Cytomegalovirus infection

• Cytomegalovirus (CMV, human herpesvirus 5) is a common herpesvirus that infects most humans, establishes lifelong latency after a usually silent first infection, and reactivates when cell-mediated immunity falls.
• In people with normal immunity it is usually harmless or causes a self-limited mononucleosis-like illness; it is most dangerous to fetuses, to premature infants, and to the immunocompromised (transplant recipients, people with HIV, people on potent immunosuppressants).
• Congenital infection affects roughly 2 to 60 per 1,000 newborns in industrialised countries, is the leading non-genetic cause of sensorineural hearing loss in children, and can also cause microcephaly, chorioretinitis and periventricular calcification.^[2][3]
• The virus is diagnosed by finding it in blood, urine, saliva, tissue or amniotic fluid with PCR, pp65 antigenaemia, culture, histology or fundoscopy, and never by serology alone in the immunocompromised.
• Severe disease is treated with intravenous ganciclovir or oral valganciclovir; foscarnet and cidofovir are alternatives; letermovir is used for prophylaxis in transplant recipients; ART is the backbone of treatment for CMV retinitis in HIV.

By the end of this page you should be able to:

1. Explain how CMV spreads, where it hides between episodes, and what makes it wake up again.
2. Describe the spectrum of congenital CMV infection and why hearing loss may be the only sign.
3. Recognise the mononucleosis-like illness of CMV and separate it from Epstein-Barr virus mononucleosis.
4. List the main diseases CMV causes in immunocompromised hosts and the CD4 threshold that puts people with HIV at risk of retinitis.
5. Choose the right diagnostic test for the right clinical question (PCR viral load, pp65 antigenaemia, owl-eye inclusions on histology, fundoscopy).
6. Plan treatment and prophylaxis of CMV infection, including doses, adverse effects, resistance and the timing of ART in CMV retinitis.
7. Describe a safe approach to CMV when tests or drugs are scarce.

It is useful to separate three situations that are often confused:

• Latent (or past) infection: CMV-specific IgG in the blood with no detectable replication. Most people are in this state for life and have no symptoms.
• CMV infection: evidence of active viral replication (positive PCR, antigenaemia, culture, or compatible histology) without symptoms.
• CMV disease: CMV infection with attributable symptoms, signs or end-organ damage.

In transplant practice the same vocabulary is used again: a seronegative recipient (R minus) who receives an organ from a seropositive donor (D plus) sits at the top of the risk scale, because infection is avoidable only while immunity and prophylaxis last.^[7]

No aspect of CMV is understood well by memorising a single rule. The virus is everywhere, it is harmless to most people most of the time, and it becomes dangerous at two moments: when the host has never met it (congenital and primary maternal infection) and when immunity can no longer hold it in check (advanced HIV, transplantation, heavy immunosuppression, critical illness).

CMV seroprevalence in women of reproductive age ranges from 45 to over 90 percent, and is higher in developing countries (over 90 percent in Brazil; 70 to 80 percent in Ghana; over 90 percent in India; 80 to 90 percent in South Africa; over 90 percent in Turkey) than in developed countries (40 to 70 percent in Western Europe, 60 to 70 percent in Australia and Canada, 50 to 60 percent in the United States).^[3] Overall, CMV infection is acquired by roughly half of people in high-income countries by adulthood and by nearly everyone in low- and middle-income countries by early childhood.^[2] In the United States a seroprevalence of 42 to 93 percent has been reported, with higher rates in women, older people, non-Hispanic black and Mexican American ethnicity, crowded households and those with low income or education.^[7]

Seroconversion, a true primary first infection, occurs in about 1 to 2 percent of seronegative pregnant women per year.^[3] Once infected, a woman can be reinfected by a different strain (non-primary infection) and can transmit virus to a fetus in any pregnancy, which is why congenital CMV is not limited to first pregnancies and why women in low-seroprevalence countries are not the only ones affected.

