et al. Screening for latent tuberculosis infection in patients with chronic inflammatory arthritis: discrepancies between tuberculin skin test and interferon-γ release assay results. J Rheumatol 2013;40:1986-93. Mariette X, Baron G, Tubach F, Lioté F, Combe B, Miceli-Richard C, et al. Influence of replacing tuberculin skin test with ex vivo interferon γ release assays on decision to administer prophylactic antituberculosis antibiotics before anti-TNF therapy. Ann Rheumat Dis 2012;71:1783-90. Shahidi N, Fu YT, Qian H, Bressler B. Performance of interferon-gamma release assays in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2012;18:2034-42. Bartalesi F, Vicidomini S, Goletti D, Fiorelli C, Fiori G, Melchiorre D, et al. QuantiFERON-TB Gold and the TST are both useful for latent tuberculosis infection screening in autoimmune diseases. Eur Respir J 2009;33:586-93.
For personal use only: See rights and reprints http://www.bmj.com/permissions
14
15
16
17 18 19 20 21
Soborg B, Ruhwald M, Hetland ML, Jacobsen S, Andersen AB, Milman N, et al. Comparison of screening procedures for Mycobacterium tuberculosis infection among patients with inflammatory diseases. J Rheumatol 2009;36:1876-84. Matulis G, Jüni P, Villiger PM, Gadola SD. Detection of latent tuberculosis in immunosuppressed patients with autoimmune diseases: performance of a Mycobacterium tuberculosis antigen-specific interferon γ assay. Ann Rheumat Dis 2008;67:84-90. Greveson K, Goodhand J, Capocci S, Woodward S, Murray C, Cropley I, et al. Yield and cost effectiveness of mycobacterial infection detection using a simple IGRA-based protocol in UK subjects with inflammatory bowel disease suitable for anti-TNF alpha therapy. J Crohns Colit 2013;7:412-8. Martyn-Simmons CL, Mee JB, Kirkham BW, Groves RW, Milburn HJ. Evaluating the use of the interferon-g response to Mycobacterium tuberculosis specific antigens in patients with psoriasis prior to anti-tumour necrosis factor alpha therapy: a prospective head-to-head cross sectional study. Br J Dermatol 2013;168:1012-8. Singanayagam A, Manalan K, Sridhar S, Molyneaux PL, Connell DW, George PM, et al. Evaluation of screening methods for identification of patients with chronic rheumatological disease requiring tuberculosis chemoprophylaxis prior to commencement of TNF-a antagonist therapy. Thorax 2013;68:955-61. Muñoz L, Casas S, Juanola X, Bordas X, Martinez C, Santin M. Prevention of anti-tumor necrosis factor-associated tuberculosis: a 10-year longitudinal cohort study. Clin Infect Dis 2015;60:349-56. Kleinert S, Tony H, Krueger K, Detert J, Mielke F, Rockwitz K, et al. Screening for latent tuberculosis infection: performance of tuberculin skin test and interferon-γ release assays under real-life conditions. Ann Rheumat Dis 2012;71:1791-5. WHO. Guidelines on the management of latent tuberculosis infection. 2015. www.who. int/tb/publications/ltbi_document_page/en/. National Institute for Health and Care Excellence. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. (Clinical guidance 117.) 2011. www.nice.org.uk/guidance/cg117/chapter/guidance. European Centre for Disease Prevention and Control. Use of interferon-gamma release assays in support of TB diagnosis. 2011. www.ecdc.europa.eu/en/publications/Publications/ 1103_GUI_IGRA.pdf.
