eMedicine Specialties > Ophthalmology > Infectious Disease

Tuberculosis

Author: Pamela S Chavis, MD, Associate Professor, Department of Ophthalmology, Consulting Staff, Department of Neuro-Ophthalmology, Medical University of South Carolina
Coauthor(s): Susannah K Mistr, MD, Resident Physician, Department of Ophthalmology, University of Maryland Medical Center
Contributor Information and Disclosures

Updated: Nov 7, 2008

Introduction

Background

Tuberculosis (TB) is an infectious disease responsible for significant morbidity and mortality worldwide. The primary causative agent, Mycobacterium tuberculosis, is endemic in the world's population. Worldwide, TB is most common in Africa, the West Pacific, and Eastern Europe, but it may be encountered anywhere. As an AIDS-related opportunistic infection, TB is associated with HIV infections, with dual infections seen frequently. International public health efforts have put a huge curb on the rate of increase in TB in recent years; however, the regions named above are plagued with various combinations of limited resources, multidrug resistant TB, and HIV, and these regions account for continued increase in global TB incidence despite the significant reductions elsewhere.

As many as 2 billion humans are estimated to be infected with the tubercle bacillus. Infection with M tuberculosis is seen most commonly from infected aerosol exposure through the lung or mucous membranes. In immunocompetent individuals, this usually results in a latent/dormant infection; only about 5% of these individuals will later evidence clinical disease. Alterations in the host immune system that can lead to decreased immune effectiveness can allow M tuberculosis organisms to reactivate, and tubercular disease results from a combination of both direct effects from the replicating infectious organism and from subsequent inappropriate host immune responses to tubercular antigens.

Over the last 50 years, anti-TB antibiotics have been developed, resulting in successful therapies for TB. Poor compliance with these therapies has promoted multiple drug resistant (MDR) strains of M tuberculosis, resulting in difficulties in controlling the disease, and threatened a global pandemic in the late 1980s and early 1990s. Reacting to these signals, the World Health Organization developed a plan to try to identify 70% of the world's cases of TB and to completely treat at least 85% of these cases by the year 2000. Out of these goals were born major TB surveillance programs and the concept of directly observed therapy requiring a third party to witness compliance with pharmacotherapy. With worldwide efforts, global detection of smear positive cases rose from 11% (1991) to 45% (2003), with 71-89% of those cases now being completely treated.

Pathophysiology

M tuberculosis primarily is spread as an airborne aerosol from infected to noninfected individuals. The organisms gain access to susceptible hosts through the lung. Initial TB infection usually results in a latent or dormant infection in hosts with normally functioning immune systems. M tuberculosis is a slow-growing obligate aerobe and a facultative intracellular parasite. Because of the unique ability to survive and proliferate within mononuclear phagocytes, M tuberculosis is able to invade local lymph nodes and spread to extrapulmonary sites, usually via hematogenous routes.

Infected end organs typically have high regional oxygen tension (apices of the lungs, kidneys, bones, meninges, eye, and choroid). The principal cause of tissue destruction from M tuberculosis infection is related to the organism's ability to incite intense host immune reactions to antigenic cell wall proteins. TB is a multisystemic disease with myriad presentations and manifestations. Mycobacteria are highly antigenic, and they promote a vigorous, nonspecific immune response. Their antigenicity is due to multiple cell wall constituents, including glycoproteins, phospholipids, and wax D, which activate Langerhans cells, lymphocytes, and polymorphonuclear leukocytes.

Mycobacterium bovis is a key constituent of Freund's adjuvant, frequently used in basic immunology research to stimulate the response to injected antigens. TB is also one of the great imitators for its well-known ability to masquerade as other infectious and disease processes within the human body. The hallmark of extrapulmonary TB histopathology is the caseating granuloma consisting of giant cells with central caseating necrosis. Rarely, if ever, are any TB bacilli seen.

