CLINICAL CHARACTERISTICS AND PROGNOSTIC FACTORS AFFECTING CLINICAL OUTCOMES IN CYTOMEGALOVIRUS RETINITIS WITH OR WITHOUT HIV INFECTION.

PURPOSE: To explore the clinical features and outcomes of cytomegalovirus retinitis (CMVR) in patients with HIV and non-HIV. METHODS: This retrospective cohort study included all patients with CMVR in National Taiwan University Hospital from 2013 to 2018. Demographic data, clinical characteristics, CMVR recurrence, and overall survival were compared between the HIV and non-HIV groups. Generalized estimating equation models were implemented to analyze the risk factors of poor visual prognosis. The Kaplan-Meier survival analysis was performed to investigate recurrence and survival. RESULTS: A total of 66 patients (95 eyes) with CMVR were enrolled, with no significant differences between the HIV (41 patients; 61 eyes) and non-HIV (25 patients; 34 eyes) groups in initial/final visual acuity, lesion area, or viral loads. Poor visual outcome was associated with poor initial visual acuity, retinal detachment, and a higher plasma cytomegalovirus titer. The HIV group had significantly longer survival rate ( P = 0.033) and lower recurrence rate ( P = 0.01) than the non-HIV group, and it also presented with better prognosis in recurrence-free survival analysis ( P = 0.01). CONCLUSION: Patients with CMVR without HIV had higher mortality and recurrence rates than the HIV group. Risk factors of poor visual outcome included poor initial visual acuity, retinal detachment, and a high plasma cytomegalovirus titer.

CMV retinitis and subsequent acute cystoid macular oedema after treatment with vitreous ganciclovir injection: a case report.

BACKGROUND: To report a very rare acute cystoid macular oedema following ganciclovir injection in patients receiving allogeneic haematopoietic stem cell transplantation. CASE PRESENTATION: A 44-year-old male patient experienced vision loss in his left eye eight months after allogeneic stem cell transplantation. Ophthalmologic examination showed posterior retinopathy with retinal haemorrhage, a yellow necrotic border, and a vascular white sheath involved in the superior temporal retina but not the posterior pole. Cytomegalovirus DNA results in both plasma and ocular fluid were positive. All tests combined with the patient's medical history suggested that his ocular disease was cytomegalovirus retinitis. Consequently, he received a weekly ganciclovir vitreous injection. The disease was visibly controlled, and the fundus condition improved after the first three treatments. However, the patient had severe vision loss in his left eye and acute cystic oedema in the macula, while the original lesion was stable two hours after the fourth treatment. The macular oedema subsided significantly on the first day. Over the next week, daily OCT findings indicated that the patient's macular oedema gradually subsided and resolved completely by the second week, and his left eye vision partially improved. CONCLUSION: Macular oedema may occur in patients with cytomegalovirus retinitis, but it rarely occurs during treatment. In this case, the patient's macular oedema appeared and resolved quickly. Macular oedema in patients with cytomegalovirus retinitis receiving vitreous cavity injections of ganciclovir needs to be further studied and discussed.

Atypical cytomegalovirus retinal disease in pyroptosis-deficient mice with murine acquired immunodeficiency syndrome.

