A retrospective cohort study of patients treated with anti-tuberculous therapy for presumed ocular tuberculosis

Intraocular inflammation, generally termed “uveitis”, may result from a hugely diverse range of causes, both infectious and non-infectious. Uveitis is classified by the predominant anatomical site of inflammation within the eye [1], the cause and whether or not it is related to an infectious agent or an underlying systemic condition [2]. Uveitis is an important cause of visual loss, often affecting the working age population [3, 4].

Uveitis related to tuberculosis is a well-recognized clinical entity, with an extensive literature dating back more than 100 years [5]. In some parts of the world, tuberculosis is one of the principle causes of uveitis [6–9].

Currently, a large proportion of patients in the developed world is described as having “non-infectious”, “idiopathic” or “undifferentiated” uveitis [10, 11]. Often no underlying systemic association or infection is identified despite extensive investigation. If such patients have significant or “sight-threatening” uveitis, they are generally treated with systemic corticosteroid, and sometimes systemic immunosuppression, including biologics [12, 13]. Such therapy is aimed at preventing relapses, as each relapse carries a risk of irreversible visual loss, morbidity and ocular complications [14].

The association between uveitis and “latent” or occult tuberculosis is not new yet has become increasingly relevant. Many patients display clinical appearances identical to those seen in patients with active TB, without demonstrating systemic manifestations of infection. Ocular appearances associated with TB are heterogeneous, making diagnosis challenging, and include (among others) choroiditis, serpiginous-like choroiditis, granulomatous uveitis, retinal vasculitis and intermediate uveitis [15]. In addition, the condition known as “Eales” disease, a bilateral occlusive retinal vasculitis, with minimal inflammation and often complicated by vitreous haemorrhage, is observed more frequently in TB-endemic populations.

A large proportion of the global population will have immunological evidence of latent TB, and consequently, a significant proportion of patients with ocular inflammation will have evidence of latent TB, whether or not it is causal.

Studies investigating intraocular samples provide support for a central role of TB. Analysis of the aqueous humor, vitreous gel or epiretinal membranes using polymerase chain reaction (PCR) methods [16–20] demonstrates that a higher proportion of samples from uveitis patients are positive for the TB genome compared with samples taken from patients in a similar population undergoing surgery for other reasons, and a positive PCR result correlates with a clinical response to anti-tuberculous treatment (ATT) [19, 20].

Traditionally, the tuberculin skin test (Mantoux) has been used to determine whether a patient is infected with TB. The test may be affected by multiple factors, making it hard to determine its significance. More recently, interferon gamma release assays (IGRAs) have added significant controversy to the diagnosis and management of “ocular TB” [21–26]. Such assays, including the T-spot or QuantiFERON GOLD tests rely on the observation that T-cells will release interferon gamma when exposed to a specific TB antigen. The test is highly specific and not affected by previous BCG vaccinations. A positive IGRA test usually indicates that a patient has been exposed to TB; however, it cannot distinguish between latent infection and active disease.

Multiple recent reports support the use of anti-tuberculous therapy (ATT) in patients with a consistent uveitic phenotype and positive TB investigations [27–30]. There is a lack of consensus regarding treatment indications, treatment regimens, investigation protocols and what constitutes a successful outcome. Even the diagnosis of “ocular TB” is not standardized [31].

Importantly, the way in which patients are managed is believed to differ significantly between units, with some uveitis specialists unable to persuade the respiratory physician of the relevance of tuberculosis, whilst other specialists are able to access anti-TB treatment easily and as a result have a very low treatment threshold [32]. Some uveitis specialists elect to refer patients for ATT only if the uveitis is severe, whilst continuing to treat “mild” recurrent anterior uveitis with topical steroid.

The principle indication for using ATT in uveitis is to treat the underlying systemic drive, which is believed to come from occult infection, antigenic mimicry or a hypersensitivity-type reaction to TB antigen. A secondary indication may be to ensure that systemic immunosuppression is safe in the face of a positive T-spot result. This is especially relevant for patients started with anti-TNF therapy [33].

The Birmingham and Midland Eye Centre is located in an inner-city part of Birmingham where the large surrounding population comprises of ethnically diverse communities with a majority of people originating from Southeast Asia, especially countries such as Pakistan, India and Bangladesh, where the prevalence of TB is high.

This was a retrospective evaluation of patient notes. Ethical approval was not required as the project was deemed to be a service evaluation.

Using the regional TB disease register obtained from the regional infectious diseases department, patients who had been diagnosed as having uveitis related to TB and who were started on ATT between 2010 and 2014 were identified. Patients who completed a course of treatment and were followed up for at least 12 months were included in the study.

