Cytomegalovirus (CMV) Retinitis

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Practice Essentials

Cytomegalovirus (CMV) retinitis (see image below) is an acquired immunodeficiency syndrome (AIDS)–defining infectious disease that can be visually debilitating and that can potentially portend poor systemic outcomes, including early mortality. It is the most common clinical manifestation of CMV end-organ disease and presents as a unilateral disease at presentation in two-thirds of cases[1] but is ultimately bilateral in most patients in the absence of therapy or immune recovery.

CMV retinitis can arise either upon acute viral introduction to the host or through viral reactivation in the context of immunocompromise.

AIDS is a classic antecedent; however, with the advent of highly active antiretroviral therapy (HAART), CMV retinitis is becoming less common in this setting. Organ transplant recipients and patients who use immunosuppressants are other affected patient populations.



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A left-eye wide-field fundus photograph demonstrating a confluent patch of intraretinal whitening, hemorrhage, and vascular attenuation nasal to the o....

Signs and symptoms

In most patients, CMV retinitis has an insidious onset that is often asymptomatic, beginning with transient visual obscurations ("floaters") and visual indistinction and haze, and eventually leading to geographic scotoma and, possibly, complete blindness.

Signs and symptoms of CMV retinitis include the following:

Physical examination should be performed to identify the following:

Guidelines for evaluation

See the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents.

Diagnosis

No test results are pathognomonic for CMV retinitis. Diagnosis is based on a combination of clinical, laboratory, historical, and imaging information. Examination of the retina by an experienced ophthalmologist is a prerequisite for diagnosis. Blood tests to identify CMV via antigen detection, culture, or polymerase chain reaction (PCR) have been shown to have poor positive predictive value. A negative plasma or tissue PCR result does not exclude CMV end-organ disease. Available laboratory tests that can support a diagnosis of CMV retinitis include the following:

The following are potentially helpful imaging studies:

Treatment

Pharmacotherapy is the mainstay of treatment when retinal detachment is absent. During the AIDS epidemic of the 1980s and early 1990s in the United States, intracameral drug-eluting devices were used but have since been discontinued. Current medical options include the following:

When retinal detachment has occurred, pars plana vitrectomy with long-acting retinal tamponade is the preferred surgical option. Among available tamponades, silicone oil has been used more frequently, although perfluoropropane has been shown effective. Scleral buckling has not shown equivalent results.[2]

Background

CMV is a beta-group herpesvirus that can cause various manifestations depending on the age and immune status of the host. Latent CMV infects monocytes and their bone marrow progenitors. It can be reactivated when immunity is attenuated. Viral infection is mostly asymptomatic. A mononucleosislike infection can occur in healthy individuals. In neonates and immunocompromised patients, CMV disease can be devastating. Infected cells, as the name indicates, exhibit gigantism of the entire cell and its nucleus. A characteristic and large inclusion called an "owl's eye" can be found.

The likely mode of CMV transmission varies by age group, as follows:

CMV not only takes advantage of suppressed immune surveillance but also induces its own transient and severe immunosuppression. The virus inhibits maturation of dendritic cells and their ability to recruit T cells. Similar to other herpesviruses, CMV can elude immune responses by down-modulating MHC class I and II molecules and producing homologues of TNF receptor, IL-10, and MHC class I molecules.

Individuals with a suppressed immune system are susceptible to serious CMV infections from either a primary event or reactivation of latent CMV. HPV is the most common opportunistic viral pathogen in individuals with AIDS.[4, 5, 6] High viral load and severe deficits in immune function combine to increase the potential for developing CMV retinitis.

When HPV infection causes end-organ nonophthalmic disease, it commonly affects the lung and gastrointestinal system. Necrosis of vital tissues within the lung induces pneumonitis and causes progression to acute respiratory distress syndrome (ARDS). Intestinal necrosis also leads to pseudomembranes and diarrhea, the end stage of which can be perforation and abdominal infiltration of intraluminal bacteria.

The most common ophthalmic manifestation in its acute phase is retinal necrosis and secondary inflammatory ischemia, whose results are diffuse intraretinal hemorrhage, retinal whitening and edema, vascular attenuation, and sclerosis.[7] The vitreous often demonstrates a haze and cellular infiltration and possibly vitreous hemorrhage. The lesions are coalescent, occur in sequence, and can be multifocal as the disease progresses (see image below).[8] Untreated CMV retinitis inexorably progresses to visual loss and blindness.[9]



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Wide-field fundus photograph showing multifocal intraretinal whitening, hemorrhage, and mild preretinal hemorrhage in a right eye. Within the inferior....