Accepted: 19 February 2015 Cite this as: BMJ 2015;350:h1060 © BMJ Publishing Group Ltd 2015
Subscribe: http://www.bmj.com/subscribe
BMJ 2015;350:h1060 doi: 10.1136/bmj.h1060 (Published 5 March 2015)
Page 4 of 5
PRACTICE
Tables Table 1| Comparison of the tuberculin skin test and interferon γ release assays Tuberculin skin test
Interferon γ release assays
False negatives Higher rate in patients taking corticosteroids (lower sensitivity)5
Lower rate in patients taking corticosteroids (higher sensitivity)5 Interferon γ release assays have similar sensitivity to tuberculin skin tests for the detection of latent tuberculosis in patients with HIV infection6
False positives Higher rate in BCG vaccinated people (lower specificity)5
Lower rate in BCG vaccinated people (higher specificity)5
Higher rate owing to crossreactivity with non-tuberculous mycobacterium (lower specificity)4
Lower rate because less crossreactivity with non-tuberculous mycobacterium4
Practical considerations Laboratory infrastructure not needed4
Laboratory infrastructure needed4
Errors in administering or interpreting the test
Indeterminate results8
7
Patient needs to return to clinic for second reading
4
Ease of testing; one blood test4 Discrepancies between the two commercially available tests9
Costs Low material costs4
For personal use only: See rights and reprints http://www.bmj.com/permissions
Higher costs4
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BMJ 2015;350:h1060 doi: 10.1136/bmj.h1060 (Published 5 March 2015)
Page 5 of 5
PRACTICE
Table 2| Summary of recommendations for latent tuberculosis screening from selected guideline bodies Guideline
Recommendation(s)
National Institute for Health and Care Excellence20
For immunocompromised patients offer an interferon γ release assay alone, or combined with a tuberculin skin test20
European Centre for Disease Prevention and Control21 In immunocompromised people (such as those with treatment induced immunosuppression) it is essential to maximise sensitivity; therefore simultaneous use of tuberculin skin test and interferon γ release assay could help identify latent tuberculosis21 World Health Organization19
For patients starting anti-tumour necrosis factor treatment, use an interferon γ release assay or the tuberculin skin test to test for latent tuberculosis19
For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
Page 1 of 5
Practice
PRACTICE RATIONAL TESTING
Screening tests for tuberculosis before starting biological therapy 1
1
Richard J Hewitt core medical trainee , Marie Francis clinical respiratory research nurse , Aran 1 Singanayagam academic clinical lecturer , Onn Min Kon consultant respiratory physician adjunct 12 professor and reader in respiratory medicine Chest and Allergy Department, St Mary’s Hospital, Imperial College NHS Trust, London W2 1NY, UK; 2Imperial College London, St Mary’s Campus, London, UK 1
This series of occasional articles provides an update on the best use of key diagnostic tests in the initial investigation of common or important clinical presentations. The series advisers are Steve Atkin, professor of medicine, Weill Cornell Medical College Qatar; and Eric Kilpatrick, honorary professor, department of clinical biochemistry, Hull Royal Infirmary, Hull York Medical School. To suggest a topic for this series, please email us at [email protected].
A 27 year old white woman born in the United Kingdom presented with diarrhoea and rectal bleeding. A diagnosis of Crohn’s disease was made after urgent flexible sigmoidoscopy and she was treated with high dose intravenous corticosteroid. She relapsed on conversion to oral drugs and was start on infliximab, a tumour necrosis factor α (TNF-α) inhibitor.
Introduction
Biological drugs that target components of the immune system, such as TNF-α antagonists, interleukin 1 receptor antagonists, and interleukin 6 receptor antagonists, are licensed for the treatment of immune mediated inflammatory conditions such as rheumatoid arthritis and Crohn’s disease. These agents suppress the host immune response, so are associated with increased risk of opportunistic infections including viral infections (odds ratio 1.91, 95% confidence interval 1.02 to 3.58), such as herpes simplex virus and varicella zoster virus, and mycobacterial infections (3.73, 1.72 to 8.13), although risk varies with different agents.1
In about 95% of people infected with Mycobacterium tuberculosis the infection is controlled by the immune system. This results in a state of “latent tuberculosis infection,” with no features of active disease.2 However 5% of those with latent tuberculosis later develop reactivation of tuberculosis and active disease.2 TNF-α antagonists can cause such reactivation of latent infection and active disease.3 People with reactivation have a significantly higher risk of disseminated tuberculosis, and deaths have been recorded.3 Crucially, screening for latent tuberculosis
before starting biological drugs and chemoprophylaxis reduced the risk of reactivation by 78%, from a tuberculosis incidence of 522 (95% confidence interval 369 to 738) to 117 (29 to 470) per 100 000 patient years.2
Initial clinical assessment to exclude active tuberculosis Before starting biological drugs, undertake a full clinical history and examination. This should focus on symptoms of active tuberculosis infection including cough, fever, weight loss, and night sweats; history of exposure to tuberculosis infected contacts; and history of tuberculosis. Perform chest radiography in all patients to look for signs of previous or active tuberculosis. Refer patients with symptoms of active tuberculosis, a history of tuberculosis, or an abnormal chest radiograph to a specialist for further assessment.