Pyroptosis is a caspase-dependent programmed cell death pathway that initiates and sustains inflammation through release of pro-inflammatory cytokines interleukin (IL)-1ß and IL-18 following formation of gasdermin D (GSDMD)-mediated membrane pores. To determine the possible pathogenic contributions of pyroptosis toward development of full-thickness retinal necrosis during AIDS-related human cytomegalovirus retinitis, we performed a series of studies using an established model of experimental murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunosuppression (MAIDS). Initial investigations demonstrated significant transcription and translation of key pyroptosis-associated genes within the ocular compartments of MCMV-infected eyes of mice with MAIDS. Subsequent investigations compared MCMV-infected eyes of groups of wildtype MAIDS mice with MCMV-infected eyes of groups of caspase-1-/- MAIDS mice, GSDMD-/- MAIDS mice, or IL-18-/- MAIDS mice to explore a possible contribution of pyroptosis towards the pathogenesis of MAIDS-related MCMV retinitis. Histopathologic analysis revealed typical full-thickness retinal necrosis in 100% of MCMV-infected eyes of wildtype MAIDS mice. In sharp contrast, none (0%) of MCMV-infected eyes of MAIDS mice that were deficient in either caspase-1, GSDMD, or IL-18 developed full-thickness retinal necrosis but instead exhibited an atypical pattern of retinal disease characterized by thickening and proliferation of the retinal pigmented epithelium layer with relative sparing of the neurosensory retina. Surprisingly, MCMV-infected eyes of all groups of deficient MAIDS mice harbored equivalent intraocular amounts of infectious virus as seen in MCMV-infected eyes of groups of wildtype MAIDS mice despite failure to develop full-thickness retinal necrosis. We conclude that pyroptosis plays a significant role in the development of full-thickness retinal necrosis during the pathogenesis of MAIDS-related MCMV retinitis. This observation may extend to the pathogenesis of AIDS-related HCMV retinitis and other AIDS-related opportunistic virus infections.

Ocular cytomegalovirus latency exacerbates the development of choroidal neovascularization.

Age-related macular degeneration (AMD) is a complex, multifactorial, progressive disease which represents a leading cause of irreversible visual impairment and blindness in older individuals. Human cytomegalovirus (HCMV), which infects 50-80% of humans, is usually acquired during early life and persists in a latent state for the life of the individual. In view of its previously described pro-angiogenic properties, we hypothesized that cytomegalovirus might be a novel risk factor for progression to an advanced form, neovascular AMD, which is characterized by choroidal neovascularization (CNV). The purpose of this study was to investigate if latent ocular murine cytomegalovirus (MCMV) infection exacerbated the development of CNV in vascular endothelial growth factor (VEGF)-overexpressing VEGF-Ahyper mice. Here we show that neonatal infection with MCMV resulted in dissemination of virus to various organs throughout the body including the eye, where it localized principally to the choroid in both VEGF-overexpressingVEGF-Ahyper and wild-type(WT) 129 mice. By 6 months post-infection, no replicating virus was detected in eyes and extraocular tissues, although virus DNA was still present in all eyes and extraocular tissues of both VEGF-Ahyper and WT mice. Expression of MCMV immediate early (IE) 1 mRNA was detected only in latently infected eyes of VEGF-Ahyper mice, but not in eyes of WT mice. Significantly increased CNV was observed in eyes of MCMV-infected VEGF-Ahyper mice compared to eyes of uninfected VEGF-Ahyper mice, while no CNV lesions were observed in eyes of either infected or uninfected WT mice. Protein levels of several inflammatory/angiogenic factors, particularly VEGF and IL-6, were significantly higher in eyes of MCMV-infected VEGF-Ahyper mice, compared to uninfected controls. Initial studies of ocular tissue from human cadavers revealed that HCMV DNA was present in four choroid/retinal pigment epithelium samples from 24 cadavers. Taken together, our data suggest that ocular HCMV latency could be a significant risk factor for the development of AMD. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

[A comparative study of retinal nerve fiber layer thickness in AIDS patients with different fundus diseases].

