Cytomegalovirus infection

Cytomegalovirus infection

CMV is a ubiquitous herpesvirus that rarely causes symptoms in normal hosts but may result in encephalitis with or without ventriculitis and myeloradiculitis in severely immunocompromised patients (CD4 <100 cells/μL). 

What are the symptoms of Cytomegalovirus infection

Meningitis presents typically as headache, fever, and altered mental status and is commonly diagnosed by CSF PCR. CSF may show either a lymphocytic pleocytosis (ventriculitis) or a polymorphonuclear pleocytosis (myeloradiculitis) with protein elevation. Treatment typically consists of a 3-week course of ganciclovir and/or foscarnet. 

Radiculitis presents as flaccid paralysis of the lower extremity with bowel and bladder symptoms due to characteristic involvement of the lumbosacral roots from caudal extension of meningitis.

What are the diagnostic findings of Cytomegalovirus infection

MRI shows spinal cord and nerve root edema as well as adherence of roots to the thecal sac.

How is Cytomegalovirus infection treated?

Treatment similarly involves ganciclovir and/or foscarnet. MRI in encephalitis may demonstrate a number of patterns, including subependymal ventricular enhancement.

• Cytomegalovirus (human herpesvirus 5) is a widespread virus that establishes lifelong latency after infection 
  • Immunocompetent patients are typically asymptomatic or have mild disease, and they recover uneventfully 
    • Patients who are symptomatic may experience malaise, fever, diaphoresis, myalgia, arthralgia, jaundice, lymphadenopathy, pharyngitis, and pneumonitis; full recovery may take several months 
  • Congenital cytomegalovirus infection may cause severe neurologic and other sequelae 
    • Signs of congenital infection include low birth weight, microcephaly, hepatosplenomegaly, jaundice, and seizures
  • Immunocompromised patients may develop life-threatening complications after reactivation of latent virus in brain, eyes, lungs, or gastrointestinal tract 
• Laboratory tests are required to confirm diagnosis
  • ELISA for specific IgM and IgG detection
  • Antigenemia assay for detection of pp65 antigen
  • Polymerase chain reaction for detection of viral DNA
  • Histopathology showing characteristic inclusion bodies
• Antiviral treatment is recommended only for infants with congenital disease, patients who are HIV-positive with end-organ disease, and immunosuppressed patients after transplant 
  • Standard antiviral treatment is IV ganciclovir or oral valganciclovir

Pitfalls

• Immunocompromised patients, the presentation may be subtle (eg, unexplained fever) and there may be few localizing symptoms; have a low threshold of suspicion in transplant recipients and persons with advanced HIV infection
  • Keep in mind that such patients may have more than one infection, and apparent failure to respond to therapy may signal a second source

• Cytomegalovirus (human herpesvirus 5) is a widespread virus that establishes lifelong latency after infection 
• Primary cytomegalovirus infection is typically asymptomatic, but it may be accompanied by a mononucleosis-like syndrome, presenting with prolonged fever, fatigue, malaise, and hepatitis; pharyngitis, tonsillitis, and cervical lymphadenopathy are less common than with Epstein-Barr mononucleosis 
• Secondary cytomegalovirus infection occurs primarily in immunocompromised patients, resulting from reactivation of latent infection 

Classification

• Primary cytomegalovirus infection
  • First infection of a seronegative person
    • May occur during childhood, adolescence, or adulthood
    • Congenital cytomegalovirus infection
      • Pregnant patients with cytomegalovirus infection can transmit virus to fetus; this is more likely to occur with primary infection but it may also occur with reactivation or reinfection with a second strain 
      • Congenital cytomegalovirus infection can cause premature birth and lead to birth defects, including microcephaly, hearing and vision loss, intellectual disabilities, and seizures 
• Latent 
  • Cytomegalovirus establishes lifelong latency, with no clinical signs in persons with healthy immune function
• Reactivation
  • Reactivation of latent infection in immunocompromised patients, causing pneumonia, retinitis, enteritis, encephalopathy, and polyradiculopathy; this is life-threatening, particularly in transplant patients 
• Superinfection may occur when virus is transmitted to a person previously infected with a different strain 

Diagnosis

Clinical Presentation

History

• Primary cytomegalovirus infection
  • Most acute cytomegalovirus infections are asymptomatic in immunocompetent patients 
  • Approximately 15% of patients who are symptomatic and immunocompetent require hospitalization 
  • In immunocompromised patients, the presentation may be subtle (eg, unexplained fever) and there may be few localizing symptoms; transplant recipients and people with advanced HIV infection have a low threshold of suspicion
  • Most common symptoms:
    • Malaise and fatigue (67%)
    • Diaphoresis
    • Myalgia
    • Respiratory symptoms (eg, sore throat, unproductive cough, dyspnea)
  • Less common
    • Arthralgia, headache, and nausea
  • Congenital cytomegalovirus infection:
    • Most patients (about 80%) have no clinical evidence of infection and will not have any long-term sequelae 
    • When clinically evident infection occurs, history may include premature birth, small size, and seizures 
      • Seizures are reported in 7% of cases 
• Immunocompromised patients with primary infection or reactivation:
  • Painless blurred vision, unilateral floaters, light flashes, and scotoma 
  • Dyspnea, cough, and chest pain 
  • Gastrointestinal symptoms are rare (eg, odynophagia, dysphagia, epigastric pain, diarrhea) 
  • Confusion, disorientation, cognitive decline, nausea, vomiting, and headache may occur 