What is the next investigation? If clinical evidence of active tuberculosis is excluded by the methods described above, the next step is to assess the patient for evidence of latent tuberculosis infection. This can be identified by: • The tuberculin skin test—intradermal injection of purified protein derivative and measurement of skin erythema and induration, which corresponds to a delayed type hypersensitivity reaction in patients with previous exposure to tuberculosis (including latent tuberculosis). Previous vaccination with BCG will also cause a skin reaction but of lower magnitude than after exposure to tuberculosis
• Interferon γ release assays (two commercially available: QuantiFERON-TB Gold In-Tube assay (QFT) and T-SPOT.TB), which measure interferon γ release by T cells
Correspondence to: O M Kon [email protected] For personal use only: See rights and reprints http://www.bmj.com/permissions
Subscribe: http://www.bmj.com/subscribe
BMJ 2015;350:h1060 doi: 10.1136/bmj.h1060 (Published 5 March 2015)
Page 2 of 5
PRACTICE
The bottom line • Biological drugs are associated with an increased risk of progression from latent to active tuberculosis • Before starting treatment, exclude active tuberculosis by asking about symptoms (such as cough, fever, weight loss, and night sweats) and possible exposure to or history of tuberculosis, and with a chest radiograph • Check for latent tuberculosis with the tuberculin skin test or an interferon γ release assay; a combination of both tests may be the most sensitive approach
in blood samples mixed with M tuberculosis antigens.4 QFT measures the interferon γ concentration (IU/mL) using ELISA (enzyme linked immunosorbent assay) technology, whereas T-SPOT.TB reports the number of T cells producing interferon γ (spot forming cells). Table 1⇓ summarises the benefits and limitations of the tuberculin skin test and interferon γ release assays.
A major problem with identifying latent tuberculosis in patients due to start biological drugs is that the tuberculin skin test and, to a lesser extent, interferon γ release assays are thought to be less reliable in immunosuppressed patients.10 11
A recent meta-analysis of the performance of interferon γ release assays versus tuberculin skin tests patients with rheumatic disease before starting biological drugs reported pooled concordances between the QFT assay and tuberculin skin test of 72% (65% to 78%) and between T-SPOT.TB and tuberculin skin test of 75% (67% to 83%). It also showed that, compared with the tuberculin skin test, interferon γ release assays have a lower rate of false negative and false positive results in patients treated with corticosteroids and those with a history of BCG vaccination.5 It is not currently possible to determine the true sensitivity or specificity of the tuberculin skin test or interferon γ release assays because a gold standard test for presence of latent tuberculosis infection is lacking. However, a closer correlation has been found between interferon γ release assays and risk factors for latent tuberculosis infection, including personal history, tuberculosis contact history, and a suggestive chest radiograph.12 13
Some studies have suggested using only an interferon γ release assay when screening for latent tuberculosis because, in the context of immunosuppression, it is more specific than the tuberculin skin test and may therefore reduce the proportion of patients needing antibiotic chemoprophylaxis.9 14 However, observational studies suggest that, given the discordance between these two types of test, use of only one test may miss some patients with latent tuberculosis who would be identified by the alternative test.12 15 16 A longitudinal cohort study reported reduced detection of latent tuberculosis infection when only a tuberculin skin test or interferon γ release assay was used, compared with the use of both tests.17 Observational studies further support combination testing. 8 10 18
What do guidelines recommend? Current international guidelines clearly support screening all patients for latent tuberculosis before starting anti-TNF drugs.19 However, given the evidence above, the optimum screening strategy is not clear, with disagreement on whether to use an interferon γ release assay or tuberculin skin test, or both (table 2⇓). There is considerable heterogeneity in the studies on which these guidelines are based, with many appraised studies having a small sample size and differing rates of BCG vaccination. In the UK, 2011 guidance from the National Institute for Health and Care Excellence (NICE) recommends testing all immunocompromised patients for latent tuberculosis with an For personal use only: See rights and reprints http://www.bmj.com/permissions
interferon γ release assay alone or together with a tuberculin skin test—a positive result in either test should prompt consideration of chemoprophylaxis.20 However the World Health Organization recommends using either test,19 whereas the European Centre for Disease Prevention and Control recommends both (table 2).21 In a BCG vaccinated or immunosuppressed population, there are some advantages to considering the interferon γ release assays as a single test if available. But in the absence of conclusive data, current evidence suggests that a combination of the tuberculin skin test and an interferon γ release assay, with preventive treatment if either test is positive, is the safest and most pragmatic approach.
