Cytomegalovirus Endotheliitis Research Articles

Cytokine analysis of aqueous humor in patients with cytomegalovirus corneal endotheliitis.

To evaluate cytokine levels of aqueous humor in patients with cytomegalovirus (CMV) corneal endotheliitis and their relationships with CMV DNA load. 44 aqueous humor samples were obtained from 26 patients with CMV corneal endotheliitis at various stages of treatment. 33 samples obtained from cataract patients during the same period were selected as a control group. Each sample was used to measure the concentration of the CMV DNA load using real-time quantitative polymerase chain reaction, and to examine the levels of IL-6, IL-8, IL-10, MCP-1, VCAM-1, VEGF, IP-10, G-CSF, ICAM-1 and IFN-γ using a cytometric bead array. All 10 cytokines were found to have statistically significant differences between the CMV endotheliitis and cataract groups. The Spearman correlation test showed that the concentration of CMV DNA load was significantly associated with the levels of IL-6 (P = 0.005, r = 0.417), IL-8 (P < 0.001, r = 0.514), IL-10 (P < 0.001, r = 0.700), MCP-1 (P = 0.001, r = 0.487), VEGF (P < 0.001, r = 0.690), IP-10 (P = 0.001, r = 0.469), G-CSF (P < 0.001, r = 0.554) and ICAM-1 (P < 0.001, r = 0.635), but not significantly associated with VCAM-1 (P = 0.056) and IFN-γ (P = 0.219). There was a combined innate and adaptive immune response in aqueous humor in patients with CMV endotheliitis. Levels of multiple cytokines were significantly correlated with viral particle. Cytokines are potential indicators to help diagnose CMV endotheliitis, evaluate disease activity and assess treatment response.

Clinical Features of Glaucoma Associated with Cytomegalovirus Corneal Endotheliitis.

PurposeThe purpose of this study was to highlight the manifestations of glaucoma associated with cytomegalovirus (CMV) corneal endotheliitis.MethodsWe reviewed the 34 patients that met the diagnostic criteria for CMV endotheliitis in our hospital, with special attention to the glaucoma status, including onset of glaucoma, glaucoma in the fellow eye, visual field defects, intraocular pressure, and final outcomes.ResultsThirty-four eyes of 34 patients (mean age, 69.1 ± 13.1 years; 31 males [91.2%]) with CMV corneal endotheliitis were enrolled. Thirty-two eyes (94.1%) had a history of a glaucoma diagnosis, which had been treated for 10.0 ± 10.1 years. Glaucoma in the fellow eye was noted in 16 cases (47.1%) and a history of Posner-Schlossman syndrome was noted in 13 cases (38.2%). Visual fields measured using a Humphrey field analyzer were normal-to-early stage (MD>-6dB) in 16 eyes (47.1%) and middle-to-late stage (MD≤-6dB) in 18 eyes (52.9%). The intraocular pressure decreased from 22.4 ± 10.6 mmHg at the initial visit to 14.9 ± 7.9 mmHg after medical treatment, including 0.5% topical ganciclovir (GCV) with and without a systemic anti-CMV agent, corticosteroid eye drops, and an anti-glaucoma agent (p<0.01). During the follow-up period of 4.8 ± 3.0 years (range, 0.2–10 years), 16 eyes (47.1%) required glaucoma surgery, including filtering surgery (7 eyes) and trabeculotomy only (9 eyes).ConclusionOur case series showed that most of the patients with CMV corneal endotheliitis had glaucoma. Although medical therapy, including 0.5% topical GCV, had efficacy in lowering the intraocular pressure, one-half of the cases required glaucoma surgery. Therefore, ophthalmologists should strive to make an earlier diagnosis of CMV corneal endotheliitis by utilizing PCR testing of aqueous humor samples to prevent sight-threatening glaucomatous damage.

Clinical Metagenomic Next-Generation Sequencing for Diagnosis of Secondary Glaucoma in Patients With Cytomegalovirus-Induced Corneal Endotheliitis.