Physical examination

• Primary cytomegalovirus infection clinical signs may include:
  • In adolescents and adults:
    • Fever (46% of cases) 
    • Lymphadenopathy 
    • Jaundice 
    • Pharyngitis 
  • Congenital cytomegalovirus infection clinical signs:
    • 10% of patients have clinical signs apparent at birth
      • Petechiae, jaundice, and hepatosplenomegaly are most common 
      • About half of affected children have low birth weight and/or microcephaly 
    • Hearing loss (detected through newborn hearing screen) 
• Reactivation in immunocompromised patients
  • Retinal exudate with flame hemorrhages; “brushfire” appearance is typical in patients with retinitis
  • Fever is a common feature
  • Dry rales may be audible in patients with cytomegalovirus pneumonia
  • Hepatosplenomegaly and/or abdominal tenderness may be present
  • Focal neurologic deficits, altered mental status, and seizures occur rarely

Causes

• Transmission occurs through direct contact with infected body fluids 
• People positive for cytomegalovirus, with or without symptoms, intermittently shed viral particles in urine, saliva, blood, tears, semen, and breast milk 
• Infection usually occurs through intimate personal contact, but it may also be transmitted by transfusion or transplant
• 30% to 40% of pregnant patients with primary infection transmit virus to fetus 
  • Risk of transmission is 30% to 40% in first and second trimesters 
  • Risk of transmission is 40% to 70% in third trimester 
• In previously infected pregnant patients who are infected with a different strain during pregnancy, risk of transmission to fetus is less than 5% 
• Infants can also acquire cytomegalovirus infection during birth or through breast milk, but unlike infection acquired in utero, it generally follows a benign course without significant sequelae 

Risk factors and/or associations

Age

• People of all ages can contract cytomegalovirus infection
  • In the United States:
    • About 33% of all 5-year-old children have been infected
    • More than 50% of all 40-year-old people have been infected
• Low-birth-weight premature infants with congenital cytomegalovirus infection have increased risk for developing complications of the infection 

Sex

• Ratio of male to female symptomatic patients has been reported as 1.2:1 

Ethnicity/race

• In the United States, incidence of seropositivity is highest in Mexican Americans, followed by non-Hispanic Black people; reason for this distribution is unknown 

Other risk factors/associations

• Higher seroprevalence is associated with low income and crowded living conditions 
• Group day care is associated with higher rates of infection in children and their mothers 
• Immunocompromised patients are at risk for life-threatening reactivation of latent cytomegalovirus infection 
  • Before the HAART era began, 21% to 45% of patients positive for HIV experienced cytomegalovirus disease 
  • Patients receiving immunosuppressive therapy after transplant
    • Degree of risk and severity of disease vary by type of transplant (eg, solid organ versus hematopoietic stem cells) and by immunosuppressive regimen
• Transplant recipients with allograft rejection are at higher risk for clinical cytomegalovirus infection 

Diagnostic Procedures

Primary diagnostic tools

• Only laboratory testing can conclusively confirm an acute or previous cytomegalovirus infection 
  • Available tests include viral culture, polymerase chain reaction, antigen detection, antibody testing (IgM and IgG), and histology (showing characteristic changes in tissue)
  • Polymerase chain reaction to detect viral DNA can be performed on whole blood, WBCs, plasma, tissue biopsies, urine, cerebrospinal fluid, bronchoalveolar lavage fluid, or amniotic fluid 
  • ELISA for antibody detection is used for patients aged 12 months or older, although clinical application of this test is limited in view of the accuracy and availability of polymerase chain reaction and antigen tests for cytomegalovirus
    • Presence of IgM indicates recent primary infection, reactivation infection, or superinfection with a new strain
    • Presence of IgG in the absence of IgM indicates past (latent) infection
    • When both IgM and IgG are present, IgG avidity testing may help to distinguish recent infection from reactivation or superinfection
      • IgG antibodies with low avidity to virus indicate recent infection (ie, within 3-4 months), whereas those with high avidity suggest infection having occurred more than 3 months previously 
      • Most common clinical application is in pregnant patients who are seropositive to assess risk of congenital infection in fetus based on estimates of whether virus was acquired in remote past (lower risk) or recently (higher risk)
  • Antigenemia assay through monoclonal antibody to matrix protein pp65 
    • Can be used to guide preemptive therapy for cytomegalovirus disease in solid organ transplant recipients
  • Histopathology in conjunction with immunohistochemistry of biopsy samples 
    • Used to confirm tissue-invasive cytomegalovirus disease (eg, gastrointestinal and transplant infection) 
  • Viral culture can be performed, but growth is slow, clinical significance is unclear in many cases, and absence of growth does not rule out infection 
    • Necessary for drug resistance assessment
• Decision to initiate testing depends on severity of symptoms and immune status of patient
  • There are no guideline recommendations to test nonpregnant immunocompetent persons with symptoms compatible with cytomegalovirus diagnosis 
    • May be clinically appropriate in work-up of heterophile-negative mononucleosis or unexplained hepatitis
  • Testing is done routinely in some immunocompromised patients
    • Transplant recipients are assessed for pre- and posttransplant cytomegalovirus status; organ donors are also routinely tested 
      • Serial quantitative testing may be used to determine need for antiviral therapy
    • Patients with HIV/AIDS are tested in the evaluation of clinical (end-organ) disease (eg, pneumonitis, esophagitis, colitis, retinitis) 
      • Patients with HIV who are at high risk for cytomegalovirus infection are presumed to be seropositive, but baseline testing may be done in low-risk patients (ie, those with no IV drug use, no contact with men who have sex with men, and no contact with children who attend day care)
  • There are no guidelines for testing newborns, but primary care clinicians should consider testing if history or clinical findings suggest the possibility of infection 
• Additional testing
  • May be determined by clinical setting and suspected site of infection 
    • CBC and liver function for a clinical syndrome compatible with diagnosis of mononucleosis
    • Imaging (chest radiograph or CT) and bronchoscopy for pneumonitis
    • MRI of spine and cerebrospinal fluid analysis for suspected polyradiculopathy
    • Endoscopy for esophagitis or colitis
  • Additional tests to detect potential complications associated with congenital disease include:
    • Cerebral ultrasonography, CT, or MRI, recommended in suspected and confirmed cases of congenital infection 
    • Audiologic evaluation, to assess for sensorineural hearing loss 
  • If antiviral therapy is indicated, obtain baseline CBC and renal function tests to aid in monitoring for drug toxicity