Congenital CMV is reported in 0.2 to 2 percent of pregnancies, with an average of about 0.64 percent, in the United States, Canada, Australia and Western Europe, and in 0.6 to 6.1 percent of pregnancies in the developing countries with available data.^[3] Chiopris and colleagues summarise industrialised-country birth prevalence as 0.2 to 6 percent and confirm the developing-country range of 0.6 to 6.1 percent.^[2] In the United States 20,000 to 40,000 infants are born congenitally infected each year.^{[1] [7]}

CMV is estimated to affect roughly one third of people with AIDS in the pre-combination-ART era in Western countries, and CMV disease still contributes to morbidity in places where HIV suppression is not achieved.^[5][6]

CMV is not cleared after primary infection. It persists for life in a resting (latent) state in cells such as CD14-positive monocytes and CD34- and CD33-positive bone marrow cells.^[3] Latent virus may reactivate whenever cell-mediated immunity slips, for example during pregnancy, while taking corticosteroids, chemotherapy or post-transplant immunosuppressants, or in critical illness.^[3]

Before latency is established the virus sheds from multiple sites: saliva, urine, breast milk, genital secretions and blood. Shedding may be constant or intermittent and can last for weeks in adults, and for months or years in young children.^[3] CMV can be transmitted in body fluids (breast milk, close contact, sexual activity, blood transfusion, organ transplantation). Mothers of toddlers in group daycare have a roughly 50 percent chance of seroconverting within one year of the child starting daycare, because young children shed large amounts of virus and adults rarely notice the mild illness.^[3]

CMV is highly species-specific and only infects humans, but it shows broad tropism inside the body, replicating in hepatocytes and macrophages in the liver and in stromal and vascular endothelial cells in the gut, among others.^[7]

After entry through a mucosal surface, CMV replicates in local epithelial cells and spreads in circulating monocytes. Infection usually resolves in the immunocompetent host but leaves a latent reservoir. Disease occurs when three conditions overlap: the virus is present (primary infection, reinfection or reactivation), the host cannot mount a cytotoxic T-cell response, and the virus reaches a target organ.

Two ideas follow from this:

1. CMV disease is a marker of failed cell-mediated immunity. Where it appears, look for the reason, not just the virus.
2. The blood viral load predicts disease. High and rising plasma CMV DNA precedes tissue involvement, which is the whole basis of pre-emptive therapy in transplant recipients.^[1][7]

Primary CMV infection in healthy adults is usually asymptomatic. When it is symptomatic it produces a mononucleosis-like picture. Severe tissue-invasive disease in immunocompetent people is rare and almost always occurs in those who are critically ill or have a relative risk factor (diabetes, renal failure, pregnancy, autoimmunity, malignancy, blood transfusion).^[7]

The typical presentation is prolonged fever, myalgia and malaise. Less than 5 percent of patients become jaundiced. Atypical lymphocytes are almost always seen, hepatosplenomegaly occurs in 10 to 38 percent of patients, and 70 to 90 percent have abnormal liver enzymes, usually within three times the upper limit of normal and rarely more than five times. Alkaline phosphatase and bilirubin may rise as well, giving a mixed hepatocellular and cholestatic pattern.^[7]

Diagnosis is a diagnosis of exclusion. In a patient with fever and atypical lymphocytes, test for Epstein-Barr virus first (heterophile antibody, EBV IgM); if these are negative, test CMV IgM. PCR of blood is not routinely recommended, because of cost and because a positive PCR may simply reflect latent virus; serology has adequate sensitivity and specificity in this setting.^[7]

CMV mononucleosis is benign and self-limited. No high-quality randomised trial supports antiviral therapy in immunologically normal people, and antivirals have not been shown to change clinically important outcomes in EBV mononucleosis. Antiviral treatment is reserved for severe disease (for example impending hepatic failure or perforation) at the treating physician's discretion.^[7]

Congenital infection may be acquired in any of three ways during pregnancy: primary maternal infection, reactivation of maternal latent virus, or reinfection with a new strain. Transmission to the fetus occurs in 14 to 52 percent of primary infections (average about 32 percent) but in only 1 to 2 percent of non-primary infections (average about 1.4 percent). Because most women of reproductive age are already seropositive, non-primary infections nevertheless account for the larger share of infected babies.^[3]

Among infants born congenitally infected, about 10 percent are symptomatic at birth; about 15 percent of those who are asymptomatic initially go on to develop long-term neurological problems before the age of five years. CMV is the leading non-genetic cause of sensorineural hearing loss in children, and the commonest long-term sequela.^[2][3]

The signs that should make you think of congenital CMV in a newborn are:

