Cytomegalovirus

What is cytomegalovirus?

Cytomegalovirus (CMV) is a member of the herpesvirus 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.

The most common disease manifestation is gastrointestinal disease. CMV pneumonia is the most serious complication but has become less common with prevention strategies for at-risk patients. Rare manifestations include retinitis and encephalitis. CMV also has an immunosuppressive effect, which can lead to an increased susceptibility to invasive bacterial and fungal disease as well as graft-versus-host disease (GvHD).¹

• After initial infection, human CMV 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.

• Clinically significant CMV disease frequently develops in patients immunocompromised as a result of HIV, solid organ transplantation and bone-marrow transplantation.

• Primary CMV infection of the immunocompromised host may cause disease in almost every organ of the body - eg, pneumonia, hepatitis, encephalitis, colitis, uveitis, retinitis and neuropathy.

Cytomegalovirus epidemiology

• Worldwide estimates of CMV infection prevalence vary from 50% to over 70% of all adults.²

• Infection may be passed via body fluids - eg, kissing, sexual intercourse and blood transfusion, or by tissue donation.

• Most HIV-infected individuals are seropositive for CMV. HIV infection accelerates the development of CMV-dependent immunological abnormalities.³

Infection in immunocompetent hosts

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

• 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 (upper and lower gastrointestinal tract).⁴

Hepatitis

• Hepatitis is commonly observed in patients with primary CMV infection and mononucleosis. LFTs 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.

Pneumonia

• Immunocompetent:⁵

  • Pneumonia may occasionally occur with CMV mononucleosis.

  • Usually, pneumonia is found on the CXR 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 with an interstitial infiltrate on the CXR.

  • 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 the developed world.⁶

• 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 both in cervical secretions and in breast milk.

• Most children infected in utero appear healthy but may manifest late sequelae. Those children born with cytomegalic inclusion disease have a poor prognosis.

• In about 10-20% of cases, follow-up shows neurological damage. The most common sequelae are sensorineural hearing loss, mental retardation and cerebral palsy.⁷

• Antiviral therapy of children with symptomatic central nervous system congenital CMV infection is effective at reducing the risk of long-term disabilities; this should be offered to families with affected newborn infants.⁶

• Cytomegalic inclusion disease:
  

  • Presents with jaundice, splenomegaly, petechiae (thrombocytopenia), intrauterine growth restriction, microcephaly, and retinitis.

  • Complications include moderate to severe learning difficulties, neurological abnormalities, and hearing loss.

  • CMV excretion is common in children with congenital infection and this may represent a reservoir for infection of other children and daycare workers.

Organ transplantation⁸

CMV is one of the most important pathogens that infect solid organ transplant recipients and is associated with increased morbidity and mortality. Solid organ transplant recipients are particularly susceptible to CMV-related disease due to the immunosuppression necessary to prevent organ rejection. Patients receiving T-cell depleting therapies are at the highest risk.⁹ The major risk factor for CMV pneumonia is a CMV-seronegative transplant recipient receiving a CMV-seropositive organ.

Because of the multiple human strains of CMV, seropositive organ recipients are at risk of re-infection with a different strain of virus. The clinical syndrome is then usually less severe than in primary infection and the onset of disease is often delayed to approximately 6-8 weeks post-transplantation.

Prevention of CMV infection

• All organ donors and recipients should be screened for CMV status, either before or at the time of transplantation.

• If both donor and recipient are seronegative for CMV, leuko-depleted blood and blood products should be used to minimise the risk of primary infection. In this scenario, no prophylaxis or monitoring is required.

• CMV-seronegative recipients who receive a solid organ transplant from a donor who is seropositive should be offered prophylaxis against primary infection, using oral valganciclovir, oral valaciclovir or intravenous ganciclovir. The same should apply where either the donor or recipient is seropositive if the patient is treated with T-cell depleting therapies.

• When the donor and recipient are both seropositive and the patient is not treated with T-cell depleting therapies:
  

  • For renal transplant recipients: no prophylaxis is recommended.

  • For liver transplant recipients: no prophylaxis is recommended.

  • For lung transplant recipients: the recommended prophylactic strategy is oral valganciclovir or oral valaciclovir.

  • For heart transplant recipients: no prophylaxis is recommended.

• Serial measurements of viral load and treatment with intravenous ganciclovir can be used when levels predictive of disease are reached.

