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Tuberculous Uveitis
Invited Commentary
Invited Commentary
Uveitis—The Tortured Tale of the Tubercle
Russell N. Van Gelder, MD, PhD
Tuberculous uveitis has been recognized for a long time
(Antoine Maitre-Jan described the first case of iritis associated with tuberculosis [TB] in 1707), and much is understood
about its mechanisms. Numerous pathology studies have demonstrated ocular presence of
Mycobacterium tuberculosis in
Related article
cases of uveitis; animal studies have demonstrated that
intraocular or miliary M tuberculosis infection will cause uveitic disease. The range of uveitis associated with TB is broad
and includes anterior, intermediate, posterior, and panuveitis (including some interesting variants such as serpiginoid
uveitis, retinal vasculitis, and choroidal tubercles). While most
patients with biopsy-proven tubercular uveitis will have positive tuberculin test results (either the tuberculin skin test or
the more recent interferon γ release assays [IGRA] such as
QuantiFERON Gold), most patients with tubercular uveitis
will have no evidence of pulmonary or other systemic disease. Multidrug treatment of true tubercular uveitis (often
with concomitant corticosteroids) will often definitively resolve the uveitis. Conversely, many patients with uveitis will
have positive tuberculin test results, particularly in endemic
areas: do these patients actually have tubercular uveitis, or do
they have 2 independent conditions?
Despite near-consensus agreement among experts on
these facts, tubercular uveitis remains very challenging to the
practicing uveitis specialist. In 2015, the Uveitis Specialists
Study Group surveyed the members of the American Uveitis
Society, presenting 2 case scenarios and asking members for
their estimation of the likelihood of tuberculous uveitis, their
preferred workup, and recommended treatment.1 The group
found essentially no consensus among uveitis specialists
with respect to any of these questions, with likelihood estimates for a single case ranging from 0% to 90%, and approximately equal numbers of respondents recommending treatment of 6, 9, and 12 months for TB in likely cases. Later, a
second group of primarily non–US-based physicians was
given the same set of scenarios. Their assessments, workup,
and suggested treatments were also highly variable and in
many cases significantly different from those of US-based
specialists.2
This difficulty arises from the lack of a gold standard diagnostic test for tubercular uveitis. It is believed that much of
the uveitis associated with tuberculosis is caused by innate and
adaptive immune responses to tubercular antigens as much
as to the organism itself. As such, very small bacterial loads,
perhaps as low as a single bacillus,3 can induce substantial
inflammation. While the polymerase chain reaction has been
successfully used in many cases to diagnose tubercular uveitis, its false-negative rate is unknown; a negative result does
not rule out tubercular disease. In the absence of a definitive
laboratory test, the presence of a compatible form of uveitis
jamaophthalmology.com
and a positive skin or IGRA test result is taken as presumptive
diagnosis for tubercular uveitis.
This approach is problematic in both TB-endemic areas and
in parts of the world where tuberculosis is rare. Exposure to
TB is extremely common in many parts of the world. In India,
for example, an estimated 40% of the population is positive
by tuberculin skin test or IGRA (most having either latent TB
or cleared TB). Because of the protean presentations of tubercular uveitis, nearly 40% of all uveitis cases could thus be attributed to TB (although this was the proportion of uveitis attributed to TB in the United States and Great Britain in the
1940s4). Clearly, many cases of uveitis of other causes occur
in patients with positive TB test results. Conversely, in the
United States, TB is rare, with fewer than 10 000 cases in the
United States in 2015 (a rate of approximately 3 per 100 000).
By Bayes’ theorem, given the reported sensitivity (approximately 0.85) and specificity (approximately 0.98) for IGRA,5
in the United States, a negative result on a screening test has
a 0.99995 negative predictive value. However, a positive
result in the general population has only a 2% likelihood of
being true positive. Even in a uveitis clinic, where the pretest probability of tubercular disease might be as high as 1%,
a positive IGRA result has only a 30% chance of representing true disease.
In this issue of JAMA Ophthalmology, Agrawal et al 6
take the significant step of collecting a large number of
presumptive ocular TB cases from 25 referral centers worldwide, characterizing the uveitis observed in these cases, and
determining a simple outcome measure for treatment with
antitubercular therapy. The authors used a 4-component
inclusion criteria, requiring uveitis signs suggestive of tuberculosis (which were fairly broad), exclusion of other uveitic
entities, and either direct demonstration of M tuberculosis by
polymerase chain reaction or pathologic specimen or a positive tuberculin skin test or IGRA result (or, rarely, chest radiography findings consistent with tuberculosis). A total of 801
cases were analyzed; 75% were from Asia, Australia, or the
Middle East.