Glaucoma is the second leading cause of blindness globally. Growing scientific evidence indicated that inflammation of the trabecular meshwork induced by corneal endotheliitis could lead to secondary glaucoma. Cytomegalovirus (CMV) has been identified as the most common herpes virus in corneal endotheliitis patients. Early detection is critical in preventing endothelial cell loss, and patient management should vary based on different pathological factors. However, routine culture and real-time polymerase chain reaction (qPCR) have difficult in distinguishing whether CMV, Varicella Zoster Virus (VZV) or Herpes Simplex Virus (HSV) causes endothiliitis. This may result in inappropriate treatment, which may prolong or aggravate the status of disease. We compared the sensitivity and specificity of qPCR and Metagenomic Next-Generation Sequencing (mNGS) in the aqueous humor of patients with suspected CMV endotheliitis in this study. Our results showed that four out of 11 (36.4%) of our patients were positive for CMV by qPCR, whereas mNGS had a 100% detection rate of CMV. Our findings implied that mNGS could be a useful diagnostic tool for CMV-induced endotheliitis.

Cytomegalovirus as a cause of recurrent corneal endotheliitis in the Canadian population

ObjectifPrésenter les manifestations cliniques, la réponse au traitement antiviral et les résultats visuels à long terme de l'endothélite à cytomégalovirus (CMV) au sein d'une cohorte canadienne. NatureÉtude rétrospective d'une série de cas. ParticipantsUn total de 7 patients (9 yeux) atteints d'endothélite cornéenne ont été adressés à une clinique spécialisée dans le traitement des troubles de la cornée intégrée à un important établissement canadien. MéthodesOn a réalisé un examen rétrospectif de tous les patients qui avaient consulté un seul et même chirurgien spécialisé dans les troubles de la cornée en raison d'une endothélite cornéenne. Les patients ont subi une ponction de chambre antérieure et obtenu un résultat positif lors d'un test de dépistage (réaction en chaîne de la polymérase) du CMV. Tous les patients ont reçu le valganciclovir par voie orale pendant un minimum de 3 mois. Les principaux paramètres de mesure comprenaient l'acuité visuelle, la maîtrise de l'hypertension oculaire, la dépendance médicamenteuse et l’état de la cornée. RésultatsLa durée moyenne du suivi a été de 76,4 ± 11,8 mois. Seuls 2 patients présentaient une atteinte bilatérale. On compte 3 types de manifestations de l'endothélite touchant la cornée : les lésions linéaires, disciformes et circinées. La meilleure acuité visuelle corrigée est passée d'une moyenne de 0,48 ± 0,19 logMAR lors de la visite initiale à 0,24 ± 0,11 logMAR lors de la dernière visite de suivi. La pression intraoculaire, pour sa part, est passée d'un maximum de 35 ± 3,1 mm Hg à 14,2 ± 4,3 mm Hg. Le nombre d'antiglaucomateux a diminué, passant de 2,6 ± 0,45 collyres à 0,89 ± 0,29. On a dû procéder à une transplantation endothéliale dans 2 yeux. Le valganciclovir a été bien toléré par l'ensemble des patients; au moment de la dernière visite de suivi, l’état de tous les patients était stable sous l'effet de faibles doses de valganciclovir (dose moyenne hebdomadaire : 1395 mg). ConclusionsLe CMV est une cause peu fréquente, mais cliniquement significative, d'endothélite cornéenne et doit être pris en considération dans le diagnostic différentiel de l'endothélite cornéenne, même au sein d'une population immunocompétente. Nos résultats étayent ceux d’études antérieures selon lesquels le CMV réagit très bien au valganciclovir par voie orale et illustrent pour la première fois l'efficacité d'un traitement antiviral d'entretien faiblement dosé au long cours.

Long-Term Outcome of Treatment with 2% Topical Ganciclovir Solution in Cytomegalovirus Anterior Uveitis and Corneal Endotheliitis.

