Ocular Immunology and Inflammation
ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: http://www.tandfonline.com/loi/ioii20
Ocular Tuberculosis—A Clinical Conundrum Cecilia Lee MD, Rupesh Agrawal FRCS, MMed & Carlos Pavesio MD To cite this article: Cecilia Lee MD, Rupesh Agrawal FRCS, MMed & Carlos Pavesio MD (2015): Ocular Tuberculosis—A Clinical Conundrum, Ocular Immunology and Inflammation, DOI: 10.3109/09273948.2014.985387 To link to this article: http://dx.doi.org/10.3109/09273948.2014.985387
Published online: 25 Jun 2015.
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Date: 27 September 2015, At: 02:57
Ocular Immunology & Inflammation, Early Online, 1–6, 2015 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2014.985387
EDITORIAL
Ocular Tuberculosis—A Clinical Conundrum Cecilia Lee,
MD
1,2
, Rupesh Agrawal,
FRCS, MMed
1,3
, and Carlos Pavesio,
MD
1
Department of Medical Retina, Moorfields Eye Hospital, London, UK, 2Department of Ophthalmology, University of Washington, Seattle, Washington, USA, and 3Department of Ophthalmology, National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore
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1
The World Health Organization (WHO) estimated 5.8 million newly diagnosed cases of tuberculosis and 8.7 million people who were ill with tuberculosis (TB) in 2011.1 Tuberculous uveitis still represents a minority of uveitis cases, with varying prevalence ranging from 1–4% to 10–26% in different areas of the world.2–4 Despite significant research over the past decades, the diagnosis of ocular TB remains a challenge and poses a major conundrum to both ophthalmologists and respiratory physicians. More often than not, there is lack of synchrony between ophthalmologists and physicians for instituting anti-tubercular treatment (ATT) due to lack of gold standard criteria to diagnose ocular TB. Published literature varies significantly on criteria for diagnosis of ocular tuberculosis, defining the relapse or recurrence of the latent tuberculosis in the eye, the duration of ATT, and the role of corticosteroids or immunosuppressive treatment. A definite diagnosis of tuberculous uveitis can be confirmed by performing acid-fast smears, mycobacterial cultures, or polymerase chain reaction (PCR)based assays on ocular fluids.5,6 However, the sensitivities of these tests are fairly low, making definitive diagnosis difficult.7–9 Recent studies with multitarget PCR for TB-related uveitis have shown promising results with high positivity rate,10 and this modality may become readily available in the future, allowing a definitive diagnosis.11 Currently, a presumptive diagnosis is mainly made clinically with positive TB skin test (TST), positive interferon gamma release assays (IGRA), and lesions on imaging of the chest (chest xray, chest CT scan, PET scan).7 Resolution of uveitis or nonrecurrence of the uveitis post treatment of TB is also supportive of the diagnosis.7
Despite its widespread use, TST has less than ideal sensitivity and specificity in detecting TB.12 It has been used in medicine for the past 100 years but has its own inherent limitations in addition to the lack of standardization for test administration and reading. One of the main difficulties with TST is a high falsepositive rate in patients who were immunized with Bacillus Calmette-Guerin (BCG) vaccine or patients exposed to nontuberculous mycobacteria.13 In patients with severe illness, including active TB and immunodeficiency, TST can be falsely negative.10 Nevertheless, TST is still a valuable screening tool in a high-risk population.14 Hong et al. reported a positive predictive value of TST of 17.2% for all patients and 30.3% for foreign-born patients in a retrospective study of 142 patients (prevalence of 4 and 8%, respectively).14 The advent of interferon gamma release assays (IGRAs) has enabled us to overcome some of the limitations pertaining to TST. IGRAs measure interferon gamma response that sensitized T cells produce to Mycobacterium tuberculosis-specific antigens, such as early secretory antigenic target-6 (ESAT-6), culture filtrate protein-10 (CFP-10), and TB7.7. Because these proteins are not present in BCG vaccine and the majority of environmental mycobacteria, IGRAs allow greater specificity than TST, which uses purified protein derivative. Neither TST nor IGRAs can differentiate between active and latent TB infection. There are two types of IGRAs: the QuantiFERONTB Gold (QFT) (Cellestis, Australia) and ELISpot assay (T-SPOT.TB) (Oxford Immunotec, Oxford, UK). QFT is an enzyme-linked immunoabsorbent assay (ELISA) that quantifies the amount of IFN-gamma released into blood plasma in response to TB antigens.
Received 22 September 2014; revised 26 October 2014; accepted 4 November 2014; published online 22 June 2015 Correspondence: Mr. Carlos Pavesio, Moorfields Eye Hospital, City Road, London EC1V 2PD, UK. E-mail: [email protected]
1
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C. Lee et al.
