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Clinical Update: Infectious Disease
Tuberculosis: Ancient Killer Can Thrive in the Eye
By Barbara Boughton, Contributing Writer
Interviewing Thomas A. Albini, MD, Petros C. Karakousis, MD, and Narsing A. Rao, MD
 
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Hippocrates apparently described its clinical characteristics almost 2,500 years ago, and wrote that it was the most common cause of illness during his time. In fact, Mycobacterium tuberculosis was one of civilization’s most lethal enemies until the middle of the last century, when the antimicrobial streptomycin was discovered to be active against it. With the development of the first oral mycobacteria-specific drug, isoniazid, in 1952 and advances in the 1970s of more antimycobacterials that hastened recovery times, most public health experts thought the battle against tuberculosis had been won. But by the 1980s, drug-resistant strains of tuberculosis had emerged, and in 1993 the World Health Organization issued a declaration of emergency to signify the magnitude of the worldwide reemergence of TB.

Even before drug-resistance became a problem, TB was endemic in many nations. It’s been estimated that one-third of the world’s population is latently infected with TB, and more than 9 million new cases are diagnosed each year.1 In about 20 percent of these cases, the infection travels to extrapulmonary sites, including the eye, according to Narsing A. Rao, MD, professor of ophthalmology at the University of California, Los Angeles. In most individuals, the immune system mounts an effective response to TB and the disease remains dormant. Yet, latent TB infection can develop into active disease in the setting of factors that dampen the immune system, such as HIV disease and/or the use of immunosuppressive drugs to treat cancer or arthritis. Old age is also a risk factor for ocular TB, since the immune system can be weaker in the elderly, said Petros C. Karakousis, MD, an infectious disease specialist and assistant professor of medicine at Johns Hopkins University. In people with healthy immune systems, the lifetime risk of reactivation of latent TB infection is about 10 percent, but the risk rises another 10 percent per year for those with immunosuppressive conditions such as AIDS.1

TB in the eye. Tuberculosis affects only five of every 100,000 people in the United States, and ocular involvement is even less common than extraocular disease, affecting just 1.4 percent of people diagnosed with pulmonary TB.1 But ocular TB can be sight-threatening if untreated. And precisely because ocular TB is uncommon in the United States and is difficult to diagnose, it is often confronted at a late stage, after irreversible blinding damage may already have occurred, according to Thomas A. Albini, MD, assistant professor of ophthalmology at the University of Miami.

Ocular TB usually manifests as uveitis and causes chorioretinal swelling and inflammation, which, given macular involvement, can result in blindness, Dr. Albini said. When TB was more prevalent in America—especially before the 1950s—almost any granulomatous inflammation of the eye was assumed to be caused by TB. Currently the reported incidence is 0.3 to 0.5 percent of patients with uveitis. But that figure may be an underestimate.2,3

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Diagnosis: Masquerades and Mistakes

Ocular TB is difficult to diagnose because it often presents with vague and variable symptoms, such as visual deficits, pain in the eye and tearing, all of which can easily be attributed to other causes, Dr. Karakousis said. In patients with HIV, for example, TB can masquerade as other infections that affect the eye, such as fungal infections.

The ophthalmologist may diagnose tuberculous uveitis as an inflammatory condition and treat it with corticosteroids, risking disastrous results. “By treating the infection with steroids, the bacteria are allowed to multiply and destroy the retina and choroid, leading to blindness. And if there is a dormant infection elsewhere, the patient may develop systemic TB, and then mortality becomes an issue,” Dr. Rao said.

When to suspect. A uveitis diagnosis in patients who come from TB-endemic areas such as Asia or Africa should raise suspicion for the disease, Dr. Albini said.

What to suspect. Dr. Rao and his colleagues published a report of the clinical features of tuberculous serpiginouslike choroiditis (Tb-SLC) in patients from endemic areas—and contrasted these with the characteristics of classic serpiginous choroiditis (SC).4 Those infected with tuberculosis had unilateral and multifocal lesions, involving the posterior pole and periphery, usually sparing the juxtapapillary area. By contrast, those with classic SC had bilateral lesions that primarily involved the posterior pole, especially around the optic disc and extending to the macula, he said.

Confirming suspicions. Once the ophthalmologist suspects TB infection, there are several methods to verify the diagnosis. But these tests all have limitations. Even biopsy—the gold standard for many other diagnoses—is difficult and risky to obtain, and then isolating M. tuberculosis from the biopsy can be elusive.