PurposeThis study aimed to evaluate the therapeutic efficacy and long-term outcomes of treatment with topical 2% ganciclovir solution in immunocompetent patients with aqueous humor polymerase chain reaction (PCR)-proven cytomegalovirus (CMV) anterior uveitis and corneal endotheliitis.MethodsWe retrospectively reviewed the findings for immunocompetent patients diagnosed with CMV uveitis or endotheliitis based on clinical manifestations and polymerase chain reaction (PCR) examination results and treated with topical 2% ganciclovir solution at National Cheng Kung University Hospital. Clinical outcome measurements included evaluations of the response rate, relapses, resolution of anterior chamber inflammation, visual acuity, and intraocular pressure.ResultsThe study included 38 eyes of 32 patients. Long-term administration of topical 2% ganciclovir significantly decreased keratic precipitates (p = 0.001), anterior chamber cells (p = 0.001), and reduced intraocular pressure (p < 0.001). Only one eye was unresponsive to topical ganciclovir treatment, and the recurrence decreased to 0.13 relapses per year. The presence of keratic precipitates and higher intraocular pressure at the initial presentation were significantly associated with recurrence (p = 0.036 and p = 0.001, respectively).ConclusionsLong-term use of topical 2% ganciclovir solution is effective, safe, and applicable when commercialized ganciclovir gel is not available.

Clinical Findings of Specular Microscopy Images in Cytomegalovirus Corneal Endotheliitis.

The aim of this study is to evaluate the usefulness of specular microscopy as an alternative diagnostic tool for cytomegalovirus (CMV) corneal endotheliitis. A retrospective study. One hundred and four patients with clinical manifestations of infectious corneal endotheliitis, iridocyclitis, and retinitis were included in this study. The presence of CMV deoxyribonucleic acid (DNA) was confirmed by multiplex polymerase chain reaction (PCR). Viral load was measured using real-time PCR. Corneal endothelium was observed by specular microscopy. The medical records and clinical manifestations of the patients were retrospectively reviewed and linked with the PCR results. Seventeen of 104 cases were CMV endotheliitis and/or iridocyclitis and had no history of intraocular surgery or corneal transplantation. There was a negative correlation between viral load and corneal endothelial cell counts. In 14 of 17 cases, owl's eye cells were observed by specular microscopy. The corneal endothelial cell counts were significantly reduced in the cases in which owl's eye cells were observed. In CMV endotheliitis, owl's eye cells were observed by specular microscopy with high probability (82%). Corneal endothelial cells significantly decreased when owl's eye cells were observed by specular microscopy. Specular microscopy represents a useful noninvasive auxiliary tool for diagnosing and monitoring CMV corneal endotheliitis.

Clinical Evaluation of Intravitreal Injection of Ganciclovir in Refractory Corneal Endotheliitis

ABSTRACTPurpose: To evaluate the efficacy and safety of intravitreal ganciclovir (GCV) injection in refractory endotheliitis.Methods: Retrospectively recruited 25 eyes with endotheliitis, proved by clinical manifestations, positive PCR for viral DNA and responded poor to topical and systemic antiviral medications. All patients received additional continued intravitreal GCV injections.Results: Cytomegalovirus (CMV), varicella zoster virus (VZV), and herpes simplex virus (HSV) DNA were detected in 64.0%, 28.0%, and 8.0% of the eyes, respectively. Within 2 weeks after the last injection, 16/25 eyes recovered corneal clarity; active keratic precipitates (KPs) were eliminated in 21/25 eyes; intraocular pressure (IOP) was controlled in 12/15 eyes with elevated IOP on study entry. Best-corrected visual acuity increased at the last follow-up (p = 0.016). Clinical recurrence occurred in three patients. No complications were detected.Conclusions: CMV endotheliitis was the main type of refractory endotheliitis. Despite its invasive nature, intravitreal GCV injection appears to be an effective method for refractory endotheliitis.