ESAT-6 and CFP-10 are two antigens used in QFT. The third generation of this test, QuantiFERON-TB Gold In-Tube (Qiagen, Carnegie, Australia) uses an additional third antigen, TB7.7. The availability of QFT vs. QuantiFERON-TB Gold In-Tube varies in different institutions and countries. QFT is more widely used than T-SPOT.TB due to higher cost and the need for trained personnel for the latter. T-SPOT.TB is a simplified enzyme-linked immunospot assay (ELISpot) that counts TB-specific interferon-gamma secreting T cells. It is both time and temperature sensitive.13 T-SPOT.TB can be more sensitive in patients with reduced T-cell counts, such as those who are immunocompromised.15 Several studies have investigated the sensitivity and specificity of IGRA tests and all agree that IGRAs are more specific than TST, while its sensitivity compared to TST varies among studies.16 A group in Spain reported 90.9% sensitivity and 82.8% specificity of QFT compared to TST, which was 87.8% sensitive and 85.7% specific.17 A retrospective study in India, where there is a high burden of TB, showed both superior sensitivity and specificity of QFT compared to TST. Only 70% of 12 patients who had radiological evidence of TB were positive on TST, while 100% were detected as positive on QFT. 18 In contrast, a study in Singapore, which has an intermediate burden of TB disease, showed that the sensitivity of TST is higher while QFT is more specific in detecting Trelated uveitis.3 The authors recommended using both studies to increase the sensitivity and specificity. Due to its less frequent use there are fewer studies on T-SPOT.TB than on QFT. Ang et al. reported that TST is more sensitive than T-SPOT.TB (72 vs. 36%) but T-SPOT.TB is more specific (75 vs. 51%).19 Positive predictive value increases when both TST and T-SPOT.TB tests are used.19 The sensitivity of TSPOT.TB to diagnose extrapulmonary tuberculosis was higher than that of TST in patients with immunosuppression and miliary TB.20 Since 2006, the UK National Health System recommends that IGRA be used in all patients with positive TST and in all immunocompromised patients. In contrast, the Centers for Disease Control and Prevention in the United States recommends replacing TST with IGRA in high-risk groups but discourages any testing in low-risk groups.16,21 Due to low pretest probability in cases of low clinical suspicion, approximately 90% of positive IGRAs can be false positives.16 Therefore, Albini et al. recommend primary use of IGRAs only in select cases of high suspicion for ocular TB, given increased pre- and post-test probability.16 Positive TST or IGRA results are helpful when accompanied by clinical findings suggestive of tuberculous uveitis. However, a positive QFT without any clinical signs should not be taken as indication for ATT, due not only to the possibility of false positivity
but also to the side effect profile of ATT.7 Interestingly, in a study of 55 patients with suspicious tuberculous uveitis and 233 control subjects, there was 30.5% TST and 25.3% ELISPOT positivity in the control group who had no previous history of uveitis or TB.22 This demonstrates that false positivity or possible latent TB can be very frequent in the general population and screening in cases with no clinical suspicions should be discouraged. One of the major limitations of the IGRA test is lack of prospective data about predicting the risk of active TB in patients with different level of IGRA. Additional points must be considered before ATT is decided in cases of positive QFT without clinical findings. First, its validity needs to be questioned. Reversion, the phenomenon of a QFT test result becoming negative after an initial positive test result, is not uncommon23–25 and has been reported to be as high as 24%.25 Reversion rate is higher in patients whose responses are close to the cutoff threshold. In addition, the test results were shown to change depending on the volume of collected blood and how vigorously the sample was shaken.26 Several articles outside of ophthalmology discuss how the threshold between a positive and negative result for QFT should change based on the prevalence of TB24,25; therefore, caution must be taken when interpreting test results in low endemic areas. As there is wide range of positive values of QFT, a stratification approach for different levels of QFT and correlation analysis with different endemic groups may give us more insight into the predictive value of the IGRA test in patients with latent TB. Second, there is no standard treatment regimen or length of therapy for tuberculous uveitis. Similarly, there are no treatment guidelines for recurrent uveitis after completion of ATT. The positive response to ATT—defined as resolution of uveitis after full course of ATT—has been reported in approximately 60–70%.27,28 One may argue that those who did not respond to ATT could have been false positives or could have been undertreated. One must carefully review a patient’s medical history, including possible exposure and immune status, and examine all the clinical findings that are associated with tuberculous uveitis. There are numerous reports describing varied clinical signs representing presumed ocular TB but the level of evidence for association still needs to be established.18,29-31 Of all the clinical manifestations, the presence of choroidal granulomas, occlusive retinal vasculitis, and multifocal serpiginoid choroiditis32,33 has been more strongly associated with presumed ocular tuberculosis. In particular, choroidal granulomas should raise a high index of suspicion34,35 and failure to recognize them could lead to devastating consequences.36 In a series of 18 cases with choroidal tuberculosis, Zhang et al. have demonstrated a positive treatment outcome with a course of Ocular Immunology & Inflammation