Multiple antiviral agents, delivered locally, systemically, or in combination, are currently in use to delay or arrest the progress of the disease.[10] In addition, highly active antiretroviral therapy (HAART) for HIV infection has revolutionized the treatment of CMV retinitis by allowing immune reconstitution in many individuals.[11, 12, 13]

Over a period of 5 years, the incidence of opportunistic infections has decreased, and newly diagnosed cases of CMV retinitis have decreased by as much as 83%.[14]

Pathophysiology

Transmission of CMV occurs through placental transfer, breast milk, saliva, sexually transmitted fluids, blood transfusions, and organ or bone marrow transplants. In the immunocompetent pediatric or adult host, infection is generally asymptomatic or limited to a mononucleosis-like syndrome with signs and symptoms including fever, myalgia, cervical lymphadenopathy, and mild hepatitis.

CMV generally dwells as a latent intracellular virus in immunocompetent children and adults. CMV may reactivate if host immunity is compromised. In immunocompromised individuals, primary infection or reactivation of latent virus can lead to opportunistic infection of multiple organ systems, including the skin (eg, rashes, ulcers, pustules), lungs (eg, interstitial pneumonitis), gastrointestinal tract (eg, colitis, esophagitis), peripheral nerves (eg, radiculopathy, myelopathy), brain (eg, meningoencephalitis), and eye (eg, retinitis, optic neuritis).[15]

In the eye, CMV commonly presents as a viral necrotizing retinitis with vitreitis and may result in retinal detachment. Untreated CMV retinitis inexorably progresses to visual loss and blindness.

Epidemiology

Frequency

United States

CMV is ubiquitous, infecting 50-80% of the adult population. Clinically evident disease is found almost exclusively in immunosuppressed individuals. Prior to HAART, CMV occurred in 25-40% of all AIDS patients and was the most common opportunistic infection in AIDS patients with a CD4 count below 50 cells/μL. While HAART has decreased the incidence of CMV retinitis by 55-83%, the decline in AIDS-related mortality has led to an increase in the number of patients with CMV disease.

In a prospective cohort study, Sugar et al estimated the incidence of CMV retinitis in the post-HAART era among 1600 AIDS patients without CMV retinitis at enrollment. They found an incident rate of 0.36/100 person-years, with the highest rate observed among patients with CD4 counts below 50 cells/μL.[16]

Patients with AIDS and CMV are also at risk of cataract, which is likely to be an increasingly important cause of visual morbidity in this population. A study of 489 AIDS patients diagnosed with CMV retinitis found a high prevalence of cataract. Potentially modifiable risk factors identified included large retinal lesion size and use of silicone oil in retinal detachment repair.[17]

CMV retinitis remains a leading cause of visual loss in patients with AIDS and is increasing in organ transplant recipients as the number of those procedures performed each year increases. In a series of 304 recipients of allogeneic hematopoietic stem cell transplantation, CMV retinitis developed in 13 (4%). This represented 23% (13 of 56) of those with significant CMV viremia.[5]

International

The frequency of CMV retinitis in other developed countries is equivalent to that of the United States. The prevalence of CMV retinitis in HIV-infected individuals in developing countries is generally lower than in North America and Western Europe. The lower reported prevalence of CMV retinitis in developing countries, particularly those on the African continent, may be attributed the fact that many HIV-infected individuals die before their immune function deteriorates to the level at which CMV retinitis typically occurs.[18] In general, the incidence of CMV in developing countries reflects the spread of the HIV virus and the availability of antiretroviral medications.[19, 20]

When identified, CMV retinitis has often progressed to the debilitating stage, and intervention is less likely to achieve visual recovery. Improved screening programs and availability of oral valganciclovir are required to improve management of CMV retinitis in this setting.[21]

Sex

Although the incidence of CMV retinitis is the same among men and women, the prevalence is higher in men than in women because of the higher prevalence of AIDS in men. The prevalence of CMV retinitis in the heterosexual community has been steadily increasing.

Age

The age of most individuals who develop CMV retinitis is 20-50 years.

Prognosis

Untreated retinitis will progress to blindness, from retinal necrosis, optic nerve injury, or retinal detachment.[22] Of treated patients, 80-95% will respond, with resolution of intraretinal hemorrhages and white infiltrates (see image below). If treatment is discontinued and the individual is still immunocompromised (ie, CD4 < 50), then the retinitis will recur in 100%. Prior to the advent of HAART, 50% of patients would experience recurrence within 6 months despite maintenance therapy. This rate is reduced if the CD4 count is elevated.



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White granular retinitis with intraretinal hemorrhage.

If a retinal detachment occurs, repair with vitrectomy and silicone oil tamponade will result in at least a 70% reattachment rate.[23]

CMV retinitis frequently results in considerable loss of visual acuity, and, without treatment, it almost universally leads to blindness.[24, 25, 26, 27] Early and aggressive treatment with antiviral medication for both CMV and HIV, combined with improved surgical techniques for RD repair, has helped to improve the visual outcomes in these patients.

Untreated CMV leads to progressive visual loss and eventual blindness. Nonfunctioning retina and/or retinal detachment occurs in up to 29% of cases.[28] CMV retinitis causes full-thickness necrosis of the retina.

