Immune Recovery Vitritis in HIV Infection

James P. Dunn, MD

JAMA. 1998;280(2):185-186. doi:10.1001/jama.280.2.185

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Journal Scan Archive, March, 1998
http://www.ama-assn.org/aids
Posted May 11, 1998

AUTHOR INFORMATION

Medical Editor: Jeanette M. Smith, MD, Contributing Editor, JAMA.

Objective

Objective To describe a syndrome of posterior segment intraocular inflammation that causes visual loss in patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. This syndrome was associated with immune recovery mediated by combination antiretroviral treatment including protease inhibitors.

Design A case-control study at 2 university medical centers.

Participants One hundred thirty patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis were examined at 2 medical centers for 15 months. In addition, the medical records of 509 patients examined at 1 center for 11 years before the initiation of protease inhibitor therapy were analyzed retrospectively.

Results Five patients with symptomatic vitritis and papillitis with cystoid macular edema or epiretinal membrane formation were documented. In each patient there was inactive cytomegalovirus retinitis that had not caused visual decrease before the onset of inflammation. All patients had elevated CD4⁺ T lymphocyte levels (median increase, 86 × 10⁶/L [86 cells/mm³]) after combination treatment including protease inhibitors. Two patients with cystoid macular edema were treated with corticosteroids and had resolution of the cystoid macular edema and an increase in visual acuity without reactivation of the retinitis. Retrospective analysis failed to disclose similar patients with intraocular inflammation in the era before the introduction of protease inhibitors.

Conclusions This newly described syndrome of posterior segment inflammation related to cytomegalovirus retinitis is a cause of visual morbidity in patients with acquired immunodeficiency syndrome. It is associated with increased immune competence as a result of combined antiretroviral treatment with protease inhibitors and may be amenable to corticosteroid therapy without reactivation of retinitis.

Purpose

Purpose To report the observation that a transient vitreous inflammatory reaction may develop in the eyes of patients with acquired immunodeficiency syndrome (AIDS), cytomegalovirus retinitis, and an increased CD4⁺ T-lymphocyte count during treatment with antiretroviral therapy including a protease inhibitor.

Methods We reviewed the medical records of eight patients with AIDS and cytomegalovirus retinitis who developed vitreous inflammatory reactions greater than those usually seen with this disease.

Results Vitreous inflammatory reactions obscured the view of the posterior pole in all patients. No iris nodules, synechiae, glaucoma, or cystoid macular edema were observed. Six patients had unilateral cytomegalovirus retinitis, and, in each, the inflammation occurred only in the eye with cytomegalovirus retinitis. The vitreous inflammatory reactions were associated with clinically inactive cytomegalovirus retinitis in six patients, with disease reactivation in one patient, and were present at diagnosis of active disease in one patient. Cytomegalovirus retinitis has not recurred in any of these patients since their episodes of vitreous inflammation. Vitreous inflammation developed in all eight patients after a substantial increase in CD4⁺ T-lymphocyte counts caused by combination antiretroviral therapy. Five patients had CD4⁺ T-lymphocyte counts of greater than 100 cells/µL at the time the vitreous inflammatory reaction developed. No other causes of uveitis were found.

Conclusions Patients with AIDS and cytomegalovirus retinitis may develop transient intraocular inflammation associated with combination antiretroviral therapy. We believe that this inflammation reflects an improved immune response against cytomegalovirus.

COMMENTARY

The introduction of highly active antiretroviral therapy (HAART) has had an enormous impact on ocular opportunistic infections (OIs). Cytomegalovirus (CMV) retinitis, while still the most common ocular OI, is notably less common than it was several years ago.¹ Improvement in immune status in patients treated with HAART has allowed some to discontinue the secondary prophylaxis, which was formerly necessary to control CMV retinitis.²

Acquired immunodeficiency syndrome (AIDS)–related CMV retinitis typically occurs in patients with CD4⁺ cell counts less than 50/µL and is characterized by only mild and often asymptomatic vitreous and anterior chamber inflammation. This feature helps to distinguish CMV retinitis from other causes of uveitis, such as toxoplasmosis and syphilis. Karavellas and colleagues³ and Zegans and colleagues⁴ have recently reported a new syndrome of intraocular inflammation in patients with controlled CMV retinitis as a result of HAART-induced immune enhancement.

