Cytomegalovirus infection

Infection with cytomegalovirus (CMV or human herpes virus 5) is generally asymptomatic in immunocompetent individuals but can cause mild, mononucleosis-like symptoms. Like all Herpesviridae infections, CMV infection remains latent for the affected individual's lifetime and reactivation may therefore occur. Immunocompromised individuals (e.g., with AIDS or posttransplantation) are especially at risk of illness following initial infection or reactivation, which can include severe manifestations such as CMV retinitis (risk of blindness) or life-threatening CMV pneumonia. Diagnosis is based on serology findings or the direct detection of the virus in blood or tissue. Treatment with antivirals (e.g., ganciclovir or valganciclovir) should be initiated based on disease severity and immune status. Preventive measures are recommended for high-risk individuals; there is currently no CMV vaccine. Screening is performed before solid organ and hematopoietic stem cell transplant. Despite the risk for congenital CMV infection, routine screening for CMV during pregnancy is not recommended.

Congenital CMV infection is discussed separately.

• Prevalence of CMV infection in the general population: 40–100%
• Seroprevalence increases with age with more than 90% in individuals > 80 years

Epidemiological data refers to the US, unless otherwise specified.

• Pathogen: cytomegalovirus (CMV, human herpes virus 5, HHV-5)
• Transmission ^[1][2]
  • Blood transfusions
  • Sexual transmission
  • Transplacentally (highest risk during the third trimester of pregnancy) ^[1]
  • Perinatal transmission (e.g., contact with contaminated blood/vaginal secretions during delivery or breastfeeding)
  • Body fluids (e.g., respiratory droplets, saliva, breast milk, urine, genital secretions)
  • Transplant-transmitted infection (e.g., bone marrow, lungs, kidneys) ^[3]

• CMV binds to integrins →; activation of integrins → induction of cellular morphological changes → activation of signal transduction pathways; such as FAK (focal adhesion kinase) and apoptotic pathways → cell damage → clinical manifestations depending on the organ/tissue affected. ^[4][5]
• After primary infection resolves, CMV remains latent in mononuclear cells (e.g., myeloid cells). Reactivation can occur if the patient becomes immunocompromised. ^[6]

CMV infection is usually asymptomatic. Severe manifestations occur in patients with immunocompromise (e.g., following organ transplantation, AIDS).

Immunocompetent patients

• > 90%: asymptomatic course ^[1]
• < 10%: CMV mononucleosis ^[7]
  • Fever, malaise, myalgia/arthralgia, fatigue, headache
  • Less common: sore throat, cervical lymphadenopathy, hepatomegaly, splenomegaly
  • Differential diagnosis: infectious mononucleosis caused by EBV
• Rare: severe infection with organ involvement (e.g., colitis, encephalitis) ^[8]

Immunocompromised patients ^[9]

• Asymptomatic CMV infection: evidence of viral replication (e.g., viral DNA or antigen in serum) but no symptoms
• Viral syndrome: malaise and fever with leukopenia and/or thrombocytopenia in individuals with a positive serum CMV antigen or PCR ^[10]
• CMV pneumonia: interstitial pneumonitis ; ^[7]
  • Epidemiology: immunocompromised patients (e.g., following bone marrow transplant or with HIV/AIDS and CD4 ≤ 50 cells/mm³) ^[11]
  • Clinical features: fever, nonproductive cough, dyspnea
  • Diagnostics
    • Chest x-ray: diffuse bilateral interstitial infiltrates
    • Detection of CMV in bronchoalveolar lavage fluid or lung tissue samples following biopsy ^[12]
  • Differential diagnoses: pneumocystis pneumonia and other viral respiratory infections
• CMV retinitis
  • Clinical features: floaters, photopsia, visual field defects
  • Fundoscopy: pizza-pie appearance (retinal hemorrhages, fluffy/granular white opacities around retinal vessels resembling cotton-wool spots, retinal detachment)
  • Differential diagnoses: HIV retinopathy, herpes simplex retinitis, varicella zoster retinitis, toxoplasmosis
• CMV esophagitis and/or CMV colitis
  • Epidemiology: Most commonly occurs in patients with HIV.
  • Clinical features: odynophagia, abdominal pain, bloody diarrhea
  • Endoscopic examination of the GI tract typically shows linear ulcers ^[11]
• CMV hepatitis: prolonged malaise and fever with mild transaminitis ^[13]
• CMV encephalitis: impaired cognitive function, neurological deficits ^[11]
• Adrenal insufficiency ^[14]

Among patients with HIV, manifestations of CMV disease usually occur when the CD4 count is < 50. ^[11]

General principles ^[7]

• In patients with clinical features of infectious mononucleosis, rule out EBV infection and consider other differential diagnoses of mononucleosis.
• In patients with clinical features of CMV, obtain CMV-specific studies based on immune status.
• Obtain directed studies (e.g., fundoscopy, chest x-ray, endoscopy) based on the clinical manifestation.
• If there are concerns for organ involvement, obtain a tissue biopsy for a definitive diagnosis.

Laboratory studies ^[7]

Routine studies

The following studies are nonspecific and should be obtained based on clinical manifestations and/or to rule out other diagnoses.