• Hearing loss, which may be present at birth or develop months to years later; it often fluctuates and may deteriorate during early childhood, and present at birth may be missed by newborn hearing screening because it can be late-onset.^[2]
• Microcephaly (head circumference at least two standard deviations below the mean for gestational age).
• Chorioretinitis, retinal haemorrhage, optic atrophy, strabismus, cataracts.
• Periventricular calcification and other central nervous system abnormalities (ventricular dilatation, cysts, white-matter changes, cortical atrophy, migration disorders) on neuroimaging.
• Petechiae or purpura, blueberry muffin rash, jaundice, hepatosplenomegaly, anaemia, thrombocytopenia, leucopenia or neutropenia, conjugated hyperbilirubinaemia, elevated transaminases.
• Small for gestational age and prematurity.^[2]

Congenital infection is also the most common congenital viral infection in humans and a leading non-genetic cause of sensorineural hearing loss and of neurodevelopmental disability.^[2][3]

Immunocompromised hosts experience the same end-organ spectrum as the immunocompetent, but more often, more severely, and at lower inocula. Their infection may be primary, reactivation, or reinfection. CMV infection also exerts indirect effects beyond its own disease: predisposition to bacterial and fungal superinfection, rejection and allograft dysfunction, cytopenias and inflammatory sequelae in the transplant recipient.^[1][7]

A practical way to organise the picture is by the host and the organ involved:

The pathologies themselves have characteristic patterns:

• CMV retinitis is the commonest ocular manifestation in immunocompromised patients. Untreated it progresses from the peripheral retina towards the posterior pole at about 24 micrometres per day, and can destroy the whole retina in 3 to 6 months. Funduscopy shows necrotic, granular yellow-white retina with haemorrhage, often in zones mapped around the optic disc and macula. Finding it by dilated fundus examination is highly sensitive and specific.^[5][6] In AIDS it occurs with CD4 counts below 50, and the risk of retinitis is 20 cases per 100 person-years at these levels; HAART has produced an estimated 80 percent reduction in incidence, with current rates around 5.6 cases per 100 person-years.^[5]
• CMV colitis and oesophagitis: odynophagia in over 60 percent with oesophageal involvement; haematochezia and abdominal pain with colonic involvement; fever, anorexia, weight loss, diarrhoea and haemorrhage possible at any gut site. Endoscopic findings range from mucosal inflammation and oedema to deep ulceration. In the colon, up to 94 percent of tissue-invasive disease in the general population is located in the colon, and in liver transplant recipients tissue-invasive disease is mostly allograft hepatitis.^[7]
• CMV pneumonitis is the characteristic life-threatening presentation after stem cell transplant, diagnosed from signs or symptoms of pulmonary disease plus CMV found in bronchoalveolar lavage or lung tissue. Untreated it is almost always fatal.^[4]
• CMV hepatitis ranges from a mild transaminitis in mononucleosis to the liver-allograft hepatitis seen after liver transplantation; granulomatous hepatitis and, rarely, fulminant hepatic failure have been reported. In transplant recipients CMV viraemia plus fever for at least two days, new fatigue or malaise, leucopenia or neutropenia, at least 5 percent atypical lymphocytes, thrombocytopenia below 100,000 cells per microlitre or a greater than 20 percent fall, or transaminases more than twice the upper limit of normal define CMV syndrome.^[7]
• Transplant recipients make up the third group. Thirty to forty percent of immunocompromised patients can present with eye findings only after systemic symptoms. The indirect, immunomodulating effects of CMV explain much of the morbidity.

PCR for viral DNA or RNA. Multiplex real-time PCR of blood, plasma, urine, cerebrospinal fluid, bronchoalveolar lavage, or tissue is the backbone of diagnosis after organ transplantation and in AIDS. It is rapid, sensitive, automatable, and reports a viral load in copies per millilitre, which is essential for pre-emptive therapy and for monitoring response. Specimen deterioration is less of a problem than with culture. Its limitations are the absence of a standardised assay in many settings and the risk of over-detection if a very sensitive assay is interpreted without clinical correlation. In liver transplant practice a greater than threefold rise in the serum CMV PCR is considered significant.^[1][7]

pp65 antigenaemia. This assay detects the CMV matrix protein pp65 in peripheral blood leucocytes by immunofluorescence. It gives a semi-quantitative count of infected cells per 200,000 leucocytes, correlates with viremia and clinical severity, and has been widely used for pre-emptive monitoring. It is labour-intensive, subjective, needs skilled staff, and samples must be processed within six hours. It is prone to false negatives when neutropenia is present and is less useful for neutropenic patients. Thresholds vary by centre and population: around 100 positive cells per 200,000 leucocytes is common in seropositive solid organ recipients; more than 10 infected cells per 200,000 leucocytes is often used after stem cell transplantation; in AIDS patients more than 100 positive nuclei per 200,000 cells is associated with CMV disease in 63 percent compared with 3 percent in those with negative antigenaemia.^[1]

