Experimental Ocular Tuberculosis in Guinea Pigs

Mycobacterium tuberculosis infects one-third of the global population and claims 2 million lives annually.1 Although the rate of infection varies geographically, it roughly reflects the economic status of a nation. Tuberculosis (TB) is hyperendemic in Africa, with more than 250 cases per 100 000 population, and there are 100 to 249 cases per 100 000 population in Southeast Asia, China, and Russia.2 The rate of infection is relatively low (<10 cases per 100 000 population) in North America, certain European countries, and Australia. However, because of population migration from highly endemic regions, the citizens of countries with low endemic TB rates remain at risk for this important infection. Extrapulmonary TB can occur during primary infection or after reactivation of a latent focus. In the United States, approximately 20% of patients with TB, but more than half of patients with human immunodeficiency virus or AIDS, have extrapulmonary TB; the risk of dissemination correlates with the degree of immunosuppression.3,4 After inhalation into the lungs, the tubercle bacilli may disseminate hematogenously or via the lymphatic system to most organ systems, including the eye. Although tuberculous ocular changes may occur in conjunction with active pulmonary infection, they are commonly seen in isolation, without clinical evidence of pulmonary disease.5 The diagnosis of ocular TB may be challenging in patients with isolated ocular findings, particularly in the absence of invasive diagnostic procedures, such as analysis of ocular fluids and/or tissue by mycobacterial culture, histological analysis, and nucleic acid amplification techniques. Of the various ophthalmic changes seen in patients with TB, uveitis is the most common clinical feature5 Among patients with uveitis, the prevalence of intraocular TB is about 10% in developing countries and less than 1% in the Los Angeles area.5,6 In both the developing and the developed world, a common clinical manifestation of intraocular TB is posterior uveitis mimicking various uveitis entities, including multifocal choroiditis, serpiginous choroiditis, retinal vasculitis, mass lesion in the choroid, or subretinal abscess.5,7–9 Establishing a diagnosis of TB in these cases may be challenging because many patients may lack systemic or pulmonary symptoms and some may have a chest radiograph without signs of TB and a negative response on a tuberculin skin test. Although polymerase chain reaction (PCR)-based detection of M tuberculosis DNA in intraocular fluids can be useful, the sensitivity of this molecular technique appears to be suboptimal.5,10 In most instances, the diagnosis of TB uveitis is a clinical one, usually made retrospectively when patients respond to empirically administered anti-TB agents.5 Because anti-TB therapy can be associated with significant adverse effects, including drug-induced hepatitis, accurate etiologic diagnosis is important. Our understanding of pulmonary TB pathogenesis has been assisted greatly by the availability of well-established animal models.11 In contrast, the pathogenesis of intraocular TB remains poorly understood, partly because of the lack of adequate animal models that accurately simulate human disease. Although experimental ocular TB has been reported in rabbits, primates, guinea pigs, and other animals, the ocular infection was induced either by direct intraocular administration or by intracarotid injection of the infectious agent.12–18 Such models are deficient because they do not reproduce the natural route of infection through the lungs. In this study, we attempted to develop a model of ocular TB resulting from hematogenous dissemination of M tuberculosis following aerosol delivery of the organisms to guinea pig lungs.19 All such exposed animals developed pulmonary TB, and several also showed ocular involvement, with histopathological features virtually identical to those observed in human ocular TB. We also assessed the efficacy of systemically administered standard anti-TB drugs in preventing intraocular changes in this model.