Clinical controversy: to treat, or not to treat? That is the tuberculosis question

Tuberculosis (TB) is a multisystem disease caused by Mycobacterium tuberculosis and has been described since ancient times. It is the most common cause of infectious disease-related mortality worldwide. Diagnosis is notoriously difficult due in part to the myriad of signs and symptoms associated with the condition. A fifth of patients with active TB have extrapulmonary disease, and of these, 60% have no pulmonary signs. In contrast, latent TB infection describes a state of persistent immune response to previously acquired M. tuberculosis antigens without evidence of clinically manifest TB. These patients do not develop active disease either because their immune system controls the mycobacteria or they are no longer infected with live bacteria. However, approximately 10% of these patients will develop active infection at some time (this is higher if the patient is immunosuppressed). The diagnosis of active extraocular TB is usually straightforward, where microbiological evidence is obtained from a tissue biopsy. Diagnosis of active intraocular TB in the absence of extraocular TB is more difficult, as ocular samples for microscopy (acid fast bacilli), culture or evidence from polymerase chain reaction are required to prove ocular TB – and such tests have a low sensitivity. The reason for this may be due to the low level of inoculum or, more commonly, that there is in fact no active disease (latent infection) and the inflammation is immune-driven. The presumptive diagnosis of active or latent TB-related uveitis in the absence of extraocular disease is therefore made on the basis of clinical suspicion in regards to ocular signs, patient contacts/ country of origin, and with the aid of adjunctive tests such as chest X-ray, interferon-gamma (IFN-g) release assays and the tuberculin skin test. IFN-g release assays (Quantiferon Gold, T-SPOT.TB) measures a component of cell-mediated immune reactivity to M. tuberculosis. The tests are based on the quantification of IFN-g released from sensitized lymphocytes in whole blood incubated overnight with purified protein derivative from M. tuberculosis and control antigens. It does not differentiate between active and latent TB. The benefit over the tuberculin skin test is that it eliminates reader error and is not affected by prior Bacilli Calmette–Guerin vaccination or immune reactivity to non-tuberculous mycobacteria. An article by Ang et al. in the current issue of this Journal attempts to identify clinical signs and their use in combination with other investigations such as chest X-ray and an IFN-g based assay to diagnose latent TB. All patients with presumed latent TB infection had no other cause for the uveitis, had received at least 6 months of anti-TB therapy and had had a positive response to treatment with no relapse for a year following completion of the course of therapy. The idea of predictive clinical signs is an attractive one, although as the authors also point out, the protean nature of TB is such that the disease is different in endemic areas compared with countries where there is a low burden of disease. The article also touches on the issue of how to treat uveitis that is presumed to be due to latent TB. Some groups advocate full treatment for TB, as it has been hypothesized that bacterial elimination will likely prevent the formation of antigen responsible for the immune response. However, the treatment of TB is arduous for doctors and patients alike. A standard regime is four drug therapies: isoniazid, rifampacin, pyrazinamide, and either ethambutol or streptomycin for 2 months; they are then treated with a continuation phase of 4 months with isoniazid and rifampicin. This is a lengthy treatment for which there are significant side-effects including neuropathy and hepatitis. In addition, there is the problem of an increasing number of drug-resistant cases because of noncompliance with this full course of therapy. It should also be noted that in many cases of uveitis associated with latent TB, inflammation is not adequately controlled without steroid use. The clinical improvements seen post-treatment could therefore be attributed to concurrent steroid therapy or regression to the mean. Nonetheless, the corollary is that once latent TB has been fully treated, then further immunosuppressive agents can be safely given without risk of causing a future active TB infection.