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Abstract
Aim To study the effect of the duration of anti-tubercular treatment (ATT) on the recurrence of uveitis associated with latent tuberculosis (TB).
Methods Retrospective review of all consecutive uveitis patients seen at a single, tertiary institution over 9 years with uveitis consistent with TB, positive tuberculin skin test with other causes ruled out, and a minimum of 6 months follow-up after completion of treatment. Clinical characteristics, treatment type, treatment duration and clinical response were recorded. Our main outcome measure was the effect of ATT duration on the recurrence of inflammation.
Results Of the 182 eligible patients, 46 received ATT of ≥6 month's duration; 18 patients defaulted and received <6 months treatment. The patients' mean age was 45.3±13.2 years and most were female (n=118, 57.6%) and of Chinese race (n=104, 50.7%). Patients who completed >9 months ATT were less likely to develop recurrence compared with those not treated with ATT (OR 0.09; 95% CI 0.01 to 0.76; p=0.027), while adjusting for potential confounders such as patient demographics, anatomical location of uveitis and corticosteroid therapy.
Conclusion Patients with uveitis and latent TB treated with ATT of >9 months duration had an 11-fold reduction in the likelihood of recurrence.
- Choroid
- infection
- inflammation
- immunology
- iris
- ciliary body
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Introduction
Most tuberculosis (TB) infections (up to 80%) are latent and 10% of these latent infections will become active later in life.1 Latent TB infection (LTBI) is diagnosed when a person is infected with Mycobacterium tuberculosis but does not manifest clinically active TB. The tuberculin skin test (TST), which has been used for more than a century,2 is still widely employed in the diagnosis of LTBI, on which hinges the decision to commence anti-tubercular treatment (ATT).3 Patients with uveitis often have no underlying aetiology detected and are commonly labelled as having ‘idiopathic uveitis’.4 In Singapore, a developed country with an intermediate burden of TB, the association of latent TB with idiopathic uveitis is controversial.5 6 Although no other underlying disease other than latent TB is found in these cases, the diagnosis of ocular TB cannot be confirmed as there is often no evidence of M. tuberculosis in their ocular samples.7
Tubercular uveitis may be due to an active ocular infection by M. tuberculosis or an immune-mediated reaction to LTBI. In order to make a definitive diagnosis, the presence of M. tuberculosis in ocular biopsies must be confirmed either by growth in cultures, the presence of acid-fast bacilli on smears or the detection of M. tuberculosis DNA using PCR.8 9 As the low sensitivity of these tests often results in negative findings, most diagnoses of tubercular uveitis are presumptive, and are based on either a positive TST, lesions suggestive of previous M. tuberculosis infection on chest x-ray (CXR), or associated systemic TB infections.8
Earlier studies suggest that tubercular uveitis is, at least in part, due to an active ocular infection by M. tuberculosis. Bansal et al reported that the addition of ATT to steroids in the treatment of uveitis associated with latent or manifest TB leads to a significant reduction in the recurrence of uveitis.10 Other studies have also reported beneficial effects of ATT in the management of uveitis associated with TB.7 11–13 However, the ATT regimen used and the treatment duration vary in these studies. There are currently no guidelines governing the management of tubercular uveitis, and randomised control trials have not yet been performed to evaluate the efficacy of the different treatment regimes.14 Thus, the aim of this study was to investigate how the duration of treatment with a standard ATT regimen affects the rate of recurrence in patients with uveitis associated with latent TB.
Materials and methods
We conducted a retrospective review of all patients who presented to the Singapore National Eye Center (SNEC) Ocular Inflammation and Immunology Service over a 9-year period (1 January 2000 – 31 December 2008). Patients who fulfilled the following criteria were included: (1) presence of clinical signs of uveitis suggesting a tubercular cause, such as granulomatous keratic precipitates, retinal vasculitis, serpiginous-like choroiditis,8 15 (2) a positive TST (defined as an induration of ≥15 mm),16 (3) exclusion of all other infectious and non-infectious causes of uveitis and (4) a minimum of 6 months of follow-up from treatment completion. Patients who did not have complete medical records were excluded from the study.