• When indicated, antiviral prophylaxis is continued for 3-6 months.¹⁰

Cytomegalovirus treatment

• Patients with CMV disease should receive intravenous ganciclovir or oral valganciclovir until the resolution of symptoms and for a minimum of 14 days. Foscarnet and cidofovir are second-line therapeutic options - unless ganciclovir resistance has been demonstrated.

• If possible, a reduction in immunosuppression should be considered.

• After treatment doses have been administered, an additional 1-3 months of appropriate prophylaxis should be considered to minimise the risk of recurrent infection.

• The duration and efficacy of treatment should be determined using PCR monitoring of viral load.

Cytomegalovirus and HIV infection

CMV can cause very serious infection in HIV-positive people.

• Retinitis:¹¹
  

  • Retinitis is the most common manifestation of CMV disease in patients who are HIV-positive, affecting up to 40% of patients and accounting for 85% of all CMV-related complications.¹² .

  • It presents with decreased visual acuity, floaters and loss of visual fields on one side.

  • Ophthalmological examination shows yellow-white areas with perivascular exudates. Haemorrhage is present. Lesions may appear at the periphery of the fundus but they progress centrally.

  • It begins as a unilateral disease but in many cases it progresses to bilateral involvement. It 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. New therapies are under evaluation.¹³

  • 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.

Investigations¹⁴

CMV can be detected by culture, serology, antigen assays, PCR and cytopathology.

• CMV antibody: IgM and IgG:
  

  • Recent CMV infection causes an increased IgM level and a four-fold increase in IgG.

  • The assessment of CMV IgM is most suitable for immunocompetent people in the community.

  • The measurement of IgM is not helpful in immunocompromised patients.

  • The diagnosis of maternal primary CMV infection in pregnancy is based on positive CMV IgG in a pregnant woman who was previously seronegative or on detection of specific IgM antibody associated with low IgG avidity.

• PCR is the fastest and most sensitive method used to detect CMV in blood and tissue samples. 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 - but viral culture has only modest sensitivity.

• CXR: 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 herpesvirus infection.

• All patients who present with clinical features of CMV should have FBC, serum creatine and LFTs performed.

Cytomegalovirus treatment and management

Immunocompetent patients usually require no treatment other than general advice to increase fluids and treat fever. However, patients with immunodeficiency require intensive antiviral treatment.

Management of patients with immunodeficiency¹⁵

There are several drugs available for treatment of CMV disease:

• Ganciclovir:
  

  • Ganciclovir is related to aciclovir but it is more active against CMV. 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 may be inserted surgically to treat immediate sight-threatening CMV retinitis.

  • For the treatment of CMV pneumonia, ganciclovir is administered with immunoglobulin.

  • 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 CMV disease following renal transplantation.

• Valganciclovir:
  

  • Is used for the initial treatment and maintenance treatment of CMV retinitis in AIDS patients.

  • It is also licensed for preventing CMV disease following solid organ transplantation from a CMV-positive donor.

• Foscarnet:
  

  • Is active against CMV but is more toxic and therefore used as a second-line agent.

• Cidofovir:
  

  • Is given in combination with probenecid for CMV retinitis in AIDS patients when ganciclovir and foscarnet are contra-indicated.

Management of congenital CMV infection¹⁶

• Valganciclovir 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), sputum and urine collected in the first days of life. However, screening for congenital CMV infection is not currently recommended in the UK.

Prognosis

• The prognosis of patients with CMV hepatitis is generally good.¹⁷ 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 transplants once carried a very high mortality rate he but the use of ganciclovir plus high-dose immunoglobulin for the treatment of CMV pneumonia in patients who have received transplants has lowered the mortality rate considerably.¹⁸

• Because patients who develop CMV disease are usually immunocompromised, their prognosis is often determined by their underlying disease.

• CMV has been implicated in the development of a variety of different cancers.¹⁹

Prevention

• Prophylaxis with antiviral medications reduces CMV disease and CMV-associated mortality in solid organ transplant recipients. They should be used routinely in CMV-positive recipients and in CMV-negative recipients of CMV-positive organ transplants.²⁰

• Ganciclovir, aciclovir and valganciclovir have been used for prophylaxis and early treatment in patients who have received solid organ and allogeneic marrow transplants.²¹

• An effective vaccine for the prevention of maternal CMV infection is being sought . None exists as yet, but research is ongoing and there are several very promising candidates.²²

• Patients should be educated as to the sources of maternal CMV infection and the importance of hygiene measures to reduce exposure.