Objective: To investigate the characteristics of retinal nerve fiber layer (RNFL) thickness in AIDS patients with normal fundus, HIV-related microvascular retinopathy (MVR), and cytomegalovirus retinitis (CMVR). Methods: In this cross-sectional study, 111 patients were diagnosed with AIDS from 2012 to 2017 by infectious disease physicians in Beijing You'an Hospital. There were 105 males and 6 females, aged 20-65 years. According to the results of ophthalmic examination, the patients were divided into three groups: 31 patients in the active-stage CMVR group, 47 patients in the MVR group, and 33 patients with normal fundus in the control group. RNFL thickness was measured by optical coherence tomography in all patients. At the same time, visual acuity, intraocular pressure, and fundus were examined, and AIDS-related systemic examination (CD4(+) T lymphocyte count, HAART treatment status, and blood cytomegalovirus DNA level) was performed. The measurement data were compared by t-test, variance analysis or rank sum test. The counting data were compared by chi square test or Fisher exact probability method. Results: In the control group, the thickness of RNFL in the superior quadrant in the left and right eyes was 145 (79, 231) µm and 142 (46, 179) µm, respectively; the difference was statistically significant (Z=-2.481, P=0.013). The RNFL thickness of the diseased and healthy eyes in the MVR group was 116 (91, 138) µm and 122 (82, 192) µm, respectively, with no significant difference (Z=-0.861, P=0.389); the best corrected visual acuity was 0.0 (0.0, 0.2) and 0.0 (0.0, 0.2), respectively, with no significant difference (Z=-0.378, P=0.705). In the CMVR group, the best corrected visual acuity of the diseased and healthy eyes was (0.23±0.48) and (0.02±0.82), respectively, and the difference was statistically significant (t=-2.944, P=0.003); the RNFL thickness was 133 (61, 219) µm and 121 (69, 146), respectively, in the whole optic disc, with statistically significant difference (Z=-2.385, P=0.017), 104 (41, 374) µm and 82 (55, 121) µm, respectively, in the nasal quadrant, and 99 (14, 173) µm and 72 (36, 111) µm, respectively, in the temporal quadrant, with statistically significant difference (Z=-2.045, -2.543; P=0.041, 0.011). The RNFL thickness in the CMVR group, the MVR group, and the control group was 149 (61, 350) µm, 126 (71, 304) µm, and 113 (87, 149) µm, respectively, with statistically significant difference (H=20.908, P=0.000). Conclusions: The fundus of AIDS patients had different characteristics on optical coherence tomography. In active CMVR patients, the thickness of RNFL was generally thickened. In MVR patients, the average thickness of RNFL was thicker than that in the normal control group.(Chin J Ophthalmol, 2020, 56:258-265).

Autophagy protects against retinal cell death in mouse model of cytomegalovirus retinitis.

BACKGROUND: Extensive death of uninfected bystander neuronal cells is an important component of the pathogenesis of cytomegalovirus retinitis (CMV). Our previous results have shown that there is a functional relationship between autophagy and apoptosis during MCMV infection of retinal pigment epithelium (RPE). The purpose of this study was to determine whether autophagy plays a significant role in the death of retinal cells during MCMV retinitis. METHODS: The retinas of adult BALB/c mice were infected with MCMV via supraciliary injection. Rapamycin, a mTOR inhibitor, was injected to MCMV-infected BALB/c mice intraperitoneally. Immunohistochemistry and western blot were performed to observe the spread pattern of virus in retinas and the levels of targeted proteins. Plaque assay was performed to determine the virus titer in different groups. Since Atg5 is a key gene regulating autophagy, we bred Atg5flox/flox; Nestin-Cre mice to deeply elucidate the role of autophagy during MCMV retinitis. Atg5flox/flox; Nestin-Cre mice were genotyped and infected with MCMV. Immunohistochemistry was performed to observe the type of virus-infected cells and apoptosis in retinas during MCMV retinitis. RESULTS: In MCMV mouse model, MCMV infection in outer nuclear layer (ONL) and inner nuclear layer (INL) in the retinas caused cleaved caspase 3 positive apoptosis, which is not co-localized with early antigen (EA) positive virus infected cells in rapamycin treated group. Rapamycin treatment increased the levels of LC3B-II by inhibiting mTOR and decreased the levels of cleaved caspase-3 during MCMV retinitis. However, virus propagation was not affected by rapamycin. In Atg5flox/flox; Nestin-Cre mice, RPE and glial cells were the main targets of viral infection, and number of EA positive retinal cells and TUNEL positive retinal cells was significantly increased compared to Atg5flox/+; Nestin-Cre mice though there was no difference of virus propagation between Atg5flox/flox; Nestin-Cre mice and Atg5flox/+; Nestin-Cre mice. CONCLUSIONS: Autophagy protects retinal cells from MCMV infection induced apoptosis through mTOR-mediated signaling pathway.

OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN CYTOMEGALOVIRUS RETINITIS: A Longitudinal Study.

PURPOSE: To evaluate the vitreal, retinal, and choroidal features using spectral domain optical coherence tomography (SD-OCT) in eyes affected by cytomegalovirus (CMV) retinitis. METHODS: Patients diagnosed with either active or inactive CMV retinitis were included in the study. Complete ophthalmic examination, serial color fundus photography, and SD-OCT (with and without enhanced depth imaging function) were performed for all the subjects at baseline and follow-up visits. The SD-OCT images were analyzed by two independent graders to evaluate the structural changes in areas of CMV retinitis. Prevalence data for vitreal, retinal, and choroidal SD-OCT features were collected. RESULTS: Twelve eyes from 9 patients (6 males, mean age: 52.7 ± 10.3 years) were enrolled. Nine eyes were diagnosed with active CMV retinitis at baseline. Active disease SD-OCT characteristic findings included nebulous vitritis (100%), posterior hyaloid thickening (83.3%), epiretinal membrane (100%), and retinal swelling (100%). Two distinct patterns of chorioretinal involvement were observed in active retinitis: 1) full-thickness retinitis (Full thickness retinitis) (n = 7 eyes) with choriocapillaris alterations and retinal pigment epithelial thickening and 2) cavernous retinitis (n = 3 eyes) characterized by inner retinal hyperreflectivity, large empty spaces in outer nuclear layer, and bridges of retinal tissue but retinal pigment epithelium and choriocapillaris sparing. Patients with cavernous retinitis develop retinal detachment during follow-up. Eyes with Full thickness retinitis developed choriocapillaris atrophy and choroidal thinning and retinal scars as the lesions healed. CONCLUSION: There are two distinct patterns of chorioretinal involvement in CMV retinitis. SD-OCT is a useful tool in the diagnosis, management, and prediction of the outcome of CMV retinitis.

SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN MACULA-INVOLVING CYTOMEGALOVIRUS RETINITIS.

PURPOSE: To evaluate the microstructural features of cytomegalovirus (CMV) retinitis by spectral domain optical coherence tomography (OCT). METHODS: Subjects were patients with macula-involving CMV retinitis with OCT imaging. The leading edge of retinitis in the macula was identified based on fundus imaging, and OCT findings were longitudinally evaluated in three areas: within the area of active retinitis, at the leading edge of retinitis, and just beyond the leading edge of retinitis. RESULTS: Optical coherence tomography imaging of macular CMV retinitis identified vitreous cells in 10 eyes (100%), posterior vitreous detachment in four eyes (40%), broad-based vitreomacular traction in one eye (10%), epiretinal membrane in eight eyes (80%), and lamellar hole-associated epiretinal proliferation associated with an atrophic hole in one eye (10%). Retinal architectural disruption, disruption of inner retinal layers, disruption of the external limiting membrane, and ellipsoid zone abnormalities were noted within the area of retinitis in all eyes and decreased in frequency and severity at and beyond the leading edge of retinitis, although all 10 eyes (100%) exhibited one of these abnormalities, especially outer retinal microabnormalities, beyond the leading edge of retinitis. CONCLUSION: Microstructural abnormalities were frequently noted on OCT of CMV retinitis, including within the retina beyond the leading edge of retinitis identified by corresponding fundus imaging. Outer retinal abnormalities were noted more frequently than inner retinal abnormalities beyond the leading edge of retinitis. These findings provide insight into the effects of CMV retinitis on retinal microstructure and potentially on vision and highlight the potential utility of OCT for monitoring microprogression of macula-involving CMV retinitis.

COMPARISON OF VISUAL PROGNOSIS AND CLINICAL FEATURES OF CYTOMEGALOVIRUS RETINITIS IN HIV AND NON-HIV PATIENTS.