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Ocular Tuberculosis—A Clinical Conundrum ATT, and emphasized that the choroidal involvement is an important phenotype of intraocular tuberculosis.37 Bansal et al. reported a decreased relapse rate in a series of 141 eyes (105 patients) with multifocal serpiginoid choroiditis after ATT.38 However, in the absence of these phenotypes, one should consider treatment of the uveitis without ATT. To our knowledge, there has been no study that has investigated the outcome of patients with positive QFT who did not receive ATT. However, few articles included subsets of patients who had positive IGRA but did not undergo ATT. In a retrospective study that included 66 patients with suspected tuberculous uveitis, there were a total of 24 positive QFT or TST.28 Fourteen out of 24 patients did not receive ATT because it was felt that the suspicion for TB-related uveitis was not high enough to justify ATT. Of these 14 patients, 6 of them improved with conventional immunosuppression treatment without ATT, while the remaining 8 did not improve on immunosuppression but still did not require ATT. The authors have not qualified the outcome further except that this group did not require further ATT and remained at status quo without further worsening or deterioration. In a study by Gineys et al.,27 17 out of 42 patients who had positive QFT tests did not receive ATT, as 5 of them refused treatment with ATT, 6 had ATT within last decade, 5 had mild anterior uveitis, and 2 were diagnosed with multiple sclerosis and sarcoidosis. Four of them were due to lack of clinical suspicion and did well without ATT during the follow-up. Third, the need for TB prophylaxis in case of systemic immunosuppression is not well defined. In a series of 12 patients with granulomatous uveitis reported by Kurup et al.,21 8 of them had positive quantiFERON-TB (first-generation QFT). Only 2 of them underwent ATT—both had posterior uveitis, one had a granuloma seen in CXR, and both were later diagnosed with TB meningitis. Four patients with positive quantiFERON-TB test were placed on multiple systemic immunosuppression agents without ATT. They were closely monitored and 2 of these patients later developed additional clinical signs, such as hilar lymphadenopathy, and were diagnosed with sarcoidosis. This study argues that patients can be treated with immunosuppression without ATT despite positive QFT when clinical suspicion is weak and patients are followed carefully during the course of the treatment. The practice pattern of treating TB-related uveitis differs widely among physicians, depending on their geographic location, prevalence of TB, and personal experience of treating TB-related uveitis. In the United Kingdom, we follow a similar approach to screening a selected cohort of patients with high index of suspicion as has been highlighted by Rosenbaum in his editorial.39 In our own experience working in a !
2015 Informa Healthcare USA, Inc.
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tertiary referral unit, the clinical signs, even though mostly nonspecific, still carry a significant weight on the decision to investigate and treat cases of suspected TB-related uveitis (Figure 1). Figure 1 shows the algorithm in evaluating any uveitic patient at our institution. During a basic uveitis workup, all patients with positive CXR are referred to pulmonary physicians regardless of QFT results. We do not routinely obtain QFT tests unless there are suspicious clinical signs, such as choroidal granulomas, occlusive retinal vasculitis, or multifocal serpiginoid choroiditis. Aqueous/vitreous sampling or intraocular tissue biopsy is not commonly performed due to low sensitivity in our setting. In patients with clinical findings suggestive of TB, it is the clinical suspicion that dictates their workup regardless of CXR or QFT results. Chest CT or positron emission tomography (PET) is considered in rare cases of high clinical suspicion. Recently, high-resolution CT scan of the chest has increased the detection rate of chest involvement in patients with presumed ocular TB with normal chest x-rays. One study of 58 patients demonstrated that up to 81% of referred patients had evidence of healed lesions suggestive of TB on chest CT.40 Furthermore, Mehta reported that the PET scan allowed accurate determination of systemic involvement in 11 patients with suspicions of TB.41 In this study, increased uptake in various organs such as chest, abdomen, and joints was detected. Thus, chest CT and PET scan can provide additional information in cases of presumed ocular TB with negative chest x-rays. There are several important points when addressing patients with positive QuantiFERON assays. First, treating ophthalmologists will likely dictate TB treatment decision. The majority of patients referred to an infectious disease unit due to a suspicion of tuberculous uveitis will lack any clinical signs of a systemic disease on routine investigations and the decision to treat will be based largely on the referring ophthalmologist. This reflects the importance of adequately referring patients for whom there is a high index of suspicion of TB uveitis, based on history of exposure and supportive clinical findings. Secondly, treating ophthalmologists should discuss with infectious disease colleagues whether further investigations such as chest CT or PET scans are necessary when clinical suspicions are high. Recent studies suggest that abnormal PET/CT could guide more selective mediastinal or hilar lymph nodes biopsies.42,43 Doycheva et al. reported on 2 patients with occlusive retinal vasculitis who showed abnormal PET/CT despite negative chest x-rays. Their QuantiFERON TB-Gold tests were positive but other workup was negative. Transbronchial needle-aspiration biopsy of these 2 patients resulted in positive culture and successful resolution of uveitis after anti-TB treatment.42
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FIGURE 1. Recommended treatment algorithm in patients with uveitis who undergo QuantiFERON-TB Gold testing. TB, tuberculosis; QFT, QuantiFERON-TB Gold; Tx, treatment; T-SPOT.TB, ELISpot assay; LTB, latent tuberculosis; ATT, anti-tubercular therapy; Eval, evaluation.
