Cytomegalovirus Retinitis Simplified

Dr. Swapnil Parchand
Dr. Anil Gangwe

Introduction:

Cytomegalovirus (CMV) retinitis is an opportunistic viral posterior uveitis that occurs mostly in severely immunocompromised Acquired Immunodeficiency Syndrome (AIDS) patients or, rarely, in those on immunosuppressive therapy after organ transplantation, or who are on systemic corticosteroids.1 More than 75% of AIDS patients with CD4+ counts less than 50 cells/μL have CMV retinitis. It is the most common ocular opportunistic infection in AIDS patients and accounts for 75-85% of all CMV end-organ disease.2 Before the introduction of Highly Active Antiretroviral Treatment (HAART), 30% of patients with Human Immunodeficiency Virus (HIV) developed CMV retinitis during their lifetime, but with the advent of HAART, there is a 75% reduction in the number of new cases of CMV retinitis.3 Rarely, CMV retinitis may occur in non-HIV patients having some degree of immune dysfunction, such as advanced age, diabetes mellitus, corticosteroid, and non-cytotoxic immunosuppressive drug usage.1

Epidemiology:

CMV, or HHV-5, is a double-stranded DNA virus that belongs to the Herpesviridae family with a genome of approximately 230 kb encoding 160 genes.4 Primary CMV infection is transmitted perinatally, by close contact, sexual contact, or parenterally. CMV infections occur in approximately 1% of all live births throughout the world, making it the most common cause of intrauterine infection in humans.6 Primary maternal infection causes more frequent and severe fetal complications than reactivation of maternal disease during pregnancy. Approximately 5-10% of congenitally infected neonates have cytoplasmic inclusion disease (CID) which is characterized by lesions of the reticuloendothelial and central nervous systems.7 Ocular manifestations of CID include chorioretinitis, optic atrophy, and cataract formation. The remaining 90% of congenital infections are undiagnosed due to their asymptomatic nature or subtle deficits, such as sensorineural hearing loss or psychomotor disturbance. Prolonged viral shedding may occur for several years in asymptomatic infected children.

In adults, the seropositive prevalence in developed countries ranges from 50-70% and approaches 100% in less developed countries.7 Seropositivity increases with age and reaches the highest incidence in individuals older than 50 years of age. Most immunocompetent individuals with positive serology have asymptomatic infection. Few develop an infectious mononucleosis-like syndrome, whereas more severe diseases may manifest in immunocompromised patients in the form of encephalitis, pneumonitis, hepatitis, colitis, and uveitis.6 The virus remains latent in mononuclear lymphocytes in immunocompetent hosts and only reactivates when immunity is suppressed in patients with AIDS and immunosuppressed transplant patients.

Cytomegalovirus and HIV interactions:

CMV and HIV transactivate each other in vitro resulting in increased yields of both the viruses.8,9 Dual infection of individual retinal cells of autopsy eyes from patients with AIDS and CMV retinitis with both CMV and HIV has been demonstrated.10 CMV produces cytokine homologues that bind to host receptors and downregulate the immune system. One key cytokine homologue appears to be an interleukin (IL) 10 homologue. IL-10 is a human cytokine that inhibits T helper type-1 (Th1) immune responses, which are key to cell-mediated immunity.11 Cytomegalovirus also produces chemokine receptors, which bind chemokines and inhibit the recruitment of inflammatory and immune cells, and it interferes with natural killer cells, thereby inhibiting the host’s ability to clear viruses.

Clinical features:

CMV retinitis is commonly seen between the age group of 30 and 60 years. Males are commonly involved. Bilateral CMV retinitis is seen in about 30% of cases but it usually begins as unilateral disease, and later involves the contralateral eye within six months probably from hematogenous spread.

CMV retinitis is asymptomatic in 50% of cases. Visual complaints related to CMV retinitis closely correlates with the area of retinal involvement. Early lesions of the peripheral retina may cause mild visual impairment or may go undetected. Symptoms associated with CMV retinitis include blurred vision, floaters, scotoma, metamorphopsia, micropsia, and ocular discomfort. CMV retinitis presents with mild anterior segment inflammation, including keratic precipitates, anterior chamber cells, and minimal vitritis.