Serology (IgG, IgM, IgG avidity). CMV IgG shows that a person has ever been infected and therefore has latent virus. IgM suggests recent infection but is often falsely positive, can persist for 6 to 9 months, and is positive in reactivation as well. IgG avidity, which is low in the first months after infection and high once immunity has matured, helps separate recent primary infection from past infection; in pregnancy low avidity in the presence of IgM points to a recent primary infection. Serology is unreliable in infants below three months of age because of transferred maternal antibody, and unreliable in immunocompromised patients because the tests depend on an intact immune response.

The cytopathic effect gives CMV its name: infected cells swell to several times their normal size and contain a large intranuclear inclusion with a clear halo, the classic owl-eye inclusion seen on haematoxylin and eosin or special stains. Owl-eye inclusions may be seen in renal tubular cells, lung, gut, liver or any infected tissue. Immunohistochemistry and PCR on tissue are more sensitive: inclusion bodies appear in only about 65 percent of cells that stain positive for CMV by immunohistochemistry, and the two methods together catch an additional 10 to 15 percent of diagnoses missed by either alone.^[7] Histological confirmation remains the reference standard for tissue-invasive disease.

CMV retinitis is diagnosed clinically on a dilated fundus examination by an ophthalmologist, who looks for necrotic, granular or haemorrhagic yellow-white retina progressing from the periphery towards the posterior pole, with little or no vitritis. Fundus photography, PCR on aqueous humour where available, optical coherence tomography and CD4 count support the diagnosis, and telemedicine retinal images have become a practical screening tool in resource-limited settings.^[5][6]

A diagnostic flow that fits most immunocompromised patients is:

These definitions are widely used and worth stating precisely, because much published research is impossible to compare without them:

• Latent CMV: CMV DNA present without detectable replication. No treatment.
• CMV infection: detectable replication without symptoms.
• CMV disease: infection with attributable symptoms, signs or end-organ damage.
• CMV syndrome (transplant recipients): CMV viraemia plus at least two of: fever of at least 38 degrees Celsius for 2 days, new fatigue or malaise, leucopenia or neutropenia, at least 5 percent atypical lymphocytes, platelets below 100,000 per microlitre or a fall greater than 20 percent, or transaminases more than twice the upper limit of normal.^[7]
• Severe tissue-invasive disease: CMV disease with an affected organ (retinitis, colitis, oesophagitis, pneumonitis, hepatitis, encephalitis, nephritis, pancreatitis, or adrenal involvement).
• Drug resistance: lack of virological response, usually after 6 or more weeks of therapy, with a rising or plateauing viral load despite treatment, or a fall of less than 0.5 log per week; suspect mutations in UL97 or UL54 and test genotypically.^[4]

1. Treat disease, not latent virus. Infection without symptoms does not need antivirals in most settings.
2. Start treatment at full doses adjusted for renal function and continue until symptoms have resolved and blood viraemia (including DNAemia) has cleared. Stopping at an arbitrary time point in a patient with a high viral load invites relapse.^[4] Relapse occurs in up to 27 percent of treated transplant recipients, and persistence of viraemia after 14 days is a risk factor.^[7]
3. Wherever it is possible, restore immunity as well as suppressing the virus: reduce post-transplant immunosuppression, use mTOR-based regimens where appropriate, and start antiretroviral therapy in patients with HIV.
4. Treat ocular and central nervous system disease systemically, because local therapy alone leaves the other eye and the rest of the body unprotected.
5. Ophthalmology and infectious diseases should manage retinitis together.