Laboratory

• Polymerase chain reaction
  • In peripheral blood, routinely used to diagnose and monitor invasive cytomegalovirus infection in immunocompromised patients
  • In cerebrospinal fluid, used to diagnose cytomegalovirus encephalitis or polyradiculopathy
  • In aqueous or vitreous humor, used to confirm a clinical diagnosis of cytomegalovirus retinitis 
  • In saliva for newborns
    • Urine testing is recommended to confirm a positive saliva test result in newborns , whose saliva might have become contaminated with maternal cytomegalovirus through the birth canal or breast milk
    • Test should be conducted within 3 weeks after birth to distinguish congenital from acquired cytomegalovirus infection
• ELISA
  • Detection of specific IgM confirms acute primary infection or reactivation of a latent infection
    • More than 300 units/mL is considered evidence of recent infection
  • Detection of specific IgG confirms current or previous infection
    • Immediately after primary infection, low-affinity IgG molecules are produced, which mature to high-affinity IgG after 2 to 4 months; avidity can be detected and can indicate timing of infection
    • In infants aged 12 months or younger, maternal IgG can cause a false-positive result
  • Diagnosis of primary infection is based on positive IgM result and low-avidity IgG result, or it can be confirmed by paired IgG results 3 months apart (first test negative, second test positive)
• Additional laboratory tests
  • Viral culture
    • Procedure takes 3 weeks to complete, with low sensitivity but high specificity
    • Shell vial centrifugation assay
      • Improves turnaround time compared with standard culture
  • Antigenemia assay
    • Detects pp65 antigen in cytomegalovirus-infected peripheral blood WBCs
    • Semiquantitative
  • Liver function tests
    • Elevated values suggest liver injury or hepatitis
    • Not specific to cytomegalovirus infection
  • CBC
    • Mononucleosis is characterized by relative lymphocytosis (more than 50%) and presence of atypical lymphocytes 
    • May detect thrombocytopenia
    • Nonspecific

Imaging

• Cerebral ultrasonography and CT in suspected and confirmed cases of congenital infection 
  • May show calcification, neuronal migration defects, and myelination abnormalities, which are common complications of cytomegalovirus disease 
• MRI
  • Nonspecific white matter abnormalities may be present in cytomegalovirus encephalitis
• Chest radiography
  • Interstitial or ground-glass infiltrates are characteristic of cytomegalovirus pneumonitis 

Functional testing

• Audiology
  • Sensorineural hearing loss is progressive and may not be present at birth; therefore, regular testing throughout childhood is required 
    • Otoacoustic emission test to assess peripheral function 
    • Auditory brainstem response test to assess auditory nerve and brainstem 