Difficulties arise when a patient with risk factors for latent tuberculosis tests negative with both the tuberculin skin test and an interferon γ release assay. Two large cohort studies noted patients who developed active tuberculosis despite having had a negative tuberculin skin test and interferon γ release assay result.7 17 WHO guidelines recommend that people with a negative tuberculin skin test or interferon γ release result should be given information about the symptoms of tuberculosis and the importance of seeking medical care if such symptoms develop.19
Outcome In this patient, active tuberculosis was excluded clinically. Before starting anti-TNF therapy she was screened for latent tuberculosis infection with both an interferon γ release assay and the tuberculin skin test, according to NICE guidelines.20 Despite being born in the UK, a low incidence country, the interferon γ release assay was positive, indicating latent tuberculosis infection. She was treated with six months of isoniazid and did not develop active tuberculosis when started on infliximab. In summary, current evidence suggests that decisions about chemoprophylaxis should be based on the results of the tuberculin skin test and an interferon γ release assay. If either test is positive, it would be appropriate to treat with chemoprophylaxis while monitoring carefully for treatment related side effects.20
Melissa Wickremasinghe, Heather Milburn, and Suranjith Seneviratne reviewed the article and provided advice on its content. Contributors: AS and OMK were responsible for the idea and conception of the article. RJH and MF did the literature review and analysis. RJH and MF drafted the article. AS and OMK revised the article critically for important intellectual content. All authors reviewed and approved the final version to be published. OMK is guarantor. Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: OMK has chaired an advisory board for Janssen and spoken on postgraduate educational sessions for Janssen and Otsuka Pharmaceuticals at the European Respiratory Society. Provenance and peer review: Not commissioned; externally peer reviewed. Subscribe: http://www.bmj.com/subscribe
BMJ 2015;350:h1060 doi: 10.1136/bmj.h1060 (Published 5 March 2015)
Page 3 of 5
PRACTICE
Patient consent not required (patient anonymised, dead, or hypothetical).
12
1
13
2
3
4 5 6
7
8
9
10 11
Kourbeti IS, Ziakas PD, Mylonakis E. Biologic therapies in rheumatoid arthritis and the risk of opportunistic infections: a meta-analysis. Clin Infect Dis 2014;58:1649-57. Carmona L, Gómez-Reino JJ, Rodríguez-Valverde V, Montero D, Pascual-Gómez E, Mola EM, et al. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum 2005;52:1766-72. Dixon WG, Hyrich KL, Watson KD, Lunt M, Galloway J, Ustianowski A, BSRBR Control Centre Consortium, Symmons DP; BSR Biologics Register. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). Ann Rheum Dis 2010;69:522-8. Pai M, Riley LW, Colford JM Jr. Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 2004;4:761-76. Ruan Q, Zhang S, Ai J, Shao L, Zhang W. Screening of latent tuberculosis infection by interferon-γ release assays in rheumatic patients: a systemic review and meta-analysis. Clin Rheumatol 2014; published online 7 Nov. Cattamanchi A, Smith R, Steingart KR, Metcalfe JZ, Date A, Coleman C, et al. Interferon-gamma release assays for the diagnosis of latent tuberculosis infection in HIV-infected individuals: a systematic review and meta-analysis. J Acquir Immune Defic Syndr 2011;56:230-8. Hsia EC, Schluger N, Cush JJ, Chaisson RE, Matteson EL, Xu S, et al. Interferon-γ release assay versus tuberculin skin test prior to treatment with golimumab, a human anti-tumor necrosis factor antibody, in patients with rheumatoid arthritis, psoriatic arthritis, or ankylosing spondylitis. Arthritis Rheum 2012;64:2068-77. Costantino F, de Carvalho Bittencourt M, Rat A, Loeuille D, Dintinger H, Béné MC, et al. Screening for latent tuberculosis infection in patients with chronic inflammatory arthritis: discrepancies between tuberculin skin test and interferon-γ release assay results. J Rheumatol 2013;40:1986-93. Mariette X, Baron G, Tubach F, Lioté F, Combe B, Miceli-Richard C, et al. Influence of replacing tuberculin skin test with ex vivo interferon γ release assays on decision to administer prophylactic antituberculosis antibiotics before anti-TNF therapy. Ann Rheumat Dis 2012;71:1783-90. Shahidi N, Fu YT, Qian H, Bressler B. Performance of interferon-gamma release assays in patients with inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2012;18:2034-42. Bartalesi F, Vicidomini S, Goletti D, Fiorelli C, Fiori G, Melchiorre D, et al. QuantiFERON-TB Gold and the TST are both useful for latent tuberculosis infection screening in autoimmune diseases. Eur Respir J 2009;33:586-93.