Ganciclovir is an acyclic guanine nucleoside analogue phosphorylated by the CMV kinase UL97 and then by cellular kinases; it inhibits the DNA polymerase UL54. Valganciclovir, its L-valyl ester prodrug, has 61 percent oral bioavailability (which increases by about 25 percent if taken with food), compared with 6 to 9 percent for oral ganciclovir, so oral ganciclovir is not recommended for treatment.^[7]

Two further comments matter for patient safety. First, intravenous ganciclovir has poor oral bioavailability and should never be given by mouth. Second, nephrotoxic agents (foscarnet, cidofovir) require baseline and repeated renal function and electrolyte testing; a single day of unchecked renal impairment can convert a reversible problem into permanent damage.^[4][6]

Genotypic resistance is rare in the first 6 weeks of therapy. Mutations in UL97 cause low- or high-level ganciclovir resistance; mutations in UL54 confer resistance to ganciclovir, foscarnet and cidofovir. Mutations appear in 2 to 7 percent of solid organ transplant recipients (2 percent overall, up to 7 percent in donor-positive, recipient-negative liver recipients).^[4][7]

When resistance is suspected, send blood or tissue for CMV genotyping and phenotypic testing where available, and change therapy empirically while waiting: switch from ganciclovir to foscarnet, or combine ganciclovir and foscarnet. Sirolimus, reduced immunosuppression, artesunate, maribavir, leflunomide and adoptive CMV-specific T-cell therapy have all been used in refractory cases. Combination therapy and specialist input are the safe route; no single regimen has been shown to be best.^[4]

In AIDS-associated CMV retinitis HAART is central. Before HAART, eye involvement occurred in roughly one third of AIDS patients; HAART has been associated with an estimated 80 percent reduction in incidence. Ocular disease is usually diagnosed on dilated fundoscopy, with CD4 below 50 as the trigger for intensive screening: every 2 to 3 months below 50, every 3 to 4 months with 51 to 250, and every 5 to 6 months with 250 to 500 cells per microlitre. When disease is found, induction therapy is given with intravenous ganciclovir 5 mg/kg every 12 hours for 14 to 21 days, or oral valganciclovir 900 mg twice daily, followed by maintenance (5 mg/kg/day intravenous, or oral valganciclovir) until immune recovery.^[5][6]

The sequencing of ART and anti-CMV therapy is a genuine area of disagreement between reviews. One treatment review suggests starting ART about 2 weeks after anti-CMV therapy to reduce the risk of immune reconstitution inflammatory syndrome affecting the retina, which can cause vitritis, retinal detachment and permanent vision loss.^[4] An ocular review stresses that immunocompromised patients with CMV retinitis should start HAART early and argues HAART should be begun before other therapy, because ART restores CD4 cells, suppresses HIV replication and reduces mortality.^[5] In practice, for anyone with sight-threatening zone 1 retinitis, anti-CMV therapy should never be delayed; the timing of ART, and the use of corticosteroids for immune recovery uveitis, should follow the local HIV and ophthalmology service. Both positions are legitimately held and the evidence is mixed.^[4][5]

Discontinuing (maintenance therapy, or secondary prophylaxis) is appropriate only when all of the following hold: retinitis non-sight-threatening and quiescent for at least 6 months, immune reconstitution with CD4 above 100 cells per microlitre for several months, stable or rising counts after at least 3 to 6 months of HAART, and no detectable CMV viraemia.^[4][5] Maintenance regimens (oral valganciclovir, intravenous ganciclovir or foscarnet, repeated intravitreal injections) are all acceptable and choice depends on toxicity and drug availability. Stopping early enough to matter yet late enough to prevent relapse is the skill; close follow-up and repeated dilated fundus examinations remain essential because relapse can occur.^[5]

Complications to warn about are immune recovery uveitis (anterior or intermediate uveitis with vitritis, with cystoid macular oedema, cataract and epiretinal membrane formation, estimated in 5 to 30 percent of patients starting HAART with pre-existing retinitis) and rhegmatogenous retinal detachment in 20 to 30 percent of patients.^[5]

For congenital infection the decision to treat is the decision to commit. Antivirals are reserved for symptomatic neonates with central nervous system disease (microcephaly, intracranial calcification, abnormal cerebrospinal fluid indices, chorioretinitis, sensorineural hearing loss) or significant tissue-invasive disease; there is no evidence of benefit for asymptomatic infants. Routine treatment is also not recommended for babies under 32 weeks gestational age, for infants more than 30 days old, or for mild single-organ disease, because of insufficient evidence. Symptomatic infants should receive valganciclovir at 16 mg/kg orally twice daily (the dose shown to give systemic exposure comparable to intravenous ganciclovir), and a 6-month course improves hearing and neurodevelopment at 12 to 24 months compared with a 6-week course, without a higher rate of neutropenia (21 versus 27 percent of infants). Intravenous ganciclovir at 6 mg/kg twice daily for 6 weeks was the original regimen. Six to twelve months of therapy has been reported to improve hearing in infants born with impairment.^[2]