Retinitis permanently destroys the retina; lesions change appearance with treatment but do not become smaller. Areas of retina affected by retinitis can develop erosive holes despite resolution of the retinitis. If the CD4 count is less than 100 cells/μL, CMV retinitis will develop in 20-30% of patients over a year, although retinitis typically develops if the CD4 count is reduced below 50 cells/μL. Of these patients, 5-10% develop other systemic infections (eg, pneumonitis, colitis, esophagitis).

With the advent of HAART and immune reconstitution, some patients suffer from a relatively new condition known as immune recovery uveitis (IRU).[29, 30, 31] IRU occurs when the poor immune response of an immunocompromised individual is suddenly increased as the patients restored immune system recognizes and reacts to viral antigens in the retina. This reaction can lead to several complications, including uveitis, leading to hypotony, cataract, and glaucoma; epiretinal membrane (ERM); and cystoid macular edema (CME).[32, 33]

CMV immune recovery retinitis denotes patients who develop active CMV retinitis within 6 months after starting antiretroviral therapy. This may occur despite a CD4 count greater than 50 cells/μL, indicating the need to conduct careful surveillance after initiation of systemic therapy.[34] Despite improvements in systemic treatment for AIDS, the 5-year mortality for those diagnosed with CMV retinitis is 3 deaths per 100 person-years for those with previously diagnosed retinitis and 26.1 deaths per 100 person-years for those with newly diagnosed CMV retinitis.[35]

Patients with newly diagnosed CMV retinitis have a 5-year rate of vision loss to less than 20/40 in 11.8 of 100 eye-years and to 20/200 or worse in 5.1 of 100 eye-years.[35]

Patient Education

Visual symptoms that require a repeat examination are vision loss, development of a visual field defect, new floaters, and photophobia.

Provide education on the following:

Patients with CMV retinitis must realize that, despite the possibility of minimal symptoms, debilitating blindness and vision loss can occur with poor compliance to therapy or nontreatment. Even when there is a lesion within the macula, patients can still experience minimal symptoms owing to overlapping visual fields contributed from the contralateral eye and integrated by the central nervous system. Patients may be under the impression that "floaters" are common and insignificant. Coupled with the fact that CMV retinitis is a painless disease, patients may feel less motivation to comply with therapy.

Closely working with an infectious disease specialist and primary care physician should be emphasized, since CMV infection touches on multiple organ systems and requires monitoring of drug toxicities and close communication between specialists. Simultaneous to management of CMV infection, the underlying cause of immune suppression should be addressed, particularly in the form of HAART in patients with HIV infection. Poor compliance with the primary treatment of HIV infection may potentiate viral resistance to common therapies and lead to more advanced disease, even in the presence of standard care.

History

Presenting symptoms of CMV retinitis vary depending on the location and surface area of the affected retina. Lesions that involve the posterior and central retina will likely cause diminished overall visual acuity or focal scotoma. Lesions found in the periphery rarely cause direct symptoms. Floaters are often noted if significant vitreous inflammation is present. The external appearance of the eye is usually white and quiet.

Active CMV retinitis usually is found in conjunction with immunosuppression, whether from AIDS, leukemia, or use of chemotherapy. These points are important in evaluating the patient history. Rarely, CMV retinitis is the first presenting manifestation of AIDS.

After initiation of therapy, some advance of the leading edge of retinitis may be noted. This does not usually signify treatment failure but rather reveals infected retina that was not clinically evident initially.

Natural history

CMV retinitis is a slowly progressive disease, requiring weeks to months to involve the entire retina.[36, 37] Vision is lost with involvement of the posterior pole (macula or optic nerve), either in the form of direct necrosis of light-sensitive and photoreceptor dense tissue, such as what is found in the macula, or indirectly through the formation of a retinal break, leading to rhegmatogenous retinal detachment that progresses to include the macula or retina near the macula.[38]

Initial reports described CMV retinitis as an end-stage disease, which indicated a life expectancy of 6 weeks. With the use of antiviral medications, the average survival after diagnosis ranged from 5.5-8 months. The advent of HAART has prolonged survival to years in some instances, and it has allowed discontinuation of medications targeted against CMV retinitis if clinical resolution occurs and the immune status recovers (reflected by a CD4 count of >100 cells/μL).

Physical

Patients with suspected CMV retinitis should have a complete ocular examination of both eyes. A careful examination should include the following.

Carefully check and record the patient's best corrected visual acuity as a baseline. Check for visual field defects that could represent optic nerve damage, retinal detachment (RD), or CNS disease from AIDS-related brain diseases (eg, encephalitis, stroke, CNS lymphoma).[39, 40] Ocular motility should be assessed as part of a cranial nerve examination. Pupils should be checked for a relative afferent pupillary defect indicating optic nerve involvement. External examination of the lids and adnexa should be performed for other AIDS-associated findings, such as Kaposi sarcoma or lymphoma. The anterior chamber may demonstrate a nonspecific uveitis with elevations or depressions of intraocular pressure.

