Cytomegalovirus (CMV) is a member of the herpes virus family. Infection is worldwide and usually asymptomatic. CMV may cause a mononucleosis infection in healthy individuals but can cause severe illness in congenital infection and in an immunocompromised host.

• After initial infection, human cytomegalovirus remains in a persistent state within the host. Immunity against the virus controls replication, although intermittent viral shedding can still take place in the immunocompetent person.
• Complications are therefore mainly seen if the immune system is immature, or is suppressed by drug treatment or co-infection with other pathogens.¹
• Clinically significant CMV disease frequently develops in patients immunocompromised as a result of HIV, solid-organ transplantation and bone-marrow transplantation.²
• Primary CMV infection of the immunocompromised host may cause disease in almost every organ of the body, e.g. pneumonia, hepatitis, encephalitis, colitis, uveitis, retinitis and neuropathy.

Epidemiology

• 50-80% of all adults are infected with CMV.
• Infection may be passed via body fluids, e.g. kissing, sexual intercourse, blood transfusion, or by tissue donation.

Infection in immunocompetent hosts

CMV is usually an asymptomatic infection. In immunocompetent individuals, symptomatic disease usually manifests as a mononucleosis syndrome.²

• Infection is usually asymptomatic in infants and children.
• In adolescence and early adulthood, primary infection is also usually asymptomatic but may cause a mild flu-like illness. CMV may also produce a mononucleosis syndrome similar to Epstein-Barr virus (causing a febrile illness with splenomegaly, impaired liver function, and abnormal lymphocytes in the blood), but without characteristic pharyngitis and lymphadenopathy.
• Complications of infection are uncommon in immunocompetent hosts, but include:
  • Guillain-Barré syndrome
  • Meningoencephalitis
  • Pericarditis
  • Myocarditis
  • Thrombocytopenia
  • Haemolytic anaemia
  • Gastrointestinal ulceration

Hepatitis

• Hepatitis is commonly observed in patients with primary CMV infection and mononucleosis. Liver function tests may show mild transient increases in liver enzymes, but elevations in alkaline phosphatase and bilirubin are much less common. Prognosis is excellent in immunocompetent individuals.
• CMV hepatitis may also cause granulomatous involvement, but again usually with complete recovery.³

Pneumonia

• Immunocompetent:
  • Pneumonia may occasionally occur with CMV mononucleosis.
  • Usually, pneumonia is found on the chest X-ray but is of no clinical significance, and rapidly resolves with the disappearance of the primary infection.
• Immunocompromised:
  • The most common clinical presentation is fever and shortness of breath, associated by an interstitial infiltrate on the chest X-ray.
  • Pneumonia is particularly severe after marrow or solid organ transplant, and then has a high mortality.
  • The differential diagnosis in patients who are immunocompromised includes pneumocystis pneumonia, pulmonary haemorrhage, drug toxicity, lymphoma and other infections.

Congenital cytomegalovirus disease

• CMV is the most common congenitally acquired infection in infants.
• Placental infection occurs more commonly during primary infection. Symptomatic congenital infection is more likely to occur in babies of women without pre-existing immunity to CMV.
• CMV may be found in both cervical secretions and in breast milk.
• Most children infected in utero appear healthy but may manifest late sequelae. The other 10% are born with cytomegalic inclusion disease and have a very poor prognosis.⁴
• Cytomegalic inclusion disease:
  • Presents with jaundice, splenomegaly, petechiae (thrombocytopenia), intrauterine growth retardation, microcephaly, and retinitis.
  • Complications include moderate to severe learning difficulties, neurological abnormalities, hearing loss.
  • CMV excretion is common in children with congenital infection, and this may represent a reservoir for infection of other children and day care workers.

Organ transplantation

• The major risk factor for CMV pneumonia is a CMV seronegative transplant recipient receiving a CMV seropositive organ. In patients who have received marrow transplants, the highest incidence of CMV disease occurs 30-60 days after transplant.
• Fatal CMV pneumonia is much less common in patients who have received solid organ transplants compared to patients who have received marrow transplants.
• Prior to the introduction of ganciclovir, CMV pneumonia had a high mortality rate in patients who received allogeneic marrow transplants (85%).
• CMV pneumonia is difficult to treat. The combination of ganciclovir and immunoglobulin is effective, but mortality is still quoted as ranging from 15% to 75%.
• Renal transplant: Active infection has been shown in majority of patients within 6 months of transplantation. Can cause overt illness or may give rise to fever, glomerulonephritis with graft rejection, hepatitis or, in a small minority, pneumonitis which carries an 80% mortality and is the main cause of death.

Cytomegalovirus and HIV infection

CMV can cause very serious infection in HIV infection.