• CBC with differential ^[9]
  • Relative lymphocytosis with > 10% atypical lymphocytes ^[7]
  • Anemia
  • Thrombocytopenia
  • Pancytopenia (uncommon) ^[15]
• LFTs: ↑ AST and ALT, normal or ↑ bilirubin
• LDH: elevated in CMV hepatitis ^[13]
• Monospot test: negative (obtained to rule out EBV infection)

In immunocompetent patients, CMV infection may manifest similarly to EBV infection. However, in CMV infection, the monospot test will be negative. ^[7]

CMV-specific studies ^[1][7]

• Serological tests: Obtain in immunocompetent patients.
  • Active disease
    • Presence of IgM antibodies
    • A four-fold increase in the levels of IgG antibodies ^[7]
  • Prior infection: presence of IgG antibodies but no IgM antibodies
• Direct viral detection: Obtain in patients with immunocompromise.
  • PCR (preferred): detects CMV DNA in blood and other bodily fluids and measures viral load ^[16]
  • Immunofluorescence antigen assay: detects CMV pp65 antigens in blood ^[16]
• Tissue biopsy
  • Histopathology: large atypical cells with intranuclear inclusion bodies that have an owl-eye appearance ^[11]
  • Immunohistochemistry: detection of CMV antigens ^[10][16]

Serological tests may be unreliable in immunosuppressed patients.

Serum viral detection (e.g., CMV PCR) is often negative and therefore not useful in patients with suspected CMV retinitis, colitis, or pneumonitis. ^[10]

Additional studies

• Chest imaging: (e.g., chest x-ray): diffuse pulmonary interstitial infiltrates in CMV pneumonitis ^[11]
• Fundoscopy: retinal hemorrhages and cotton-wool spots (“pizza-pie” appearance) in CMV retinitis ^[17][18]
• Endoscopy: : ulcerations of the mucosa seen in CMV colitis and CMV esophagitis ^[11]

General principles ^[1][10][11]

• Consult infectious disease and/or transplant specialists for patients with severe disease or an immunocompromised state.
• Immunocompetent patients: supportive care; consider antivirals in severe or tissue-invasive disease. ^[8]
• Immunocompromised patients
  • Initiate antiviral therapy based on disease severity.
  • Decrease level of immunosuppression.
  • Initiate or optimize antiretroviral therapy in patients with HIV.
  • Prophylaxis and preemptive therapy may be considered with specialist guidance in select populations (e.g., at-risk transplant patients); see “Prevention of CMV infection.”

CMV infection in immunocompetent patients typically resolves without treatment.

Antiviral therapy for CMV ^[9][10][11]

• Preferred agents: ganciclovir ; valganciclovir
• Alternative agents: foscarnet ; cidofovir
• Other: maribavir ; letermovir
• Indications
  • Viral syndrome
    • Preferred: ganciclovir or valganciclovir based on disease severity and ability to tolerate and absorb oral medications
    • Alternatives: foscarnet, cidofovir
  • CMV retinitis
    • Severe infection (lesions within 1.5 mm of the fovea): ganciclovir OR valganciclovir with or without intravitreal injections of ganciclovir or foscarnet
    • Peripheral lesions: valganciclovir
  • CMV esophagitis or CMV colitis: ganciclovir followed by valganciclovir if oral medications can be absorbed and tolerated
  • CMV pneumonitis: ganciclovir; consider adjunctive IV immunoglobulin (IVIG) ^[9]
  • CMV encephalitis: ganciclovir PLUS foscarnet

Treatment is based on patient factors (e.g., stem cell transplant, drug resistance) and disease manifestations, and should be specialist-guided.

Treatment for CMV encephalitis should be started immediately.

Monitoring ^[10][11]

Patients receiving antiviral therapy should have the following laboratory studies performed frequently (at least weekly).

• CMV viral load (e.g., serum PCR)
• CBC to assess for cytopenias
• BMP to monitor renal function

Valganciclovir and ganciclovir can induce bone marrow suppression, leading to new or worsening leukopenia or thrombocytopenia. ^[11]

Primary prevention of CMV

• There is currently no CMV vaccine. ^[2][19]
• CMV prevention is not recommended for healthy individuals.

Primary prevention in high-risk individuals

• The risk of CMV infection or complications from infection is increased in selected groups, e.g.:
  • Immunosuppressed individuals, including individuals with HIV ^[11][20][21]
  • Pregnant individuals ^[22]
  • Premature and low birth weight infants ^[22]
• Use CMV-negative blood products for high-risk individuals. ^[9][20][22]
• Recommend condoms during intercourse. ^[11][23]
• For pregnant individuals or those planning pregnancy: ^[22][23][24]
  • Advise caution attending schools, child care centers, health care facilities, and large gatherings.
  • Avoid contact with bodily fluids, e.g.:
    • Use standard precautions for workplace exposures to bodily fluids.
    • Practice rigorous hand hygiene after changing a child's diaper.
    • Avoid contact with children's saliva (e.g., sharing of utensils, kissing).
  • For child care workers and health care workers, discuss reassignment to avoid exposure. ^[22][23][24]
• For individuals who are immunocompromised, additional CMV precautions depend on the nature of immunocompromise.

Educate pregnant individuals about the risk for congenital CMV infection and ways to reduce the risk of contracting CMV infection. ^[22]

Screening for CMV

• Recommended before HSCT or solid organ transplant ^[9][20]
• Not routinely recommended for pregnant individuals or those planning pregnancy ^[2][11]

Prevention of CMV transmission

• Individuals with CMV infection do not need to isolate; advise good hand hygiene and respiratory hygiene. ^[22]
• Recommend standard precautions for anyone caring for an individual with CMV infection. ^[22]
• CMV infection during pregnancy: Refer to a specialist (e.g., infectious diseases, maternal-fetal medicine). ^[27]
• CMV infection while breastfeeding ^[2][28]
  • Continuation of breastfeeding is usually recommended for full-term infants. ^[28]
  • Consult infectious diseases for low birth weight or premature infants because of the risk of severe infection.

Children with presumed or confirmed CMV infection do not require exclusion from group child care or school. ^[22]