PURPOSE: To compare the visual prognosis and clinical features of cytomegalovirus (CMV) retinitis between HIV and non-HIV patients. METHODS: Retrospective cross-sectional study on patients diagnosed with CMV retinitis. Depending on the presence of HIV infection, best-corrected visual acuity (VA) and clinical feature of CMV retinitis were analyzed. The clinical characteristics associated with poor visual prognosis after antiviral treatment were also identified. RESULTS: A total of 78 eyes (58 patients) with CMV retinitis were included in this study: 21 eyes and 57 eyes in HIV and non-HIV patients, respectively. Best-corrected VA was not significantly different between HIV and non-HIV patients. The rate of foveal involvement, retinal detachment, involved zone, and mortality did not significantly differ between the two groups. Visual acuity after antiviral treatment was significantly worse (pretreatment logarithm of the minimal angle of resolution best-corrected VA, 0.54 ± 0.67 [Snellen VA, 20/63]; posttreatment logarithm of the minimal angle of resolution best-corrected VA, 0.77 ± 0.94 [Snellen VA, 20/125]; P = 0.014). Poor visual prognosis was significantly associated with Zone 1 involvement, retinal detachment, and a poor general condition. CONCLUSION: The overall visual prognosis and the clinical features of CMV retinitis do not differ between HIV and non-HIV patients. The visual prognosis of CMV retinitis still remains quite poor despite advancements in antiviral treatment. This poor prognosis after antiviral treatment is associated with retinal detachment during follow-up, Zone 1 involvement, and the poor general condition of the patient.

Treatment outcomes of reduced-dose intravitreal ganciclovir for cytomegalovirus retinitis.

BACKGROUND: Cytomegalovirus retinitis (CMVR) is one of the most common opportunistic infection in immunocompromised individuals. Intravitreal ganciclovir injection has been used successfully but no standard regimen was established. Risks of drug toxicity, endophthalmitis, and injection-related complications increased with number and frequency of injection. The aim of this study is to evaluate the outcomes of reduced-dose intravitreal ganciclovir (2 mg/0.04 mL) for the treatment of CMVR. METHODS: A prospective observational cohort study involving 67 eyes of 49 patients with CMVR was performed. Induction therapy involved intravenous ganciclovir (10 mg/kg/day) for 2 weeks unless contraindicated or patients refused. Patients were then treated with reduced-dose intravitreal ganciclovir every week for 4 weeks, and then every other week until the lesion healed. The patients' demographic data were recorded, and vision parameters were examined every visit. RESULTS: Twenty eyes (29.9 %) presented with initial visual acuities less than 6/60. The majority of patients were diagnosed with CMVR in zones 1 or 2 (63 eyes, 94 %), and, at least, one quadrant of the retina was involved (56 eyes, 83.6 %). Forty-one eyes (61.2 %) completely resolved after treatment within the 6-month follow-up. There was no significant difference in healing time, whether or not patients received induction treatment with intravenous ganciclovir (111.00 ± 12.96 vs 105.00 ± 28.32 days, p = 0.8). Five eyes (12.2 %) of patients with healed CMVR had visual acuities less than 6/60. CONCLUSIONS: Reduced-dose intravitreal ganciclovir is a safe and effective treatment option. It provides comparable results to other weekly regimens. Induction with intravenous ganciclovir is not crucial in a resolution of retinitis, although it may be necessary to reduce systemic cytomegalovirus loads and mortality rates. TRIAL REGISTRATION: The trial was registered with Thai Clinical Trials Registry (TCTR) on 16 March 2016 - TCTR20160316001 .

Proposed clinical case definition for cytomegalovirus-immune recovery retinitis.

