Utility of Ultra-Widefield Retinal Imaging in the Follow-up and Management of Patients with Cytomegalovirus Retinitis

ABSTRACT

Cytomegalovirus (CMV) retinitis is an opportunistic infection classically described in patients with acquired immune deficiency syndrome and other immune-compromising situations. As the diagnosis is based on clinical findings, classic retinal imaging montages have been a useful tool, being able to detect up to 140º of the retina. Since ultra-widefield (UWF) imaging systems have been available we can now detect more area of peripheral lesions in the diagnosis and follow-up of patients’ response to antiviral treatment. We present a series of cases in which UWF was used as the main tool for diagnosis, monitoring, and management in patients with CMV retinitis.In all the cases presented, UWF imaging with fundus autofluorescence was able to capture peripheral CMV retinitis areas and discern active from inactive lesions. This, added to the comfort of use, seem to make UWF imaging a useful tool to detect changes in the follow-up of patients with CMV retinitis.     

Management of Ganciclovir Resistant Cytomegalovirus Retinitis in a Solid Organ Transplant Recipient: A Review of Current Evidence and Treatment Approaches

ABSTRACT

Purpose: Cytomegalovirus retinitis (CMVR) is a serious and potentially sight-threatening infection in immunocompromised individuals. Strategies for the management of drug-resistant CMVR are described.

Methods: A case of severe bilateral CMVR in a single lung transplant patient, with UL97 mutation conferring ganciclovir-resistance, is presented. Treatment with standard antiviral agent and adjuvant leflunomide, immunosuppression modifications (calcineurin inhibitors and corticosteroid), intravitreal antiviral therapy and novel use of CMV-immunoglobulin is described. A literature review to support drug-resistant CMVR management is presented.

Results: Severe and progressive CMV retinitis was refractory to intravitreal foscarnet and systemic leflunomide. Drug-toxicity restricted systemic antiviral therapy options. The use of combined leflunomide and CMV-immunoglobulins, in the absence of viremia, has not been previously reported. Loss of ganciclovir-resistance was eventually observed permitting successful treatment with systemic and intravitreal ganciclovir.

Conclusions: Drug-resistant CMVR is a complex clinical challenge. Multiple systemic and local treatment strategies may be necessary but toxicity, resistance, and co-morbidities may severely restrict available options.     

Presenting Features,Treatment and Clinical Outcomes of Cytomegalovirus Retinitis: Non-HIV Patients Vs HIV Patients

ABSTRACT

Purpose

To compare clinical features, complications, and outcomes of CMV retinitis in non-HIV immunocompromised patients with HIV infected patients.     

Cytomegalovirus Retinitis Following Intravitreal Triamcinolone Acetonide in a Patient with Chronic Uveitis on Systemic Immunosuppression

Abstract

Purpose: To report a case of cytomegalovirus (CMV) retinitis in an HIV-negative, iatrogenically immunosuppressed patient with chronic uveitis following intravitreal triamcinolone acetonide (IVTA).

Design: Observational case report. Methods: A 56-year-old female with chronic idiopathic panuveitis on azathioprine received a single 4-mg IVTA injection for macular edema and presented after 6 months with severe retinitis.

Results: CMV was confirmed by polymerase chain reaction of vitreous fluid. The retinitis responded well to intravitreal ganciclovir, but she developed a rhegmatogenous retinal detachment and underwent vitrectomy with silicone oil tamponade.

Conclusions: Sight-threatening CMV retinitis may develop in HIV-negative, immunosuppressed individuals after IVTA. Regular fundoscopy for up to 9 months after IVTA is recommended.     

Spectrum of Newly Diagnosed Cytomegalovirus Retinitis in a Developing Country in the HAART Era

ABSTRACT

Purpose: To characterize the presenting features of cytomegalovirus (CMV) retinitis in HIV-positive patients in a developing country in the HAART era.

Methods: Retrospective chart review of all patients with CMV retinitis seen at a tertiary-care referral center between January 2006 to June 2017. Demographic and clinical data were collected to study the presenting features and risk factors for blindness.

Results: Fifty-five patients with treatment-naïve CMV retinitis were enrolled; 75% were males. CD4 counts were below 50 cells/µL in 51.1%. Bilateral presentation was seen in 61.5%. Half (50.6%) of the eyes were blind at first examination. Zone 1 involvement was present in 46% of the eyes. Retinal area involvement > 25% was the only factor associated significantly with higher incidence of blindness (p = 0.016).

Conclusions: There was extensive and bilateral presentation of CMV retinitis due to delayed presentation. Screening for CMV retinitis, irrespective of CD4 counts, may help in developing nations.     

