Interferon-γ Release Assay in Tuberculous Scleritis

Scleritis is a painful, often chronic, and potentially destructive ocular inflammation caused by either infectious agents or noninfectious immune reactions. Tuberculosis (TB) is one possible infectious cause of scleritis. In this report, we describe 3 patients in whom use of an interferon (IFN)-γ release assay assisted in the diagnosis of tuberculous scleritis.

A 29-year-old woman was referred for bilateral anterior scleritis refractory to topical corticosteroids. On examination, corrected visual acuities were 1.2 with normal intraocular pressure in both eyes. The sclera was markedly hyperemic in all 4 quadrants bilaterally (Figure 1A). Mild inflammatory cells were present in the anterior chambers in both eyes but the fundi were unremarkable. Laboratory investigations revealed normal chemistry results and blood cell counts; however, the erythrocyte sedimentation rate was elevated at 46 mm/h and results of a tuberculin skin test (TST) were positive with 38 mm of erythema and 18 mm of induration. The initial chest radiograph was unremarkable; however, subsequent chest computed tomography revealed multiple nodular lesions in the lung parenchyma. Results of testing using QuantiFERON-TB 2G (QFT) (Cellestis, Carnegie, Australia), an IFN-γ release assay, were found to be positive (defined as IFN-γ levels >0.35 IU/mL by the laboratory). The patient was diagnosed with tuberculous scleritis and treated with a 3-drug regimen (isoniazid, 300 mg/d; rifampicin, 450 mg/d; and ethambutol hydrochloride, 750 mg/d) for the initial 2 months, followed by the same doses of isoniazid and rifampicin for an additional 7 months. The bilateral scleritis resolved within 1 month after initiating anti-TB treatment (Figure 1B). No recurrences of scleritis were observed over 6 months of follow-up since completing therapy.

A 72-year-old man was referred for unilateral scleritis refractory to topical corticosteroid therapy. His history was remarkable for having been diagnosed with unilateral uveitis in the left eye in 2005 at another hospital, the details of which were unknown. On examination, the corrected visual acuities were 0.5 OU, with normal intraocular pressure. The right eye was entirely normal, but the left eye exhibited marked scleral hyperemia in all 4 quadrants (Figure 2A). In addition, although the vitreous was clear, retinal and choroidal folds in the superior macular area were noted. Laboratory investigation results were positive for the presence of perinuclear antineutrophil cytoplasmic antibodies and an elevated erythrocyte sedimentation rate of 41 mm/h. The TST results showed 40 mm of erythema and 10 mm of induration; however, chest radiography examination was normal. Results of subsequent QFT testing were positive. An orbital computed tomographic scan confirmed diffuse thickening of the posterior eye wall and unilateral anterior and posterior scleritis was diagnosed, possibly due to TB. The patient was treated with a 4-drug regimen (isoniazid, 300 mg/d; rifampicin, 450 mg/d; ethambutol hydrochloride, 750 mg/d; and pyrazinamide, 1500 mg/d) for the first 2 months, followed by the same doses of isoniazid and rifampicin for 7 months. The scleritis improved within 2 months of initiating anti-TB therapy, and no recurrences were observed over 3 months of follow-up since completing treatment (Figure 2B).

A 68-year-old man was referred for unilateral anterior scleritis refractory to topical corticosteroid therapy. On examination, the corrected visual acuities were 1.2, with normal intraocular pressure in both eyes. The right eye was normal, but the left eye showed marked hyperemia of the sclera in 3 quadrants (Figure 3A) but no anterior chamber or posterior segment inflammation. Results of blood tests were unremarkable with a normal erythrocyte sedimentation rate. The chest radiograph was normal; however, the TST results showed 40 mm of erythema and 8 mm of induration. This raised our suspicion of possible TB, and QFT testing was subsequently performed and results were found to be positive. The patient received the same 4-drug regimen as in case 2, and the inflammation responded favorably within 1 month of starting anti-TB treatment, with no recurrences noted (Figure 3B).

Pulmonary TB remains a major health concern in Japan, with an estimated incidence of 21 in 100 000 and an estimated prevalence of 35 767 for 2007, roughly 4 to 5 times that for the United States.¹ Extrapulmonary disease accounts for about 20% of TB cases and can involve virtually any organ of the body, including the lymph nodes, central nervous system, skeletal system, pleura, liver, kidney, and skin.² Although the TST has long been used to support a diagnosis of active or latent TB, it is believed to have low specificity in populations that routinely receive BCG vaccination such as in Japan.³ Recently, IFN-γ release assays have been developed to aid in the diagnosis of TB. The QFT assay measures IFN-γ released when whole blood is stimulated with 2 synthetic peptides, the early secreted antigenic target 6-kDa protein (ESAT-6) and the 10-kDa culture filtrate protein (CFP-10), both found in Mycobacterium tuberculosis but not in the BCG vaccine or in the vast majority of atypical mycobacterium.⁴

In the present report, the TST results were positive or with induration large enough to raise our suspicion of TB and warrant additional QFT testing. We have previously reported that the rate of TST result positivity (induration >10 mm) was roughly 20% among patients with uveitis referred to our Ocular Inflammation Service.³ Although the TST result positivity rate is not known for our patient population with scleritis, our experience in uveitis strongly suggests that a positive TST result alone is insufficient to diagnosis tuberculous ocular inflammation. Recently, Ang and colleagues⁵ have demonstrated that the combination of a positive TST result and a positive QFT result increases the accuracy of diagnosing tuberculous uveitis. The present report also supports the use of both TST and QFT in the diagnosis of tuberculous scleritis.

In summary, our 3 patients presented with scleritis refractory to topical corticosteroid therapy, standard community-based treatment for this condition in Japan. Based on positive TST and QFT results, anti-TB therapy was initiated, with all patients exhibiting improvement of inflammation within 1 to 2 months. Our experience highlights the difficulty in assessing TB as a possible cause of ocular inflammation and the potential of IFN-γ release assays for assisting in that assessment.

Correspondence: Dr Okada, Department of Ophthalmology, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo 181-8611, Japan (aokada@eye-center.org).

Financial Disclosure: None reported.