Procedures

• Collection of a sample of cells for identification and analysis
  • Excisional biopsy: an entire lump or suspicious area is removed
  • Incisional biopsy: a sample of tissue is removed with preservation of the histologic architecture of the sample tissue
  • Needle biopsy: a sample of tissue or fluid is removed with a needle without preservation of the histologic architecture of the sample tissue cells
• Viremia is not always present in end-organ cytomegalovirus disease; therefore, end-organ biopsies may be required 
  • In transplant rejection, a biopsy might find acute cytomegalovirus disease in the transplanted organ 
  • Biopsy specimens can be obtained during endoscopy to diagnose cytomegalovirus esophagitis and colitis
  • Brain biopsies can be used to diagnose cytomegalovirus encephalitis, but cerebrospinal fluid testing is preferred 
• Uncontrolled bleeding diathesis
• Polymerase chain reaction may be applied to detect cytomegalovirus in tissue
• Characteristic histopathologic changes (inclusion bodies)
  • Sensitivity improved by immunohistochemical staining 
• Insertion of a hollow-bore needle between the vertebral bodies into the subarachnoid space to obtain a specimen of cerebrospinal fluid or to measure opening pressure
• Suspected meningitis, encephalitis, or infectious polyradiculopathy
• Uncontrolled coagulopathy
• Skin infection at site of needle insertion
• Patient at risk of brain herniation
  • Best predictors of precipitating herniation (even with normal CT result) include: 
    • Deteriorating level of consciousness (particularly to a Glasgow Coma Scale score of 11 or less)
    • Brainstem signs (eg, pupillary changes, abnormal posturing, irregular respirations)
    • Very recent seizure
• Post–lumbar puncture headache occurs in 32% of patients who undergo lumbar punctures and usually resolves within 10 days 
• Back pain
• Radicular injury
• Infection
  • Epidermal abscess
  • Meningitis
  • Diskitis
  • Vertebral osteomyelitis
• Epidural hematoma
• Cerebral herniation
• Epidermoid tumor formation
• Demonstration of cytomegalovirus by polymerase chain reaction confirms diagnosis
• Passage of fiberoptic endoscope per rectum to terminal ileum (through ileocecal valve), allowing direct visualization of colonic lumen and mucosa
  • Biopsy specimens can be obtained if abnormalities are seen
• Typically performed by gastroenterologist or surgeon
• Requires adequate bowel preparation and conscious (moderate) sedation
• Suspected colitis
• Signs or symptoms of peritoneal irritation
• Inadequate bowel preparation
• Unstable cardiorespiratory condition
• Obstructing lesion
• Perforation
• Hemorrhage
• Ulceration and erosion are common findings in cytomegalovirus colitis 
• Biopsies of abnormal areas can be used for: 
  • Polymerase chain reaction to detect viral DNA
  • ELISA to detect viral antigens and specific antibodies
  • Histopathology to detect characteristic inclusion bodies
• A fiberoptic endoscopic device is inserted into esophagus for visual inspection of mucosal surfaces
• Biopsy specimens can be obtained
• Suspected esophagitis
• Bleeding diathesis
• Bleeding
• Perforation
• Aspiration pneumonia
• Cardiac arrhythmias
• Hypertension, hypotension, and/or vasovagal reaction
• Finds single or multiple ulcers, typically in distal esophagus, in cytomegalovirus esophagitis
• Rarely, giant ulcers (larger than 2 cm) have been observed
• Tissue samples from affected areas can be used for:
  • Polymerase chain reaction to detect viral DNA
  • ELISA to detect viral antigens and specific antibodies
  • Histopathology to detect characteristic inclusion bodies

Other diagnostic tools

• Dilated-pupil funduscopic examination
  • Experienced ophthalmologist can identify characteristic changes in retina 