Cytomegalovirus and the eye

Following primary infection, cytomegalovirus (CMV) establishes latent infection in myeloid progenitor cells and intermittent viral reactivation from activated macrophages or dendritic cells, which is brought under control by strong virus-specific CD4+ T-cell and CD8+ T-cell responses. CMV retinitis characterized by spreading retinal necrosis due to viral cytopathic effect occurs in patients who have impaired T-cell function as a result of transplantation, AIDS, or immuno-suppressive treatment. The diagnosis of CMV retinitis can be confirmed by PCR amplification of viral DNA in aqueous. When administered intravenously, the antiviral drugs Ganciclovir and Foscarnet have modest penetration into the vitreous compared with direct intra-vitreal injection. In randomized trials of HIV-associated CMV retinitis, a Ganciclovir implant was consistently superior to intravenous Ganciclovir in preventing progression of retinitis. CMV is also implicated in two forms of anterior segment disease in immuno-competent adults, namely CMV anterior uveitis and CMV corneal endotheliitis.     

Bilateral Cytomegalovirus Retinitis in a Patient with Systemic Lupus Erythematosus

PurposeThe purpose of this study was to report the case of a patient who underwent vitrectomy for bilateral rhegmatogenous retinal detachment caused by cytomegalovirus (CMV) retinitis while undergoing steroid and immunosuppressant therapy for systemic lupus erythematosus (SLE).ConclusionThe findings of this study show that strict attention must be paid to SLE patients on immunosuppressive therapy due to the possible association of CMV retinitis.     

CMV Retinitis in a Patient with Good Syndrome

Purpose: To describe cytomegalovirus (CMV) retinitis in a patient with Good syndrome. Methods: A 48-year-old patient with Good syndrome presented with a necrotizing retinitis in the left eye. Quantitative touchdown real-time polymerase chain reaction (PCR) was performed on aqueous fluid. Results: Quantitative PCR showed 152 copies of CMV per ml and was negative for varicella zoster virus (VZV), Epstein-Barr virus (EBV), herpes simplex virus (HSV-1), and HSV-2. The positive CMV PCR suggested CMV retinitis and the patient was treated with intravitreal ganciclovir injections (2.5 mg/0.05 ml), followed by ganciclovir implant. The retinal lesions showed decreasing activity two weeks after the onset of the therapy. A repeat PCR showed a decreasing number of CMV copies at one and two weeks (122 copies/ml and 0 copies/ml, respectively) that correlated clinically with the decreasing retinitis activity. Conclusions: Quantitative PCR can be useful in diagnosing as well as assessing the response to therapy of CMV retinitis in patients with Good syndrome.     

Cytomegalovirus Retinitis in Immunocompetent Patients: Case Reports and Literature Review

Purpose: The purpose of this study was to examine 2 cases of cytomegalovirus (CMV) retinitis, occuring in 2 immunocompentent adult patients.

Methods: Case selection and literature review.

Results: Both patients cited significantly decreased vision despite systemic, topical, and/or local corticosteroid use. Neither patient was using high-dose immunosuppressant therapy at the time of diagnostic testing. Both patients exhibited confirmed CMV infection via polymerase chain reaction DNA testing. Oral antivirals were employed and have stabilized both patients.

Conclusion: The cases described herein serve to inform ophthalmologists of the urgent need to include CMV in their differential when encountering an immunocompetent adult with significant comorbidities or with a history of previous exposure. Proper treatment is heavily reliant on proper diagnosis.     

Cytomegalovirus retinitis in children following bone marrow transplantation

The authors describe three children, aged one, 13 and 24 months, who developed cytomegalovirus (CMV) retinitis seven to 18 months following allogeneic BMT. The underlying disease in two patients was severe combined immunodeficiency disease (SCID) and acute myeloid leukemia (AML) M5 in the third. All three patients developed chronic graft-versus-host-disease (GVHD) and received massive immunosuppressive therapy. The CMV retinitis was treated with ganciclovir. Clinical improvement was observed in the two SCID patients. The AML patient whose acute inflammatory retinitis was controlled, nevertheless developed optic atrophy in both eyes and VEP and ERG responses disappeared.

The incidence of cytomegalovirus retinitis in our pediatric population of bone marrow transplant (BMT) recipients in the last three years was higher than expected: 3/85 (3.5%). Alertness to the possibility of intraocular complications is advocated. Early detection of CMV retinitis and intensive treatment with ganciclovir can save vision. It is therefore suggested to perform ocular examinations as part of the routine follow-up of BMT patients, especially in children with profound immune deficiency.     