BACKGROUND: Cytomegalovirus (CMV) retinitis has been extensively described in patients with advanced or late human immunodeficiency virus (HIV) disease under ineffective treatment of opportunistic infection and antiretroviral therapy (ART) failure. However, there is limited information about patients who develop active cytomegalovirus retinitis as an immune reconstitution inflammatory syndrome (IRIS) after successful initiation of ART. Therefore, a case definition of cytomegalovirus-immune recovery retinitis (CMV-IRR) is proposed here. METHODS: We reviewed medical records of 116 HIV-infected patients with CMV retinitis attending our institution during January 2003-June 2012. We retrospectively studied HIV-infected patients who had CMV retinitis on ART initiation or during the subsequent 6 months. Clinical and immunological characteristics of patients with active CMV retinitis were described. RESULTS: Of the 75 patients under successful ART included in the study, 20 had improvement of CMV retinitis. The remaining 55 patients experienced CMV-IRR; 35 of those developed CMV-IRR after ART initiation (unmasking CMV-IRR) and 20 experienced paradoxical clinical worsening of retinitis (paradoxical CMV-IRR). Nineteen patients with CMV-IRR had a CD4 count of ≥50 cells/µL. Six patients with CMV-IRR subsequently developed immune recovery uveitis. CONCLUSIONS: There is no case definition for CMV-IRR, although this condition is likely to occur after successful initiation of ART, even in patients with high CD4 T-cell counts. By consequence, we propose the case definitions for paradoxical and unmasking CMV-IRR. We recommend close follow-up of HIV-infected patients following ART initiation.

Bilateral intraocular calcification in necrotizing cytomegalovirus retinitis.

We report a unique case of bilateral intraocular calcification due to necrotizing cytomegalovirus (CMV) retinitis associated with congenital CMV infection. A 7-month-old boy with a history of congenital CMV infection showed bilateral intraocular calcific plaques on computed tomography (CT) and ultrasonography. We reviewed the patient's medical files for the purpose of this report. The patient had a prior medical history of hospitalization for fever and swelling in the neck at 3 months of age. Systemic findings (anemia, neutropenia, hepatosplenomegaly, and reactive lymphadenomegaly) in association with a low CD4 count, high blood CMV viral load, and positivity for urine CMV DNA by polymerase chain reaction led to the diagnosis of bone marrow suppression and congenital CMV infection. At 7 months, he developed horizontal nystagmus and bilateral leukocoria over 20 days. Cranial CT and ultrasonography revealed bilateral intraocular calcific plaques and the patient was referred to rule out retinoblastoma. Fundoscopy was consistent with bilateral hemorrhagic, necrotizing CMV retinitis. Significant resolution of the retinal infiltrations occurred 2 weeks after initiation of systemic treatment with ganciclovir. Intraocular calcification may be a sign of active CMV retinitis. To our knowledge this is the first report of bilateral intraocular calcification serving as the presenting clinical manifestation of necrotizing CMV retinitis.

Evidence for multiple cell death pathways during development of experimental cytomegalovirus retinitis in mice with retrovirus-induced immunosuppression: apoptosis, necroptosis, and pyroptosis.

AIDS-related human cytomegalovirus (HCMV) retinitis remains a major ophthalmologic problem worldwide. Although this sight-threatening disease is well characterized clinically, many pathogenic issues remain unresolved, among them a basic understanding of the relative roles of cell death pathways during development of retinal tissue destruction. Using an established model of experimental murine cytomegalovirus (MCMV) retinitis in mice with retrovirus-induced immunosuppression (MAIDS), we initially investigated MCMV-infected eyes for evidence of apoptosis-associated molecules in mice with MAIDS of 4 weeks' (MAIDS-4) and 10 weeks' (MAIDS-10) duration, which were resistant and susceptible to retinal disease, respectively, but which harbored equivalent amounts of infectious MCMV. Whereas MCMV-infected eyes of MAIDS-4 mice showed little evidence of apoptosis-associated molecules, MCMV-infected eyes of MAIDS-10 mice showed significant amounts of tumor necrosis factor alpha (TNF-α), TNF receptors 1 and 2, active caspase 8, active caspase 3, TNF-related apoptosis-inducing ligand (TRAIL), TRAIL-R(DR5), Fas, and Fas ligand mRNAs and/or proteins, all detected at peak amounts prior to development of most severe retinal disease. Immunohistochemical staining showed macrophages, granulocytes (neutrophils), Müller cells, and microglial cells as TNF-α sources. Remarkably, quantification of apoptosis by terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) assay suggested that apoptosis contributed minimally to retinal disease in MCMV-infected eyes of MAIDS-10 mice. Subsequent studies demonstrated that MCMV-infected eyes of MAIDS-10 mice, but not MAIDS-4 mice, showed evidence of significant increases in molecules associated with two additional cell death pathways, necroptosis (receptor-interacting protein 1 [RIP1] and RIP3 mRNAs) and pyroptosis (caspase 1, interleukin 1ß [IL-1ß], and IL-18 mRNAs). We conclude that apoptosis, necroptosis, and pyroptosis participate simultaneously during MAIDS-related MCMV retinitis, and all may play a role during AIDS-related HCMV retinitis.