However, this imaging modality may not be available or affordable in most settings. Thirdly, ophthalmologists should determine whether patients need prophylaxis before initiating any systemic immunosuppression. Tuberculosis must be excluded when considering the use of biologics such as anti-TNF agents given the evidence of increased risk for systemic, disseminated TB with the use of these agents.44–46 However, we recommend repeating the IGRA test, especially in weakly positive patients. In a study of 1485 patients who were tested for IGRA prior to starting biologics for autoimmune diseases, a high proportion (69%) of weakly positive cases yielded negative result within 10 weeks of positive tests (the reversion phenomenon previously discussed).47 Furthermore, 48% of 25 IGRA-positive patients who had a repeat test after 1 year without TB had reverted to negative result.47 The evidence is not as clear for the risk of reactivation of tuberculosis with the use of other anti-metabolites or calcineurin inhibitors. A recent meta-analysis of 49 studies reported significantly increased risk of TB with the use of TNF inhibitors compared to other synthetic disease-modifying anti-
rheumatic drugs.48 Few reports documented the reactivation of TB in patients whose regimen had switched from azathioprine to mycophenolate mofetil.49,50 At the moment there are no standard recommendations for TB screening, treatment, or prophylaxis in patients on anti-metabolites or calcineurin inhibitors. Tuberculosis is an important multisystemic disease in both endemic and nonendemic settings. The diagnosis of ocular TB is often difficult to make and IGRAs must be interpreted in conjunction with clinical findings and collaboration with other subspecialties. Prompt treatment of uveitis and determination of need for ATT is critical and can lead to favorable outcomes. Further studies are needed to establish the standard approach in TB diagnosis, treatment, and prophylaxis regimen.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Ocular Immunology & Inflammation
Ocular Tuberculosis—A Clinical Conundrum This work was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.
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19. Ang M, Wong W, Ngan CCL, Chee S-P. Interferon-gamma release assay as a diagnostic test for tuberculosis-associated uveitis. Eye. 2012;26:658–665. 20. Lee Y-M, Park K-H, Kim S-M, et al. Risk factors for falsenegative results of T-SPOT.TB and tuberculin skin test in extrapulmonary tuberculosis. Infection. 2013;41:1089–1095. 21. Kurup SK, Buggage RR, Clarke GL, et al. Gamma interferon assay as an alternative to PPD skin testing in selected patients with granulomatous intraocular inflammatory disease. Can J Ophthalmol. 2006;41:737–740. 22. Modorati G, Berchicci L, Miserocchi E, et al. Clinical application of an in-house ELISPOT assay in patients with suspicious tuberculous uveitis and no signs of active tuberculosis. Eur J Ophthalmol. 2012;22:808–813. 23. Itty S, Bakri SJ, Pulido JS, et al. Initial results of QuantiFERON-TB Gold testing in patients with uveitis. Eye. 2008;23:904–909. 24. Slater ML, Welland G, Pai M, et al. Challenges with QuantiFERON-TB Gold assay for large-scale, routine screening of U.S. healthcare workers. Am J Respir Crit Care Med. 2013;188:1005–1010. 25. Pai M, Joshi R, Dogra S, et al. Serial testing of health care workers for tuberculosis using interferon-gamma assay. Am J Respir Crit Care Med. 2006;174:349–355. 26. Gaur RL, Pai M, Banaei N. Impact of blood volume, tube shaking, and incubation time on reproducibility of QuantiFERON-TB Gold in-tube assay. J Clin Microbiol. 2013;51:3521–3526. 27. Gineys R, Bodaghi B, Carcelain G, et al. QuantiFERON-TB gold cut-off value: implications for the management of tuberculosis-related ocular inflammation. Am J Ophthalmol. 2011;152:433–440.e1. 28. Vos AG, Wassenberg MWM, de Hoog J, Oosterheert JJ. Diagnosis and treatment of tuberculous uveitis in a low endemic setting. Int J Infect Dis. 2013;17:e993–e999. 29. Gupta V, Gupta A, Rao NA. Intraocular tuberculosis—an update. Surv Ophthalmol. 2007;52:561–587. 30. Gupta A, Bansal R, Gupta V, et al. Ocular signs predictive of tubercular uveitis. Am J Ophthalmol. 2010;149:562–570. 31. Ang M, Hedayatfar A, Zhang R, Chee S-P. Clinical signs of uveitis associated with latent tuberculosis. Clin Exp Ophthalmol. 2012;40:689–696. 32. Nazari Khanamiri H, Rao NA. Serpiginous choroiditis and infectious multifocal serpiginoid choroiditis. Surv Ophthalmol. 2013;58:203–232. 33. Cunningham ET, Gupta A, Zierhut M. The creeping choroiditides—serpiginous and multifocal serpiginoid choroiditis. Ocul Immunol Inflamm. 2014;22:345–348. 34. Grosse V, Bange FC, Tischendorf J, et al. A mass in the eye. Lancet. 2002;360:922. 35. Ang M, Hedayatfar A, Wong W, Chee S-P. Duration of antitubercular therapy in uveitis associated with latent tuberculosis: a case-control study. Br J Ophthalmol. 2012;96: 332–336. 36. Basu S, Das T. Pitfalls in the management of TB-associated uveitis. Eye. 2010;24:1681–1684. 37. Zhang M, Zhang J, Liu Y. Clinical presentations and therapeutic effect of presumed choroidal tuberculosis. Retina (Philadelphia, Pa). 2012;32:805–813. 38. Bansal R, Gupta A, Gupta V, et al. Tubercular serpiginouslike choroiditis presenting as multifocal serpiginoid choroiditis. Ophthalmology. 2012;119:2334–2342. 39. Rosenbaum JT. To be or not TB? Br J Ophthalmol. 2014;98:999–1000. doi:10.1136/bjophthalmol-2014-304883. 40. Ganesh SK, Roopleen, Biswas J, Veena N. Role of high-resolution computerized tomography (HRCT) of the chest in granulomatous uveitis: a tertiary uveitis clinic experience from India. Ocul Immunol Inflamm. 2011;19: 51–57.