On presentation to our clinic, all patients undergo a thorough systemic review and ocular examination. We tailor our evaluation of patients according to clinical findings. If there is no clear diagnosis, the minimum baseline investigations include a complete blood count, erythrocyte sedimentation rate, C-reactive protein, syphilis screen, urine microscopy, CXR and TST. Interferon-gamma release assays (IGRAs) from blood samples and sputum smear for acid-fast bacilli are performed for patients with suspected TB infection. TST is performed by using the standard Mantoux method via intradermal injection of 2 tuberculin units (TU) of purified protein derivative (PPD) (RT23 SSI – 2 TU/0.1 ml; Statens Serum Institut, Copenhagen, Denmark). The induration is measured at 72 h with a ruler by an independent observer and considered positive if it measures ≥15 mm (cut-off validated for our BCG-vaccinated and intermediate TB endemic population to prevent false-positive results).17 IGRAs such as QuantiFERON-TB Gold In-Tube (QFT, Cellestis Inc., Carnegie, Victoria, Australia) and T-SPOT.TB (Oxford Immunotec, Abingdon, UK) are performed and interpreted according to recommended guidelines.18 Any CXR with evidence of pulmonary TB such as nodules, with or without visible calcification and/or fibrotic scars in the hilar area or upper lobes is considered as a positive CXR finding.3
All patients with a positive TST were referred to infectious disease (ID) physicians in the Singapore General Hospital (SGH) for systemic evaluation. There is minimal incorporation bias in our study, as the decisions for treatment by the ID physicians were independently made, and they were blinded to ocular findings and interpretation of tests by the ophthalmologists. Patients found to have systemic or active TB infection received ATT, while uveitis patients with latent TB (positive TST with no signs of systemic TB infection) were advised on the risk–benefit ratio of receiving ATT—a reduced risk of recurrence of inflammation versus the risk of side effects.19 Patients who consented to treatment received standard ATT according to Centers for Disease Control and Prevention (CDC) guidelines for a minimum of 6 months in total (2 months of four-drug therapy (isoniazid 5 mg/kg daily, rifampicin 450 mg daily, pyrazinamide 30 mg/kg daily and ethambutol 15 mg/kg daily) followed by a 4-month continuation phase of two drugs as recommended).3 Compliance to ATT was monitored by the government hospital (SGH) and TB control unit (TBCU). Patients were initially reviewed at 2 weeks after starting ATT and prescribed corticosteroids if intraocular inflammation was observed to have not changed or to have increased.20 In patients with posterior segment inflammation where ATT was not indicated or who had decided against ATT, oral prednisolone was the systemic corticosteroid of choice, usually with a starting dosage of 1 mg/kg body weight, tapering slowly over the clinical course and discontinued after remission. Any anterior segment inflammation was treated with topical corticosteroids. Patients were reviewed every 2 weeks for 8 weeks, then 2 to 3 monthly (or more frequently as required) to monitor response to therapy.
Patients' demographics, uveitis, investigation results and treatment regimen, including duration of ATT and/or corticosteroid therapy, were recorded. Each patient's uveitis was classified according to the International Uveitis Study Group (IUSG) criteria based on anatomical location.21 The therapeutic response was monitored by one ophthalmologist (SPC) using the SUN Working Group activity score: a two-grade decrease in inflammation was considered an improvement and a repeat episode of two-grade increase in uveitis separated by at least 3 months of inactivity without treatment was considered a recurrence.21 Our main outcome measure was a positive response to treatment, which was based on two aspects: (1) a significant improvement in response to treatment; and (2) no recurrence of inflammation within 6 months from completion of ATT and/or corticosteroid therapy, or a minimum of 1 year from initiation of treatment in patients not prescribed ATT. Our secondary outcome was final best-corrected visual acuity (logarithm of the minimum angle of resolution (logMAR)) and percentage change from presentation compared with visual acuity at 6 months from completion of ATT and/or corticosteroid therapy; or at 1 year from initiation of treatment in patients not prescribed ATT.
Statistical analysis included descriptive statistics, where the mean and SD was calculated for the continuous variables, while frequency distribution and percentages were used for categorical variables. Comparisons between categorical variables were conducted by Fisher's exact test, and the one-way ANOVA test was used for means. Multiple regression (Cox regression) analysis was performed to determine the independent predictors of the hazard of developing a recurrence of uveitis. The estimate of OR and its relative 95% CI were calculated. We estimated that our sample size could detect a difference of 30% in recurrences between groups10 with a power of 80% and α error of 0.05. A p value <0.05 was considered statistically significant. All analyses were performed using STATA version 11 (StataCorp LP).
