Cytomegalovirus: What every physician needs to know

Cytomegalovirus (CMV), also known as Human herpesvirus 5, is a member of the Herpesviridae virus family. CMV can cause a spectrum of manifestations, from asymptomatic infection to severely debilitating viral morbidity.Despite CMV being the leading cause of birth defects and developmental delays in the United States (surpassing Down syndrome and neural tube defects), relatively few women in the US know about CMV and how it can affect pregnancy.CMV can infect individuals of any age and sex, often presenting asymptomatically. Newborns who are immunosuppressed and patients who are immunosuppressed or pregnant are particularly vulnerable to serious complications of CMV.¹

Epidemiology

CMV has an estimated seroprevalence of 83% in the general population, 86% in women of childbearing age, and 86% in donors of blood or organs. CMV infection is prominent globally, and its prevalence is impacted by geographical region and socioeconomic status. In women of reproductive age, CMV IgG seroprevalence ranges from 45% to 95% globally (Europe: 45.6%-95.7%; Japan: 60%; Latin America: 58.3%-94.5%), with a rate of 24% to 81% in North America. Lower-income countries have higher rates of seropositivity, with a 3-fold greater infection burden in low- and middle-income countries vs high-income countries.²

The discrepancies in CMV seroprevalence among different income groups have been attributed to general disparities in health care access and specific CMV risk factors that align with income trends (household composition, crowding, contact with children).³

Transmission

CMV is transmitted through direct contact with infected bodily fluid, including saliva, urine, blood, semen, tears, and breast milk. Patients can become infected through vertical transmission, sexual contact (including saliva), blood transfusion, and organ transplantation. Vertical transmission can occur through 3 routes: intrauterine, intrapartum, and post natal, with intrauterine transmission having the highest association with neurological sequelae.⁴

CMV has a complex relationship with the immune system and has evolved to disseminate systemically and evade host inflammatory responses. CMV remains latent in mononuclear leukocytes, which can spread the virus to multiple organs. Like many of its Herpesviridae family members, CMV can establish a lifelong latency. Reactivation is often triggered by bouts of immunosuppression, including medications or disease. Common triggers include immunosuppressant drugs, HIV infection, and pregnancy.⁵

Because of the lifelong latency of and many possible vulnerable states to CMV, the patient’s exposure timeline will not always align with symptom presentation (which is more likely to align with states of immunosuppression).5 According to the CDC, the risk for vertical transmission of a primary infection increases as the pregnancy progresses, with a 30% to 40% risk of transmission in first and second trimesters and a 40% to 70% risk of transmission in the third trimester.⁶

Clinical Signs

Clinical manifestations of CMV vary widely depending on the patient’s age, underlying conditions, and mode of transmission.

Clinical signs in the pregnant patient

CMV is notoriously difficult to identify through its clinical signs, even in its more serious presentations. Up to 90% of pregnant patients infected with CMV are asymptomatic.¹ Symptomatic cases may mimic mononucleosis or a viral-like syndrome (fever, chills, malaise, myalgia, mild hepatitis, lymphadenopathy). CMV infection results in leukocytosis and atypical lymphocytes (“owl-eye” inclusion bodies) in the blood. In extreme cases, patients may also present with thrombocytopenia, HELLP syndrome (a combination of hemolysis, elevated liver enzymes, and low platelets), hemolytic anemia, meningoencephalitis, myocarditis, and gastrointestinal ulcers.⁵

Clinical signs in fetus in utero

Ultrasound findings suggestive of CMV infection include the following⁷:

• fetal growth restrictions
• ventriculomegaly
• periventricular calcifications
• placentomegaly
• echogenic bowel

Ultrasound abnormalities correlate with severe CMV infections and indicate adverse outcomes in pregnancy. Intracranial features (ventriculomegaly and periventricular calcifications) observed on ultrasound are correlated with central nervous system (CNS)–related symptoms of congenital CMV. Hyperechogenic bowel (HB) is the most common extracranial ultrasound finding in fetal CMV.⁸ Physiologically, these ultrasound findings are present because of the ganglionic involvement of CMV in the myenteric plexus (Auerbach plexus). In CMV-infected fetuses with HB, CMV-positive ganglion cells of the myenteric plexus are present and BCL2 (a protooncogene that inhibits apoptosis) is weakly expressed.⁸ There is decreased neuronal functionality and peristalsis impairment (paralytic ileus), which manifested as HB.⁸ In CMV-infected fetuses without HB, CMV-positive ganglion cells of the myenteric plexus are present and BCL2 is strongly expressed, indicating a potential protective factor against HB9 (Figure).