The characteristic feature is a focal or discrete lesion of full-thickness yellow-white necrotizing retinitis with granular borders.1,5,12 It has perivascular distribution and expands centrifugally. There may be mild vitritis, retinal edema, hemorrhage, and vasculitis, usually in the form of retinal arteritis, which is called “pizza pie retinopathy”. (Figure 1)

Figure 1: Pizza pie retinopathy with disc edema and retinal vasculitis.

There are two stages in CMV retinitis5,12:

I] Stage 1: The first stage is active retinitis. Three patterns of active retinal lesions have been described:

  1. Fulminant/oedematous pattern: It consists of large areas of confluent retinal necrosis with overlying retinal haemorrhage. This form progresses as a brushfire-like extension from each discrete lesion. (Figure 2)
  2. Indolent/granular pattern: It consists of granular satellite lesions with little or no
    retinal haemorrhage. (Figure 3)
  3. Frosted branch angiitis: It is also called as exudative pattern. This form presents as
    extensive vascular sheathing .

II] Stage 2: Stage 1 can progress to extensive necrosis. This leads to development of large multiple retinal tears leading to retinal detachment. Occasionally, disease can become quiescent manifesting as disc pallor, retinal atrophy, fibrosis, calcification and sclerotic vessels. (Figure 4)

Figure 2: Fulminant pattern of CMV retinitis.

Figure 3: Granular pattern of CMV retinitis.

Figure 4: Healed CMV retinitis is clinically seen as retinal atrophy, fibrosis, and sclerotic vessels.

Zones of CMV Retinitis13:

Complete retina is divided into 3 zones to decide on treatment of CMV retinitis (Figure 5):

Zone 1: Area of the retina extending 3000 microns from the center of the fovea and 1500 microns from the edge of the optic nerve. Zone 1 disease is considered immediate sight threatening and require more urgent therapy than do more peripheral lesions.

Zone 2: Extends from the edge of zone 1 to a circle identified by the vortex ampullae.

Zone 3: Extends from the anterior edge of zone 2 to the ora serrata.

Figure 5: Various zones of CMV retinitis.

Differential diagnosis:

  • In the early stage of CMV retinitis, it may mimic large cotton wool spots. Cotton wool spots don’t cause blurred vision and are not associated with vitritis and retinal haemorrhages. They have feathery borders rather than granular borders. Examining again after 1-2 weeks may help in making a diagnosis as they will not progress.
  • In the later stage, it may resemble other infections of the retina mainly toxoplasmic retinochoroiditis, herpetic infection, bacterial or fungal infections like syphilitic retinitis, aspergillosis, or candida retinitis. (Table 1)

Sr No

Features

Acute Retinal Necrosis (ARN)

Progressive outer Retinal Necrosis (PORN)

CMV Retinitis

Toxoplasmic retinitis

1

Immune status

Healthy/ rarely immunosuppressed

Immunosuppressed

Immunosuppressed

Healthy but also seen in immunosuppressed

2

Laterality

Bilateral (30%)

Bilateral (70%)

Bilateral (30-50%)

Unilateral in acquired disease

3

Visual loss

Initially mild, later gross

Early loss of central vision

Variable, depending on the site of involvement

Early if macula involved or significant vitritis

4

Anterior segment

Mild to moderate uveitis

May have granulomatous uveitis

Mild non-granulomatous uveitis

Mild non-granulomatous uveitis

Mild to moderate granulomatous uveitis

5

IOP

Raised

Normal

Normal

Normal/ Raised

6

Vitreous reaction

Significant vitritis

Minimal/ No vitritis

Minimal/ No vitritis

Seen mainly overlying retinitis lesion may be significant

7

Retinal involvement

Full thickness

Deep retinal involvement without granular border

Full thickness involvement with granular borders

Necrotising Retinochoroiditis surrounded by edema, occasionally adjacent to previous scar

8

Pattern of involvement

Multifocal, predominantly peripheral tongue shaped lesion progressing centripetally