Adverse effects matter because every infant treated so far has been symptomatic: significant neutropenia, usually in the first month; thrombocytopenia and hepatotoxicity in up to 30 percent; the possible long-term gonadal toxicity and carcinogenicity seen in animal models. Regular clinical review with blood counts and liver function tests is essential. Oral valganciclovir removes the need for central venous lines and the complications that follow.^[2]

These are two different strategies and labelled as such:

• Universal (primary) prophylaxis gives antivirals to all at-risk recipients for a fixed period, reducing CMV infection by up to 80 percent during the first 90 days and reducing indirect effects such as graft dysfunction. A minimum of 90 days is recommended, extending to 200 days with valganciclovir in donor-positive, recipient-negative kidney recipients where appropriate. Letermovir 480 mg daily for up to 100 days post-transplant is the other licensed prophylactic agent and is now used widely after stem cell transplantation because it is well tolerated, has minimal myelotoxicity and needs less monitoring. Oral ganciclovir at 1000 mg three times daily was previously used in allograft recipients. Total duration and choice should account for donor and recipient serostatus: donor-positive, recipient-negative carries a risk of 78 to 88 percent without prophylaxis, while donor-negative, recipient-negative sits at 0 to 13 percent.^[6][7]
• Pre-emptive therapy tests at-risk recipients weekly (usually with plasma PCR or pp65 antigenaemia) for the first 3 months and treats only when replication is detected, so that a smaller number of patients receive antivirals. In the earliest randomised comparison, universal prophylaxis and pre-emptive therapy showed broadly similar efficacy in lower-risk recipients, with possible graft-survival advantages for prophylaxis. The practical defect of the strategy is human: specimens must be processed quickly, patients must not miss blood draws, and the assay must be interpreted by a threshold that matches the population. Thresholds such as more than 11 positive leucocytes per 200,000 cells have been derived as predictors of disease, but they vary by centre, transplant type and assay, and no single viral load cut-off is universally accepted.^[1][4][7]

When treatment of established disease is needed, first-line therapy is intravenous ganciclovir 5 mg/kg twice daily or oral valganciclovir 900 mg twice daily, adjusted for renal function, with reported efficacy up to 85 percent in HIV and post-transplant patients. Therapy continues to undetectable viraemia, confirmed on repeat testing at least 2 weeks apart, and is shortened only if toxicity intervenes. Immunosuppression should be reduced and an mTOR-containing regimen considered where possible. Relapse rates reach 27 percent and are higher with high initial viral burden; secondary prophylaxis delays relapse without preventing it.^[7]

CMV colitis and oesophagitis in immunocompromised patients are diagnosed on endoscopy and biopsy (deep ulcer base preferred, with histology, immunohistochemistry and PCR), treated with 2 to 3 weeks of antivirals, and in practice a 5 to 10 day intravenous course followed by oral valganciclovir is commonly used. In inflammatory bowel disease, treatment is reserved for high CMV burden that is likely to be driving inflammation, with evidence of response in steroid-refractory ulcerative colitis carrying more than 250 copies per milligram of tissue. Surgical emergencies (perforation, toxic megacolon, uncontrollable haemorrhage) need surgery as well as antivirals.^[7]

CMV pneumonitis remains the highest-mortality presentation in stem cell recipients and is treated with intravenous ganciclovir plus CMV-specific or standard immunoglobulin; with this combination historical survival improved to about 52 to 69 percent compared with the near-universal mortality of untreated disease. Foscarnet is an alternative when the patient is severely neutropenic.^[4]

CMV hepatitis in immunocompetent mononucleosis and in the immunocompromised is largely treated on the same principles, with intravenous or oral therapy as severity dictates; the key is to recognise it, since massive transaminase rises and jaundice can be mistaken for other viral hepatitides.^[7]

CMV-specific hyperimmune immunoglobulin (CMVIG) has strongest evidence in primary prophylaxis and as an adjunct, rather than as stand-alone treatment. CMV immune globulin is a standard component of treatment for CMV pneumonitis after stem cell transplantation and is used in combination with ganciclovir in cases of resistant disease. Reducing immunosuppression and switching to mTOR inhibitors both lower the incidence of CMV infection, and cellular immunotherapy with donor-derived or third-party CMV-specific T cells is an increasingly reported option for refractory infection in transplant recipients.^[4][7]

