Association of Age-related Macular Degeneration With Mortality in Patients With Acquired Immunodeficiency Syndrome; Role of Systemic Inflammation

Abstract

Purpose: To evaluate the relationships among age-related macular degeneration (AMD), mortality, and biomarkers of systemic inflammation in patients with the acquired immunodeficiency syndrome (AIDS). Design: Case control study. Participants: Participants with intermediate-stage AMD at enrollment in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) and 2:1 controls matched for age and gender.Methods: Cryopreserved baseline plasma specimens were assayed for biomarkers of inflammation, including high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, interferon-γ inducible protein (IP)-10, soluble CD14 (sCD14), soluble CD163 (sCD163), kynurenine/ tryptophan (KT) ratio, and intestinal fatty acid binding protein (I-FABP).

Association of Systemic Inflammation With Retinal Vascular Caliber in Patients With AIDS

“…Nevertheless, Mendelian randomization studies cast doubt on a direct causal contribution of CRP to cardiovascular disease in man 34. IL-6 is a proinflammatory cytokine, secreted by several innate immune cells and B-cells, and it is an inducer of CRP synthesis in the liver 29,30. The association of retinal venous dilation with both CRP and IL-6 levels in the simple linear regression strengthens the inference that retinal venous dilation is related to systemic inflammation, since these biomarkers are mechanistically linked in vivo.…”

“…That the association of retinal venular dilation remains associated with IL-6 but not CRP in the multiple linear regression is consistent with the role of IL-6 role as an inducer of CRP. IP-10 is a marker of type I and type II interferon responses typically induced by bacterial or viral infection, and its association with retinal venous dilation suggests that HIV infection or infections with co-pathogens may contribute to this inflammatory state 29,30. Elevations of CRP, IL-6, and IP-10 are associated with mortality in persons with HIV infection and AIDS 29,30,35–40.…”

“…Baseline photographs were taken on all participants and evaluated for retinal vascular caliber at the Reading Center in the Department of Ophthalmology and Visual Sciences at the University of Wisconsin, Madison, School of Medicine and Public Health by graders masked as to clinical data, as previously described 18,19,28. As part of a study of AMD, mortality, and biomarkers of systemic inflammation, participants with AMD at enrollment were matched on decade of age, race/ethnicity-, and sex with 2 controls from LSOCA for a case control study,29 resulting in a study population of 454 persons with AIDS. Retinal vascular indices were determined using previously-described semi-automated methods.…”

“…Computer software measured the caliber of the individual vessels, then combined them into two summary measures: the central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) 18,19,28. Intermediate-stage AMD was graded at the reading center as previously described 16,17,19,29…”

“…Phlebotomy was performed at enrollment, and plasma specimens cryopreserved. Cryopreserved specimens were thawed and assayed for biomarkers of inflammation using commercially available immunoassay kits in the Core Immunology Laboratories of the University of California, San Francisco, School of Medicine as previously described 29,30. Inflammatory biomarkers included high-sensitivity CRP (UBI Magiwel, Mountain View, CA, USA), IL-6 (hsIL-6, R&D Systems, Minneapolis, MN, USA), soluble CD14 (sCD14, R&D Systems), soluble CD163 (sCD163, R&D Systems), and interferon-γ inducible protein (IP)-10 (IP-10, R&D Systems), also known as CXCL10.…”