Frequency

United States

The United States has lower rates of TB infection than rates seen worldwide; these rates are comparable to other industrialized nations. An estimated 4-6% of the US population (10-15 million individuals) carries a latent TB infection, while 14,511 new cases of active TB were reported in 2004. A decrease in the number of cases has occurred in the new millennium compared to the dramatic increases of TB in the late 1980s and early 1990s, owing to substantial public health efforts for early detection and therapy compliance. While the initial flare in TB cases in the United States was associated with comorbid HIV, most US cases are now in non-US born individuals who are often immunocompetent.

International

Globally, latent TB infections are comparatively much more frequent and present in one third of the world's population with 20 million cases of active TB and 8-10 million new cases diagnosed each year. The World Health Organization estimated 9 million cases and 2 million deaths from TB for 2005. In Africa, TB incidence has tripled in association with high levels of HIV. Home to 13% of the world's population and 13 of the 15 countries with the highest TB incidence, Africa shoulders over 25% of the annual global TB burden in terms of both cases and deaths. Other areas plagued by high and/or increasing rates of TB include certain regions of Eastern Europe and Southeast Asia.

Mortality/Morbidity

TB is the principal infectious disease cause of morbidity and mortality in the world. TB is responsible for more deaths (2-3 million individuals annually) worldwide than all other infectious diseases combined. In the United States, 2800 TB deaths are reported annually. Immunocompromised patients are particularly vulnerable, with TB as the cause of death in 32% of AIDS patients and a contributor to death in the next 15%. Abnormal leukocyte function occurs with uremia, immunosuppressive medications, and hemodialysis; hence, tuberculosis can be an opportunistic infection in these groups as well. Recently, TNF inhibitors have been noteworthy for their association with tuberculosis.

• In problem areas, multiple drug resistant tuberculosis (MDR-TB) is on the rise. Increasingly mutable strains are suspected. In Russia, 66% of cases of MDR-TB are associated with a specific strain known as the Beijing strain. These infections are much more difficult to treat because of resistance to standard therapy. In California, despite enormous effort to promote therapy compliance, MDR-TB prevalence persisted at 1-2% from 1999-2003.
• Extrapulmonary involvement occurs in one fifth of all TB cases, and 60% of patients with extrapulmonary manifestations of TB have no evidence of pulmonary infection on chest roentegram or sputum culture. Ocular TB can be especially difficult to identify for both its mimickry and its lack of accessible sampling; a high index of suspicion is required. In patients with confirmed active pulmonary or active nonocular extrapulmonary TB, ocular incidence ranges from 1.4-5.74%, but ocular involvement can also occur with nonpulmonary TB. In HIV patients, the incidence may be higher, reported from 2.8-11.4%.

Race

TB has no racial preferences for disease development. Within the United States, minorities account for approximately 70% of diagnosed TB cases. This skewed distribution is most likely due to socioeconomic factors. Elevated rates of TB infection are seen in individuals immigrating from Mexico, Philippines, Africa, Southeast Asia, the Caribbean, and Latin America.

Sex

TB has no sexual predilection for disease development.

Age

Higher rates of TB infection are seen in young nonwhite adults (peak incidence, 25-40 y) compared to white adults who manifest disease later (peak incidence, 70 y).

Clinical

History

TB can affect any structure in the eye and typically presents as a granulomatous process. Keratitis, iridocyclitis, intermediate uveitis, retinitis, scleritis, and orbital abscess are within the spectrum of ocular disease. Choroidal tubercles and choroiditis are the most common ocular presentations of TB. Adnexal or orbital disease may be seen with preauricular lymphadenopathy. Because of the wide variability in the disease process, presenting complaints will vary.

• Most often, patients will complain of blurry vision that may or may not be associated with pain and red eye. In the rare case of orbital disease, proptosis, double vision, or extraocular muscle motility restriction may be the presenting complaint. Preseptal cellulitis in children with spontaneous draining fistula has also been recently reported. In cases of pulmonary and extrapulmonary TB, there may be ocular findings without ocular complaints.
• Careful history taking may reveal a history of HIV, recent immigration, homelessness, and/or known exposure to TB. Clinician suspicion for TB should increase in the presence of any of the above risk factors.
• Careful review of systems may, although rarely, reveal night sweats, fevers, weight loss, or productive cough.
• Mycobacterium avium-intracellulare complex (MAC) should be considered in AIDS patients, in addition to M tuberculosis.