Differential Diagnosis

Most common

• Differential diagnosis depends on clinical presentation
• For primary infection, which most often presents as a mononucleosis-like syndrome:
  • Epstein-Barr virus infection
    • Most common cause of mononucleosis
    • Cytomegalovirus infection may present similarly to classic Epstein-Barr mononucleosis, with fever, relative lymphocytosis with atypical lymphocytes, and elevated liver transaminase levels
    • Cytomegalovirus infection is less likely to present with the pharyngitis and posterior cervical lymphadenopathy that is common in Epstein-Barr virus infection
    • Diagnosis is confirmed by demonstration of heterophile antibodies or IgM antibody to viral capsid antigen
  • Toxoplasmosis
    • Infection with the parasite Toxoplasma gondii
    • Acute infection may mimic mononucleosis
    • Nonspecific symptoms are similar to those of cytomegalovirus infection, with fever, myalgia, and lymphadenopathy; therefore, a distinction based on clinical presentation is difficult
    • Diagnosis is based on laboratory test results
      • Serologic testing for specific IgM and IgG
  • Hepatitides
    • Infection with a hepatitis virus
    • Symptomatic cytomegalovirus infection is often associated with hepatitis; nausea, vomiting, abdominal discomfort, hepatosplenomegaly, and jaundice may occur in both cytomegalovirus infection and other forms of viral hepatitis
    • Pneumonitis occasionally occurs in primary cytomegalovirus infection but is unusual in other forms of viral hepatitis
    • Diagnosis is based on laboratory test results
      • Serologic tests can detect hepatitis virus antigens and specific antibodies
      • Polymerase chain reaction can detect viral DNA and RNA
  • Acute HIV infection 
    • A mononucleosis-like syndrome may occur within days to weeks of acquiring HIV infection
    • Nonspecific signs and symptoms are similar to those of cytomegalovirus infection, so a distinction based on clinical presentation is challenging 
      • Common signs and symptoms include fever, fatigue, myalgia, arthralgia, diaphoresis, lymphadenopathy, pharyngitis, nausea, and vomiting 
      • Additional manifestations may include diarrhea and oral and genital ulcers 
    • Diagnosis is based on laboratory test results
      • Fourth-generation testing includes p24 antigen and antibodies to HIV-1 and HIV-2
      • Nucleic acid test is done when results are equivocal
• Congenital cytomegalovirus infection
  • Congenital infections due to TORCH agents (eg, Toxoplasma gondii, Treponema pallidum, rubella virus, cytomegalovirus, HSV) present with a similar syndrome of hepatosplenomegaly, petechiae, chorioretinitis, and other abnormalities 
    • Treponema pallidum infection
      • May also be associated with glaucoma
      • Diagnosed with VDRL test or rapid plasma reagin test on infant serum, confirmed by a treponemal test such as fluorescent antibody absorption or microhemagglutination
    • Toxoplasmosis
      • May also be associated with either hydrocephalus or microcephaly and the presence of intracranial calcifications
      • Diagnosed by IgM and IgA capture enzyme immunoassay on infant serum; if a lumbar puncture is done, polymerase chain reaction may be performed on cerebrospinal fluid
    • Rubella
      • May also be associated with cardiac anomalies, cataracts, microphthalmia, and hearing deficits
      • Diagnosed by detection of IgM antibodies to rubella virus in infant serum, a rise in IgG antibodies in the months after birth, or demonstration of viral RNA in blood, urine, nasopharyngeal secretions, or cerebrospinal fluid
    • Herpes simplex
      • Skin lesions may have a vesicular component; may also be associated with myocarditis, hydrocephalus or microcephaly, encephalitis, cataracts, and hearing deficit
      • Diagnosed by polymerase chain reaction on urine, cerebrospinal fluid, or swabs of nasopharynx, rectum, open skin lesions, and conjunctivae
  • Congenital infection with parvovirus B19
    • Like congenital cytomegalovirus infection, may present at birth with a petechial rash, hepatosplenomegaly, and retinal abnormalities
    • Unlike in congenital cytomegalovirus infection, microcephaly and intracranial calcifications are not characteristic
    • Polymerase chain reaction of blood or amniotic fluid may find viral DNA
  • Congenital Zika virus infection
    • Like congenital cytomegalovirus infection, may present with microcephaly and intracranial calcifications
    • Unlike cytomegalovirus infection, acquired from infected mosquitoes or through sexual exposure to an infected partner; a history of residence in or travel to an endemic area by the mother or her sexual partner suggests the possibility
    • Diagnosed with serum IgM antibody to Zika virus and Zika RNA nucleic acid test on serum and urine
• Reactivation infection:
  • Cytomegalovirus encephalitis
    • Toxoplasmosis
      • Parasitic infection characterized by cyst formation and prolonged latency, with reactivation during immunosuppression states
      • Like cytomegalovirus encephalitis, may present in immunocompromised patients with fever, confusion, focal neurologic deficit, and seizures
      • Unlike cytomegalovirus encephalitis, usually presents as well-defined mass lesions seen on CT or MRI
      • Diagnosis can be made by polymerase chain reaction on cerebrospinal fluid or characteristic findings on tissue obtained by stereotactic needle biopsy
    • Progressive multifocal leukoencephalopathy
      • Severe, progressive form of encephalitis caused by reactivation of JC virus, primarily in advanced HIV infection
      • Presents with altered mental status, gait disturbance, focal neurologic signs, and seizures
      • May be difficult to distinguish clinically from cytomegalovirus encephalitis
      • Diagnosis may be made by distinctive MRI findings or demonstration of JC virus in cerebrospinal fluid by polymerase chain reaction
  • Cytomegalovirus retinitis
    • Toxoplasma chorioretinitis
      • Like cytomegalovirus, occurs primarily in patients with severe T-cell immunodeficiency and presents as painless visual defect
      • Funduscopic examination by an experienced ophthalmologist, with supporting serologic testing, is usually sufficient; polymerase chain reaction on aqueous or vitreous humor can be performed if confirmation is needed
  • Cytomegalovirus esophagitis
    • Candidal esophagitis
      • Like cytomegalovirus esophagitis, presents with dysphagia and/or odynophagia in an immunocompromised host
      • In some patients, a clue to the diagnosis is the presence of oral thrush
      • In other cases, esophagoscopy is required to distinguish the 2 conditions by visual inspection and/or biopsy; some patients have concurrent infection with both agents
    • Herpetic esophagitis
      • Due to primary or reactivated herpes simplex
      • Like cytomegalovirus esophagitis, presents with dysphagia and/or odynophagia in an immunocompromised host
      • Presence of oral and/or perioral ulcerations may provide a clue to the diagnosis
      • Herpes simplex can be diagnosed by direct fluorescent antigen or polymerase chain reaction and has characteristic histopathologic features (eg, multinucleated giant cells)
    • Mucositis
      • Inflammatory condition commonly associated with cancer chemotherapy and characterized by mucosal ulceration
      • Like cytomegalovirus esophagitis, presents with dysphagia and/or odynophagia in an immunocompromised host
      • Diagnosis of exclusion in patients who have received chemotherapy and who do not have evidence of an infectious cause
  • Cytomegalovirus colitis
    • Clostridium difficile colitis
      • Like cytomegalovirus colitis, presents with fever, diarrhea, and abdominal pain
      • Diarrhea tends to be more profuse in Clostridium difficile colitis
      • Distinction can be made by demonstrating evidence of Clostridium difficile in stool specimen (eg, enzyme immunoassay, polymerase chain reaction) or by visualizing pseudomembranes on colonoscopy
    • Inflammatory bowel disease
      • Involves colitis
        • Crohn disease
        • Ulcerative colitis
      • Noninfectious cause of severe, debilitating diarrhea, often accompanied by abdominal pain and fever
      • Onset does not usually occur in the context of immunocompromise, unlike in cytomegalovirus colitis
      • Distinction can be made on colonoscopic visualization and biopsy
    • Mucositis
      • Inflammatory condition of colonic mucosa usually associated with cancer chemotherapy
      • May cause diarrhea and fever
      • Diagnosis of exclusion in patients who have received chemotherapy and who do not have evidence of an infectious cause
  • Cytomegalovirus pneumonia
    • Pneumonia due to other viruses
      • Immunocompromised patients may develop pneumonia due to other viruses (eg, influenza virus, respiratory syncytial virus)
      • These may appear clinically very similar to cytomegalovirus pneumonia
      • Influenzal pneumonia may be suggested by seasonality (winter, spring) in temperate climates and by presence of rhinorrhea, sore throat, and severe myalgias
      • Influenza and respiratory syncytial virus infection can be diagnosed by rapid antigen testing or polymerase chain reaction
    • Pneumocystis pneumonia
      • Pneumonia caused by Pneumocystis jirovecii, usually in patients with advanced HIV infection, in those with severe immunosuppression after organ transplant, or after chemotherapy for certain lymphomas
      • Radiographic appearance and clinical course (which is often very severe) are similar to those of cytomegalovirus pneumonia in these settings; occasionally, the 2 pathogens are found concurrently
      • Diagnosis is made by bronchoalveolar lavage or bronchoscopic biopsy