A thorough slit lamp examination should show a white and quiet conjunctiva. A red hot eye in an immunocompromised patient should alert the clinician to another possible diagnosis. Fine, stellate keratitic precipitates (KP) characteristic of CMV may be seen on the corneal endothelium.[41] Uveitis may be present in the anterior chamber and, if severe, may require treatment. The level of vitreitis can be assessed in the anterior vitreous and may be important for monitoring response to treatment or the occurrence of IRU.

A dilated fundus examination with indirect ophthalmoscopy is essential for assessing the location and extent of retinal involvement as well as for evaluating for retinal breaks or detachment. Retinal lesions have several characteristics,[42, 43] as follows:



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Wide-field fundus photograph illustrating numerous blood vessels within the inferior and nasal periphery that appear attenuated and without flowing bl....

Peripheral holes and tears frequently occur in areas of necrosis (see image below).



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Retinal detachment due to peripheral tear in area of necrosis.

Rate of progression of untreated retinitis is 250-350 µm per week. Skip lesions can occur. Serial examinations may be necessary at early stages to distinguish CMV retinitis from HIV retinopathy with multiple cotton-wool spots. Optic neuritis can develop without apparent retinitis.[47] Most patients with CMV retinitis will initially present with unilateral disease. Untreated, the immunocompromised patient has a 50% risk of developing disease in the contralateral eye within 6 months.[48, 49] This is reduced to 20% with antiviral treatment and further reduced with HAART.

Causes

Any immunosuppression due to disease or medication may allow clinical CMV infection to develop, as follows:

Congenital CMV retinitis is acquired from vertical transmission during pregnancy. When primary maternal infection occurs during pregnancy, the risk of transmission to the fetus ranges between 30% and 40%. Transmission during the first half of pregnancy generally causes more severe disease.

Complications

Untreated retinitis will progress to blindness, from retinal necrosis, optic nerve involvement, or retinal detachment.[52, 53]

CMV retinitis can relapse despite ongoing treatment. Drug levels need to be assessed. Reinduction, a change in medication, combination drug therapy, or an ocular implant are alternatives for management.

Retinal detachment is a potential complication of CMV retinitis, with a 1-year risk of 5-50%. Repair requires laser photocoagulation or vitrectomy with silicone oil tamponade.[54, 27]

Approach Considerations

CMV viremia can be detected via polymerase chain reaction (PCR), antigen assays, or culture and is usually, but not invariably, present in patients with end-organ disease, even when the CD4 count is low. Serum tests to detect CMV via antigen detection, culture, or PCR are not recommended for diagnosis of CMV end-organ disease because of their poor positive predictive value[55] A negative serum or plasma PCR assay result also does not rule out CMV end-organ disease.

CMV DNA is detected in the vitreous in approximately 80% of patients with CMV retinitis, but in serum in only 70%, with the remaining cases diagnosed via clinical criteria plus response to therapy.[56, 57] CMV PCR can be particularly useful in assessing CSF or vitreous or aqueous humor specimens; a positive result is highly suggestive that CMV infection is the cause of end-organ disease. However, PCR assays are not standardized; therefore, sensitivity, specificity, and interassay comparability are not clearly delineated.

The presence of serum antibodies to CMV is not diagnostically useful, although a negative immunoglobulin G antibody level indicates that CMV is unlikely to be the cause of the disease process.

A dilated fundus examination performed by a skilled and experienced ophthalmologist is a prerequisite for diagnosis and has a 95% positive predictive value.[58] In rare cases, diagnosis may be difficult, and PCR of aqueous or vitreous specimens for CMV and other pathogens, especially herpes simplex virus, varicella zoster virus, and toxoplasmosis, can be useful for establishing the diagnosis.

Laboratory Studies

CD4 count

The CD4 count is a marker of immune dysfunction in patients infected with HIV.[59] Patients may be asymptomatic with CMV retinitis; therefore, ophthalmic screening frequency is based on CD4 count.[60, 61]

The CD8+ T-lymphocyte count is also predictive of CMV retinitis in patients with AIDS. The risk for retinitis appears higher when the CD8+ T-lymphocyte count is below 520 cells/mm3. The CD8+ T-lymphocyte count is of no additional and independent predictive value if the CD4+ T-lymphocyte count is already known.

The above screening regimen was used prior to the routine use of HAART. The frequency of examinations likely will be modified by assessing viral load, result of CMV DNA capture, CD4 count, and response to treatment.

CMV DNA

A PCR test can be qualitative or quantitative. Specimens can be obtained from blood buffy coat, semen, or urine. Detection of CMV in the blood by DNA PCR is most predictive of developing CMV disease but has poor positive predictive value.[63, 64] Patients with AIDS who test positive have a 60% chance of developing CMV end-organ disease.[65, 66] Responders to ganciclovir prophylaxis convert to PCR-negative with treatment. In case series, survival is increased 2.4 times at 12 months when PCR shows a treatment response. DNA PCR analysis is increasingly applied to ocular fluids.[18, 67, 68]

PCR-based analysis of vitreous humor offers high diagnostic specificity and sensitivity. Vitreous sampling is usually reserved for patients with atypical lesions, for individuals in whom disease is not responsive to treatment, or for patients for whom a vitreous biopsy would carry little added risk (eg, those already scheduled to undergo vitrectomy for retinal detachment repair).