  • PPD. A tuberculin skin test, which tests skin hypersensitivity to mycobacterial antigens, is notable if positive, but results are not always indicative of active TB because the test can also be positive from BCG vaccination or exposure to other atypical mycobacteria. It also does not differentiate between latent infections and active disease.
     
  • CXR and sputum. A positive chest x-ray can also indicate that a patient has active pulmonary TB, as can systemic symptoms such as weight loss, fever and night sweats, or cultured TB organisms from sputum, according to Dr. Karakousis. But most patients with ocular TB, especially those from nonendemic areas, will have negative findings on chest x-ray, Dr. Rao said. Ocular TB, in fact, can manifest without apparent systemic symptoms or evidence of lung involvement on chest x-ray, Dr. Albini said. “One of the misconceptions is that if you have a normal chest x-ray but have ocular symptoms, then it can’t be ocular tuberculosis. But studies have shown that up to half of patients who have extrapulmonary TB do not have findings on a chest x-ray because there may not be enough pathology to be picked up radiologically. Patients can even have a negative skin test and still have extrapulmonary TB.” A sputum sample may be negative if the pulmonary infection is latent, Dr. Rao noted.
     
  • IGRA or PCR. Newer methods for diagnosing TB include the interferon-gamma release assay (IGRA) and polymerase chain reaction (PCR) measure of ocular fluids or tissue. While a positive result on IGRA is a stronger indicator of TB infection than the skin test, this test also lacks specificity because it does not distinguish latent from active TB infection, and it can be influenced by immunosuppressive conditions.

    PCR testing, while a powerful tool for rapid diagnosis, has high specificity but variable sensitivity. 

  • Presumptive Tx. If TB tests are inconclusive or there are symptoms of uveitis but treatment with steroids has been unsuccessful or has made the disease worse, then diagnosis comes down to a therapeutic trial of anti-TB medications. “This is when clinical acumen is important, and when the clinician may have to rely on guesswork,” Dr. Rao said.

Animal model is valuable. Because there have been few modern studies on just how clinically useful different diagnostic tools are for ocular TB, Drs. Rao, Albini and Karakousis have established a guinea pig model at Johns Hopkins.5 Although previous animal models of ocular TB were established when the disease was more rampant during the 1940s, these involved injecting bacilli directly into the eye or carotid artery, which is not analogous to real-life human TB infection, according to Drs. Albini and Rao. In the new model, guinea pigs were infected via aerosol. “TB is acquired primarily by inhalation, and then travels hematogenously to the eye. Our new animal model mimics that method of transmission, and it will allow us to study the characteristics of the granulomas in the eye and to quantify how well various diagnostic strategies work,” Dr. Albini said.

The research so far has revealed that when the animals inhale virulent M. tuberculosis, they will develop pulmonary and extrapulmonary TB, including ocular TB, if untreated.5 Dr. Rao hopes that the team will eventually quantify the bacterial load in the lung necessary for ocular infection.

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Treatment: Available and Successful

Once ocular TB is established, then treatment with medications is continued for six to nine months. As with systemic TB, drug resistance can be a problem. Patients who come from endemic areas, where undertreatment may have predisposed patients to resistance, should undergo a therapeutic trial with four drugs to counteract any possible drug-resistant strains of TB, Dr. Rao said. Small doses of oral steroids administered at a reduced dose of 0.5 or 0.75 mg per kg can also be helpful to reduce inflammation and prevent swelling and scarring of the retina that may be sight-threatening, said Dr. Albini.

Cross-discipline management. Dr. Rao said that if an ophthalmologist encounters ocular TB, it’s important to have the patient also see a pulmonologist. TB generally requires a team approach because the drugs can lead to serious complications, including damage to the optic nerve or liver, and adverse interactions with antiretrovirals for HIV, Dr. Karakousis said.
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1 Cutrufello, N. J. et al. Ocul Immunol Inflamm 2010;18(4):281–291.
2 Vasconcelos-Santos, D. V. et al. Ocul Immunol Inflamm 2009;17(5):351–355.
3 Albini, T. A. et al. Am J Ophthalmol 2008; 146(4):486–488.
4 Vasconcelos-Santos, D. V. et al. Arch Ophthalmol 2010;128(7):853–858.
5 Rao, N. A. et al. Arch Ophthalmol 2009;127(9):1162–1166.

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