Cytomegalovirus infection

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

CMV spreads through saliva, urine, genital secretions, breast milk, blood products, transplanted organs and transplacental transmission. After primary viraemia, latent viral genomes persist in monocytes and marrow-lineage cells. Effective cellular immunity usually contains replication, whereas transplantation, advanced HIV, chemotherapy or potent immunosuppression permits high-level reactivation and organ invasion.

A well adult with fever and atypical lymphocytes usually needs supportive care, while the same positive serology does not establish invasive disease in a transplant recipient. In an immunocompromised patient, syndrome, quantitative blood PCR and tissue or ophthalmic findings must be integrated because viraemia can exist without organ disease and tissue disease can occasionally occur with low blood viral load.

Congenital CMV follows maternal primary infection, reinfection or reactivation during pregnancy. Most infected babies appear well, but fetal neurotropism and placental inflammation can cause growth restriction, microcephaly, intracranial abnormalities, chorioretinitis and sensorineural hearing loss. Hearing impairment may be delayed or progressive, so a normal newborn examination does not finish surveillance.

Antiviral decisions are specialist-led because ganciclovir exposure suppresses viral DNA synthesis but also injures marrow and reproductive cells. The route depends on severity and gastrointestinal absorption; dose depends on renal clearance; duration depends on organ, virological response and restoration of host immunity. Prevention in transplantation follows organ-specific donor-recipient risk protocols rather than one universal course.

Key points

CMV is a betaherpesvirus that remains latent after primary infection and reactivates most dangerously when T-cell immunity is impaired.
Primary infection in an immunocompetent adult is often asymptomatic or produces a heterophile-negative mononucleosis with fever, fatigue, lymphocytosis and mild hepatitis.
Blood quantitative CMV PCR measures replication and treatment response in immunocompromised hosts, but DNAaemia alone does not prove gastrointestinal, pulmonary or retinal tissue disease.
CMV colitis requires compatible endoscopy and tissue evidence; CMV retinitis is principally a clinical diagnosis made by urgent dilated retinal examination.
Severe tissue-invasive adult disease is usually induced with intravenous ganciclovir 5 mg/kg every 12 hours; stable absorptive disease may use oral valganciclovir 900 mg twice daily.
Active CMV retinitis uses valganciclovir 900 mg twice daily for 21 days, then 900 mg once daily maintenance when renal function permits, with ophthalmic and immune-recovery follow-up.
Confirm congenital CMV with saliva and urine PCR obtained within 21 days of birth; a later positive sample cannot reliably distinguish congenital from postnatal acquisition.
Universal antenatal or newborn CMV screening is not currently recommended in the UK; test promptly when maternal, fetal, neonatal or hearing findings create a clinical indication.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Body-fluid transmission

Saliva, urine, genital secretions and breast milk carry replicating CMV, with close contact with young children creating frequent exposure.

Healthcare acquisition

Transplanted organs, stem cells and inadequately protected blood products can transmit CMV or import latently infected donor cells into a susceptible recipient.

Transplacental infection

Maternal primary infection, reinfection with another strain or reactivation can cross the placenta and establish congenital infection.

Latent reactivation

Profound T-cell dysfunction after transplantation, advanced HIV or immunosuppressive therapy allows a previously contained latent virus to replicate again.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Monocyte latency
After primary viraemia, CMV genomes persist in myeloid-lineage cells and reactivate as these cells differentiate during inflammatory or immunosuppressed states.
2
Tissue cytopathology
Replicating virus enlarges infected cells, disrupts endothelium and epithelium and recruits inflammation, producing ulceration, pneumonitis, hepatitis and retinal necrosis.
3
Immune containment
CMV-specific cellular immunity normally limits replication, while falling T-cell function permits rising viral burden and transition from asymptomatic DNAaemia to organ disease.
4
Fetal neurotropism
Placental infection and viral injury to developing neural, sensory and haematopoietic tissues cause microcephaly, calcification, hearing loss, chorioretinitis and cytopenias.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Primary CMV mononucleosis

Prolonged fever, marked fatigue, myalgia, lymphadenopathy, atypical lymphocytosis and mild transaminitis occur with a negative heterophile antibody test and usually little pharyngitis.

CMV retinitisRed flag

Painless floaters, blurred vision, photopsia or field loss accompanies haemorrhagic white retinal necrosis in severe cellular immune deficiency.

Gastrointestinal CMVRed flag

Odynophagia, dysphagia, abdominal pain, fever, diarrhoea or bleeding reflects ulcerative oesophagitis, gastritis or colitis in an immunocompromised host.