Viral load

Increased viral load can be a predictor of development of CMV end-organ disease.

HIV test

HIV testing should be performed in any patient with an unclear medical history, any patient with systemic signs and symptoms of AIDS, or any patient who is making his or her first visit to the physician.

Complete blood cell count with differential

Complete blood cell (CBC) count with differential is important in evaluation for causes of immunosuppression and in assessment for adverse effects of ganciclovir use.

Blood urea nitrogen and creatinine

Blood urea nitrogen (BUN) and creatinine baseline assessment and serial measurements are used to evaluate for side effects of foscarnet or cidofovir use. They can also be used to evaluate systemic inflammatory status and to monitor for potential sepsis.

Imaging Studies

See the list below:

Other Tests

See the list below:

Procedures

Ganciclovir implant [69]

No longer available in the United States, this intravitreal implant released ganciclovir at a steady state for up to 8 months.[70] The implant provided treatment of CMV retinitis in one eye only. No systemic effect occurs. The initial implant usually is placed in the inferotemporal quadrant. It may be visualized through a dilated pupil. Possible complications included vitreous hemorrhage, retinal detachment, hypotony, and endophthalmitis.[71, 72]  After 8 months, if still required, a second implant may be placed. The first implant can be left in place or removed.[73]

Vitreoretinal surgery

Retinal detachment repair is required in 5-50% of patients with CMV retinitis (depending on the trial).[74] Multiple small holes that have resulted from vitreous contraction or direct retinal necrosis are often responsible for the retinal detachment. These occur at the junction of healthy and necrotic retina.

Primary repair with vitrectomy, fluid-air exchange, endolaser, and silicone oil tamponade has improved surgical outcome.[75, 76, 77, 78] A second surgery is performed to remove the silicone oil in 4-6 months if the retina remains stable. Oil removal is associated with a risk of redetachment.

Laser photocoagulation

Small peripheral retinal detachments can be repaired with laser photocoagulation.

Intravitreal injections of ganciclovir, foscarnet, [79] or cidofovir [80]

These injections offer high levels of intraocular drug for short periods of time.[81] Ganciclovir and foscarnet are given once or twice per week; cidofovir is given once every 5-6 weeks. They are useful in acute vision-threatening cases when rapid drug delivery is needed prior to instituting longer-term therapy or if the response to intravenous therapy is poor and/or the patient is intolerant to systemic therapy.

Risks of intravitreal injection include hemorrhage, retinal detachment, and endophthalmitis.

Intravitreal cidofovir can cause idiosyncratic iritis and hypotony. The risk of iritis can be reduced from 70% to 18% if oral probenecid is given. Iritis can be treated with topical steroids and cycloplegia. A 20% asymptomatic reduction in intraocular pressure is nearly universal; however, only 1% develop vision changes due to profound hypotony. Given the increased side effect profile, cidofovir is typically reserved until after ganciclovir and foscarnet are attempted.

Fomivirsen is a fourth-line drug that is no longer available in the United States.

Histologic Findings

The healthy retina is sharply demarcated from infected retinal cells, which show edema, cytomegalic inclusions, necrosis, and few surrounding inflammatory cells (consistent with a compromised immune response). CMV-infected cells contain eosinophilic cytoplasmic and nuclear viral inclusion bodies giving an "owl's eye" appearance on hematoxylin and eosin staining (see image below).



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Intranuclear inclusions (arrows) found in cytomegalovirus retinitis. Referred to as owl's eye because of the dark intranuclear inclusion surrounded by....

Infected cells lyse, leaving an area of full-thickness necrosis and releasing virus particles that infect adjacent retinal cells. The histopathology correlates well with the clinical picture of a posteriorly advancing edge of active disease with formerly active areas undergoing necrosis, scarring, and atrophy.[82, 83]

Staging

CMV retinitis is described by the stage and zone of involvement.[84, 85, 86]

Stage

Active retinitis - 3 general patterns, as follows:

Necrotic stage - End result of all patterns of active retinitis is the progression to necrosis. Retinal tears or holes can develop in these areas.

Geographic patterns and anatomy

The retina can be divided into specific zones that may have prognostic value. These zones are as follows:

Several studies have shown significant posterior pole involvement.[87] Retinitis that spreads from zone to zone usually moves along the leading edge, although skip lesions can occur. Progression occurs at a rate of 250-350 µm/wk if untreated.[88]

Medical Care

After diagnosis, the first step in treatment is to administer systemic medications either in the form of intravenous infusion or oral administration. The most common choice is oral valganciclovir given its ease of use and excellent pharmacokinetics. This is the recommended regimen given CMV's broad presence, both in the eyes and other organs. Local/regional ocular therapy is largely reserved for cases in which systemic therapy is contraindicated or not well tolerated. The most common reason for cessation of systemic therapy is myelosuppression, following by kidney injury.[89] An internist or infectious disease specialist coordinates medical care. Ophthalmic assessment is required on a regular basis, with frequency dependent on existence of CMV retinitis and on CD4 count. The immunosuppressed individual requires evaluation for other opportunistic infections and surveillance for side effects of prescribed medications.