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C. Lee et al. 46. Fonseca JE, Lucas H, Canha˜o H, et al. Recommendations for the diagnosis and treatment of latent and active tuberculosis in inflammatory joint diseases candidates for therapy with tumor necrosis factor alpha inhibitors: March 2008 update. Acta Reumatol Port. 2008;33:77–85. 47. Felber A, Graninger W. Weakly positive tests and chronologic variation of the QuantiFERON assay: a retrospective appraisal of usefulness. Tuberculosis (Edinb). 2013; 93:647–653. 48. Ramiro S, Gaujoux-Viala C, Nam JL, et al. Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2014. doi:10.1136/annrheumdis-2013-204575. 49. Mercadal L, Foltz V, Isnard-Bagnis C, et al. Tuberculosis after conversion from azathioprine to mycophenolate mofetil in a long-term renal transplant recipient. Transplant Proc. 2005;37:4241–4243. 50. Skhiri H, Guedri Y, Souani Y, et al. Primary tuberculosis 1 year after conversion from azathioprine to mycophenolate in recipient kidney transplantation: a case report. Transplant Proc. 2003;35:2678–2679.
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41. Mehta S. Patterns of systemic uptake of 18-FDG with positron emission tomography/computed tomography (PET/CT) studies in patients with presumed ocular tuberculosis. Ocul Immunol Inflamm. 2012;20: 434–437. 42. Doycheva D, Pfannenberg C, Hetzel J, et al. Presumed tuberculosis-induced retinal vasculitis, diagnosed with positron emission tomography (18F-FDG-PET/CT), aspiration biopsy, and culture. Ocul Immunol Inflamm. 2010;18: 194–199. 43. Doycheva D, Deuter C, Hetzel J, et al. The use of positron emission tomography/CT in the diagnosis of tuberculosis-associated uveitis. Br J Ophthalmol. 2011; 95:1290–1294. 44. van der Klooster JM, Bosman RJ, Oudemans-van Straaten HM, et al. Disseminated tuberculosis, pulmonary aspergillosis and cutaneous herpes simplex infection in a patient with infliximab and methotrexate. Intensive Care Med. 2003;29:2327–2329. 45. Nacci F, Matucci-Cerinic M. Tuberculosis and other infections in the anti-tumour necrosis factor-alpha (anti-TNF-a) era. Best Pract Res Clin Rheumatol. 2011;25:375–388.
Ocular Immunology & Inflammation
ISSN: 0927-3948 (Print) 1744-5078 (Online) Journal homepage: http://www.tandfonline.com/loi/ioii20
Ocular Tuberculosis—A Clinical Conundrum Cecilia Lee MD, Rupesh Agrawal FRCS, MMed & Carlos Pavesio MD To cite this article: Cecilia Lee MD, Rupesh Agrawal FRCS, MMed & Carlos Pavesio MD (2015): Ocular Tuberculosis—A Clinical Conundrum, Ocular Immunology and Inflammation, DOI: 10.3109/09273948.2014.985387 To link to this article: http://dx.doi.org/10.3109/09273948.2014.985387
Published online: 25 Jun 2015.