• Embolic and thrombotic complications occur in stem cell transplant recipients with CMV gastrointestinal infection and pneumonitis.
• Toxicity of the drugs is itself an important complication: myelosuppression with ganciclovir, nephrotoxicity and electrolyte wasting with foscarnet and cidofovir, catheter sepsis with long-term intravenous therapy.
• Drug resistance develops in patients who receive long courses of antivirals, especially with high baseline viral loads and prolonged viraemia.
• Retinal detachment in 20 to 30 percent of patients with CMV retinitis; immune recovery uveitis in 5 to 30 percent after HAART.^[5]
• In transplant recipients, CMV infection drives indirect damage: rejection (including chronic rejection and graft loss), fungal and bacterial super-infection, post-transplant lymphoproliferative disease, cardiovascular disease, and prolonged hospitalisation.^[7]
• Fetal damage (hearing loss, microcephaly, chorioretinitis, periventricular calcification) is the main long-term complication of congenital infection, sometimes progressive into childhood.
• Enhanced suffering in people with advanced HIV before immune recovery, with polyradiculopathy, encephalitis, and gastric or oesophageal disease.

The outlook varies far more by host than by virus. Immunocompetent patients almost always recover fully. People with transplant CMV who are treated early usually clear viraemia and recover, but relapse, graft dysfunction and drug toxicity keep the stakes high. In AIDS, HAART has transformed the outlook: retinitis that once destroyed sight can now be controlled, and maintenance therapy can be safely stopped once immunity returns. In congenital infection, prognosis depends on the presence of symptoms at birth and on timely treatment: in symptomatic infants 6 months of valganciclovir improves hearing and developmental scores at 12 to 24 months; late-onset hearing loss can appear in about 10 to 15 percent of asymptomatic infants anyway, which is why all infected infants need serial audiological follow-up.^[2][5]

Prevention has four levels:

1. Personal hygiene for pregnant women and other carers of young children: hand washing after changing nappies, feeding or wiping, not sharing food, drinks, dummies or toothbrushes, avoiding saliva contact, cleaning surfaces that contact urine or saliva. These simple behavioural measures remain the most effective primary prevention. CMV awareness among pregnant women (13 to 60 percent) remains low in most countries.^{[3][7] [2]}
2. Blood and organ safety: screening donors serologically and (in stem cell transplantation) by nucleic acid testing; use leukoreduced blood products where available.^[1]
3. Vaccines: no licensed CMV vaccine is available; candidates are in development with mixed early results. Prophylaxis in high-risk pregnancy has been tested with hyperimmune globulin and valaciclovir and remains trial-based.^[2]
4. Primary and secondary prophylaxis in transplantation as described above, plus screening strategies in HIV: dilated fundus examination for CD4 below 50, with follow-up intervals by CD4 band; and routine audiology for all infants with congenital infection.

Screening strategies differ by setting. Newborn screening with dried blood spot PCR is highly specific but has a sensitivity of under 40 percent in the largest multicentre study, so it cannot be recommended for mass screening at present; salivary PCR has far better sensitivity and specificity but needs infrastructure. Better newborn screening is an active research area because hearing loss can be prevented only if it is predicted or detected early. ^[1]

Low- and middle-income countries carry the highest seroprevalence and the highest birth prevalence of congenital CMV (0.6 to 6.1 percent). Behavioural measures (hand washing, not sharing saliva or utensils, not sharing toothbrushes or dummies) remain the practical primary prevention, because they are the intervention that does not depend on laboratory capacity. Breast milk transmission can be severe in preterm infants, and fresh breast milk is generally reserved for infants above 32 weeks gestation or over 1000 grams, with donor or pasteurised milk for the smallest babies depending on local policy. Where dilated ophthalmoscopy and validated PCR are unavailable, screening people with advanced HIV and teaching them to report early visual symptoms is the realistic way to prevent blindness from CMV retinitis, and repeated intravitreal ganciclovir injections, while labour-intensive, are effective, relatively safe and inexpensive. When tests or drugs are scarce, ganciclovir or foscarnet should be directed to life- and sight-threatening disease first; oral valganciclovir may be the only feasible step-down where intravenous access and line care are limited. Sending biopsy material for histological demonstration of owl-eye inclusions wherever possible helps avoid unnecessary prolonged antiviral courses in patients who do not need them. Early antiviral therapy is also the cheapest intervention available because it reduces retinal detachment, disability and later cochlear implantation, and it is worth more to health systems than late rescue.^{[3][5][6] [2]}

