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 [6,7,8,9].
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 [16,17,18,19,20] 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” [21,22,23,24,25,26]. 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 [27,28,29,30]. 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.
Aims and objectives
The aims of this study were first, to define and report the treatment outcomes of patients, who received anti-tuberculous therapy for uveitis, and second, to characterize the patient cohort seen at the Birmingham and Midland Eye Centre who were diagnosed as having ocular TB.