• Retinitis:
  • Retinitis is the most common manifestation of CMV disease in patients who are HIV positive.
  • Presents with decreased visual acuity, floaters, and loss of visual fields on one side.
  • Ophthalmologic examination shows yellow-white areas with perivascular exudates. Haemorrhage is present. Lesions may appear at the periphery of the fundus, but they progress centrally.
  • Begins as a unilateral disease, but in many cases it progresses to bilateral involvement. May be accompanied by systemic CMV disease.
  • Ganciclovir has been used to treat retinitis, but it only slows the progression of the disease. The optimal treatment is using ganciclovir implants in the vitreous, accompanied by intravenous ganciclovir therapy.
  • Oral ganciclovir may be used for prophylaxis of CMV retinitis. It should not be used for treatment.
• CMV pneumonia in patients who are HIV positive is uncommon. The reason for this is unknown.
• Gastrointestinal tract:
  • In the upper gastrointestinal tract, CMV has been isolated from oesophageal, gastric and duodenal ulcers. Patients with oesophageal disease may present with painful dysphagia.
  • In the lower gastrointestinal tract, patients with CMV may present with diarrhoea due to colitis.
• CMV may cause disease in the peripheral and central nervous system.

Investigations

CMV can be detected by virus culture, antigen detection or, increasingly, by molecular detection. Serological diagnosis is of no help in determining infection in the immunocompromised host.⁵

• CMV antibody: IgM and IgG.
• Antigen detection: Antigenaemia has been used to predict CMV pneumonia in patients who have received transplants, and therefore used as an indication to start ganciclovir therapy.
• Polymerase chain reaction (PCR): Has been used to detect CMV in blood and tissue samples. The test is very sensitive. It is positive before the antigenaemia test in patients with viraemia who have received transplants.
• Shell vial assay: Reduces the time required for tissue culture to 24-48 hours, and therefore allows much quicker and more effective initiation of treatment.⁶
• Chest X-ray: Findings consistent with pneumonia and positive CMV serology is a common method for diagnosis.
• CT scan is more sensitive for the identification of lung infiltrates.
• Biopsy: The histological hallmark of CMV infection is the finding of intranuclear inclusions consistent with herpes virus infection.

Management

• Ganciclovir:
  • Ganciclovir is related to aciclovir but it is more active against cytomegalovirus. It is also much more toxic than aciclovir.
  • Oral ganciclovir provides much lower serum levels than intravenous, and so oral ganciclovir is mainly restricted to use as prophylaxis for CMV disease.
  • Intravenous ganciclovir is used for the initial treatment of CMV retinitis.
  • Slow-release ocular implants containing ganciclovir have the highest efficacy and may be inserted surgically to treat immediate sight-threatening CMV retinitis.⁷
  • For the treatment of CMV pneumonia, ganciclovir is administered with immunoglobulin.⁸
  • Other uses of ganciclovir include treatment of gastrointestinal disease in patients who have received transplants and in patients who are HIV positive.
  • Ganciclovir has also been used to treat CNS disease, including encephalitis and neuropathy, but with mixed results.
• Valaciclovir:
  • Valaciclovir is licensed for prevention of cytomegalovirus disease following renal transplantation.
• Valganciclovir:
  • Used for the initial treatment and maintenance treatment of CMV retinitis in AIDS patients.
  • Also licensed for preventing CMV disease following solid organ transplantation from a cytomegalovirus-positive donor.
• Foscarnet:
  • Active against cytomegalovirus but is more toxic and therefore used as a second-line agent.
• Acyclovir prophylaxis:
  • High-dose valacyclovir, penciclovir, famciclovir, and acyclovir have been used for CMV prophylaxis in patients who have received organ transplants.
• Cidofovir prophylaxis:
  • Has been used in combination with probenecid for refractory CMV retinitis in HIV positive patients if ganciclovir and foscarnet are contra-indicated.

Management of congenital CMV infection

• Ganciclovir may be used to treat neonates with symptoms at birth.
• Congenitally infected infants, both symptomatic and asymptomatic at birth, require follow-up evaluation to detect sequelae.
• Congenital CMV infection can be diagnosed at birth by detection of viral DNA by PCR in dried blood spots (Guthrie card) collected in the first days of life. However screening for congenital CMV infection is not currently recommended in the UK.⁹

Prognosis

• The prognosis of patients with CMV hepatitis is generally good. Most patients recover completely.
• Symptoms can persist, usually in the form of fatigue, for several months after primary infection.
• CMV pneumonia in patients who have received marrow transplants once carried a mortality rate higher than 85%. The use of ganciclovir plus high-dose immunoglobulin for the treatment of CMV pneumonia in patients who have received allogeneic marrow transplants has lowered the mortality rate to 30-60%.
• Because patients who develop CMV disease are immunocompromised, their prognosis is determined by their underlying disease.

Prevention

• Antiviral agent (acyclovir or ganciclovir) have been shown to be effective in reducing the risk of cytomegalovirus infection following solid organ transplantation.
• Ganciclovir, acyclovir and valacyclovir have been used for prophylaxis and early treatment in patients who have received allogeneic marrow transplants.
• Prophylactic antiviral treatment and intensive monitoring, followed by pre-emptive antiviral treatment, are both commonly used management strategies to reduce risk of cytomegalovirus infection following renal transplantation.¹⁰
• Acyclovir has also been used in patients who have received other types of transplants.