Multifocal, early macular involvement

Usually unifocal, fovea relatively spared

Usually unifocal, macula can get involve early

9

Classic appearance

Late swiss cheese

Cracked mud

Cottage cheese with pizza-pie

Head light in fog appearance

10

Vasculitis

Common

Uncommon

Seen, but not common

Seen,

Kyrieleis plaques

11

Retinal haemorrhages

Common

Uncommon

Common in active lesion

Uncommon,

Rarely seen if associated with vascular occlusion

12

Treatment

Acyclovir

Valacyclovir

Famciclovir

Limited success

Acyclovir+Foscarnet

Ganciclovir

Ganciclovir,

Valganciclovir,

Foscarnet,

Cidofovir

Pyrimethamine+sulfadiazine,

Clindamycin,

Spiramycin

Table 1: Differentiating features of various causes of Retinitis

Diagnosis:

Diagnosis of CMV retinitis is mostly based on characteristic ophthalmological findings. Retinal imaging including fundus photography, fundus fluorescein angiography, wide-field retinal imaging, and optical coherence tomography are useful in establishing the diagnosis and monitoring the response to treatment. Viral isolation, serodiagnosis, detection of the viral genome, and biopsy are ways for laboratory diagnosis.1,5

  1. Viral Isolation: Isolation of the virus in culture with detection of viral cytopathic effect and early nuclear antigen by immunofluorescence is an important diagnostic modality. Viral isolation is the gold standard for CMV diagnosis but is slow and often takes weeks to yield positive results. Aqueous fluid, vitreous sample, or subretinal fluid can be used for culture but the yield is low.
  2. Serodiagnosis: Different methods of serodiagnosis include enzyme-linked immunoassay, indirect hemagglutination, radioimmunoassay, and complement fixation. The presence of antibodies to CMV indicates prior infection but is neither indicative of concurrent clinical disease nor productive of future disease.
  3. Polymerase chain reaction: The tetraplex PCR analysis of intraocular fluids for HSV, VZV, and CMV are effective in confirming the etiological pathogen. It has a sensitivity of 80.9 - 84% and a specificity of 97.4 - 100%.1 An elevated CMV viral load is the most predictive risk factor for the end-organ disease.
  4. Biopsy: In atypical cases, endoretinal biopsy taken at the junction of necrotic and actively infected tissue may be necessary. The pathognomonic finding is the presence of intranuclear and intracytoplasmic inclusion bodies with an ‘owl’s eye’ appearance or positive CMV staining by immunohistochemistry. Electron microscopy also helps in demonstrating viral particles.

Treatment:

The mainstay of treatment in CMV retinitis is the reversal of immunodeficiency. Prior to the introduction of HAART, patients often experienced a catastrophic loss of vision due to CMV retinitis. The development of HAART in 1996 has dramatically changed the incidence rates of CMV retinitis and associated complications.15-16 As per Longitudinal Study of Ocular Complications of AIDS (LSOCA) study research groups (2012), the four-year cumulative incidence of CMV retinitis in AIDS patients with lowered CD4 counts was 7%, a 72% reduction in the post-HAART era.17 Kempen et al showed a 30% reduction in mortality in patients treated with systemic anti-CMV therapy along with HAART.18

FDA had approved four drugs for the treatment of CMV retinitis: ganciclovir, valganciclovir, foscarnet, and cidofovir; all are selective viral DNA polymerase inhibitors. All these drugs are virostatic, not virucidal. These drugs are generally commenced at higher induction doses for two to three weeks followed by maintenance doses to prevent relapses of retinitis. Individual drugs with doses and side-effects are given in Table 2. Anti-CMV drugs should be continued in the maintenance phase until patients have complied with HAART for at least 18 months, there are documented CD4+ counts ≥100 cells/μL for at least 3 months and the retinitis is quiescent with prolonged relapse-free interval.19

Drugs

Induction phase

Maintenance phase

Laboratory tests

Side effects

Consideration

Ganciclovir (Intravenous)

5mg/kg IV BD x 14 days

5 mg/kg IV per day

1. Complete blood counts twice a week during induction, weekly during maintenance.

2. Serum creatinine monthly

Anaemia, thrombocytopenia, neutropenia

1. Dose adjustment for renal disease

2. Avoid other bone marrow suppressing medications

3. Cytokine support: (granulocyte colony- stimulating factor) for neutropenia (absolute neutrophil count <500/mm3)

Ganciclovir (Oral)