Submit your article to this journal
Article views: 69
View related articles
View Crossmark data
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ioii20 Download by: [41.190.173.211]
Date: 27 September 2015, At: 02:57
Ocular Immunology & Inflammation, Early Online, 1–6, 2015 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2014.985387
EDITORIAL
Ocular Tuberculosis—A Clinical Conundrum Cecilia Lee,
MD
1,2
, Rupesh Agrawal,
FRCS, MMed
1,3
, and Carlos Pavesio,
MD
1
Department of Medical Retina, Moorfields Eye Hospital, London, UK, 2Department of Ophthalmology, University of Washington, Seattle, Washington, USA, and 3Department of Ophthalmology, National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore
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The World Health Organization (WHO) estimated 5.8 million newly diagnosed cases of tuberculosis and 8.7 million people who were ill with tuberculosis (TB) in 2011.1 Tuberculous uveitis still represents a minority of uveitis cases, with varying prevalence ranging from 1–4% to 10–26% in different areas of the world.2–4 Despite significant research over the past decades, the diagnosis of ocular TB remains a challenge and poses a major conundrum to both ophthalmologists and respiratory physicians. More often than not, there is lack of synchrony between ophthalmologists and physicians for instituting anti-tubercular treatment (ATT) due to lack of gold standard criteria to diagnose ocular TB. Published literature varies significantly on criteria for diagnosis of ocular tuberculosis, defining the relapse or recurrence of the latent tuberculosis in the eye, the duration of ATT, and the role of corticosteroids or immunosuppressive treatment. A definite diagnosis of tuberculous uveitis can be confirmed by performing acid-fast smears, mycobacterial cultures, or polymerase chain reaction (PCR)based assays on ocular fluids.5,6 However, the sensitivities of these tests are fairly low, making definitive diagnosis difficult.7–9 Recent studies with multitarget PCR for TB-related uveitis have shown promising results with high positivity rate,10 and this modality may become readily available in the future, allowing a definitive diagnosis.11 Currently, a presumptive diagnosis is mainly made clinically with positive TB skin test (TST), positive interferon gamma release assays (IGRA), and lesions on imaging of the chest (chest xray, chest CT scan, PET scan).7 Resolution of uveitis or nonrecurrence of the uveitis post treatment of TB is also supportive of the diagnosis.7
Despite its widespread use, TST has less than ideal sensitivity and specificity in detecting TB.12 It has been used in medicine for the past 100 years but has its own inherent limitations in addition to the lack of standardization for test administration and reading. One of the main difficulties with TST is a high falsepositive rate in patients who were immunized with Bacillus Calmette-Guerin (BCG) vaccine or patients exposed to nontuberculous mycobacteria.13 In patients with severe illness, including active TB and immunodeficiency, TST can be falsely negative.10 Nevertheless, TST is still a valuable screening tool in a high-risk population.14 Hong et al. reported a positive predictive value of TST of 17.2% for all patients and 30.3% for foreign-born patients in a retrospective study of 142 patients (prevalence of 4 and 8%, respectively).14 The advent of interferon gamma release assays (IGRAs) has enabled us to overcome some of the limitations pertaining to TST. IGRAs measure interferon gamma response that sensitized T cells produce to Mycobacterium tuberculosis-specific antigens, such as early secretory antigenic target-6 (ESAT-6), culture filtrate protein-10 (CFP-10), and TB7.7. Because these proteins are not present in BCG vaccine and the majority of environmental mycobacteria, IGRAs allow greater specificity than TST, which uses purified protein derivative. Neither TST nor IGRAs can differentiate between active and latent TB infection. There are two types of IGRAs: the QuantiFERONTB Gold (QFT) (Cellestis, Australia) and ELISpot assay (T-SPOT.TB) (Oxford Immunotec, Oxford, UK). QFT is an enzyme-linked immunoabsorbent assay (ELISA) that quantifies the amount of IFN-gamma released into blood plasma in response to TB antigens.
Received 22 September 2014; revised 26 October 2014; accepted 4 November 2014; published online 22 June 2015 Correspondence: Mr. Carlos Pavesio, Moorfields Eye Hospital, City Road, London EC1V 2PD, UK. E-mail: [email protected]
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ESAT-6 and CFP-10 are two antigens used in QFT. The third generation of this test, QuantiFERON-TB Gold In-Tube (Qiagen, Carnegie, Australia) uses an additional third antigen, TB7.7. The availability of QFT vs. QuantiFERON-TB Gold In-Tube varies in different institutions and countries. QFT is more widely used than T-SPOT.TB due to higher cost and the need for trained personnel for the latter. T-SPOT.TB is a simplified enzyme-linked immunospot assay (ELISpot) that counts TB-specific interferon-gamma secreting T cells. It is both time and temperature sensitive.13 T-SPOT.TB can be more sensitive in patients with reduced T-cell counts, such as those who are immunocompromised.15 Several studies have investigated the sensitivity and specificity of IGRA tests and all agree that IGRAs are more specific than TST, while its sensitivity compared to TST varies among studies.16 A group in Spain reported 90.9% sensitivity and 82.8% specificity of QFT compared to TST, which was 87.8% sensitive and 85.7% specific.17 A retrospective study in India, where there is a high burden of TB, showed both superior sensitivity and specificity of QFT compared to TST. Only 70% of 12 patients who had radiological evidence of TB were positive on TST, while 100% were detected as positive on QFT. 18 In contrast, a study in Singapore, which has an intermediate burden of TB disease, showed that the sensitivity of TST is higher while QFT is more specific in detecting Trelated uveitis.3 The authors recommended using both studies to increase the sensitivity and specificity. Due to its less frequent use there are fewer studies on T-SPOT.TB than on QFT. Ang et al. reported that TST is more sensitive than T-SPOT.TB (72 vs. 36%) but T-SPOT.TB is more specific (75 vs. 51%).19 Positive predictive value increases when both TST and T-SPOT.TB tests are used.19 The sensitivity of TSPOT.TB to diagnose extrapulmonary tuberculosis was higher than that of TST in patients with immunosuppression and miliary TB.20 Since 2006, the UK National Health System recommends that IGRA be used in all patients with positive TST and in all immunocompromised patients. In contrast, the Centers for Disease Control and Prevention in the United States recommends replacing TST with IGRA in high-risk groups but discourages any testing in low-risk groups.16,21 Due to low pretest probability in cases of low clinical suspicion, approximately 90% of positive IGRAs can be false positives.16 Therefore, Albini et al. recommend primary use of IGRAs only in select cases of high suspicion for ocular TB, given increased pre- and post-test probability.16 Positive TST or IGRA results are helpful when accompanied by clinical findings suggestive of tuberculous uveitis. However, a positive QFT without any clinical signs should not be taken as indication for ATT, due not only to the possibility of false positivity