Highly active antiretroviral therapy (HAART) [90]

This treatment regimen has altered the long-term management of CMV retinitis.[91, 92] Because the antiviral medications used to treat CMV are virustatic, patients needed to continue their use for the rest of their lives. The advent of HAART, with consequent recovery of immune function (2 consecutive CD4+ T-cell counts of ≥ 100 cells/μL at least 6 months apart) allows individuals to discontinue their CMV therapy if the retinitis has resolved adequately with antiviral treatment.[13] As long as the CD4 count remains elevated, disease recurrence is unlikely.[93]

Intravenous or oral therapy can be discontinued, or a scheduled implant replacement can be delayed indefinitely.[94, 95] Careful monitoring of both immune status and ophthalmic findings are necessary to prevent retinal damage from an asymptomatic recurrence.

Surgical Care

Individuals with CMV retinitis commonly require surgical intervention, whether for repair of a retinal detachment or for intravitreal instillation of ganciclovir by injection. Ganciclovir-eluting implants are no longer used in the United States.

Retinal detachment due to CMV retinitis

This condition occurs in 5-29% of eyes in various case series. High incidence of bilaterality exists.[96] Repair is most successful with vitrectomy, endolaser, and silicone oil endotamponade.[97, 98]

Intravitreal ganciclovir implant [99, 100]

This is not currently available in the United States. Dosing is 1 µg/h sustained release with life span of 8 months.[101] Study of immediate versus deferred therapy:

Advantages include the following:

Disadvantages include the following:

Intravitreal ganciclovir injection [104]

Details are as follows:

Intravitreal foscarnet [79] or cidofovir [80] injection

High-dose injection (2.4 mg) of foscarnet once to twice per week as an alternative to ganciclovir in patients who are intolerant. Cidofovir is given every 5-6 weeks. Potential side effects include iritis (18% with prophylactic oral probenecid) and/or visually significant hypotony (1%).

Consultations

See the list below:

Complications

Drug resistance

Resistance to ganciclovir,[106]  foscarnet,[107, 108]  or cidofovir may occur since these drugs are administered long term; however, no in vitro studies or tissue sample studies have evaluated this theory definitively. Resistance is claimed based on an aberrant response to otherwise effective therapy. The chance of this occurring may increase with time. In a study of 76 newly diagnosed patients treated for CMV retinitis with intravenous ganciclovir, likely resistant isolates were obtained from blood or urine samples in 5.4% of patients at 3 months, 11.4% of patients at 6 months, and 27.5% of patients at 9 months.

Management of drug resistance leading to reactivation of CMV retinitis or occurrence in the other eye involves combination therapy.[109, 110, 111, 112]  Ganciclovir and foscarnet are synergistic and may be combined in intravenous or intravitreal therapy.

Prevention

CMV retinitis occurs in immunocompromised individuals. Treatment of underlying disorders can prevent the development of retinitis. Prevention practices to reduce the transmission of HIV would concomitantly reduce the incidence of CMV retinitis.

In patients with HIV infection, CMV retinitis and other end-organ disease is best prevented using HAART to maintain the CD4 count above 100 cells/µL. Before HAART was widely available, several randomized trials evaluated the use of oral prophylactic therapy such as ganciclovir and valganciclovir.[113, 114] While ganciclovir is not available in this formulation in the United States, both did not show and preventative benefit both for patients receiving and not receiving HAART.[113, 114]

The primary method for preventing severe CMV disease is recognizing the early manifestations of the disease and instituting proper therapy. Patients should be made aware of the implications of increased floaters in the eye and should establish care with a local ophthalmologist should symptoms arise. In the pre-modern HAART era, some specialists recommended ophthalmologic examinations every 3-4 months for patients with CD4 cells of less than 50 cells/µL, as up to half of early CMV retinitis cases were asymptomatic.[115] However, with the decline in CMV incidence in the modern HAART era, the value of this recommendation is unknown.

Long-Term Monitoring

Ophthalmic follow-up care depends on stage of disease (ie, active vs atrophic retinitis), and CD4 count.

Transplant-related CMV retinitis may occur late after transplantation. In a large series of pediatric allogeneic hematopoietic stem cell transplantation, CMV retinitis developed at a median of 199 days after transplantation. In addition, this occurred with a higher CD4 T-cell count (≥200/μL) and a lower CMV load than is generally associated with AIDS or with other organ system involvement following transplantation. This indicates the need for dilated examination, particularly if viremic.[5]

Guidelines Summary

See the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents.

