Cytomegalovirus Inclusion Disease – Causes, Symptoms, Diagnosis, Treatment and Ongoing care
Cytomegalovirus (CMV) infection is highly prevalent as illustrated by seroprevalence in 40–100% of the population (1). Serious disease can result in the perinatal period and in immunocompromised patients. Immunocompetent patients may become symptomatic with reinfection with different CMV strains. Prompt treatment and prophylaxis are the current mainstays of infection control.
- β-infection from cytomegalovirus (CMV), a DNA virus in theHerpesvirus family
- Primary infection: Often asymptomatic; may remain latent throughout a person’s life if no immunocompromise
- Severe disease can result from primary infection of newborns or reactivation in setting of immunocompromise or organ transplantation.
- Name derives from the infected cells, which are large and contain intranuclear inclusions, described as “owl’s eye” inclusions
- Not highly contagious:
- Spread via close contact with persons shedding virus from saliva, urine, blood, breast milk, or semen.
- Also acquired via infected transplant organs.
- Any organ can be affected.
- Categories of CMV infections:
- Congenital: Vary greatly from mild viremia in a normal infant to the cause of abortion, stillbirth, postnatal morbidity and death from hemorrhage, anemia, or liver or central nervous system damage (including hearing loss, developmental delay and mental retardation) (2)
- Acute infection in a normal host: Symptomatic infection commonly presents with acute mononucleosis syndrome (3).
- Latent infection: Higher IgG titers may contribute to development of atherosclerotic disease (4).
- Infection in bone marrow and solid organ transplant patients:
- Bone marrow transplant: Usually interstitial pneumonia
- Liver transplant: Hepatitis
- Kidney transplant: CMV syndrome
- Infection in patients with AIDS: Most commonly retinitis, 2nd most common is colitis, followed by esophagitis and neurologic disease (5)
- Infections in other immunocompromised patients: Pulmonary, gastrointestinal (GI), or renal disease
- System(s) affected: Ophthalmic; Pulmonary; GI; Neurologic; Renal; Skin/Exocrine
- Synonym(s): Giant cell inclusion disease; CID CMV
- CMV infection during pregnancy can be hazardous to the fetus.
- May lead to stillbirth, brain damage, birth defects, or to severe neonatal illness.
- May occur congenitally or postnatally.
- Breastfeeding can transmit virus to high-risk preterm infants. However there is low risk of symptomatic disease and no evidence of long-term sequelae from transmission from breastfeeding. Currently there are no recommendations for avoidance or treated breast milk (6).
- Common, but frequently asymptomatic
- <2–3 cases of end-organ disease per 100 person-years in HIV patients
- CMV infection is even more prevalent in populations at higher risk for HIV infection (IV drug users 75%, homosexual males 90%).
- Predominant age: All ages, peaks at <3 months, 16–40 years, and 40–75 years
- Predominant sex: Male > Female
- Occurs worldwide
- 40–100% of the general US population is seropositive from prior exposure during childhood or early adulthood (1).
- 20% of children in the US are seropositive before reaching puberty (1).
- Most common perinatally transmitted infection: 0.2–2.2% of births in the US (7)
- HIV infection with specific risks, including:
- CD4 count <50 cells/µL (5)[B]
- Absence of treatment with or failure to respond to ART (5)[B]
- Previous opportunistic infections (5)[B]
- HIV viral load >100,000 (5)[B]
- Organ transplantation
- Blood transfusion
- Living in closed population
- Corticosteroid therapy
- Day care environment, infant or geriatric (8)[B]
- For congenital infection, maternal infection during pregnancy
- Low socioeconomic status (7)[C]
- Critically ill immunocompetent adults in intensive care unit settings (up to 1/3 develop CMV, primarily between days 4–12 after admission) (9)[A]
- Handwashing/basic hygiene (8)[A]
- Avoid immunosuppression
- Highly active antiretroviral therapy (HAART) is the best method for high-risk HIV patients (1)[A].
- Chronic maintenance therapy for life in HIV patients with CMV end-organ disease unless successfully treated with ART (3)[A]
- Options include:
- Parenteral or oral ganciclovir (3)[A]
- Parenteral foscarnet (3)[A]
- Combined parenteral ganciclovir and foscarnet (3)[A]
- Parenteral cidofovir (3)[A]
- Ganciclovir administration via intraocular implant or repetitive intravitreous injection of fomivirsen (3)[A]
- CMV antibody+, HIV+ children who are severely immunosuppressed require oral ganciclovir 30 mg/kg t.i.d. (8)[C]
- Antiviral suppression of CMV reactivation in CMV+ transplant recipients or recipients of CMV+ organs:
- Solid organ transplant: Prophylactic or preemptive treatment with oral ganciclovir, valganciclovir (10)[A]
- Bone marrow transplant: IV ganciclovir
- CMV immunoglobulins decrease rate of severe disease after liver transplant (11)[A] and decrease incidence of disease after renal transplant.