A total of 13 patients were included in the 2 studies. All patients had a CD4⁺ cell nadir of 70/µL or less. The vitreous inflammation began 1 to 6 months after elevation of CD4⁺ cell counts; the increase ranged from 41 to 283/µL, and the absolute CD4⁺ cell count was greater than 63/µL at the onset of inflammation. Cystoid macular edema, papillitis, and epiretinal membranes were noted in some patients. None of the patients with unilateral CMV retinitis demonstrated inflammation in the contralateral eye. Visual loss was mild to moderate (as low as 20/100 in 1 eye) but recovered 20/40 or better in the absence of other complications, such as retinal detachment. No patient had recurrent CMV retinitis during follow-up, even when treated with oral or periocular corticosteroids. Control groups (patients with CMV retinitis who did not have an increase in CD4⁺ cell counts following initiation of HAART and patients without CMV retinitis who responded to HAART) did not demonstrate increased intraocular inflammation. In 2 of the patients reported by Zegans and colleagues,⁴ CMV retinitis was detected shortly after successful initiation of HAART (CD4⁺ cell count of 195/µL or greater); this phenomenon has been noted elsewhere.⁵

The cause of the inflammation is unknown. Currently available anti-CMV drugs are virostatic, not virucidal. Replicative intermediates containing CMV DNA are present in treated infected cells,⁶ and the retained antigen may act as the source of the inflammatory reaction during immune recovery. A comparable clinical presentation may be found in Mycobacterium avium complex (MAC) infections. Race and colleagues⁷ described a series of patients who developed lymphadenitis, fever, and leukocytosis due to MAC within 3 weeks of initiating the use of protease inhibitors. None of the patients had been on MAC prophylaxis. Finally, the degree of immunosuppression may affect the manifestations of ocular infections such as CMV retinitis⁸^- 9 or toxoplasmosis retinitis¹⁰ in patients without AIDS.

The studies did not determine the incidence of immune recovery vitritis and no definite conclusions could be drawn as to ideal therapy. No patient developed sequelae of severe anterior uveitis, such as hypopyon or iris synechiae. Improvement in vitreous inflammation was noted within 2 months, regardless of therapy; in some patients there was spontaneous resolution of inflammation. Fortunately, immune recovery vitritis is uncommon, and affected patients appear to respond well to oral or periocular corticosteroids without reactivation of the CMV retinitis. In some cases, the reaction is even self-limited. Clinicians should not assume that a new inflammatory reaction in a patient with successfully treated CMV retinitis is due to immune enhancement until other infectious and drug-induced causes have been ruled out.

Published literature selected for posting on the JAMA Web sites receives postpublication peer review. Posted abstracts may be accompanied by commentaries prepared for the Web sites that may be selected for republishing in THE JOURNAL.

The JAMA HIV/AIDS Information Center is made possible by grant support from Glaxo Wellcome Inc.

REFERENCES

Jabs DA, Bartlett JG. AIDS and ophthalmology: a period of transition. Am J Ophthalmol.1997;124:227-233.

Reed JB, Schwab IR, Gordon J, Morse LS. Regression of cytomegalovirus retinitis associated with protease-inhibitor treatment in patients with AIDS. Am J Ophthalmol.1997;124:199-205.

Karavellas MP, Lowder CY, MacDonald JC, Aliva Jr CP, Freeman WR. Immune recovery vitritis associated with inactive cytomegalovirus retinitis: a new syndrome. Arch Ophthalmol.1998;116:169-175.

Zegans ME, Walton RC, Holland GN, O'Donnell JJ, Jacobson MJ, Margolis TP. Transient vitreous inflammatory reactions associated with combination antiretroviral therapy in patients with AIDS and cytomegalovirus retinitis. Am J Ophthalmol.1998;125:292-300.

Jacobson M, Zegans ME, Pavan P. et al. Cytomegalovirus retinitis after initiation of highly active antiretroviral therapy. Lancet.1997;349:1443-1445.

Burd EM, Pulido JS, Puro DG, O'Brien WJ. Maintenance of replicative intermediates in ganciclovir-treated human cytomegalovirus-infected retinal glia. Arch Ophthalmol.1996;114:856-861.

Race EM, Adelson-Mitty J, Kriegel GR. et al. Focal mycobacterial lymphadenitis following initiation of protease-inhibitor therapy in patients with advanced HIV-1 disease. Lancet.1998;351:252-255.

Maguire AM, Nichols CW, Crooks GW. Visual loss in cytomegalovirus retinitis caused by cystoid macular edema in patients without the acquired immune deficiency syndrome. Ophthalmology.1996;103:601-605.

Coskuncan NM, Jabs DA, Dunn JP. et al. The eye in bone marrow transplantation, VI: retinal complications. Arch Ophthalmol.1994;112:372-379.

Elkins BS, Holland GN, Opremcak EM. et al. Ocular toxoplasmosis misdiagnosed as cytomegalovirus retinopathy in immunocompromised patients. Ophthalmology.1994;101:499-507.

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