Medication Summary

A number of different antiviral medications are available for the treatment of CMV retinitis.[116, 117, 118, 119, 120] Routes of delivery and adverse effect profiles vary significantly.[121] Therefore, treatment programs are tailored to individual patients and their response to treatment. Current therapies use an induction dose to halt active disease followed by a lower maintenance dose that must be continued indefinitely unless immune recovery occurs.[122, 123] In recent years, several developments have drastically improved the quality of life for patients with CMV retinitis.[124]

HAART therapy has allowed immune recovery that may allow discontinuation of anti-CMV medication.[125, 126] This often obviates the need for multiple implant procedures or the long-term dose related adverse effects of anti-CMV medications.

Valganciclovir, a prodrug of ganciclovir that possesses excellent oral bioavailability and antiviral activity, has been shown to be effective in both the induction phase[127] and the maintenance phase of CMV retinitis treatment.[128] It is available in convenient once daily or twice daily dosing. Valganciclovir has largely replaced other treatments[129, 130, 131, 132] since it avoids the need for frequent intravenous infusions and long-term intravenous access.[133, 134, 106, 135]

Neupogen (granulocyte colony stimulating factor) can be used in conjunction with ganciclovir or valganciclovir in patients experiencing neutropenia, although no trials have been conducted to assess its efficacy, nor is it clear that AIDS outcomes differ when neutropenia resolves.

Foscarnet[136] and cidofovir[137, 138, 139, 140, 141] are effective alternatives in the treatment of CMV retinitis.[142, 143, 144, 141] However, because of their adverse effect profiles[145, 146, 147, 148] and the lack of an orally bioavailable form, they have become second-line treatments. Combination treatment has been used for resistant disease.[149, 150, 151, 152] Intravitreal implants are no longer available in the United States. Intravitreal injections are used less frequently but are still needed in patients who have reactivation of retinitis despite systemic treatment or in those who cannot tolerate systemic treatment.

At this time, primary treatment generally consists of induction with either valganciclovir (900 mg PO bid for 2-3 wk) or ganciclovir (5 mg/kg IV bid for 2-3 wk) followed by maintenance with valganciclovir (900 mg PO qd) until the CD4 count is above 100 cells/μL for at least 6 months.

Finally, immune recovery uveitis has added a new postscript to the treatment of CMV retinitis.[29] Treatment is based on managing the uveitis, primarily with topical, subtenons, or intravitreal corticosteroids, and close follow-up is needed to guard against vision-threatening complications.

Ganciclovir (Cytovene, Vitrasert)

Clinical Context:  Analog of guanosine, 10-100 times more potent than acyclovir versus CMV in vitro. Selectively inhibits DNA polymerase of CMV cells. Renal excretion.

Virostatic - Discontinuation of use leads to 100% relapse rate within 4 weeks.

Effective - 88% complete response, 9% partial.

Long-term IV access is necessary. Oral administration is possible, but the bioavailability of oral ganciclovir is limited to less than 10%. Although use of this medication for prophylaxis reduces the incidence of CMV end-organ disease by up to 50%, its use usually is not recommended because most patients would be using it unnecessarily and the incidence of side effects is high. A valine ester prodrug of ganciclovir, valganciclovir, has good bioavailability and can be used in place of intravenous ganciclovir for maintenance dosing and for the prevention of recurrences.

Oral ganciclovir - Two trials for maintenance treatment. A faster rate of progression was found in the first trial. With higher dosing (1 g tid), there was an equal rate of progression. A dose dependent increase in neutropenia exists.

Foscarnet (Foscavir)

Clinical Context:  Analog of pyrophosphate. Inhibits DNA polymerase of CMV and reverse transcriptase of HIV. Virostatic; renal excretion. As effective as ganciclovir. Median time to relapse on Rx is 53 d. Foscarnet/ganciclovir CMV retinitis trial: 234 newly diagnosed patients randomized. Same efficacy for controlling retinitis and preserving vision. Survival with foscarnet 12.6 mo versus 8.5 for ganciclovir group; mortality risk 1.79x. Controlling for antiretroviral use, still better survival with foscarnet. Foscarnet has anti-HIV activity but has more dose-limiting toxicity.

Cidofovir (Vistide)

Clinical Context:  Nucleotide analog that selectively inhibits viral DNA production in CMV and other herpes viruses.

Valganciclovir (Valcyte)

Clinical Context:  L-valyl ester prodrug of ganciclovir used to treat CMV retinitis in patients with AIDS. Ganciclovir is synthetic analogue of 2'-deoxyguanosine, which inhibits replication of human CMV in vitro and in vivo. Inhibits viral activity by inhibiting viral DNA synthesis. Has the advantage of qd or bid PO administration. Achieves levels comparable to those obtained with IV ganciclovir.

Class Summary

Direct action is to inhibit the DNA polymerase of CMV, preventing viral replication.