- Primary infection
- Reinfection with different CMV strains
- Reactivation of latent virus in patients who are immunosuppressed
Commonly Associated Conditions
- Corticosteroid therapy
- Asymptomatic cytomegaloviremia
- Symptomatic: Small for gestational age, purpura/petechiae, jaundice, hepatosplenomegaly, chorioretinitis, microcephaly, intracranial calcifications, hearing impairment
- 90% have late complications: Sensorineural hearing loss occurs in 14%; 3–5% moderate to severe (11)[A]
- Mental retardation, chorioretinitis, optic atrophy, seizures, learning disabilities (7)
- Acquired: Acute infection in a normal host:
- Usually asymptomatic
- Mononucleosis syndrome: Fever, malaise, sore throat, headache, antibiotic rash (3)
- Less common: Exudative pharyngitis, splenomegaly, cervical adenopathy, rash (3)
- Infections in AIDS patients:
- Retinitis: Usually unilateral, floaters, scotomata, peripheral field defects. Diagnosis made when characteristic retinal changes noted by ophthalmologist on funduscopic exam (5)
- Colitis: Fever, weight loss, anorexia, abdominal pain, diarrhea, malaise; hemorrhage or perforation rare but serious (5)
- Esophagitis: Fever, odynophagia, nausea, abdominal discomfort (5)
- Pneumonitis: Dyspnea with or without exertion, nonproductive cough, hypoxemia (5)
- Neurologic disease: Dementia, lethargy, confusion, fever, focal neurologic signs (5)
- Infections in transplant recipients:
- Persistent fever (most common) (8)
- Bone marrow transplant: Interstitial pneumonia (10)
- Liver transplant: Hepatitis (10)
- Kidney transplant: CMV syndrome (fever, leucopenia, atypical lymphocytes, hepatomegaly, myalgia, arthralgia) (10)
Diagnostic Tests & Interpretation
- Acute infection in a normal host:
- Elevated liver transaminases in 92%, although transaminases rarely increase to >5 times normal ranges (3)
- Anemia (3)
- Thrombocytopenia (3)
- Positive cold agglutinins (3)
- Lymphocytosis with >10% atypical (3)
- Negative heterophil antibody test (rules out Epstein Barr virus mononucleosis) (3)
- Positive CMV IgM antibodies; may not peak until 4–7 weeks after acute infection (3)
- CMV IgG should increase 4–fold during acute infection (3)
- <12 months: Positive CMV antibody indicates maternal infection, but not necessarily child infection (8)
- >12 months: Positive CMV antibody assay or culture indicates previous infection, but not necessarily active disease (8)
- Recovery of virus from tissue in symptomatic patient (GI or pulmonary tissue) indicates infection, although 1–6 weeks are required for distinctive cytopathic events to occur (8)
- Quantitative DNA polymerase chain reaction (PCR) evidences disease and can be used to monitor therapy (8)
- Direct hyperbilirubinemia >3 mg/dL (8)
- Thrombocytopenia (<75,000/mL) (7)
- Elevated liver transaminases (7)
- Viremia: PCR, antigen assays (pp65 lower-matrix protein in leukocytes), blood culture, although viremia can be present without CMV disease (5)[A]
- Serum CMV antibodies not useful; can be falsely negative due to immunosuppression (5)[C]
- Neurologic disease: CMV detected in cerebrospinal fluid or brain tissue clinches diagnosis. Enhanced by PCR analysis (5)[A].