Treatment Goals

• Reduce viral load
• Prevent end-organ complications
• Relieve symptoms

Disposition

Admission criteria

Immunocompromised patients with end-organ disease often require hospitalization for diagnosis and IV antiviral treatment

Infants with severe congenital cytomegalovirus disease require hospital admission for evaluation and treatment 

Criteria for ICU admission

• Patients with severe pneumonitis may require ICU care for close monitoring and possibly mechanical ventilation

Recommendations for specialist referral

• Infectious disease specialist to select and manage antiviral therapy
• Gastroenterologist or pulmonologist for fiberoptic visualization and biopsy, as well as appropriate specialized supportive care (eg, ventilator management, nutritional support)
• Ophthalmologist for dilated-pupil funduscopic examination, intravitreal injection of medication, and serial follow-up examinations
• Neurologist and/or neurosurgeon
  • In congenital cytomegalovirus infection, to evaluate extent of neurologic impairment and guide therapy to optimize development
  • In case of suspected cytomegalovirus encephalitis, for diagnostic confirmation (including brain biopsy if required) and supportive management (eg, seizure control)
• Otolaryngologist
  • In confirmed congenital cytomegalovirus infection
    • For auditory assessment if neonatal hearing test results are negative; sensorineural hearing loss is common, but it may not be present at birth, and more audiologic testing is needed later

Treatment Options

No treatment is recommended for mmunocompetent patients, including those who are pregnant 

Studies have shown beneficial effects of antiviral therapy in infants with central nervous system involvement, including sensorineural hearing loss and serious end-organ disease 

A European Expert Consensus Statement recommends that babies with evidence of central nervous system disease should receive antiviral treatment, preferably for 6 months; the statement also recommends treatment of babies with evidence of life-threatening disease or severe single-organ disease or multiorgan involvement, although duration of therapy is uncertain 

• Oral valganciclovir is the drug of choice 
• Treatment is not recommended for babies with no clinical/laboratory findings consistent with cytomegalovirus disease 

Antiviral therapy is recommended for patients with advanced HIV infection and clinical evidence of cytomegalovirus infection 

Antiviral therapy is also recommended for patients who are immunosuppressed after solid-organ transplant or hematopoietic stem cell transplant

IV ganciclovir is used for initial treatment of cytomegalovirus disease in most cases, followed by oral valganciclovir to complete treatment and for long-term maintenance therapy (secondary prophylaxis) in patients with continued immune dysfunction 

• Initial therapy with valganciclovir appears to be as effective as IV ganciclovir in patients with solid-organ transplants who have mild to moderate disease 

Foscarnet and cidofovir are alternate agents for patients in whom ganciclovir cannot be used owing to viral resistance or adverse effects; foscarnet is sometimes used in conjunction with ganciclovir in severe infections (eg, encephalitis) 

High-titer cytomegalovirus immunoglobulin may be used in conjunction with antiviral agents for the treatment of severe infection (eg, pneumonia in hematopoietic stem cell transplant recipients) 