Prevalence and clinical consequences of cytomegalovirus DNA in the aqueous humour and corneal transplants

AimTo determine the prevalence and clinical consequences of cytomegalovirus (CMV) DNA in the aqueous and corneal tissues obtained at the time of corneal transplantation to evaluate the diagnostic value of...

The Effect of Topical Ganciclovir and Corticosteroid on Cytomegalovirus Corneal Endotheliitis in Korean Patients

ABSTRACTPurpose: To report long-term outcomes of topical ganciclovir (GCV) and corticosteroids in Korean patients with cytomegalovirus (CMV) corneal endotheliitis.Methods: This retrospective study included 13 eyes from 13 patients with CMV corneal endotheliitis, with a follow-up period of 24.5 ± 8.2 months. The patients were consistently maintained with topical 2% GCV and 1% prednisolone acetate eyedrop.Results: All patients demonstrated unilateral typical coin-shaped keratic precipitates (KPs) or linear KP, and positive CMV polymerase chain reaction of aqueous humor. After 2 weeks of treatment, all patients showed decrease of clinical signs. During the follow-up, four patients developed mild anterior chamber inflammation with increased intraocular pressure without typical coin-shaped KPs or edema, started to use the initial dose, and resolved the clinical signs. One patient showed recurrence of corneal edema twice, and was administered systemic valgancyclovir for 2 weeks upon second recurrence with resolution of clinical signs.Conclusion: Long-term maintenance therapy with topical GCV and corticosteroids are effective and maintain corneal endothelial function in Korean patients with CMV endotheliitis.

Topical ganciclovir treatment post-Descemet’s stripping automated endothelial keratoplasty for patients with bullous keratopathy induced by cytomegalovirus

Background/aimsTo investigate the efficacy of topical ganciclovir (GCV) for preventing disease recurrence and improving the surgical outcome post-Descemet’s stripping automated endothelial keratoplasty (DSAEK) in patients with cytomegalovirus (CMV) endotheliitis.MethodsThis prospective,...

Corneal endothelial cells activate innate and acquired arm of anti-viral responses after cytomegalovirus infection

Infection of the corneal endothelial cells by human cytomegalovirus (CMV) is an important cause of corneal endotheliitis. CMV endotheliitis is difficult to completely cure and relapses are frequent. This can cause blinding corneal bullous keratopathy. However, the pathogenesis of CMV endotheliitis remains undetermined. To understand the immunopathology of endotheliitis, we examined how corneal endothelial cells prime the anti-viral immunity after CMV infection based on global transcriptional responses. To accomplish this, human corneal endothelial (HCEn) cells were infected with CMV, and the global transcriptional responses were determined by microarray analyses for primary anti-viral responses using network analysis. Real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and protein array analyses were used to examine whether anti-viral cytokines were induced, i.e., to determine whether innate immune responses were activated. To examine whether priming of acquired immune response was activated, CMV-infected HCEn cells were co-cultured with allogeneic CD8+ T cells from CMV seropositive donors and tested for priming activity for the CD8+ effector T cells by measuring interferon-γ secretion. The CMV-induced responses of HCEn cells were characterized by type I interferon and pattern recognition receptor pathways which represent innate immune priming. The global transcriptional activation was specifically associated with antigen presentation with the antimicrobial response functions. Protein array analyses indicated a significant increase in the secretion of anti-viral inflammatory cytokines including CXCL10 as innate immune responses. When HCEn cells were examined to determine whether CMV infection activated anti-viral acquired immunity, CMV-infected HCEn cells directly stimulated the proliferation of CD8+ T cells from CMV-seropositive donors, and pp65 viral epitope induced interferon-γ secretion from the CD8+ T cells. We conclude that CMV-infected HCEn cells induce innate immune priming along with provisions of acquired immune priming of CD8+ effector T cells. This information should help in the development of useful diagnostic procedures and efficacious therapeutic strategy to treat refractory corneal endotheliitis.

