Sandbox: Reddy

Classification

Cytomegalovirus infection can be classified based on the organ system involved into the following:

CMV retinitis

• It is the most common clinical manifestation of cytomegalovirus infection.
• Retinitis is initially unilateral but progress to affect the contralateral side in the absence of therapy and immunosuppression.
• In patients with CD4 < 50cells/mm³ bilateral retinal involvement is high.
• Peripheral retinitis can be asymptomatic or present with floaters, scotomata, or peripheral visual field defects whereas central retinal lesions or lesions impinging on the macula or optic nerve are result in decreased visual acuity and central field defects.
• On fundus examination the following findings can be demonstrated:
  • Fluffy yellow-white retinal lesions, with or without intraretinal hemorrhage.
  • Inflammation of the vitreous can be demonstrated in patients with severe immunosuppression.
  • Blood vessels appear sheathed.
  • If left untreated, retinitis is a rapidly progressive condition and on fundus examination it demonstrates a characteristic brushfire pattern, with a granular, white leading edge advancing before an atrophic gliotic scar.

CMV colitis

• Colitis is seen in 5 to 10% of patients with AIDS and cytomegalovirus end organ disease.
• Colitis presents with weight loss, anorexia, abdominal pain, debilitating diarrhea, fever and malaise. Patients with perforation of the bowel present with acute abdominal pain.
• CT abdomen in patients with cytomegalovirus colitis demonstrates colonic thickening.
• Complications of cytomegalovirus colitis include bowel perforation and hemorrhagic enteritis.
• Colonoscopy demonstrates mucosal lesions and the diagnosis is confirmed by the presence of characteristic intranuclear and intracytoplasmic inclusions on microscopic examination of the colonic biopsy.

CMV esophagitis

• Cytomegalovirus esophagitis can be seen in few patients with AIDS and cytomegalovirus end organ disease.
• Patients present with symptoms of odynophagia, nausea, mid-epigastric or retrosternal discomfort and fever.
• Endoscopy will reveal ulcers in the distal esophagus and diagnosis is confirmed by the demonstration of characteristic intranuclear inclusion bodies in the endothelial cells of the biopsy specimen.
• Culture of cytomegalovirus from the esophageal biopsy is not sufficient to confirm the diagnosis in the absence of microscopic findings as majority of patients with low CD4 counts have positive culture.

CMV pneumonitis

• Cytomegalovirus pneumonitis is a uncommon condition and is usually asymptomatic.
• It is usually diagnosed on bronchoalveolar lavage and co-exists with an underlying pulmonary infection.
• Chest X-Ray demonstrates diffuse pulmonary interstitial infiltrates and diagnosis confirmation requires a correlation of the clinical features to imaging findings.

Neurologic disease

Cytomegalovirus infection of the neurological system includes dementia, ventriculoencephalitis and polymyeloradiculopathies. Diagnosis of neurological disease requires correlation between the clinical symptoms and a positive PCR for cytomegalovirus of the cerebrospinal fluid.

• CMV Encephalitis
  • Patients with cytomegalovirus encephalitis presents with fever, lethargy and confusion.
  • Cerebrospinal fluid demonstrates lymphocytic pleocytosis, low-to-normal glucose levels, and normal-to-elevated protein levels.
• CMV Ventriculoencephalitis
  • Patients have an acute onset of symptoms with focal neurological deficits, cranial nerve palsies, nystagmus and rapid progression to death.
  • Presence of periventricular enhancement on CT or MRI is highly suggestive of CMV infection.
• CMV polyradiculomyelopathy
  • Patients present with similar features of Guillian Barre Syndrome.
  • Patients with bladder incontinence and paraplegia with gradual worsening of symptoms over weeks.
  • Cerebrospinal fluid analysis demonstrates neutrophilic pleocytosis, low glucose levels and elevated protein levels.

Pathogenesis

Transmission

• CMV is transmitted through body fluids, including saliva, urine, human milk, genital secretions, and blood.

CMV Retinitis

• Retinitis, caused by cytomegalovirus (CMV), involves the infection of all layers of the retinal tissue.
• Spread of the the infection will occur at approximately 24 nanometers per day.
• Primarily infected areas include the retinal pigment epithelium and the subjacent choroid.
• Infection will result in cellular necrosis across the retina; with the enlargement of infected cells, evidently hosting viral inclusions.
• CMV retinitis, post-treatment, will commonly persist on the previously scarred, retinal tissue.
• Progression of infection may result in the development of small holes across previously scarred and healed tissue.
• Formation of these tiny holes may result in rhegmatogenous, retinal detachments.

Risk Factors

• Patients with the following conditions are at a higher risk for developing symptomatic cytomegalovirus infection:
  • Solid organ transplant
  • Hematological stem cell transplant
  • AIDS
  • T-cell deficiency

Epidemiology and Demographics

• Cytomegalovirus (CMV) infects approximately 40-90% of the world population.
• CMV seroprevalence in developing countries reaches more than 90% by adolescence and exceeds 95% by early adulthood.

Diagnosis

Serological Tests

• Serological tests are not useful for the diagnosis of cytomegalovirus infection, however absence of CMV IgG excludes the presence of infection.

Polymerase Chain Reaction

• In patients with cytomegalovirus retinitis CMV DNA is detected in the vitreous in majority of patients.
• PCR for demonstration of CMV DNA is useful for the diagnosis of retinitis and neurologic disease.
• PCR of blood for demonstration of viremia is not useful for diagnosis of cytomegalovirus end organ disease as a negative result is not consistent with the absence of disease.

Microscopic Pathology

• Demonstration of characteristic intranuclear inclusion bodies in the biopsy from esophagus and colon confirms the diagnosis of esophagitis and colitis.