Fomivirsen sodium (Vitravene)

Clinical Context:  A phosphorothioate oligonucleotide. The nucleotide sequence is complimentary to the CMV viral mRNA, which encodes proteins responsible for regulation of viral gene expression. Inhibition of viral protein synthesis is achieved when fomivirsen binds the target mRNA. This medication is not available in the United States and is often considered a second-line agent elsewhere.

Class Summary

Inhibit viral replication by interfering with the regulation of viral gene expression.

Filgrastim (Neupogen)

Clinical Context:  Up to 40% of ganciclovir users experience dose-limiting neutropenia, which may require discontinuation. GCSF has limited this effect markedly in some studies; however, the mortality or morbidity benefit of supporting granulocyte colonies is unclear.

Class Summary

Stimulation of stem cells to produce differentiation, proliferation, and increased functional activity of neutrophils, monocytes, eosinophils, and macrophages.

Author

Michael Altaweel, MD, FRCSC, Professor, Fellowship Director for Vitreoretinal Surgery, Department of Ophthalmology and Visual Science, University of Wisconsin School of Medicine and Public Health

Disclosure: Nothing to disclose.

Coauthor(s)

Michael E Possin, MD, Fellow in Vitreoretinal Surgery, Department of Ophthalmology, University of Wisconsin Health Care

Disclosure: Nothing to disclose.

Zackery B Oakey, MD, Fellow in Vitreoretinal Surgery, Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health

Disclosure: Nothing to disclose.

Specialty Editors

Simon K Law, MD, PharmD, Clinical Professor of Health Sciences, Department of Ophthalmology, Jules Stein Eye Institute, University of California, Los Angeles, David Geffen School of Medicine

Disclosure: Nothing to disclose.

Steve Charles, MD, Founder and CEO of Charles Retina Institute; Clinical Professor, Department of Ophthalmology, University of Tennessee College of Medicine

Disclosure: Received royalty and consulting fees for: Alcon Laboratories.

Chief Editor

Andrew A Dahl, MD, FACS, Assistant Professor of Surgery (Ophthalmology), New York College of Medicine (NYCOM); Director of Residency Ophthalmology Training, The Institute for Family Health and Mid-Hudson Family Practice Residency Program; Staff Ophthalmologist, Telluride Medical Center

Disclosure: Nothing to disclose.

Additional Contributors

Peter N Youssef, MD, Vitreoretinal Fellow, Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health

Disclosure: Nothing to disclose.

V Al Pakalnis, MD, PhD, Professor of Ophthalmology, University of South Carolina School of Medicine; Chief of Ophthalmology, Dorn Veterans Affairs Medical Center

Disclosure: Nothing to disclose.

Acknowledgements

Matthew D Reed, MD Fellow, Department of Ophthalmology and Visual Sciences, University of Wisconsin Clinical Science Center

Disclosure: Nothing to disclose.

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A left-eye wide-field fundus photograph demonstrating a confluent patch of intraretinal whitening, hemorrhage, and vascular attenuation nasal to the optic nerve consistent with CMV retinitis.

Wide-field fundus photograph showing multifocal intraretinal whitening, hemorrhage, and mild preretinal hemorrhage in a right eye. Within the inferior macula is a vision-threatening lesion.

White granular retinitis with intraretinal hemorrhage.

Retinitis typically starts in the midperiphery and can progress in a "brush fire" pattern.

Early necrosis at periphery.

Frosted branch angiitis.

Wide-field fundus photograph illustrating numerous blood vessels within the inferior and nasal periphery that appear attenuated and without flowing blood.

Retinal detachment due to peripheral tear in area of necrosis.

Intranuclear inclusions (arrows) found in cytomegalovirus retinitis. Referred to as owl's eye because of the dark intranuclear inclusion surrounded by a clear halo.

White granular retinitis with intraretinal hemorrhage.

Early necrosis at periphery.

Attenuation of vessels in area affected by retinitis.

Retinitis typically starts in the midperiphery and can progress in a "brush fire" pattern.

Progression of retinitis toward the optic nerve.

Frosted branch angiitis.

Inactive cytomegalovirus retinitis.

Cytomegalovirus papillitis.

Intranuclear inclusions (arrows) found in cytomegalovirus retinitis. Referred to as owl's eye because of the dark intranuclear inclusion surrounded by a clear halo.

Retinal detachment due to peripheral tear in area of necrosis.

CMV retinitis with new lesion nasally and older lesion temporally that is starting to pigment.

A left-eye wide-field fundus photograph demonstrating a confluent patch of intraretinal whitening, hemorrhage, and vascular attenuation nasal to the optic nerve consistent with CMV retinitis.

Wide-field fundus photograph showing multifocal intraretinal whitening, hemorrhage, and mild preretinal hemorrhage in a right eye. Within the inferior macula is a vision-threatening lesion.

Wide-field fundus photograph illustrating numerous blood vessels within the inferior and nasal periphery that appear attenuated and without flowing blood.