- Head computed tomography or magnetic resonance imaging: Periventricular enhancement (CMV neurologic disease)
- Chest X-ray: Interstitial infiltrates (CMV pneumonitis)
- Bronchoscopy: Identification of CMV inclusion bodies in lung tissue in context of pulmonary infiltrates (pneumonitis)
- Endoscopic exam of GI tract: Mucosal ulcerations and colonoscopic, rectal, or esophageal biopsy (colitis, esophagitis) (5)[B]
Giant cells with basophilic inclusion bodies (owl’s eye)
- Congenital: Toxoplasmosis, rubella, herpes, syphilis
- Acquired in immunocompetent: Epstein-Barr virus (EBV) mononucleosis, viral hepatitis
- Acquired immunocompromised: Other viral, bacterial, fungal opportunistic infections
- Congenital disease: Ganciclovir 12 mg/kg IV q12h for 6 weeks (7)[B]
- Pediatric disseminated disease: IV ganciclovir (3)[A]
- CMV mononucleosis/asymptomatic viremia: No treatment (5)
- Retinitis: Effective treatments include the following and should be chosen in consultation with a specialist:
- Oral valganciclovir (for peripheral lesions) (5)[A]
- IV ganciclovir followed by oral valganciclovir (5)[A]
- IV foscarnet (5)[A]
- IV cidofovir (5)[A]
- Ganciclovir intraocular implant with oral or IV valganciclovir (5)[A]
- Treat until CD4 >100 for 3–6 months (5)[A]
- Colitis or esophagitis: IV ganciclovir or foscarnet for 21–28 days or until symptom resolution (5)[B]
- Neurologic disease: Prompt treatment with ganciclovir and foscarnet (5)[B]
- CMV disease in transplant patients: IV ganciclovir for 2–4 weeks (10)[B]
- Adult CMV retinitis: Fomivirsen (7)[A]
- Pediatric disseminated disease: Foscarnet 60 mg/kg q8h for 14–21 days (7)[A], combination ganciclovir and foscarnet (7)[B]
- CMV disease in transplant patients: Valganciclovir (10)[C]
- CMV in bone marrow transplant patients:
- Prophylaxis: Valacyclovir (10)[B]
- Preemptive: Foscarnet (10)[B]
- CMV urine culture at birth for all HIV-infected or -exposed (8)[C] and annual testing for CMV seronegative/HIV+ children (8)[C]
- Patients with CD4 counts <50 should have ophthalmologic screening every 3–6 months (8)[C].
- Patients on therapy should be followed for neutropenia, anemia, and thrombocytopenia.
Severe disease with primary infection in newborns and reactivation in immunocompromised
- Congenital: Hearing loss, mental retardation, optic atrophy, seizures, learning disabilities
- Colitis: Hemorrhage and perforation
1. Salzberger B, Hartmann P, Hanses F, et al. Incidence and prognosis of CMV disease in HIV-infected patients before and after introduction of combination antiretroviral therapy. Infection.2005;33:345–9.
2. Yinon Y, Farine D, Yudin MH et al. Cytomegalovirus infection in pregnancy. J Obstet Gynaecol Can. 2010;32:348–54.
3. Taylor GH. Cytomegalovirus. Am Fam Phys. 2003;67(3):519–24.
4. Crumpacker CS. Invited commentary: human cytomegalovirus, inflammation, cardiovascular disease, and mortality. Am J Epidemiol. 2010;172(4):372–4.
5. Benson CA, Kaplan JE, Masur H, et al. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Diseases Society of America. MMWR Recomm Rep. 2004;53:1–112.
6. Kurath S, Halwachs-Baumann G, Müller W et al. Transmission of cytomegalovirus via breast milk to the prematurely born infant: a systematic review. Clin Microbiol Infect. 2010;16:1172–8.
7. Mofenson LM, Oleske J, Serchuck L et al. Treating opportunistic infections among HIV-exposed and infected children: recommendations from CDC, the National Institutes of Health, and the Infectious Diseases Society of America. MMWR Recomm Rep.2004;53:1–92.
8. Cohen J, et al. Infectious diseases, 2nd ed. New York: Elsevier, 2004.
9. Osawa R, Singh N. Cytomegalovirus infection in critically ill patients: a systematic review. Crit Care. 2009;13:R68.
10. Razonable RR, Emery VC, 11th Annual Meeting of the IHMF (International Herpes Management Forum). Management of CMV infection and disease in transplant patients. 27–29 February 2004.Herpes. 2004;11:77–86.
11. Grosse SD, Ross DS, Dollard SC. Congenital cytomegalovirus (CMV) infection as a cause of permanent bilateral hearing loss: a quantitative assessment. J Clin Virol. 2008;41:57–62.
Patel R, Paya CV. Infections in solid-organ transplant recipients.Clin Microbiol Rev. 1997;10:86–124.
13. Sun HY, Wagener MM, Singh N. Prevention of posttransplant cytomegalovirus disease and related outcomes with valganciclovir: a systematic review. Am J Transplant. 2008;8:2111–8.
- 078.5 Cytomegaloviral disease
- 771.1 Congenital cytomegalovirus infection
- 28944009 Cytomegalovirus infection (disorder)
- 59527008 congenital cytomegalovirus infection (disorder)
- CMV mono has much less cervical adenopathy and/or splenomegaly than EBV mono in adults.
- CMV is a major cause of sensorineural hearing loss in young children.