Not recommended

1 gram PO TDS

1. Complete blood count every1–2 weeks;

2. Serum creatinine monthly

Anaemia, thrombocytopenia, neutropenia

1. Dose adjustment for renal disease

2. Avoid other bone marrow suppressing medications

3. Cytokine support: (granulocyte colony- stimulating factor) for neutropenia (absolute neutrophil count <500/mm3)

Ganciclovir (Intravitreal)

2 mg/0.1 mL twice a week for 3 weeks

2 mg/0.1 mL per week

None

Risk of endophthalmitis, cataract, increases IOP, uveitis, vitreous haemorrhage, retinal detachment

Mainly used in Zone 1 disease

Valganciclovir (Oral)

900mg PO BD x 14 days

900 mg PO OD per day

Complete blood count weekly

Bone marrow suppression, nausea, diarrhoea

1. Avoid other bone marrow suppressing medications

2. Cytokine support for neutropenia

Foscarnet (Intravenous)

90 mg/kg BD x 14 days or

60 mg/kg TID

90-120 mg/kg per day

Serum creatinine, potassium, magnesium, calcium, phosphorous biweekly during induction, and weekly during maintenance

Nephrotoxicity,

hypokalaemia,

hypocalcaemia,

hypomagnesemia,

genital ulcers,

anaemia,

headache

1.Dose adjustment for renal disease

2. IV pre-hydration with 1 L 0.9% NaCl

3. Slow infusion if hypocalcaemia symptoms

4. Electrolyte replacement

Foscarnet (Intravitreal)

2.4 mg biweekly for 3 weeks

2.4 mg weekly

None

Risk of endophthalmitis, cataract, increases IOP, uveitis, vitreous haemorrhage, retinal detachment

Mainly used in Zone 1 disease and ganciclovir resistant cases

Cidofovir (Intravenous)

5 mg/kg per week x 14 days

3–5 mg/kg IV every 2 weeks

Serum creatinine, urinary protein, complete blood count before each infusion

Nephrotoxicity, proteinuria, Fanconi- like syndrome, hypocalcaemia, neutropenia, uveitis, hypotony

1. IV prehydration with 1 litre 0.9% NaCl

2. Oral probenecid 2 gram PO 3 hours before, 1 gram 2 hour after and 1 gram 8 hour after each infusion

3. Discontinue if IOP < 50% of baseline

4. Discontinue if dipstick proteinuria > 2+ or serum Creatinine increases by 0.5 mg/dL

Fomivirsen (Intravitreal)

300 microgram every 2 weeks for 4 weeks

300 microgram every 4 weeks

None

Risk of endophthalmitis, cataract, increases IOP, uveitis, vitreous haemorrhage, retinal detachment

Resistant cases

Table 2: List of anti-CMV drugs

In a large randomized trial Foscarnet-Gancyclovir CMV Retinitis Trial, designed to compare both drugs in terms of relative efficacy and safety in patients with AIDS, revealed no difference in terms of the rate of retinitis progression.20 In 1996, HPMPC trial demonstrated the efficacy of cidofovir in 64 newly diagnosed CMV retinitis patients randomized to treatment and deferred arms.21 Further, the Spanish Cidofovir Study Group highlighted the efficacy of compassionate use of cidofovir in 51 patients on HAART with previously treated retinitis who had relapsed or were unresponsive to induction with other anti-CMV agents.22 Cidofovir has the advantage of weekly dose in the induction phase and fortnightly dose in maintenance phase because of its prolonged intracellular half-life but is highly nephrotoxic. Hence, it is used in ganciclovir resistant cases.

Valganciclovir was a useful addition to the existing list of anti-CMV drugs in 2000. It is an L-valyl ester prodrug of ganciclovir, with high oral bioavailability (60%) and convenient once daily dosing. In a randomized study involving 80 patients with CMV retinitis, a satisfactory response to induction therapy was achieved in 77% of patients assigned to intravenous ganciclovir and 72% assigned to oral valganciclovir.23 Compared with intravenous therapy, oral valganciclovir equally prevents and treats non-ocular CMV disease, and hence has become a preferred treatment option for most experts. (Figure 6)

Figure 6: A 34-years-old patient suffering from AIDS (CD4 count: 41 cells/μL) presented with CMV retinitis in Zone 2 (A). He received Oral Valgancyclovir 900 mg twice a day for 14 days followed by 900 mg once a day. At 6 weeks on a maintenance dose, his CMV lesions healed with the atrophic retina and pigmentary changes.