• Pregnancy and the fetus: universal prenatal screening is not generally recommended, but education about hygiene is. Mothers of toddlers in childcare should be targeted. Primary infection is diagnosed by seroconversion; in its absence a combination of IgM and low IgG avidity suggests recent infection, and amniocentesis PCR at 20 to 21 weeks and at least 6 weeks after estimated seroconversion remains the diagnostic method of choice for fetal infection. No therapy has proven benefit for the fetus in randomised trials, so management is specialist.
• Neonates and infants: fresh breast milk is the best nutrition even for preterm infants, but CMV in milk from a seropositive mother can cause severe disease in very premature babies. Treat symptomatic congenital infection for 6 months where possible.
• Older adults: CMV drives immunosenescence in ways still under investigation and may contribute to age-related immune dysfunction; chronic low-grade infection can matter, although this is not yet a routine clinical problem. Persistent CMV excretion is common in infants and toddlers who acquire it postnatally, but disease in older children is unusual unless conditions (such as HIV infection or immunosuppression) lower cellular immunity.
• People with autoimmunity or critical illness: tissue-invasive CMV (especially colitis, oesophagitis, gastritis or hepatitis) can present in this group; reactivation should be considered in anyone with an unexpectedly severe or treatment-refractory course, and blood or tissue PCR with histology is used to confirm.

• CMV is a ubiquitous herpesvirus that infects nearly everyone in low- and middle-income countries and about half of high-income populations by adulthood; it persists for life in a latent state and reactivates when cell-mediated immunity falls.
• Transmission is via body fluids (saliva, urine, breast milk, semen, blood and transplanted organs); shedding is long in young children, so mothers of toddlers are at high risk of primary infection.
• Non-primary infection (reactivation or reinfection) still transmits to the fetus, especially in the first half of pregnancy, and accounts for most congenital cases in high-seroprevalence countries.
• Congenital CMV affects about 0.6 percent of pregnancies in high-income countries and up to 6 percent in low- and middle-income countries, is the commonest non-genetic cause of sensorineural hearing loss, and only about 10 percent of infected infants are symptomatic at birth; sensorineural hearing loss is the commonest long-term sequela.
• The congenital signs to memorise are hearing loss, microcephaly, chorioretinitis and periventricular calcification, with hepatosplenomegaly, thrombocytopenia, rash and growth restriction.
• In immunocompetent adults CMV is usually silent or causes self-limited mononucleosis-like illness: fever, myalgia, malaise, atypical lymphocytes, hepatomegaly and abnormal liver enzymes; jaundice occurs in fewer than 5 percent.
• AIDS-related CMV retinitis usually appears when CD4 is below 50 cells per microlitre. CMV disease in AIDS is commoner above an HIV viral load of 100,000 copies per millilitre and occurs in 10 percent with CD4 below 250 and over 20 percent with CD4 below 100. ^[1]
• Diagnosis rests on detecting virus (PCR, pp65 antigenaemia, culture, histology with owl-eye inclusions, fundoscopy) and not on serology alone in infants and the immunocompromised.
• First-line antiviral therapy is intravenous ganciclovir or oral valganciclovir at full doses adjusted for renal function; foscarnet and cidofovir are alternatives for resistance or neutropenia; letermovir is used for prophylaxis; maribavir is reserved for refractory post-transplant infection.
• In HIV-associated retinitis, ART should be started with expert timing; many authorities start anti-CMV therapy first (or after about 2 weeks of antivirals) to limit immune recovery uveitis. Maintenance or secondary prophylaxis can stop once CD4 is above 100 for several months and the retina has been quiescent for 6 months.
• Low-resource care rests on hand hygiene and awareness for pregnant women, dilated retinal examination and simple, repeated intravitreal ganciclovir, and on biopsy-proven histology to direct limited antiviral use. CMV cure and prevention are possible only with attention to detail at every stage.

HIV and opportunistic infection, transplant infectious diseases, congenital infections, neonatal screening, ophthalmology of uveitis and retinitis, audiology and hearing loss, gastroenterology of CMV colitis, and liver transplantation are all natural neighbours of this topic; this page deliberately stays with CMV itself rather than linking to them, so that readers meeting the subject for the first time can master it in one place.