Concurrent Herpes Simplex and Cytomegalovirus,Retinitis and Encephalitis in the Acquired Immune Deficiency Syndrome (AIDS)

We present a case of bilateral herpes simplex and cytomegalovirus retinitis and concurrent encephalitis following acyclovir therapy in a homosexual male with the acquired immune deficiency syndrome (AIDS). At autopsy, herpes simplex virus antigens were readily detected in all retinal layers, retinal pigment epithelium, and choriocapillaris, using an immunoperoxidase technique, whereas herpes simplex antigens in the brain were localized in restricted foci of vascular and subependymal parenchymal cells. Cytomegalovirus antigens were identified in cells in all layers of retina, in retinal pigment epithelium, and in subependymal parenchymal cells in the brain. No cytomegalovirus antigens were detected in any vascular endothelium, in choroid, or anterior to the ora serrata. The widespread expression of herpes simplex virus antigens in this patient's retinas is in marked contrast to the restricted foci of herpes simplex antigens limited to the subependymal region of the brain, and is similar to that seen in murine models of herpes simplex retinitis produced by acyclovirresistant viral mutants.     

Cytomegalovirus Retinitis in a Human Immunodeficiency Virus-negative Cohort: Long-term Management and Complications

Abstract

Purpose: To examine the clinical outcomes achieved by using intravitreal ganciclovir injections combined with systemic anti-viral therapy in treating cytomegalovirus (CMV) retinitis in patients without human immunodeficiency virus (HIV) infection.

Methods: Twenty-three eyes of 15 HIV-negative patients diagnosed with CMV retinitis were included in this retrospective study.

Results: The median follow-up was 68 weeks (range, 12–156), and median number of injections was 10 (range, 2–22). The retinal lesions stopped progressing within 1–2 weeks following treatment. All of the eyes showed either unchanged or ≥2?line improvements of BCVA at last visit. There was no development of CMV retinitis in a fellow eye, or recurrence in a studied eye. Systemic complications such as neutropenia were not detected.

Conclusions: Intravitreal ganciclovir injections combined with systemic anti-viral treatment is a good therapeutic option for treating CMV retinitis without HIV infection. Such treatment provided favorable visual outcomes, with minimal ocular and systemic complications.     

Cytokine profile in response to Cytomegalovirus associated with immune recovery syndrome after highly active antiretroviral therapy

BACKGROUND: Several changes have occurred in the presentation and course of cytomegalovirus (CMV) retinitis in patients with AIDS since the introduction of HAART (highly active antiretroviral therapy). In some individuals who take HAART, retinitis is kept under control even after the discontinuation of anti-CMV therapy. However, many of these patients develop intraocular inflammation. Uveitis, cataract, vitreitis, cystoid macular edema, epiretinal membrane, and disc edema may occur in patients with immune recovery syndrome (IRS). METHODS: We evaluated the CMV-specific immune response in 55 patients by assessing CMV-specific lymphocyte proliferation, cytotoxicity, and cytokine production and correlated it with the clinical outcome. RESULTS: Our data suggest that control of CMV retinitis is associated with acquisition of cytotoxic and lymphoproliferative responses to CMV. In addition, the upsurge of macular and disc edema seems associated with the production of interleukin-4 and tumor necrosis factor-alpha, whereas vitreitis is associated with the production of interleukin-2 and interferon-gamma. INTERPRETATION: The type of T-cell response that develops after HAART may determine the side effects of immune recovery and these effects are predictable based on the lymphokine profile produced by CMV-specific cells.     

Cytokine Profiles in Aqueous Humor and Plasma of HIV-infected Individuals with Ocular Syphilis or Cytomegalovirus Retinitis

Purpose: To characterize the immunologic profile in aqueous humor (AqH) of HIV-infected individuals with cytomegalovirus retinitis (CMVr) or ocular syphilis and to assess if AqH and plasma represent independent cytokine compartments.

Methods: Concentrations of 27 cytokines in AqH and plasma of HIV-infected individuals with CMVr (n = 23) or ocular syphilis (n = 16) were measured by multiplex assay. Cytokine profiles of both groups were compared.

Results: Individuals with CMVr had higher plasma concentrations of interleukin (IL)-7, IL-8, IL-10, interferon (IFN)-γ, IFN-α2, G-CSF, IP-10 and IL-1α; as well as higher AqH concentrations of IL-1α, IP-10 and GM-CSF than those with ocular syphilis. AqH and plasma levels correlated only for IP-10 in both ocular infections.

Conclusions: Individuals with CMVr had higher plasma cytokine levels than those with ocular syphilis. The immunologic profiles in AqH and plasma are independent. Therefore, AqH cytokine concentrations cannot be inferred from plasma cytokine concentrations in the population studied.     