Murine cytomegalovirus downregulates interleukin-17 in mice with retrovirus-induced immunosuppression that are susceptible to experimental cytomegalovirus retinitis.

Interleukin-17 (IL-17), a pro-inflammatory cytokine produced by CD4+ Th17 cells, has been associated with the pathogenesis of several autoimmune diseases including uveitis. The fate of IL-17 during HIV/AIDS, however, remains unclear, and a possible role for IL-17 in the pathogenesis of AIDS-related diseases has not been investigated. Toward these ends, we performed studies using a well-established animal model of experimental murine cytomegalovirus (MCMV) retinitis that develops in C57/BL6 mice with retrovirus-induced immunosuppression (MAIDS). After establishing baseline levels for IL-17 production in whole splenic cells of healthy mice, we observed a significant increase in IL-17 mRNA levels in whole splenic cells of mice with MAIDS of 4-weeks (MAIDS-4), 8-weeks (MAIDS-8), and 10-weeks (MAIDS-10) duration. In contrast, enriched populations of splenic CD4+ T cells, splenic macrophages, and splenic neutrophils exhibited a reproducible decrease in levels of IL-17 mRNA during MAIDS progression. To explore a possible role for IL-17 during the pathogenesis of MAIDS-related MCMV retinitis, we first demonstrated constitutive IL-17 expression in retinal photoreceptor cells of uninfected eyes of healthy mice. Subsequent studies, however, revealed a significant decrease in intraocular levels of IL-17 mRNA and protein in MCMV-infected eyes of MAIDS-10 mice during retinitis development. That MCMV infection might cause a remarkable downregulation of IL-17 production was supported further by the finding that systemic MCMV infection of healthy, MAIDS-4, or MAIDS-10 mice also significantly decreased IL-17 mRNA production by splenic CD4+ T cells. Based on additional studies using IL-10 -/- mice infected systemically with MCMV and IL-10 -/- mice with MAIDS infected intraocularly with MCMV, we propose that MCMV infection downregulates IL-17 production via stimulation of suppressor of cytokine signaling (SOCS)-3 and interleukin-10.

Extralesional microvascular and structural macular abnormalities in cytomegalovirus retinitis.

To evaluate extralesional microvascular and structural changes of the macula using optical coherence tomography angiography (OCTA) and structural OCT in cytomegalovirus retinitis (CMVR). An observational study of CMVR patients were performed. Complete ophthalmic examination, serial color fundus photography, structural OCT and OCTA were performed at baseline and follow-up visits for up to 12 months. The structural OCT was analyzed to evaluate macular areas within, bordering and beyond the CMVR lesions. Extralesional retinal capillary plexus of the macula were evaluated by OCT angiography and compared with the unaffected fellow eyes. Thirteen eyes from 13 patients were enrolled. At baseline, macular areas without CMVR lesions showed decreased vessel density (VD) of both the superficial (P = 0.0002) and deep (P < 0.0001) retinal capillary plexus in eyes with CMVR as compared with the corresponding macular areas of the unaffected fellow eyes. The decrease of VD persisted through the follow-up period for up to 12 months after adjusting for degree of vitreous haze. Structural macular OCT characteristics at the borders and beyond the lesions included intraretinal hyperreflective dots, cystoid macular edema, subretinal fluid and selective ellipsoid zone (EZ) loss. The selective EZ loss found in 6 of 12 eyes showed recovery in 4 eyes after receiving anti-viral treatment. In CMVR eyes, there were microvascular and microstructural abnormalities in the macular area without clinically visible CMVR lesions. Our results provided interesting insights into CMV infection of the retina.