Not surprisingly, the range of observed uveitic disease was
broad, including anterior, intermediate, posterior, and pan uveitis, both granulomatous and nongranulomatous. Retinal vasculitis was seen in 42% of patients. Most patients had no extraocular involvement of tuberculosis. All patients were treated
for tuberculosis. Per the authors’ definition of treatment success (no recurrence of inflammation within 6 months of completing therapy, ability to taper oral or topical corticosteroids
below specific levels, and absence of recalcitrant inflammation requiring steroid sparing immunomodulation), 88% were
treatment successes. Monocular involvement, posterior uveitis, a normal chest radiography, and absence of vitreous haze
were all statistically associated with successful treatment with
antitubercular therapy.
(Reprinted) JAMA Ophthalmology Published online October 26, 2017
© 2017 American Medical Association. All rights reserved.
Downloaded From: by a National University of Singapore User on 10/26/2017
E1
Invited Commentary
Tuberculous Uveitis
The retrospective nature of the study limits its power. There
was no standardization in TB treatment regimen. In particular,
there was no algorithm of treatment for latent vs full 4-drug antiTB therapy. Use and tapering of corticosteroids was determined
by individual investigators. The sole outcome was “uveitis treatment success.” Ocular and systemic adverse events were not collected nor were visual outcomes, such as visual acuity, analyzed.
Nonetheless, this study strongly suggests that most
patients in endemic areas with presumed tubercular uveitis
ARTICLE INFORMATION
Author Affiliation: Departments of
Ophthalmology, Biological Structure, and
Pathology, University of Washington School of
Medicine, Seattle.
Corresponding Author: Russell N. Van Gelder, MD,
PhD, Department of Ophthalmology, University of
Washington School of Medicine, CB 369608, 325
9th Ave, Seattle, WA 98104 (russvg@uw.edu).
Published Online: October 26, 2017.
doi:10.1001/jamaophthalmol.2017.3514
Conflict of Interest Disclosures: The authors has
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
REFERENCES
1. Lou SM, Larkin KL, Winthrop K, Rosenbaum JT;
Uveitis Specialists Study Group. Lack of consensus
E2
(ie, uveitis consistent with TB and a positive screening test result) will have their uveitis resolve if treated with antitubercular therapy (with or without concomitant corticosteroids).
The work ahead is to determine which patients truly have
tubercular uveitis; to determine the optimal regimen for treatment; and to determine the predictors of outcome, particularly in the developing world where most cases are found. Such
questions will require either significant prospective studies or
large registry studies.
in the diagnosis and treatment for ocular
tuberculosis among uveitis specialists. Ocul
Immunol Inflamm. 2015;23(1):25-31.
2. Lou SM, Montgomery PA, Larkin KL, Winthrop K,
Zierhut M, Rosenbaum JT; Uveitis Specialists Study
Group. Diagnosis and treatment for ocular
tuberculosis among uveitis specialists: the
international perspective. Ocul Immunol Inflamm.
2015;23(1):32-39.
3. Wroblewski KJ, Hidayat AA, Neafie RC, Rao NA,
Zapor M. Ocular tuberculosis: a clinicopathologic
and molecular study. Ophthalmology. 2011;118(4):
772-777.
of Interferon-gamma release assays for the
diagnosis of Mycobacterium tuberculosis infection
in children: a 2013 update. BMC Infect Dis. 2014;14
(suppl 1):S6.
6. Agrawal R, Gunasekeran DV, Grant R, et al;
Collaborative Ocular Tuberculosis Study (COTS)–1
Study Group. Clinical features and outcomes of
patients with tubercular uveitis treated with
antitubercular therapy in the Collaborative Ocular
Tuberculosis Study (COTS)-1 [published online
October 26, 2017]. JAMA Ophthalmol. doi:10.1001
/jamaophthalmol.2017.4485
4. Silverstein AM. Changing trends in the etiologic
diagnosis of uveitis. Doc Ophthalmol. 1997;94(1-2):
25-37.
5. Sollai S, Galli L, de Martino M, Chiappini E.
Systematic review and meta-analysis on the utility
JAMA Ophthalmology Published online October 26, 2017 (Reprinted)
© 2017 American Medical Association. All rights reserved.
Downloaded From: by a National University of Singapore User on 10/26/2017
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