but also to the side effect profile of ATT.7 Interestingly, in a study of 55 patients with suspicious tuberculous uveitis and 233 control subjects, there was 30.5% TST and 25.3% ELISPOT positivity in the control group who had no previous history of uveitis or TB.22 This demonstrates that false positivity or possible latent TB can be very frequent in the general population and screening in cases with no clinical suspicions should be discouraged. One of the major limitations of the IGRA test is lack of prospective data about predicting the risk of active TB in patients with different level of IGRA. Additional points must be considered before ATT is decided in cases of positive QFT without clinical findings. First, its validity needs to be questioned. Reversion, the phenomenon of a QFT test result becoming negative after an initial positive test result, is not uncommon23–25 and has been reported to be as high as 24%.25 Reversion rate is higher in patients whose responses are close to the cutoff threshold. In addition, the test results were shown to change depending on the volume of collected blood and how vigorously the sample was shaken.26 Several articles outside of ophthalmology discuss how the threshold between a positive and negative result for QFT should change based on the prevalence of TB24,25; therefore, caution must be taken when interpreting test results in low endemic areas. As there is wide range of positive values of QFT, a stratification approach for different levels of QFT and correlation analysis with different endemic groups may give us more insight into the predictive value of the IGRA test in patients with latent TB. Second, there is no standard treatment regimen or length of therapy for tuberculous uveitis. Similarly, there are no treatment guidelines for recurrent uveitis after completion of ATT. The positive response to ATT—defined as resolution of uveitis after full course of ATT—has been reported in approximately 60–70%.27,28 One may argue that those who did not respond to ATT could have been false positives or could have been undertreated. One must carefully review a patient’s medical history, including possible exposure and immune status, and examine all the clinical findings that are associated with tuberculous uveitis. There are numerous reports describing varied clinical signs representing presumed ocular TB but the level of evidence for association still needs to be established.18,29-31 Of all the clinical manifestations, the presence of choroidal granulomas, occlusive retinal vasculitis, and multifocal serpiginoid choroiditis32,33 has been more strongly associated with presumed ocular tuberculosis. In particular, choroidal granulomas should raise a high index of suspicion34,35 and failure to recognize them could lead to devastating consequences.36 In a series of 18 cases with choroidal tuberculosis, Zhang et al. have demonstrated a positive treatment outcome with a course of Ocular Immunology & Inflammation
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Ocular Tuberculosis—A Clinical Conundrum ATT, and emphasized that the choroidal involvement is an important phenotype of intraocular tuberculosis.37 Bansal et al. reported a decreased relapse rate in a series of 141 eyes (105 patients) with multifocal serpiginoid choroiditis after ATT.38 However, in the absence of these phenotypes, one should consider treatment of the uveitis without ATT. To our knowledge, there has been no study that has investigated the outcome of patients with positive QFT who did not receive ATT. However, few articles included subsets of patients who had positive IGRA but did not undergo ATT. In a retrospective study that included 66 patients with suspected tuberculous uveitis, there were a total of 24 positive QFT or TST.28 Fourteen out of 24 patients did not receive ATT because it was felt that the suspicion for TB-related uveitis was not high enough to justify ATT. Of these 14 patients, 6 of them improved with conventional immunosuppression treatment without ATT, while the remaining 8 did not improve on immunosuppression but still did not require ATT. The authors have not qualified the outcome further except that this group did not require further ATT and remained at status quo without further worsening or deterioration. In a study by Gineys et al.,27 17 out of 42 patients who had positive QFT tests did not receive ATT, as 5 of them refused treatment with ATT, 6 had ATT within last decade, 5 had mild anterior uveitis, and 2 were diagnosed with multiple sclerosis and sarcoidosis. Four of them were due to lack of clinical suspicion and did well without ATT during the follow-up. Third, the need for TB prophylaxis in case of systemic immunosuppression is not well defined. In a series of 12 patients with granulomatous uveitis reported by Kurup et al.,21 8 of them had positive quantiFERON-TB (first-generation QFT). Only 2 of them underwent ATT—both had posterior uveitis, one had a granuloma seen in CXR, and both were later diagnosed with TB meningitis. Four patients with positive quantiFERON-TB test were placed on multiple systemic immunosuppression agents without ATT. They were closely monitored and 2 of these patients later developed additional clinical signs, such as hilar lymphadenopathy, and were diagnosed with sarcoidosis. This study argues that patients can be treated with immunosuppression without ATT despite positive QFT when clinical suspicion is weak and patients are followed carefully during the course of the treatment. The practice pattern of treating TB-related uveitis differs widely among physicians, depending on their geographic location, prevalence of TB, and personal experience of treating TB-related uveitis. In the United Kingdom, we follow a similar approach to screening a selected cohort of patients with high index of suspicion as has been highlighted by Rosenbaum in his editorial.39 In our own experience working in a !