Apart from systemic anti-CMV therapy, intravitreal drug injection of available drugs are important options especially in sight-threatening zone 1 disease.13,24 Various reports have documented the efficacy of intravitreal injections of ganciclovir and foscarnet solution. Cidofovir is no longer recommended due to its ocular toxicities like uveitis, hypotony, and occasionally, irreversible severe visual loss. In 1996, a sustained-release ganciclovir implant was approved for intraocular use.25 It releases intraocular ganciclovir at the rate of 1 μg/hour for up to eight months obviating the need for weekly injections during the maintenance phase.Although combining the ganciclovir implant with oral ganciclovir therapy has shown synergistic efficacy against the progression of retinitis, it is no longer commercially available due to the favorable ease of use of oral valganciclovir. Intravitreal therapy alone is associated with a higher risk of retinitis to the fellow eye, extraocular CMV-related diseases, and increased morbidity. Hence, systemic anti-CMV therapy should be added to local therapy. Table 3 shows the treatment algorithm for CMV retinitis.

Retinitis Location

Highly Active Antiretroviral Therapy (HAART)

Experienced

Naive

Zone 1

Oral Valgancyclovir +

intravitreal ganciclovir

Oral Valgancyclovir +

intravitreal ganciclovir

Zone 2 and 3 only

Oral Valgancyclovir +/-

intravitreal ganciclovir

Oral Valgancyclovir

Table 3: Treatment algorithm for CMV Retinitis

Resistance and Relapse:

Resistance is defined as persistent active retinitis lesions despite six weeks of induction therapy. It occurs in 25 to 35 percent of patients by nine months of therapy. Management includes combining therapies such as foscarnet with ganciclovir or adding an intravitreal injection to systemic therapy. In some patients, there may be a need to switch therapies altogether. Importantly subtherapeutic doses should not be confused with resistance.

The chance of relapse increases if CD4 counts are less than 100. In order to detect early relapses comparison of serial fundus photos is necessary. Relapse is defined as a quiescent CMV retinitis that becomes active. UL97 mutation may plan an important role in resistance and relapses. Hence, PCR sequencing for the detection of the UL97 mutation should be done. In case of relapse, current therapy should be continued at the induction schedule and compliance with HAART should be checked.

Complications:

1. Immune recovery uveitis (IRU):

The reported incidence ranges widely from 0.109 cases per person-year to 0.83 cases per person-year.26 Patients initially treated with cidofovir may be at higher risk for IRU. IRU usually occurs 2-16 weeks after the elevation of the CD4+ lymphocyte counts above 100 cells/μL, which is typically noted 2.5-8 months after starting HAART.27 Symptoms include painless decreased vision and floaters without any redness. The vision loss is generally mild. Ocular examination reveals moderate to severe vitritis, papillitis, cystoid macular edema, and /or epiretinal membrane. Rarely, the patient might present with vitreous haemorrhage, retinal neovascularization, optic disc neovascularisation, vitreomacular traction, proliferative vitreoretinopathy, posterior and anterior subcapsular cataracts, posterior synechiae, and angle-closure glaucoma.28 Eyes with inactive retinitis involving over 30% of the retinal area are at a higher risk of developing immune recovery uveitis when compared to eyes with less extensive involvement, presumably because those eyes with a larger area of CMV retinitis may generate a greater antigenic stimulus, prompting a more aggressive inflammatory response. Few small cohort studies have reported improvement in vision with periocular or systemic steroids. Contrarily, Zegans found that the vitreous cells resolved and vision improved within 6 weeks with or without anti-inflammatory therapy.29 Role of systemic steroids is controversial considering severe immunodeficiency in AIDS.