Early-Onset X-Linked Retinitis Pigmentosa in a Heterozygous Female Harboring an Intronic Donor Splice Site Mutation in the Retinitis Pigmentosa GTPase Regulator Gene

Purpose: To report a heterozygous female presenting with an early-onset and severe form of X-linked retinitis pigmentosa (XLRP).

Patients and Methods: This is a case series presenting the clinical findings in a heterozygous female with XLRP and two of her family members. Fundus photography, fundus autofluorescence, ocular coherence tomography, and visual perimetry are presented.

Results: The proband reported here is a heterozygous female who presented at the age of 8 years with an early onset and aggressive form of XLRP. The patient belongs to a four-generation family with a total of three affected females and four affected males. The patient was initially diagnosed with retinitis pigmentosa (RP) at the age of 4 years. Genetic testing identified a heterozygous donor splice site mutation in intron 1 (IVS1?+?1G?>?A) of the retinitis pigmentosa GTPase regulator gene. The father of the proband was diagnosed with RP when he was a young child. The sister of the proband, evaluated at the age of 6 years, showed macular pigmentary changes.

Conclusions: Although carriers of XLRP are usually asymptomatic or have a mild disease of late onset, the proband presented here exhibited an early-onset, aggressive form of the disease. It is not clear why some carrier females manifest a severe phenotype. A better understanding of the genetic processes involved in the penetrance and expressivity of XLRP in heterozygous females could assist in providing the appropriate counseling to affected families.     

Incidence Rates and Risk Factors for Vision Loss among AIDS-Related Cytomegalovirus Retinitis Patients in Southern Thailand

Purpose: To describe the incidence of and risk factors for visual acuity (VA) loss in patients with AIDS and cytomegalovirus (CMV) retinitis.

Methods: A total of 132 patients were included. The main outcome measurements were the incidences of VA loss to ≤20/50 and ≤20/200.

Results: The incidences of VA loss to ≤20/50 and ≤20/200 were 0.22/eye-year (EY) and 0.12/EY, respectively. Risk factors for the incidence of VA loss to ≤20/50 were low nadir CD4⁺ T-cell count (adjusted hazard ratio [aHR], 3.1), large area of retinitis (aHR, 3.7), and no immune recovery (IR) (aHR, 13.9). Risk factors for the incidence of VA loss to ≤20/200 were not receiving highly active antiretroviral therapy (HAART) (aHR, 4.4) and large retinitis area (aHR, 2.1).

Conclusions: The incidence of VA loss in eyes affected by CMV retinitis was high. The use of HAART, particularly with subsequent immune recovery, substantially reduced the incidence of VA loss.     

Cytomegalovirus retinopathy and the immune deficiency syndrome: Results of treatment with ganciclovir

Cytomegalovirus (CMV) infection of the retina is the commonest potentially blinding ocular manifestation of AIDS. Recently the acyclic nucleoside dihydroxypropoxymethyl guanine (DHPG, ganciclovir) has become available to treat sight-threatening CMV retinopathy. This paper reports the clinical features and results of ganciclovir therapy in 48 patients seen over a four-year period. Seven patients were excluded from the study due to inadequate followup, leaving 41 patients as the study group. All patients responded clinically to this therapy. Patients were treated initially with high-dose ganciclovir (1 0 mglkglday) and then continued on lower dose treatment (5 mg/kg/day) indefinitely. Significant bone marrow toxicity developed in 12 patients (29.3%) requiring temporary cessation of therapy. Patients treated with ganciclovir retained vision and had increased survival times when compared to untreated patients. A poor visual outcome occurred when there was involvement of the macula or optic acquired nerve head at presentation or when there was an interruption of ganciclovir therapy.     

Cytomegalovirus Retinitis and Immune Recovery Uveitis in AIDS Patients Treated with Highly Active Antiretroviral Therapy in Taiwanese

Purpose: To determine the characteristics of cytomegalovirus (CMV) retinitis and immune recovery uveitis (IRU) in the era of highly active antiretroviral therapy (HAART). Methods: We reviewed data from 47 of 79 consecutive patients with acquired immunodeficiency syndrome (AIDS) and CMV retinitis. Results: The incidence of CMV retinitis in AIDS patients has markedly decreased over the recent 10 years. The characteristics of CMV retinitis have changed. Development of IRU occurred in 24.4%. Conclusions: Symptomatic IRU develops in a significant number of patients with inactive CMV retinitis following successful HAART. Eyes with IRU respond favorably to antiinflammatory therapy without reactivation of retinitis.