Drug therapy

• Antiviral therapy
  • IV ganciclovir
    • Cytomegalovirus encephalitis
      • Ganciclovir Solution for injection; Neonates: 6 mg/kg/dose IV every 12 hours for 6 weeks.
      • Ganciclovir Solution for injection; Infants and Children: 5 mg/kg/dose IV every 12 hours with IV foscarnet until symptomatic improvement followed by secondary prophylaxis (chronic maintenance therapy).
      • Ganciclovir Solution for injection; Adults and Adolescents: 5 mg/kg/dose IV every 12 hours with IV foscarnet; optimal duration not established.
    • Cytomegalovirus retinitis
      • Intravenous dosage:
        • Ganciclovir Solution for injection; Infants† and Children†: 5 mg/kg/dose IV every 12 hours for 14 to 21 days; may increase dose to 7.5 mg/kg/dose IV every 12 hours if needed. Follow with chronic maintenance therapy.
        • Ganciclovir Solution for injection; Adults: 5 mg/kg/dose IV every 12 hours for 14 to 21 days. Follow with chronic maintenance therapy.
      • Intravitreal dosage:
        • Ganciclovir Sodium Solution for injection; Adults and Adolescents: For patients with immediate sight-threatening lesions (i.e., within 1,500 microns of the fovea), give 2 mg intravitreal injections once weekly until lesion inactivity is achieved. Intravitreal injections are given to achieve rapid high intraocular drug concentrations and should be administered in combination with systemic induction therapy 
    • Cytomegalovirus esophagitis or colitis
      • Ganciclovir Solution for injection; Infants and Children: 5 mg/kg/dose IV every 12 hours for 14 to 21 days for patients with disseminated disease; may increase to 7.5 mg/kg/dose IV every 12 hours if needed.
      • Ganciclovir Solution for injection; Adolescents: 5 mg/kg/dose IV every 12 hours; may switch to PO valganciclovir when able to tolerate PO; treat for 21 to 42 days or until resolution of signs and symptoms.
      • Ganciclovir Solution for injection; Adults: 5 mg/kg/dose IV every 12 hours is recommended by the HIV guidelines for 21 to 42 days or until resolution of signs and symptoms; when patient can tolerate PO, switch to oral valganciclovir to complete therapy. Maintenance therapy is usually not necessary, but should be considered after relapse.
    • Cytomegalovirus pneumonitis
      • Ganciclovir Solution for injection; Infants and Children: 5 mg/kg/dose IV every 12 hours for 14 to 21 days. For HIV-infected patients with disseminated disease, may increase to 7.5 mg/kg/dose IV every 12 hours if needed. 5 mg/kg/dose IV every 12 hours for 14 days, then 5 mg/kg/dose IV once daily for 5 to 7 days/week for 3 weeks was used in 3 patients after allogenic stem cell transplant.
      • Ganciclovir Solution for injection; Adolescents: 5 mg/kg/dose IV every 12 hours; 5 mg/kg/dose IV every 12 hours for 14 days, then 5 mg/kg/dose IV once daily for 5 to 7 days/week for 3 weeks was used in 3 patients after allogenic stem cell transplant.
      • Ganciclovir Solution for injection; Adults: Experience is limited in HIV-infected patients; 5 mg/kg/dose IV every 12 hours is suggested by HIV guidelines; optimal duration not established. 2.5 mg/kg/dose IV every 8 hours for 14 days, with CMV-IVIG (on days 1, 2, 7, and 14), was studied in an open BMT trial. Patients with continued symptoms got 5 mg/kg/dose IV once daily for 14 more days and CMV-IVIG on day 21; 12 of 25 patients died a median of 12 days after treatment. In another trial, 2.5 mg/kg/dose IV every 8 hours for 20 days, then 5 mg/kg/dose IV once daily 3 to 5 times per week for 20 more doses with IVIG was also studied in BMT patients; combination therapy was successful in 7 of 10 patients.
    • For infants with congenital cytomegalovirus infection
      • Although not approved by the FDA for use in children, its use in this setting has been shown to be safe and effective and is supported by guidelines 
      • Ganciclovir Solution for injection; Neonates and Infants: 6 mg/kg/dose IV every 12 hours for 6 weeks; may adjust dose if neutropenia develops. If a neonate is confirmed HIV-positive during the 6-week treatment course, some experts recommend extending treatment beyond 6 weeks.
  • Oral valganciclovir
    • Cytomegalovirus retinitis, esophagitis, or colitis
      • Valganciclovir Hydrochloride Oral tablet; Adults: 900 mg PO twice daily for 21 to 42 days or until symptoms have resolved in patients with mild disease who are able to tolerate oral therapy.
    • For infants with congenital cytomegalovirus infection
      • Valganciclovir Hydrochloride Oral solution; Neonates: 16 mg/kg/dose PO every 12 hours for at least 6 weeks; treatment for 6 months may lead to improved audiologic/neurodevelopmental outcomes.
      • Valganciclovir Hydrochloride Oral solution; Infants: 16 mg/kg/dose PO every 12 hours for at least 6 weeks; treatment for 6 months may lead to improved audiologic/neurodevelopmental outcomes.