A retrospective analysis of patient notes was undertaken. Ethical approval was not required as this was deemed to be a service evaluation and made use of anonymized retrospective patient information. Data pertaining to patient characteristics, uveitis phenotype, vision, duration of uveitis prior to therapy, date of commencement of ATT, treatment details, duration of follow-up and disease activity were collected. Data were also collected regarding systemic investigations for TB.

At presentation to the uveitis service, patients underwent a full ophthalmic examination and were assessed with regard to the site and severity of their uveitis, using the SUN criteria [1]. A full systemic workup was undertaken, and patients underwent an extensive panel of investigations, with the aim of excluding other causes. All underwent chest radiograph or CT scan, with most also undergoing Mantoux testing or interferon gamma release assay, usually using T-spot. Investigations were not protocolized, and patients were investigated appropriately in an individualized fashion.

A consistent ocular phenotype, together with findings on chest imaging and/or positive T-spot or Mantoux testing, with the exclusion of other causes of uveitis, led to a diagnosis of presumed ocular TB.

Following this diagnosis, patients were referred urgently to the respiratory team where they were investigated further as necessary. Throughout the course of the study, the availability and use of interferon gamma release assays increased. This meant that some patients were not diagnosed with TB-related uveitis until a significant period of ocular inflammation had lapsed.

In most patients, disease activity was observed as a number of relapses, rather than continual inflammation. Treatment with anti-inflammatory medication, mainly corticosteroids, was used. These were administered topically, peri-ocularly or systemically. Relapse on withdrawal of therapy warranted repeat treatment.

Ocular disease activity was quantified using the number of “flare-ups” of uveitis. A uveitis “flare” was defined as the need for augmentation of treatment, with high-dose oral steroid (usually at least 40 mg daily tapered over several weeks), intravenous steroid, periocular steroid or hourly topical steroid. Where possible, “flare rate” prior to ATT was defined as the number of flare-ups per unit time of disease. Calculating a “flare rate” was not possible if a patient was treated with ATT immediately or had a very short duration of disease prior to ATT.

The principal finding from this study is that ATT in a real-life clinical setting appears to significantly reduce the number of flare-ups and to enable long-term remission in patients with presumed ocular tuberculosis. This beneficial effect appears to persist even in patients who experienced a long delay between the onset of uveitis and the diagnosis of ocular TB.

The patient cohort is diverse and strict diagnostic criteria are absent, requiring a high degree of clinical judgment and collaboration between specialists when treating such patients.

The study has limitations in view of the “real-life” clinical setting. Many were lost to follow-up or non-compliant with ATT. “Flare rate” was used as a measure of disease activity but may not accurately reflect disease in patients with ongoing activity, where uveitis is chronically uncontrolled, or being suppressed with corticosteroid. ATT was not standardized, and consequently, patients received a range of regimens. The majority however received at least 6 months of therapy. There is evidence to support treating patients for at least 9 months [29] although a wide range of treatment regimens and durations is reported in the literature.

Recent studies investigate therapeutic outcomes and the beneficial effects of ATT. One meta-analysis concluded that ATT in the management of patients with presumed ocular TB enabled remission in 84% [30]. Another large analysis explored whether any factors were associated with a poorer outcome and found that prior immunosuppression and/or a high absolute QuantiFERON GOLD level were associated with poorer resolution of inflammation post-ATT or an ongoing need for systemic steroid [34].

This study highlights challenges and controversies in defining outcomes in such cohorts. We attempted to look at therapeutic outcomes in a number of ways, including comparing flare rates pre and post, reporting time to flare using Kaplan-Meier survival curves and also calculating “flare rates” before and after treatment. We also recognize that such measures may introduce bias and favour a benefit in patients with a short period of disease prior to the use of ATT. For this reason, we compared results between patients with a long duration of disease and a shorter duration of disease prior to ATT. Despite some patients experiencing significant delays in being started on ATT, we showed that such patient still displayed a clear benefit from treatment.

We did not report visual outcomes or complications. Whilst we show that there is a significant treatment benefit, even when duration of uveitis is long, patients with longer disease courses prior to ATT will be more likely to suffer visual loss and complications. Therefore, early treatment should be recommended [35].

In conclusion, this retrospective study shows that despite the unresolved controversies regarding diagnosis, the relevance of interferon gamma assays and what exactly ocular tuberculosis is, if patients have a consistent uveitis phenotype and other uveitic causes are excluded, then ATT is likely to have a beneficial effect.