Figure. Mild Bilateral Ventriculomegaly

Mild bilateral ventriculomegaly (measuring 10-mm bilaterally) can be seen with congenital cytomegalovirus infection. (Image provided by authors)

Clinical signs in infants

CMV is the most common cause of fetal viral infection in the United States.¹ Congenital CMV (cCMV) impacts 40,000 infants annually, with approximately 13% of these infants symptomatic at birth.¹ Clinical signs of infants born with congenital exposure include those illustrated in Table 1. Of the 13% of newborns with symptomatic cCMV, 11% experienced moderate or severe outcomes.¹ Symptomatic cases exhibit diverse clinical presentations, with sensorineural hearing loss being the most common long-term sequelae.

Current Testing Guidelines and Management Strategies

Testing for pregnant patients with CMV

According to CDC guidelines, universal prenatal screening for CMV in the United States is not recommended because the lack of highly effective treatment for an infected fetus precludes the potential benefit of prenatal testing.¹⁰ Newer data indicate 8 g/d of valacyclovir significantly reduces vertical transmission following primary maternal infection in the periconceptional period and the first trimester.¹⁰ As treatments advance, potential benefits from testing may also increase and guidelines may evolve. Patients who qualify as a high-risk population, such as parents with young children and health care workers, can discuss CMV testing with their providers but must balance the limitation and utility of testing. The National CMV Foundation recommends all parents get tested prior to conception and provides patient resources at their website

(www.nationalcmv.org/overview/cmv-pregnancy).

• Antibody serology

Antibody serology (IgG and IgM) and IgG avidity testing (Table 26) are useful, noninvasive blood tests to assess for current, recent, or remote CMV infection. When an infection is suggested and there is concern for fetal CMV exposure, amniocenteses remain the gold standard for diagnosing CMV in utero.¹¹

CMV, cytomegalovirus.

• IgG avidity testing

Because it is possible for patients to have secondary CMV infections (defined as reactivation of endogenous or latent virus), IgG avidity assays can be helpful. An IgG avidity assay tests binding strength between IgG and the CMV antigen. Following a primary CMV infection, IgG is low and takes 2 to 4 months to become high avidity, allowing the provider to estimate the relative timing of infection. IgM positivity alone is a sensitive marker for primary CMV infection but lacks specificity. IgM positivity with low IgG avidity suggests reliable evidence for primary infection. Because IgM testing alone is nonspecific, IgG avidity testing in IgM-negative patients with suspected CMV infection (through symptoms or exposure) can be a beneficial screening tool.¹²

It should be noted that avidity testing is not FDA approved because it can be unreliable in certain scenarios.

• Amniocentesis

Because IgG avidity testing can be unreliable, if ultrasound abnormalities are detected, an amniocentesis should be performed to confirm the presence of vertical transmission. Amniotic fluid should be tested for the detection of CMV in culture and for the viral genome through polymerase chain reaction (PCR) testing. Both the results of the viral culture and the PCR testing should be used in the diagnosis. Viral isolation in amniotic fluid can be falsely negative, and CMV DNA results have much higher sensitivity. If either result is positive, the CMV DNA is quantified through quantitative PCR. After fetal infection, it takes 5 to 7 weeks for the virus to be detectable in the amniotic fluid. Testing for CMV in the amniotic fluid, therefore, should occur at least 7 weeks following suspected infection.¹³

Testing for congenital CMV

In the United States, cCMV testing is not part of routine newborn screening. In 2023, Minnesota became the first US state to mandate universal cCMV testing using quantitative PCR to detect CMV in dried blood spots.¹⁴

Traditionally, cCMV testing is indicated through a failed newborn hearing screening (NBHS), and evidence shows that newborns and infants (from birth to 9 months of age) with cCMV potentially benefit from pharmaceutical (antivirals) and nonpharmaceutical (hearing aids and developmental/intervention services) treatment. There is a lack of evidence of potential benefit from treatment for children with delayed (after 24 months) hearing loss and vision impairment. Early screening (within 3 weeks of birth) proves to be most effective for disease management.¹⁵

Rather than testing for cCMV following a failed NBHS, the newer testing model in Minnesota employs cCMV testing regardless of NBHS results. This model helps to overcome the poor reliability of a NBHS (more than 80% of newborns who fail their screening will have normal follow-up hearing tests) and takes into account the population of children with CMV who have delayed-onset hearing loss with normal NBHS. A positive cCMV test (regardless of NBHS results) is also used as an indicator for more detailed hearing tests.¹⁶

Management

Management of CMV is achieved through prevention, antivirals, and specific symptom management.