2. Retinal detachment:

Extensive retinal necrosis can lead to multiple large retinal tears and subsequently retinal detachment within 3-6 months of diagnosis.30 Retinitis lesions located in the periphery where the vitreous body is firmly adherent to the retina are more likely to be associated with retinal detachment than those located in the posterior pole. Eyes with large lesions and a longer duration of active lesions have a higher risk of retinal detachment. (Figure 7) Vitrectomy with long term tamponade with high-density oil is often necessary due to multiple holes in atrophic or gliotic retina.30,31

Prevention:

Reconstitution of immune system of the patient with HAART had dramatically reduced the morbidity and mortality in AIDS. Regular CD4 counts must be monitored in these patients with instituting secondary prophylaxis in the presence of immunological failure. Routine fundus screening should be done with indirect ophthalmoscopy inpatient with CD4 counts of < 50 cells/μL to detect peripheral lesions early. Routine use of primary prophylaxis with anti-CMV therapy is not recommended due to its high cost, potential toxicity, and concern about the development of drug resistance.

CMV Retinitis in non-HIV patients:

CMV retinitis in non-HIV cases has been observed in patients undergoing immunosuppressive therapies for hematologic malignancies, autoimmune disease, bone marrow and solid organ transplantation, and after local steroid administration.32,33 The clinical presentation is more or less similar in HIV and non-HIV patients. It has also been observed that vitreous inflammation, arteritis, and vascular occlusion outside of the areas of active retinitis can be more severe in non-HIV patients and the degree may vary depending on the level of immune suppression in non-HIV immunosuppressed patients. The treatment of CMV retinitis in HIV and non-HIV is similar requiring anti-CMV drugs in both the induction and maintenance phases. Induction therapy is typically administered for 14 to 21 days. The maintenance phase should be continued till there are signs of immune recovery. This can be achieved by either stopping or decreasing the dose of immunosuppressive drugs. The recurrence rate of 33 to 44% has been reported in various studies after discontinuation of anti-CMV therapy. The overall visual prognosis and clinical features of CMV retinitis have not been found to differ between HIV and non-HIV patients. Despite advances in anti-viral treatment, the visual prognosis of CMV retinitis remains poor. Poor prognosis is associated with retinal detachment during treatment, macular involvement, and poor general health of the patient. The incidence of retinal detachment also has not been found to significantly differ comparing HIV and non-HIV CMV retinitis patients.

References:

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Dr. Swapnil Parchand
Consultant, Retina and Uvea Services, MGM Eye Institute, Raipur
Dr Swapnil Madhukar Parchand completed his MS (Ophthalmology) from prestigious Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh in 2010. He was also awarded DNB Degree in Ophthalmology. He was awarded FAICO Fellowship degree in Retina and Vitreous by AIOS in 2019. He was Senior Resident in Retina and Uveitis Services at PGIMER, Chandigarh from 2010 to 2013. After completing his Senior Residency, he worked as Assistant Professor in Department of Ophthalmology at Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry from 2014 to 2017. He was incharge of Retina, Uveitis and Retinopathy of Prematurity (ROP) Services at JIPMER. He joined MGM Eye Institute in 2017 as Consultant in Vitreo-retina and Uveitis Services. His areas of interest are Retinal diseases, uveitis, ROP and ocular trauma. Dr Swapnil M Parchand has presented many research papers in various National and International conferences. He is reviewer of International Journals like Ocular Immunology and Inflammation, International Ophthalmology, Indian Journal of Ophthalmology and BMJ Case Reports. To his credit he has more than 25 publications in reputed national and international journals highlighting his work in Retina and Uveitis.
Dr. Anil Gangwe
Consultant, Retina and Uvea Services, MGM Eye Institute, Raipur
Dr. Anil Babanrao Gangwe completed his MBBS from Seth G. S. Medical College & KEM hospital, Mumbai in 2008. He completed his post graduate degree (MD) in Ophthalmology from Dr. R.P Centre for Ophthalmic Sciences, AIIMS, New Delhi in 2011. He was Senior Resident in Vitreo Retina and ROP services at AIIMS, New Delhi from 2012 to 2015. He has trained general ophthalmologist in ROP screening and management at AIIMS under the National program for control of blindness. He also worked as Consultant- Vitreo Retinal services at Gomabai Netralaya, Neemuch (Madhya Pradesh) from Feb. to Oct. 2015. He joined the Vitreo-Retinal Services at MGM Eye Institute in November 2015. His area of interest are Retinopathy of Prematurity (ROP), ocular trauma, diabetic retinopathy and complex retinal detachment. He has many publication in national and international peer reviewed journals.
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