Results
During this 9-year period, 189 patients met our inclusion criteria, and seven patients with incomplete medical records were excluded. Of the remaining 182 patients, 64 patients were prescribed ATT. Eighteen of these patients defaulted on the therapy and received <6 months of ATT, of which nine stopped ATT due to side effects such as rash (n=5) or mild transient hepatitis (n=4). The remaining 46 patients tolerated and completed at least 6 months of ATT. The overall mean age of our study cohort was 45.3±13.2 years. Most were female (n=118, 57.6%) and of Chinese race (n=104, 50.7%). The overall mean follow-up time was 12.7±6.1 months after completing ATT and/or corticosteroid therapy (if prescribed). There was no significant difference in demographics between patients who were prescribed ATT and those on systemic or topical corticosteroids only. Most of the patients (174/182, 95.6%) had unremarkable CXR and did not have findings suggestive of pulmonary TB as defined in our study. We compared patients who had received standard ATT only (Group A, n=23), standard ATT with systemic corticosteroids (Group B, n=23) and patients who were on systemic or topical corticosteroids only (Group C, n=118)—table 1. Eleven patients (24.0%) of patients who received ATT had a significant improvement in response to treatment with no recurrence of inflammation within 6 months from completion of ATT. On the other hand, 17/118 (14.4%) patients who had corticosteroids only had a positive response to treatment with no recurrence of inflammation within 6 months from completion of corticosteroid therapy.
Characteristics of patients who completed anti-tubercular therapy (ATT) with and/or without steroids
We analysed the effect of ATT duration on the likelihood of recurrence in our study cohort (table 2). We found that patients who had received >9 months of ATT (median 10 months, range 9–15 months) were significantly less likely to develop recurrence compared with those who had not been treated with ATT (OR 0.09, 95% CI 0.01 to 0.76; p=0.027) while adjusting for potential confounders such as age, sex, anatomical location of uveitis or corticosteroid treatment. There was a reduction in recurrence with other treatment durations (<6 months or 6–9 months), which was not statistically significant. Female sex was an independent risk factor for recurrence (OR 2.30, 95% CI 1.18 to 4.48; p=0.015). We also found that there was no effect of corticosteroid therapy on the likelihood of recurrence of inflammation. IGRA positivity was also not found to be significantly associated with higher recurrence rates. Patients who completed at least 9 months of ATT had better visual outcomes at 1 year post-treatment compared with those who had less than 9 months (improvement in best corrected visual acuity from baseline, 20.6% vs 1.9% respectively; p=0.019).
Factors associated with recurrence of inflammation (Cox regression analysis)
Discussion
In our study, patients with uveitis with evidence of latent TB and no other underlying disease, who were treated with ATT for more than 9 months duration, were approximately 11 times less likely to develop recurrence of inflammation compared with patients who had not received ATT. This association was independent of potential confounders such as demographics, classification of uveitis and corticosteroid therapy. On the other hand, patients who were treated with ATT for <6 months or 6–9 months duration did have a reduction in recurrence, but this was not statistically significant—a finding that differs from a previous study.10
There are currently no guidelines for commencement or duration of ATT in patients with uveitis with latent TB. It is known, however, that ATT eliminates LTBI and decreases a person's lifetime risk of developing active TB by 80–90%.3 Although the relationship of LTBI to uveitis is still uncertain, there is growing evidence that ATT could help eliminate M. tuberculosis that is inciting ocular inflammation either from within the eye or elsewhere in the body.7 10 14 15 This is further supported by reports of extra-ocular M. tuberculosis acting as the source of antigen that incites ocular inflammation.22–24 Certain clinical features, such as choroidal abscesses, are associated with a true ocular infection with evidence of M. tuberculosis.25–27 However, most patients with tubercular uveitis do not present with these clinical signs, but instead may have non-specific signs of ocular inflammation.28 As a result, tubercular uveitis is often under-diagnosed.29
Up to 60% of all patients with uveitis are considered to have no known aetiology or to have ‘idiopathic’ disease and may be treated with corticosteroid therapy alone.4 30 Corticosteroids alone dampen the inflammation but need to be continued as long as the inciting trigger is removed. As the role of latent TB in idiopathic uveitis is controversial, many patients with uveitis and no other underlying disease other than LTBI were still treated with corticosteroid therapy without ATT even after consulting with ID physicians. However, we observed recurrences in some of these patients a year after ceasing therapy. This observation supports suggestions that some forms of tubercular uveitis may be an immune-mediated reaction to TB antigens from an insidious infection.22–24 Thus, we believe that ATT eradicates either an unseen M. tuberculosis infection from the body or a small inoculum within the eye, thereby removing the inciting agent for recurrent ocular inflammation.