Juxtapapillary cytomegalovirus retinitis with optic neuritis.

A 49-year-old man with AIDS developed acute monocular visual loss and an ipsilateral swollen optic disc with a large right relative afferent pupillary defect, a nerve fiber bundle visual field defect, and a peripapillary retinal infiltrate. Lumbar puncture disclosed cytomegalovirus (CMV) DNA on polymerase chain reaction (PCR). Treatment with oral valganciclovir produced complete resolution of the visual deficits and the fundus abnormality. This case differs from previously reported cases of CMV optic neuritis in which visual function has been irreversibly lost.

A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis.

BACKGROUND: Valganciclovir is an orally administered prodrug that is rapidly hydrolyzed to ganciclovir. We compared the effects of oral valganciclovir with those of intravenous ganciclovir as induction therapy for newly diagnosed cytomegalovirus retinitis in 160 patients with the acquired immunodeficiency syndrome (AIDS). METHODS: The primary end point was photographically determined progression of cytomegalovirus retinitis within four weeks after the initiation of treatment. Secondary end points included the achievement of a prospectively defined satisfactory response to induction therapy and the time to progression of cytomegalovirus retinitis. After four weeks, all patients received valganciclovir as maintenance therapy. RESULTS: Eighty patients were randomly assigned to each treatment group. Of the patients who could be evaluated, 7 of 70 assigned to intravenous ganciclovir (10.0 percent) and 7 of 71 assigned to oral valganciclovir (9.9 percent) had progression of cytomegalovirus retinitis during the first four weeks (difference in proportions, 0.1 percentage point; 95 percent confidence interval, -9.7 to 10.0). Forty-seven of 61 patients (77.0 percent) assigned to intravenous ganciclovir and 46 of 64 (71.9 percent) assigned to valganciclovir had a satisfactory response to induction therapy (difference in proportions, 5.2 percentage points; 95 percent confidence interval, -20.4 to 10.1). The median times to progression of retinitis were 125 days in the group assigned to intravenous ganciclovir and 160 days in the group assigned to oral valganciclovir. The mean values for the area under the curve for the ganciclovir dosage interval were similar at both induction doses and maintenance doses. The frequency and severity of adverse events were similar in the two treatment groups. CONCLUSIONS: Orally administered valganciclovir appears to be as effective as intravenous ganciclovir for induction treatment and is convenient and effective for the long-term management of cytomegalovirus retinitis in patients with AIDS.

Cytomegalovirus retinitis in a patient with secondary acute lymphosarcoma leukemia undergoing allogeneic hematopoietic stem-cell transplantation: A rare case report: a care-compliant article.

RATIONALE: Cytomegalovirus (CMV) retinitis is a common opportunistic infection in immunocompromised patients, which may lead to blindness. CMV retinitis is not an uncommon infectious disease in patients with immune regulatory abnormalities, for example, human immunodeficiency virus (HIV) patients. However, CMV retinitis in a patient with acute lymphosarcoma leukemia (ALL) undergoing allogeneic hematopoietic stem-cell transplantation (HSCT) phase is very rare. PATIENT CONCERNS: A case of CMV retinitis in a patient receiving immunosuppressive therapy as a part of ALL allogeneic HSCT is described including the pathogenesis, clinical signs, and therapy. DIAGNOSES: CMV retinitis. INTERVENTIONS: Ganciclovir intravitreal injection at weekly intervals for 4 weeks. OUTCOMES: Patient's vision had improved and the load of CMV deoxyribonucleic acid (DNA) in the aqueous humor declined. The CMV retinitis and perivascular of retina infiltration regressed. LESSONS: We propose that the concentration of CMV DNA load in the aqueous humor could be useful in making the diagnosis and in selecting the optimal treatment in this kind of CMV retinitis.