Descemet Stripping Automated Endothelial Keratoplasty Outcomes in Patients With Cytomegalovirus Endotheliitis.

There is currently limited information regarding the outcomes of endothelial keratoplasty in eyes with cytomegalovirus (CMV) endotheliitis. We report the results of Descemet stripping automated endothelial keratoplasty (DSAEK) for endothelial failure secondary to CMV. This is a retrospective review of 4 eyes of 4 patients with CMV endotheliitis and DSAEK. CMV was confirmed in each case by a positive aqueous tap on qualitative polymerase chain reaction. The clinical characteristics of the patients and postoperative outcomes were studied. The mean age of the 4 patients was 69.6 ± 8.1 years. Two were ethnically Vietnamese, 1 Chinese, and 1 Lebanese. All were immunocompetent. Three eyes had presented with hypertensive uveitis and 1 with bullous keratopathy. Twelve DSAEKs were performed in total in the 4 eyes. Five grafts were performed without any perioperative treatment with oral valganciclovir. All subsequently failed after a mean of 8.0 ± 3.8 months. Seven grafts were managed with oral valganciclovir; 2 of these grafts failed after 18 and 37 months, and 1 graft had primary graft failure. Four grafts are currently surviving, despite an episode of CMV reactivation in 2 grafts. In cases of unexplained corneal decompensation or early graft failure after uncomplicated DSAEK, a diagnosis of CMV infection must be considered. Subsequent management of DSAEK in such cases remains challenging. The postoperative course can be complicated by CMV reactivation, which may masquerade either as graft rejection or graft failure. Long-term treatment with oral valganciclovir or topical ganciclovir may be required to decrease graft failure rates.

Clinical features, diagnosis and treatment outcomes of cytomegalovirus endotheliitis in Hong Kong

Clinical features, diagnosis and treatment outcomes of cytomegalovirus endotheliitis in Hong Kong

Clinical Manifestations and Outcomes of Treatment in Cytomegalovirus Endotheliitis

Clinical Manifestations and Outcomes of Treatment in Cytomegalovirus Endotheliitis

Review of clinical and basic approaches to corneal endotheliitis.

Corneal endotheliitis was first reported as an autoimmune disease by Khodadoust in 1982. Thereafter, herpes simplex virus (HSV) was detected as a causative agent, and corneal endotheliitis was classified as an infectious disease. However, most primary corneal endotheliitis had been idiopathic. In 2006, cytomegalovirus (CMV) DNA was detected in a case of corneal endotheliitis, and other reports on CMV endotheliitis from Asian countries established it as a new clinical entity. Limited studies have reported clinical findings, and the pathogenesis of HSV and CMV corneal endotheliitis is unknown. Therefore, this review describes what is currently known about the pathogenesis of HSV and CMV endotheliitis by way of previously reported case studies and basic research. In addition, we review work by our own group regarding the role of Toll-like receptor 9 and the results of transcriptome analysis after HSV infection in an in vitro model using immortalized human corneal endothelial cells. It is critical to diagnose corneal endotheliitis early to provide effective treatment with ganciclovir or valganciclovir and prevent the loss of corneal endothelial cells. Therefore, we hope that these in vitro results may provide further information to help elucidate the in vivo pathogenesis of HSV and CMV endotheliitis.

Clinical features and management of cytomegalovirus corneal endotheliitis: analysis of 106 cases from the Japan corneal endotheliitis study

AimsThe purpose of this study is to elucidate the clinical manifestations and the current treatment status of cytomegalovirus (CMV) endotheliitis via a large case series obtained from a national survey...