CT Scan

• In patients with cytomegalovirus ventriculoencephalitis periventricular enhancement is suggestive of CMV infection.
• Colonic thickening can be demonstrated in patients with cytomegalovirus colitis.

Treatment

Antiviral therapy is the primary modality of treatment. Duration of therapy and the antiviral agents are selected based on the severity of the disease, location of the disease and the level of immunosuppression.

CMV Retnitis

The choice of therapy is based on the location of the lesions and level of immunosuppression of the patient. Systemic antiviral therapy is preferred as infection rate of the contralateral eye is reduced.

• Initial Therapy for patients with immediate sight-threatening lesions (Adjacent to the optic nerve or fovea)
  • Preferred Regimen(1): Ganciclovir intraocular implant + valganciclovir 900 mg PO (BID for 14–21 days, then once daily) AND One dose of intravitreal ganciclovir may be administered immediately after diagnosis until ganciclovir implant can be placed
  • Alternate Regimen (1): Ganciclovir 5 mg/kg IV q12h for 14–21 days, then 5 mg/kg IV daily OR
  • Alternate Regimen (2): Ganciclovir 5 mg/kg IV q12h for 14–21 days, then valganciclovir 900 mg PO daily OR
  • Alternate Regimen (3): Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h for 14–21 days, then 90–120 mg/kg IV q24h OR
  • Alternate Regimen (4): Cidofovir 5 mg/kg/week IV for 2 weeks, then 5 mg/kg every other week with saline hydration before and after therapy and probenecid 2 g PO 3 hours before the dose followed by 1 g PO 2 hours after the dose, and 1 g PO 8 hours after the dose (total of 4 g)
    • Note(1): This regimen should be avoided in patients with sulfa allergy because of cross hypersensitivity with probenecid.
    • Note(2): If systemic anti-CMV treatment is not available, use sequential ganciclovir intravitreal injections until immune reconstitution in response to anti retroviral viral therapy is achieved.
• For Small Peripheral Lesions
  • Preferred Regimen: Valganciclovir 900 mg PO BID for 14–21 days, then 900 mg PO daily AND One dose of intravitreal ganciclovir may be administered immediately after diagnosis to deliver high local concentration until systemic ganciclovir concentration is reached.
• Chronic Maintenance Therapy (Secondary Prophylaxis) for CMV Retinitis
  • The drug of choice for chronic maintenance therapy and the preferred route (i.e., implant, intravitreal injection, IV, oral, or combination; and which drug) should be made in consultation with an ophthalmologist. Considerations should include the anatomic location of the retinal lesion, vision in the contralateral eye, the patient’s immunologic and virologic status and response to antiretroviral therapy.
  • Patients with sight-threatening retinitis will most benefit from ganciclovir implant to control retinitis progression, due to the delivery of high concentration of ganciclovir at the site of infection.
    • Preferred Regimen (1): Valganciclovir 900 mg PO daily + ganciclovir intraocular implant (for sight-threatening retinitis) OR
    • Preferred Regimen (2): Valganciclovir 900 mg PO daily (for small peripheral lesions) AND
    • Note(1): Ganciclovir intraocular implant should be replaced every 6–8 months until sustained immune recovery is documented.
    • Alternate Regimen (1): Ganciclovir 5 mg/kg IV 5–7 times weekly OR
    • Alternate Regimen (2): Foscarnet 90–120 mg/kg IV once daily OR
    • Alternate Regimen (3): Cidofovir 5 mg/kg IV every other week with saline hydration and probenecid as above.
• Immune Restoration Uveitis (IRU)
  • Preferred Regimen (1): Periocular corticosteroid or a short course of systemic steroid
• Stopping Chronic Maintenance Therapy for CMV Retinitis
  • CMV treatment for at least 3–6 months, with CD4 count >100 cells/mm3 for >3 to 6 months in response to ART.
  • Therapy should be discontinued only after consultation with an ophthalmologist, taking into account magnitude and duration of CD4 count increase, anatomic location of the lesions, vision in the contralateral eye, and the feasibility of regular ophthalmologic monitoring.
  • Routine (i.e., every 3 months) ophthalmologic follow-up is recommended for early detection of relapse or immune restoration uveitis, and then annually after immune reconstitution.
• Reinstituting Chronic Maintenance/Secondary Prophylaxis for CMV Retinitis
  • CD4 + count <100 cells/mm³

CMV Colitis and Esophagitis

Duration of therapy: 21–42 days or until signs and symptoms have resolved

• Preferred Regimen (1): Ganciclovir 5 mg/kg IV q12h, may switch to valganciclovir 900 mg PO q12h once the patient can absorb and tolerate PO therapy.
• Alternate Regimen (1): Foscarnet 60 mg/kg IV q8h or 90 mg/kg IV q12h for patients with treatment limiting toxicities to ganciclovir or with ganciclovir resistance OR
• Alternate Regimen (2): Oral valganciclovir may be used if symptoms are not severe enough to interfere with oral absorption OR
• Alternate Regimen (3): For mild cases: If ART can be initiated or optimized without delay, withholding CMV therapy may be considered.
  • Note (1): Maintenance therapy is usually not necessary, but should be considered after relapses.

CMV Pneumonitis

• Doses are the same as for CMV retinitis.
• Treatment experience for CMV pneumonitis in HIV patients is limited. Use of IV ganciclovir or IV foscarnet is reasonable.
• The role of oral valganciclovir has not been established.
• The duration of therapy has not been established.

Neurologic Disease

• Doses are the same as for CMV retinitis.
• Treatment should be initiated promptly.
• Combination of ganciclovir IV + foscarnet IV to stabilize disease and maximize response; continue until symptomatic improvement
• Continue therapy until resolution of neurologic symptoms
• Optimize ART to achieve viral suppression and immune reconstitution