Physical

Ocular TB usually is a granulomatous process but also may be nongranulomatous. The ocular inflammatory response may be unilateral or bilateral. This response can result from hematogenous spread; from direct local extension from the skin, mucous membranes, or sinuses; or, possibly, as a hypersensitivity response to distant infection. Phlyctenules, Eales disease, and interstitial keratitis are considered as hypersensitivity reactions, but organisms have been isolated with specialized techniques and PCR techniques in these conditions. Vision usually is decreased proportionately with increased duration and severity of the uveitis. The vision is ultimately limited by chronic cystoid macular edema (CME) or irreversible cystic macular edema.

• External ocular findings
  • Keratitis, phlyctenules, and conjunctival granulomas may be seen. A chronic unilateral conjunctivitis due to TB can have a thick white discharge.
  • Scleritis can be diffuse, posterior, or nodular and associated with localized granuloma development.
  • Orbital periosteal rim, dacryoadenitis, and sinus infections with a nonhealing, draining fistula are characteristic of TB. There may be a preauricular lymph node.
• Anterior chamber findings
  • Iridocyclitis with cells in the anterior chamber are present. Iridocyclitis commonly leads to the development of mutton-fat keratic precipitates (KP) or large greasy appearing cellular deposits on the corneal endothelial surface. The classic inferior distribution of KP appears in the lower one third of the cornea, known as the Arlt triangle. KP on the endothelium may produce corneal edema, and KP in the angle may produce pressure elevations, particularly in individuals with preexisting peripheral anterior synechiae or poor outflow facility. HIV patients on retroviral therapy can show an immune recovery uveitis associated with concomitant tuberculosis even if they are not on rifabutin.
  • The iris may have posterior or anterior synechia development as well as iris granulomas. Granulomas may be seen at the angle of the iris base and over the trabecular meshwork. Long-standing inflammation can lead to cataract and secondary inflammatory glaucoma. Implanted intraocular lenses may adhere to persistent inflammatory cell precipitates.
• Vitreous findings
  • Anterior vitreous cell with the development of cellular aggregates known as "snowballs" in the anterior and inferior vitreous.
  • Pars plana "snowbanking" or granulomas can be seen. TB is an important diagnosis in the differential of pars planitis syndrome, especially if it is unilateral.
  • Panophthalmitis or endophthalmitis may also occur.
• Posterior segment findings
  • Active and inactive multifocal choroidal with subretinal neovascular membranes and retinal scarring can be seen. The appearance can be consistent with multifocal choroiditis, serpiginous choroiditis, or panuveitis pattern. Granulomas can become necrotic and give the appearance of a subretinal abscess.
  • Typically, choroidal granulomas develop singly or in a multifocal pattern, especially in the posterior pole, and are a hallmark of ocular TB. They can be one half to several disc diameters in size, and there can be a retinal pigment epithelitis evident on fluorescein.
  • The retina overlying choroidal inflammation may exhibit secondary retinitis, localized retinal vasculitis, and serous retinal detachment. Eales disease is a recurrent retinal vasculitis in young men with vitreous hemorrhage. While Eales disease is idiopathic, it is especially common in endemic areas for TB. The retinal vasculitis in TB is considered a hypersensitivity reaction, but small amounts of infective material have also been implicated.
  • CME frequently accompanies intraocular inflammation in ophthalmic TB. CME may be reversible if treated aggressively early in its course, but it may progress to permanent structural damage in the form of cystic macular edema with irreversible visual loss.
  • Optic nerve edema and inflammation may occur alone or in conjunction with other posterior segment inflammation. This papillitis is differentiated from anterior ischemic optic neuropathy by inflammation and concurrent vasculitis, and it is differentiated from papilledema by the absence of elevated intracranial pressure.

Causes

Uveitis caused by TB is the local inflammatory manifestation of a previously acquired primary systemic tubercular infection. The organism M tuberculosis is acquired through exposure to infected material, usually an aerosol from the lungs of an infected individual. There is some debate regarding molecular mimicry as well as a nonspecific response to noninfectious tubercular antigens, which may produce active ocular inflammation in the absence of bacterial replication.

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