Topical ganciclovir treatment in patients with cytomegalovirus endotheliitis receiving penetrating keratoplasty

To report seven cases diagnosed as cytomegalovirus endotheliitis and treated with topical 2% ganciclovir following penetrating keratoplasty. A retrospectively comparative case series. A retrospective interventional case series, including seven eyes of seven patients with cytomegalovirus endotheliitis after penetrating keratoplasty. Clinical and immunological characteristics were studied in seven penetrating keratoplasty cases with positive quantitative polymerase chain reaction results for cytomegalovirus DNA from aqueous taps and treated with topical 2% ganciclovir. Clinical features and responses to topical 2% ganciclovir. Seven immunocompetent patients experienced acute anterior inflammation with graft oedema and pigmented keratic precipitates after penetrating keratoplasty. Their immunological profiles showed immunoglobulin G cytomegalovirus (+) and immunoglobulin M cytomegalovirus (-) in all cases. Topical 2% ganciclovir was prescribed every 2 to 3 h daily as induction therapy and every 4 h as long-term maintenance therapy. All cases had undetectable cytomegalovirus DNA after follow-up aqueous taps. Topical 2% ganciclovir preserved endothelium of cytomegalovirus-infected grafts at early stage and also provided a steady anticytomegalovirus environment for further regrafting in failed grafts at late stage. Acute inflammation reactivated in two cases and was suppressible by steroid under topical ganciclovir. No delayed re-epithelialization and any toxicity were observed. To date, no case treated in this way had displayed cytomegalovirus recurrence. Continuous topical 2% ganciclovir and a topical steroid adjusted by anterior inflammation are suggested after penetrating keratoplasty in all cases with cytomegalovirus endotheliitis to prevent cytomegalovirus recurrence.

Post-phacoemulsification cytomegalovirus corneal endotheliitis diagnosis and management

Quantitative polymerase chain reaction is essential in diagnosing and monitoring cytomegalovirus endotheliitis. Treatment with long-term anti-virals and endothelial surgery can offer successful visual rehabilitation.

Treatment outcome and risk factors for visual loss in Cytomegalovirus endotheliitis

To determine treatment outcome and risk factors for visual loss in Cytomegalovirus (CMV) endotheliitis. Retrospective case-note review of all CMV positive endotheliitis patients seen at the Singapore National Eye Center, for demographics, visual acuity (VA), extent of corneal edema, anterior chamber (AC) activity, ocular history, glaucomatous optic neuropathy (GON), and ganciclovir therapy. Outcome measures were VA, corneal edema, and AC activity. Median age at diagnosis of the 19 patients (21 eyes) was 57 years. Median duration of follow up was 37 months. Sixteen eyes received systemic ganciclovir, and four eyes received ganciclovir gel. The AC inflammation resolved in 19 eyes. The corneal edema resolved in eight eyes, but persisted in 12 eyes. One patient resolved spontaneously. Pre-treatment corneal edema exceeding 75%, older age, GON, and previous corneal graft were risk factors for persistent corneal edema post treatment (P = <0.001, 0.001, 0.02 and 0.02 respectively, Fisher's exact test), and VA worse than 6/60. Anterior chamber inflammation resolves with ganciclovir therapy, but severe pre-treatment corneal edema, older age, previous corneal graft, and GON are associated with a poor visual outcome.

Cytomegalovirus Endotheliitis after Fluocinolone Acetonide (Retisert) Implant in a Patient with Behçet Uveitis

Purpose: To report a case of cytomegalovirus (CMV) endotheliitis after insertion of an intravitreal fluocinolone acetonide (Retisert) implant.Design: Interventional case report.Methods: Retrospective chart review.Results: A 40-year-old man received a Retisert implant in the left eye for recurrent Behçet uveitis. Although inflammation became quiescent within a month, corneal edema developed 4 months after insertion. Polymerase chain reaction analysis for aqueous humor detected 3.9 × 104 copies/mL of CMV DNA. After treatment with oral valganciclovir, CMV DNA nearly disappeared but visual outcome was poor due to corneal decompensation resulting from severe endothelial cell loss.Conclusions: After Retisert implant, clinicians should be attentive to the potential risk of CMV endotheliitis.