Prevention

Pregnant and immunosuppressed patients should be educated about CMV. CMV prevention is achievable through commonplace practices like hand hygiene, safe sex practices, and avoiding contact with young children with viral illnesses. The latter proves to be difficult because many pregnant patients have young children whom they already care for. Specific advice (avoid kissing young children on the mouth, avoid sharing utensils, and practice immediate handwashing following contact with urine, tears, and saliva) can be recommended to patients.

Vaccine Development for Adults

Approximately 10 pharmaceutical companies are working toward a CMV vaccine.¹⁷ In 2023, Moderna published phase 2 findings for an mRNA-based CMV vaccine in healthy adults. The study investigators concluded that the mRNA-1647 vaccine was well tolerated and induced antigen-specific immune responses at all dose levels in CMV-seronegative and CMV-seropositive adults.¹⁷ The vaccine has progressed to phase 3 testing. Sanofi Pasteur’s glycoprotein B with MF59 squalene adjuvant vaccine to prevent maternal acquisition of CMV during pregnancy is in phase 2 testing.¹⁸ Development of a CMV vaccine has been given level 1 priority by the National Academy of Medicine since 1999, and promising progress is occurring.¹⁸

Treatment

Treatment for adults

Ganciclovir (GCV) is the parent compound of CMV antiviral treatments and requires intravenous (IV) administration. Treatment with IV GCV shows prevention against sensorineural hearing loss. Current data have demonstrated IV GCV efficacy in symptomatic newborns with CNS disease. In ganciclovir-resistant CMV (UL97 gene mutation), foscarnet is used.¹⁹

Ganciclovir can be used in pregnant patients with symptomatic CMV when the benefits outweigh the risks, but it is not FDA approved in pregnant populations. Ganciclovir is also used to treat CMV in patients with HIV or patients undergoing organ transplantation.

Alternatives to ganciclovir include valganciclovir, maribavir, and valacyclovir (Table 3^10,19,20). Ganciclovir and valganciclovir are known to cause myelosuppression, which can cause serious complications in the already-immunosuppressed population acquiring CMV infections.

Foscarnet is noted to cause electrolyte imbalances and nephrotoxicity and is contraindicated in patients with renal disease.^10,19,20

Treatment for fetuses in utero

Passive immunization has demonstrated efficacy for in utero treatment of fetal CMV infection through CMV-specific hyperimmunoglobulin treatment. Compared with the placentas of seronegative and seropositive women prior to conception, the placenta of women with primary CMV infections during pregnancy is enlarged. It is hypothesized that the primary benefit of hyperimmunoglobulin treatment comes from improving placental function. Cytogam is the primary preparation available in the United States. Although hyperimmunoglobulin treatment can be quite expensive, cost-benefit analysis has demonstrated the cost of severe disabilities in an affected offspring is much more exorbitant.²⁰

Treatment for newborns

Various palliative treatments are available for newborns presenting with symptomatic CMV including cochlear implants, retinal surgeries, prothrombotic agents, and occupational and physical therapy.

Patient Resources

The National CMV Foundation provides many patient resources, such as health care provider finders, podcasts, parent stories, information about ongoing clinical trials, patient education tools, registries to connect with other families, and childcare providers. In addition, the CDC (https://www.cdc.gov/cmv/index.html) offers many educational tools and specific recommendations regarding screening, ongoing clinical trials (Table 4²¹), and care timelines.

CMV, cytomegalovirus; CMV IVIG, cytomegalovirus intravenous immune globulin.

References

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16. Gievers LL, Holmes AV, Loyal J, et al. Ethical and public health implications of targeted screening for congenital cytomegalovirus. Pediatrics. 2020;146(1):e20200617. doi:10.1542/peds.2020-0617
17. Panther L, Basnet S, Fierro C, et al. 2892. Safety and immunogenicity of mRNA-1647, an mRNA-based cytomegalovirus vaccine in healthy adults: results of a phase 2, randomized, observer-blind, placebo-controlled, dose-finding trial. Open Forum Infect Dis. 2023;10(suppl 2):ofad500.2475. doi:10.1093/ofid/ofad500.2475
18. Nelson CS, Jenks JA, Pardi N, et al. Human cytomegalovirus glycoprotein B nucleoside-modified mRNA vaccine elicits antibody responses with greater durability and breadth than MF59-Adjuvanted gB protein immunization. J Virol. 2020;94(9):e00186-20. doi:10.1128/JVI.00186-20
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