For personal use only: See rights and reprints http://www.bmj.com/permissions
14
15
16
17 18 19 20 21
Soborg B, Ruhwald M, Hetland ML, Jacobsen S, Andersen AB, Milman N, et al. Comparison of screening procedures for Mycobacterium tuberculosis infection among patients with inflammatory diseases. J Rheumatol 2009;36:1876-84. Matulis G, Jüni P, Villiger PM, Gadola SD. Detection of latent tuberculosis in immunosuppressed patients with autoimmune diseases: performance of a Mycobacterium tuberculosis antigen-specific interferon γ assay. Ann Rheumat Dis 2008;67:84-90. Greveson K, Goodhand J, Capocci S, Woodward S, Murray C, Cropley I, et al. Yield and cost effectiveness of mycobacterial infection detection using a simple IGRA-based protocol in UK subjects with inflammatory bowel disease suitable for anti-TNF alpha therapy. J Crohns Colit 2013;7:412-8. Martyn-Simmons CL, Mee JB, Kirkham BW, Groves RW, Milburn HJ. Evaluating the use of the interferon-g response to Mycobacterium tuberculosis specific antigens in patients with psoriasis prior to anti-tumour necrosis factor alpha therapy: a prospective head-to-head cross sectional study. Br J Dermatol 2013;168:1012-8. Singanayagam A, Manalan K, Sridhar S, Molyneaux PL, Connell DW, George PM, et al. Evaluation of screening methods for identification of patients with chronic rheumatological disease requiring tuberculosis chemoprophylaxis prior to commencement of TNF-a antagonist therapy. Thorax 2013;68:955-61. Muñoz L, Casas S, Juanola X, Bordas X, Martinez C, Santin M. Prevention of anti-tumor necrosis factor-associated tuberculosis: a 10-year longitudinal cohort study. Clin Infect Dis 2015;60:349-56. Kleinert S, Tony H, Krueger K, Detert J, Mielke F, Rockwitz K, et al. Screening for latent tuberculosis infection: performance of tuberculin skin test and interferon-γ release assays under real-life conditions. Ann Rheumat Dis 2012;71:1791-5. WHO. Guidelines on the management of latent tuberculosis infection. 2015. www.who. int/tb/publications/ltbi_document_page/en/. National Institute for Health and Care Excellence. Tuberculosis: clinical diagnosis and management of tuberculosis, and measures for its prevention and control. (Clinical guidance 117.) 2011. www.nice.org.uk/guidance/cg117/chapter/guidance. European Centre for Disease Prevention and Control. Use of interferon-gamma release assays in support of TB diagnosis. 2011. www.ecdc.europa.eu/en/publications/Publications/ 1103_GUI_IGRA.pdf.
Accepted: 19 February 2015 Cite this as: BMJ 2015;350:h1060 © BMJ Publishing Group Ltd 2015
Subscribe: http://www.bmj.com/subscribe
BMJ 2015;350:h1060 doi: 10.1136/bmj.h1060 (Published 5 March 2015)
Page 4 of 5
PRACTICE
Tables Table 1| Comparison of the tuberculin skin test and interferon γ release assays Tuberculin skin test
Interferon γ release assays
False negatives Higher rate in patients taking corticosteroids (lower sensitivity)5
Lower rate in patients taking corticosteroids (higher sensitivity)5 Interferon γ release assays have similar sensitivity to tuberculin skin tests for the detection of latent tuberculosis in patients with HIV infection6
False positives Higher rate in BCG vaccinated people (lower specificity)5
Lower rate in BCG vaccinated people (higher specificity)5
Higher rate owing to crossreactivity with non-tuberculous mycobacterium (lower specificity)4
Lower rate because less crossreactivity with non-tuberculous mycobacterium4
Practical considerations Laboratory infrastructure not needed4
Laboratory infrastructure needed4
Errors in administering or interpreting the test
Indeterminate results8
7
Patient needs to return to clinic for second reading
4
Ease of testing; one blood test4 Discrepancies between the two commercially available tests9
Costs Low material costs4
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Higher costs4
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BMJ 2015;350:h1060 doi: 10.1136/bmj.h1060 (Published 5 March 2015)
Page 5 of 5
PRACTICE
Table 2| Summary of recommendations for latent tuberculosis screening from selected guideline bodies Guideline
Recommendation(s)
National Institute for Health and Care Excellence20
For immunocompromised patients offer an interferon γ release assay alone, or combined with a tuberculin skin test20
European Centre for Disease Prevention and Control21 In immunocompromised people (such as those with treatment induced immunosuppression) it is essential to maximise sensitivity; therefore simultaneous use of tuberculin skin test and interferon γ release assay could help identify latent tuberculosis21 World Health Organization19
For patients starting anti-tumour necrosis factor treatment, use an interferon γ release assay or the tuberculin skin test to test for latent tuberculosis19
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