Transplant CMV syndromeRed flag

Fever, malaise, cytopenias and rising viral load may precede pneumonitis, hepatitis, enteritis or graft dysfunction after solid-organ or stem-cell transplantation.

Congenital CMVRed flag

Petechiae, jaundice, hepatosplenomegaly, microcephaly, growth restriction, seizures, chorioretinitis, abnormal hearing or periventricular brain changes suggest infection acquired before birth.

Red flags requiring action

New floaters, flashing lights, visual-field loss or reduced acuity in advanced HIV or transplantation requires same-day ophthalmology for possible CMV retinitis.
Profuse diarrhoea, gastrointestinal bleeding, dysphagia or severe abdominal pain during major immune suppression can indicate CMV colitis or oesophagitis and needs urgent endoscopic tissue diagnosis.
Hypoxia, pneumonitis, hepatitis, marrow suppression or encephalopathy after transplantation may represent tissue-invasive or disseminated CMV rather than uncomplicated viraemia.
A neonate with petechiae, jaundice, hepatosplenomegaly, microcephaly, seizures, growth restriction, abnormal neuroimaging or failed hearing screening needs CMV PCR within the first 21 days.
Primary maternal CMV serology or compatible fetal ultrasound findings require prompt fetal-medicine and virology assessment rather than interpretation of IgM in isolation.
Falling neutrophils, platelets or renal function during ganciclovir or valganciclovir can make continued standard dosing unsafe and demands same-day dose review.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
CMV IgG, IgM and avidityFirst step
Why
Assess prior exposure and support timing of primary maternal or immunocompetent infection.
Interpretation and limitations
IgM can persist, recur or cross-react and must not stand alone; documented IgG seroconversion is strongest evidence of primary infection, while low IgG avidity supports recent acquisition after virology review.
02
Quantitative blood CMV PCR
Why
Detect and trend viral replication during immune suppression or antiviral therapy.
Interpretation and limitations
Interpret serial results from the same assay against the transplant or HIV protocol; a rising load supports active replication but neither a positive nor low result alone proves or excludes every form of tissue disease.
03
Dilated retinal examination
Why
Diagnose and map suspected CMV retinitis before vision is lost.
Interpretation and limitations
Characteristic necrotising retinitis with haemorrhage is diagnosed clinically by ophthalmology; ocular fluid PCR is reserved for atypical lesions or competing viral retinitis.
04
Endoscopy with tissue histology
Why
Confirm CMV oesophagitis, gastritis or colitis and exclude competing pathology.
Interpretation and limitations
Biopsy the ulcer edge and base for histology, immunohistochemistry and tissue PCR where available; blood PCR or a superficial swab cannot replace evidence of tissue invasion.
05
Gold-standard neonatal urine and saliva PCR
Why
Confirm congenital CMV during the diagnostic window after birth.
Interpretation and limitations
Urine and saliva are the diagnostic gold-standard sample types; collect both within the first 21 days, take saliva at least one hour after breast milk and confirm a positive saliva result with urine.
06
Congenital disease staging
Why
Define organ involvement and whether specialist antiviral benefit may outweigh toxicity.
Interpretation and limitations
Obtain FBC, renal and liver tests, cranial imaging, formal audiology and ophthalmology; use MRI and additional tests when examination or ultrasound indicates central nervous system disease.
07
Fetal assessment after maternal infection
Why
Assess transmission and fetal consequences after specialist interpretation of maternal results.
Interpretation and limitations
Fetal medicine coordinates serial ultrasound, possible amniotic-fluid PCR at an appropriately delayed gestation and counselling; an isolated maternal IgM result must not trigger prognostic conclusions.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Epstein-Barr virus

EBV more often causes prominent exudative pharyngitis, posterior cervical nodes and a positive heterophile test, although specific serology may be needed.

Drug-related colitis

Mycophenolate and other transplant medicines can cause diarrhoea and similar histological injury, so tissue morphology and medication chronology require joint interpretation.

Other viral retinitis

HSV and VZV acute retinal necrosis can progress rapidly with pain or vasculitis and may need ocular-fluid multiplex PCR.

Congenital toxoplasmosis

Chorioretinitis and intracranial abnormalities overlap, but serology, imaging pattern and organism-specific PCR distinguish toxoplasma from congenital CMV.

Graft rejection

Fever and organ dysfunction after transplantation may reflect rejection, another infection or drug toxicity, frequently requiring parallel graft-specific investigation.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01IMMUNOCOMPROMISEDSeparate replication from invasionFirst stepA person with HIV, transplantation or major immunosuppression has compatible symptoms or a rising CMV viral load.