As there are currently no guidelines on ATT duration; most of our patients with uveitis and latent TB received 6 months of the standard regimen.31 Our study results suggest that a longer duration of more than 9 months of ATT is required for treatment of uveitis associated with latent TB, which is further supported by the following observations. First, our senior author (SPC) observed that many of these patients improved within 2–4 weeks of initiating ATT; by 6 months many patients were quiescent and ATT could be stopped. However, recurrences were seen months after stopping ATT. Some patients required more than 9 months of ATT in order to control the ocular inflammation, and these patients were less likely have recurrence. Second, due to the anatomical barriers that are similar to the eye, we believe that the treatment regimen used for tubercular uveitis should similar to that used for TB meningitis or central nervous system infections.32 Third, ATT is less effective against non-replicating populations of M. tuberculosis; therefore a longer duration of ATT may be required to eradicate M. tuberculosis that replicate slowly in anaerobic sites, such as within the eye.33 Finally, a longer duration of ATT is more effective in eradicating M. tuberculosis, thereby reducing the development of multi-drug resistance that may be a cause for recurrence of infection or inflammation.34 In eyes that develop paradoxical worsening following ATT, ocular structures may harbour actively replicating M. tuberculosis thus requiring high doses of systemic steroid.20 In such eyes, intraocular inflammation often persists beyond 6–9 months, requiring prolonged ATT during steroid therapy. Hence, some of our patients were treated with 9–15 months of ATT (n=25).
Patients with LTBI treated with systemic corticosteroid therapy alone face the potential danger of flare or disseminated manifest TB. Moreover, patients with tubercular uveitis treated with systemic corticosteroids without ATT were found to have poorer visual outcomes.35 Patients in our study who experienced side effects due to ATT (n=9/64, 14.1%) discontinued ATT and did not receive systemic immunosuppressive therapy. Of these, four patients had recurrence of uveitis within 1 year of follow-up. We did not study visual acuity as a main outcome measure, as the course of patients with uveitis would develop a varying degree of complications such as cataract or retinal scarring even after cessation of inflammation. However in our sub-analysis, we did find that patients who received ATT for >9 months had a better visual outcome at 1 year compared with those who did not receive any ATT. We also found that being female was an independent risk factor for recurrence of inflammation, which was also found in another study.10 Though interesting, we too could not find any plausible explanation.
The recommended TST cut-off diagnosis of LTBI is 10 mm.3 In Singapore, we use a TST cut-off of >15 mm to reduce the chances of false positivity and over-treating with ATT.16 We found that TST (>15 mm) and IGRA positivity were not significantly associated with increased recurrence, suggesting that these may not be useful biomarkers for determining likelihood of recurrence. However, we are currently conducting prospective studies to examine this.
Ideally, a randomised control trial is required to confirm our hypothesis. However, the long duration of ATT and follow-up to monitor recurrence would mean that such a study would be difficult to conduct. Thus, we conducted a retrospective cohort study while recognising its limitations. Patients were divided and analysed in groups that were not completely homogeneous for variables such as race and anatomical location of uveitis. However, we used a multivariate analysis to control for these factors to determine our final outcome. Another limitation of our study is the relatively short follow-up duration period. However, we had a mean follow-up of at least 6 months post-completion with mean duration of more than 1 year post-completion, which is comparable to other studies published.10 Further prospective studies should be conducted to confirm our observations.
In conclusion, patients with uveitis associated with latent TB treated with ATT of >9 months duration were less likely to suffer from recurrences compared with those who received corticosteroids without ATT. We recommend that patients with uveitis associated with latent TB, and with no known aetiology other than LTBI to account for their uveitis, be treated with ATT of at least 9 months duration.
References
Footnotes
Competing interests None to declare.
Patient consent Obtained.
Ethics approval Singhealth Institutional Review Board.
Provenance and peer review Not commissioned; externally peer reviewed.