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tertiary referral unit, the clinical signs, even though mostly nonspecific, still carry a significant weight on the decision to investigate and treat cases of suspected TB-related uveitis (Figure 1). Figure 1 shows the algorithm in evaluating any uveitic patient at our institution. During a basic uveitis workup, all patients with positive CXR are referred to pulmonary physicians regardless of QFT results. We do not routinely obtain QFT tests unless there are suspicious clinical signs, such as choroidal granulomas, occlusive retinal vasculitis, or multifocal serpiginoid choroiditis. Aqueous/vitreous sampling or intraocular tissue biopsy is not commonly performed due to low sensitivity in our setting. In patients with clinical findings suggestive of TB, it is the clinical suspicion that dictates their workup regardless of CXR or QFT results. Chest CT or positron emission tomography (PET) is considered in rare cases of high clinical suspicion. Recently, high-resolution CT scan of the chest has increased the detection rate of chest involvement in patients with presumed ocular TB with normal chest x-rays. One study of 58 patients demonstrated that up to 81% of referred patients had evidence of healed lesions suggestive of TB on chest CT.40 Furthermore, Mehta reported that the PET scan allowed accurate determination of systemic involvement in 11 patients with suspicions of TB.41 In this study, increased uptake in various organs such as chest, abdomen, and joints was detected. Thus, chest CT and PET scan can provide additional information in cases of presumed ocular TB with negative chest x-rays. There are several important points when addressing patients with positive QuantiFERON assays. First, treating ophthalmologists will likely dictate TB treatment decision. The majority of patients referred to an infectious disease unit due to a suspicion of tuberculous uveitis will lack any clinical signs of a systemic disease on routine investigations and the decision to treat will be based largely on the referring ophthalmologist. This reflects the importance of adequately referring patients for whom there is a high index of suspicion of TB uveitis, based on history of exposure and supportive clinical findings. Secondly, treating ophthalmologists should discuss with infectious disease colleagues whether further investigations such as chest CT or PET scans are necessary when clinical suspicions are high. Recent studies suggest that abnormal PET/CT could guide more selective mediastinal or hilar lymph nodes biopsies.42,43 Doycheva et al. reported on 2 patients with occlusive retinal vasculitis who showed abnormal PET/CT despite negative chest x-rays. Their QuantiFERON TB-Gold tests were positive but other workup was negative. Transbronchial needle-aspiration biopsy of these 2 patients resulted in positive culture and successful resolution of uveitis after anti-TB treatment.42
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FIGURE 1. Recommended treatment algorithm in patients with uveitis who undergo QuantiFERON-TB Gold testing. TB, tuberculosis; QFT, QuantiFERON-TB Gold; Tx, treatment; T-SPOT.TB, ELISpot assay; LTB, latent tuberculosis; ATT, anti-tubercular therapy; Eval, evaluation.
However, this imaging modality may not be available or affordable in most settings. Thirdly, ophthalmologists should determine whether patients need prophylaxis before initiating any systemic immunosuppression. Tuberculosis must be excluded when considering the use of biologics such as anti-TNF agents given the evidence of increased risk for systemic, disseminated TB with the use of these agents.44–46 However, we recommend repeating the IGRA test, especially in weakly positive patients. In a study of 1485 patients who were tested for IGRA prior to starting biologics for autoimmune diseases, a high proportion (69%) of weakly positive cases yielded negative result within 10 weeks of positive tests (the reversion phenomenon previously discussed).47 Furthermore, 48% of 25 IGRA-positive patients who had a repeat test after 1 year without TB had reverted to negative result.47 The evidence is not as clear for the risk of reactivation of tuberculosis with the use of other anti-metabolites or calcineurin inhibitors. A recent meta-analysis of 49 studies reported significantly increased risk of TB with the use of TNF inhibitors compared to other synthetic disease-modifying anti-
rheumatic drugs.48 Few reports documented the reactivation of TB in patients whose regimen had switched from azathioprine to mycophenolate mofetil.49,50 At the moment there are no standard recommendations for TB screening, treatment, or prophylaxis in patients on anti-metabolites or calcineurin inhibitors. Tuberculosis is an important multisystemic disease in both endemic and nonendemic settings. The diagnosis of ocular TB is often difficult to make and IGRAs must be interpreted in conjunction with clinical findings and collaboration with other subspecialties. Prompt treatment of uveitis and determination of need for ATT is critical and can lead to favorable outcomes. Further studies are needed to establish the standard approach in TB diagnosis, treatment, and prophylaxis regimen.
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Ocular Immunology & Inflammation
Ocular Tuberculosis—A Clinical Conundrum This work was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health.
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