1Assess visual, gastrointestinal, respiratory, neurological and graft symptoms alongside immune status, current prophylaxis and competing opportunistic infections.
2Send quantitative blood CMV PCR, FBC, renal and liver tests, but arrange the relevant retinal examination, endoscopy or organ sample when tissue invasion is suspected.
3Use intravenous ganciclovir for severe or non-absorptive disease and oral valganciclovir for selected stable disease, applying renal adjustment from the product and local specialist protocol.
4Trend clinical response, blood counts, renal function and viral load, then determine step-down, maintenance and immunosuppression changes with the responsible HIV or transplant team.

02RETINAPreserve vision urgentlyNew floaters, visual blur, photopsia or field loss occurs during advanced cellular immune deficiency.

1Arrange same-day dilated retinal examination and document acuity, lesion location, extent, macular or optic-disc threat and involvement of the fellow eye.
2Begin systemic induction with oral valganciclovir 900 mg twice daily when absorption is reliable or intravenous ganciclovir 5 mg/kg every 12 hours when disease or illness is severe.
3Consider additional intravitreal treatment for immediately sight-threatening lesions through ophthalmology because local therapy alone does not protect the other eye or other organs.
4After 21-day induction, use renal-adjusted maintenance and frequent retinal review until lesions are inactive and durable immune recovery permits specialist-supervised withdrawal.

03GUTBiopsy before labelling colitisAn immunocompromised patient develops persistent diarrhoea, bleeding, abdominal pain, dysphagia or odynophagia.

1Stabilise fluid loss, bleeding and sepsis, test common bacterial, parasitic and other viral causes, and review medicines that can mimic enterocolitis.
2Arrange endoscopy with multiple biopsies from abnormal and relevant normal-appearing mucosa for histology, immunostaining and virological testing.
3Treat severe CMV colitis with intravenous ganciclovir 5 mg/kg every 12 hours; consider valganciclovir 900 mg twice daily only when disease is non-severe and absorption is dependable.
4Continue for two to four weeks or until symptoms resolve under the BHIVA or transplant pathway, reassessing diagnosis, resistance and immune restoration if response is inadequate.

04NEWBORNUse the 21-day windowA baby fails hearing screening or has findings compatible with congenital CMV.

1Collect saliva and urine for CMV PCR immediately and within 21 days of birth; confirm saliva detection with urine and record feeding timing.
2Stage confirmed infection with examination, FBC, renal and liver tests, cranial imaging, formal hearing evaluation and ophthalmology.
3Discuss symptomatic central nervous system or focal-organ disease urgently with neonatal infection specialists, including off-label oral valganciclovir 16 mg/kg twice daily for six months when indicated.
4Provide serial weight-based dose adjustment, FBC and renal or liver monitoring plus long-term audiology, vision and neurodevelopment surveillance whether or not antiviral treatment is used.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

First-line systemic induction for severe tissue-invasive CMV, unreliable gastrointestinal absorption or a patient too unwell for oral therapy.

Intravenous ganciclovir

Give 5 mg/kg intravenously every 12 hours for induction, with course length set by organ response; CMV colitis usually requires two to four weeks or until symptoms resolve.

Calculate by renal function and local weight convention, infuse as directed, and monitor FBC closely because neutropenia, thrombocytopenia, anaemia, renal toxicity, teratogenicity and impaired fertility can occur.

Oral ganciclovir prodrug for retinitis and selected non-severe tissue disease when absorption and adherence are reliable.

Oral valganciclovir induction

Give 900 mg orally twice daily with food for 21 days for active CMV retinitis when creatinine clearance is at least 60 mL/min; use the SmPC renal table below that threshold.

Do not extrapolate 900 mg twice daily across renal impairment or haemodialysis; monitor FBC, creatinine and liver tests, review interacting marrow-toxic medicines, and apply pregnancy and contraception precautions.

Suppresses recurrent CMV retinitis while cellular immunity remains inadequate and is also used in organ-specific transplant prevention protocols.

Oral valganciclovir maintenance

Give 900 mg orally once daily with food after successful retinitis induction when creatinine clearance is at least 60 mL/min; adjust dose and interval using the current SmPC renal table.

Maintenance duration depends on retinal inactivity and sustained immune recovery; breakthrough disease requires adherence, absorption, resistance and immune-status review rather than automatic dose escalation.