Comorbidities

• HIV infection
  • Low CD4 count leads to a reactivation of latent cytomegalovirus infection
  • In patients with HIV, cytomegalovirus complications are best prevented by HAART, maintaining CD4 count at more than 100 cells/mm³ 
  • Prophylactic antiviral therapy is not recommended

Special populations

• Immunocompromised patients and who have received transplants may be treated with prophylactic antiviral therapy to prevent cytomegalovirus end-organ diseases 

Monitoring

• Clearance rates of ganciclovir and valganciclovir are directly proportionate to renal function, which must be closely monitored 
  • In infants, also monitor for development of neutropenia 
• Immunosuppressed patients after solid-organ transplant or hematopoietic stem cell transplant are monitored for presence of cytomegalovirus infection
  • Quantitative nucleic acid tests or pp65 antigen levels in blood samples are preferred for monitoring 
  • Monitoring may be used to prompt preemptive treatment in patients who are not receiving prophylaxis
  • Weekly monitoring during treatment determines when antiviral drugs may be discontinued or switched to prophylactic doses (generally 2 weeks after viral load is undetectable) 
• Recommended follow-up of babies with congenital cytomegalovirus infection
  • Audiology assessment is recommended every 3 to 6 months in the first year, then every 6 months until 3 years of age and then every 12 months until 6 years of age 
  • Pediatric infectious disease clinic review recommended annually until at least 2 years of age 
  • Neurodevelopmental follow-up is suggested at 1 and 2 years of age, ideally with formal neurodevelopmental assessment 
  • Ophthalmic follow-up is recommended annually at least until children can talk, in those with clinically detectable disease at birth; not recommended in those without clinically detectable disease 

Complications

• Congenital cytomegalovirus infection
  • 40% to 60% of patients have long-term sequelae
    • Sensorineural hearing loss in 50% of symptomatic infants and 10% of asymptomatic infants 
      • Arrange for regular hearing tests in infants to identify emerging hearing loss; late-onset hearing loss is possible
    • Developmental disability with IQ less than 70 (50% of cases) 
    • Chorioretinitis may result in permanently impaired vision
    • Hepatitis usually resolves
    • Microcephaly in 50% of symptomatic infants and 10% of asymptomatic infants 
• Reactivation of latent cytomegalovirus infection in immunocompromised patients with HIV or immunosuppressed patients after solid-organ transplant or hematopoietic stem cell transplant
  • Encephalitis
    • Late-stage complication of immunosuppression
    • Rapid cognitive decline, often with permanent deficit despite treatment
  • Retinitis
    • Before the introduction of HAART (mid-1990s), about 30% of all patients with HIV developed cytomegalovirus retinitis; incidence is currently down to 1.5% 
    • Can initially be asymptomatic or with floaters and visual field defects
    • Cytomegalovirus retinitis can lead to permanently impaired vision and blindness
    • Rapid recognition and treatment of retinitis may save vision
  • Colitis develops in 5% to 10% of patients with HIV and 2% of transplant patients
    • Characterized by fever, weight loss, anorexia, abdominal pain, debilitating diarrhea, and malaise
    • Can cause colon perforation and acute abdomen
  • Among recipients of hematopoietic stem cell transplant, pneumonia develops in 1% to 6% of autologous transplant recipients and in 10% to 30% of allogeneic transplant recipients
    • 50% mortality 
  • Esophagitis
    • Fairly common complication in patients with HIV/AIDS, owing to immunosuppression; similar in incidence to colonic disease
    • May result in weight loss, aspiration pneumonia, or rarely esophageal perforation

Prognosis

• Primary cytomegalovirus infection in immunocompetent patients
  • Symptoms can last 1 to 32 weeks
• Cytomegalovirus infection in immunocompromised patients
  • Prognosis varies greatly depending on degree and duration of immunosuppression and site of infection
  • Immunosuppressive therapy associated with hematopoietic stem cell transplant poses the highest risk for severe life-threatening infection; pneumonia carries the highest site-specific mortality
• Congenital cytomegalovirus infection
  • 5% of symptomatic newborns die during the newborn phase 

Screening

At-risk populations

• Transplant donors and recipients are screened serologically (IgG ± IgM) 

Screening tests

• No general screening is recommended, including for pregnant patients 
• Newborn hearing screens, while not specific for cytomegalovirus, may serve as a proxy for identifying children with otherwise undetected congenital cytomegalovirus infection 

Prevention

• Primary infection
  • Regular hand washing, in particular after contact with bodily fluids, is recommended to prevent primary infection 
  • Health care professionals should strictly follow general hygiene algorithms 
  • No vaccine is available yet 
  • Seronegative transplant recipients should be paired with seronegative donors, if possible
• Congenital infection
  • No strategies for prevention have been studied enough to document efficacy 
  • Educate pregnant patients about how cytomegalovirus infection is acquired and about precautions to avoid it; this education is mandated in some jurisdictions
• Reactivation infection
  • For patients with HIV, medical prophylaxis is aimed at maintaining CD4 count at more than 100 cells/mm³ 
  • For transplant recipients: 
    • There are 2 approaches to preventing clinical cytomegalovirus infection, and controversy remains as to the best approach, which may vary with the transplanted organ and the serologic status of donor and recipient:
      • Antiviral prophylaxis with valganciclovir, in which half of the treatment dose is administered for the period of most intensive immunosuppression
      • Preemptive therapy, in which patients are monitored weekly for appearance of cytomegalovirus in the blood by pp65 or quantitative cytomegalovirus DNA, and treatment is initiated at a specified threshold
        • Specific thresholds are not universally defined; they depend on individual laboratory experience

Seek Additional Information

CDC: Cytomegalovirus (CMV) and Congenital CMV Infection: About CMV. CDC website. Updated April 29, 2020. Accessed June 22, 2020. https://www.cdc.gov/cmv/overview.html
Cross Reference