Cytomegalovirus Infection

Cytomegalovirus is a ubiquitous herpesvirus that establishes lifelong latency after primary infection. Primary infection is frequently entirely asymptomatic or mild in the immunocompetent host.

Clinical significance arises predominantly in three distinct contexts. The first is congenital infection following transplacental transmission, the leading infective cause of congenital sensorineural hearing loss and neurodevelopmental disability.

The second is reactivation disease in significantly immunocompromised patients (particularly advanced HIV infection and solid organ or haematopoietic stem cell transplant recipients).

The third, less commonly, is a mononucleosis like illness in otherwise immunocompetent adults with primary infection.

Pathophysiology and reactivation risk

• After primary infection, the virus establishes lifelong latency within myeloid lineage cells. Reactivation occurs with significant impairment of cell mediated immunity.
• This explains the particular relevance of infection in advanced HIV infection (typically at CD4 counts below 50 cells per microlitre) and in therapeutic immunosuppression after organ transplantation.
• Congenital infection results from primary maternal infection during pregnancy, which carries the highest risk of severe fetal disease.
• Less commonly, and generally with milder consequences, it results from reactivation or reinfection with a different viral strain during pregnancy in a mother with pre-existing immunity.
• The risk and severity of congenital disease are influenced by the gestational timing of maternal infection.

• Primary infection in the immunocompetent adult is frequently asymptomatic or produces a mild, non specific illness. A minority develop a mononucleosis like syndrome (fever, malaise, myalgia).
• In contrast to Epstein Barr virus mononucleosis, pharyngitis and lymphadenopathy are generally less prominent. Heterophile antibody testing is characteristically negative, which distinguishes it from classical Epstein Barr virus mononucleosis.
• Cytomegalovirus retinitis occurs in significantly immunocompromised patients. It presents with painless progressive visual disturbance (floaters, blurred vision, visual field loss).
• Characteristic fundoscopic findings are retinal haemorrhage and yellow white areas of retinal necrosis (classically described as a "pizza pie" or "cottage cheese and ketchup" appearance). Retinitis is a sight threatening emergency requiring prompt recognition and treatment.
• Cytomegalovirus colitis presents with abdominal pain, diarrhoea (which may be bloody), weight loss and fever. Cytomegalovirus oesophagitis presents with odynophagia and dysphagia.
• Both occur predominantly with significant immunosuppression, and endoscopy shows characteristic mucosal ulceration.
• Cytomegalovirus pneumonitis is particularly relevant in the haematopoietic stem cell transplant population. It presents with fever, cough and breathlessness, with characteristic interstitial infiltrates on imaging.
• Central nervous system involvement (encephalitis, polyradiculopathy) occurs, particularly in advanced HIV infection.
• Congenital cytomegalovirus infection is asymptomatic at birth in the majority. A proportion of these infants subsequently develop late onset sensorineural hearing loss, so even initially asymptomatic infants need long term audiological surveillance.
• Symptomatic disease at birth reflects more severe intrauterine infection. It presents with microcephaly, intracranial calcification, hepatosplenomegaly, jaundice, petechiae and chorioretinitis.

• Cytomegalovirus polymerase chain reaction quantification on blood (viral load) is the standard method for diagnosing and monitoring active, clinically significant infection in the immunocompromised population. Quantitative trends are particularly useful for both diagnosis and monitoring response to treatment over time.
• Tissue diagnosis by biopsy (colonic, oesophageal, or other affected site) confirms end organ disease at a specific site. Histology shows characteristic cytomegalovirus inclusion bodies (large cells with a characteristic "owl's eye" intranuclear inclusion), with immunohistochemistry.
• This is important because a positive blood viral load alone does not necessarily equate to symptomatic end organ disease at a particular anatomical site.
• Cytomegalovirus retinitis is diagnosed clinically by an ophthalmologist from the characteristic fundoscopic appearance. Tissue biopsy is generally unnecessary, given the distinctive, recognisable picture in the appropriate immunocompromised context.
• Congenital infection is diagnosed by cytomegalovirus polymerase chain reaction testing on urine or saliva obtained within the first three weeks of life. Testing beyond this window cannot reliably distinguish congenital from postnatally acquired infection.
• Prenatal diagnosis, where maternal primary infection is identified or suspected during pregnancy, uses amniotic fluid polymerase chain reaction testing. It is generally performed from at least six weeks after presumed maternal infection and from twenty one weeks gestation onward, to optimise sensitivity.
• Serology (immunoglobulin M and immunoglobulin G, with immunoglobulin G avidity testing where relevant) is useful for establishing maternal infection status and, where positive for recent primary infection, timing during pregnancy.
• Serology has more limited utility for diagnosing active reactivation disease in the immunocompromised population than direct viral load quantification.

• First line treatment for cytomegalovirus end organ disease in the immunocompromised host is valganciclovir 900 mg orally twice daily. Use intravenous ganciclovir 5 mg per kg twice daily for more severe disease or where oral absorption is unreliable.
• Give an induction period, typically two to three weeks, guided by clinical and virological response. Then continue a reduced maintenance dose (valganciclovir 900 mg once daily) until adequate immune reconstitution has occurred. This is particularly relevant in HIV, with antiretroviral therapy driven CD4 count recovery.
• Cytomegalovirus retinitis may additionally be treated with intravitreal ganciclovir injection for rapid, high concentration local therapy. This is particularly useful for sight threatening lesions close to the macula or optic nerve. Use it alongside systemic therapy, given the risk of contralateral or systemic disease.
• Foscarnet 90 mg per kg intravenously twice daily, or cidofovir, are alternative agents for ganciclovir resistant disease or where significant myelosuppression limits ganciclovir use.
• Foscarnet has a distinct adverse effect profile, predominantly nephrotoxicity rather than myelosuppression. It requires careful renal function monitoring and adequate hydration.
• Individualise the choice according to clinical context, prior treatment, and relevant contraindications, under specialist infectious disease guidance.
• Initiating or optimising effective antiretroviral therapy is an essential component of managing HIV associated cytomegalovirus disease.
• Sustained CD4 count recovery allows discontinuation of maintenance antiviral therapy, once a defined threshold of immune reconstitution (generally CD4 count above 100 to 150 cells per microlitre for a sustained period) has been achieved.
• Symptomatic congenital cytomegalovirus infection is treated with valganciclovir at weight based paediatric dosing for six months. This prolonged duration is supported by evidence of improved hearing and neurodevelopmental outcomes.
• Monitor full blood count regularly, given the risk of neutropenia with this agent.
• Continue audiological surveillance long term regardless of initial symptom status, given the recognised risk of late onset or progressive hearing loss.
• Prevention strategies include preemptive or prophylactic antiviral therapy in high risk transplant recipients, guided by donor and recipient cytomegalovirus serostatus and the specific transplant type.
• Give general hygiene advice to pregnant women, particularly those in regular contact with young children, a recognised significant source of exposure. Advise hand hygiene after contact with young children's saliva and urine.
• No vaccine is currently available, and primary maternal infection during pregnancy accounts for a significant burden of congenital disease.