First-line off-label oral antiviral therapy for selected newborns with significant symptomatic congenital CMV, particularly central nervous system or hearing involvement.

Valganciclovir for symptomatic congenital CMV

Neonatal specialist regimen: give oral valganciclovir 16 mg/kg per dose twice daily for six months, recalculating with growth; intravenous ganciclovir 6 mg/kg every 12 hours is used when severe disease or enteral absorption prevents oral therapy.

Begin through neonatal infection specialists, ideally during the first month; monitor neutrophils, platelets, haemoglobin, renal and liver function and do not routinely treat an asymptomatic PCR-positive infant without specialist indication.

Second-line polymerase inhibitor when ganciclovir cannot be used or phenotypic or genotypic resistance is clinically important.

Intravenous foscarnet

For CMV colitis with ganciclovir toxicity or resistance, BHIVA lists 90 mg/kg intravenously every 12 hours for two weeks; other organs require their specialist protocol.

Nephrotoxicity, hypocalcaemia, magnesium, phosphate and potassium disturbances, seizures and genital ulceration require pre-hydration, renal adjustment and intensive electrolyte monitoring.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Irreversible visual loss

Retinal necrosis involving the macula or optic disc, retinal detachment and immune-recovery uveitis can permanently reduce sight.

Gastrointestinal catastrophe

Deep CMV ulcers can cause major haemorrhage, perforation, toxic megacolon, malnutrition and bacterial translocation during profound immune suppression.

Graft and organ injury

Pneumonitis, hepatitis, encephalitis and indirect immune effects increase graft dysfunction, secondary infection, rejection risk and mortality.

Congenital disability

Sensorineural hearing loss, visual impairment, epilepsy, cerebral palsy, learning difficulty and developmental delay may emerge or progress over years.

Antiviral resistance

Prolonged replication during drug exposure selects UL97 kinase or UL54 polymerase mutations, causing persistent viraemia and progressive tissue disease.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

During ganciclovir or valganciclovir, check FBC and renal function at baseline and frequently during induction, adjusting dose promptly as creatinine clearance or neutrophil count changes.
Trend quantitative CMV PCR with the same laboratory assay in transplant and HIV care, but judge cure by organ response as well as blood viral kinetics.
Repeat dilated retinal examination frequently during induction, then at specialist-defined intervals through maintenance and immune recovery because opposite-eye and relapse risk persists.
For gastrointestinal disease, document stool frequency, bleeding, nutrition and systemic recovery; persistent symptoms require competing-diagnosis, absorption and resistance reassessment.
In treated congenital CMV, recalculate valganciclovir dose as weight changes and monitor FBC, liver and renal indices according to the neonatal protocol.
All congenital CMV needs structured audiology because hearing loss can emerge or progress after a normal newborn screen; add ophthalmic and neurodevelopmental review according to disease staging.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Viraemia is not invasion

A positive blood PCR supports active replication but gastrointestinal and many other organ syndromes still require disease-specific evidence before toxic therapy is attributed to CMV.

The retina is examined

CMV retinitis is usually diagnosed from its retinal appearance; waiting for blood PCR can lose vision and a negative blood result cannot safely defer ophthalmology.

Saliva needs confirmation

Breast-milk contamination can make neonatal saliva PCR positive, so collect after a feeding interval and confirm detection in urine within the congenital window.

IgM lacks chronology

CMV IgM may persist or reappear during reactivation, making paired IgG results, avidity, gestation and specialist interpretation more informative than a single reactive test.

Marrow toxicity is predictable

Ganciclovir-class drugs suppress haematopoiesis, so an unexplained falling neutrophil count during therapy should trigger dose, renal and interacting-drug review before sepsis follows.

11Common pitfallsFrequent interpretation and management errors.

01
Do not call a positive blood CMV PCR colitis or pneumonitis without organ-specific evidence; asymptomatic replication and alternative pathology are common after transplantation.
02
Do not reassure an immunocompromised patient with new floaters while awaiting routine blood results; retinal examination is the urgent diagnostic step.
03
Do not interpret isolated CMV IgM in pregnancy as proven recent primary infection or as a fetal prognosis without avidity, prior sera and specialist review.
04
Do not miss the first 21 days for neonatal urine and saliva PCR because later detection cannot reliably establish congenital timing.
05
Do not prescribe valganciclovir 900 mg twice daily without checking creatinine clearance and blood counts; standard dosing can cause profound toxicity in renal impairment.
06
Do not treat every asymptomatic congenitally infected infant or every positive transplant viral load identically; disease staging and the responsible specialist protocol determine benefit.