Clinical manifestations

Presentation and course

Human cytomegalovirus is a clinically relevant pathogen in both immunocompetent and immunosuppressed individuals. The spectrum of clinical presentations is broad due to the virus’ ability to establish a complex virus-host interaction through broad tissue tropisms. In immunocompetent individuals, cytomegalovirus is often asymptomatic but may present as infectious mononucleosis. Though clinically similar to infectious mononucleosis caused by Epstein-Barr virus and associated with a mononuclear lymphocytosis with atypical lymphocytes noted on a peripheral blood smear, there are important differences. Cytomegalovirus-related infectious mononucleosis is characterized by the predominance of systemic symptoms without marked lymphadenopathy, tonsillitis, or the presence of heterophile antibody, all of which are associated with Epstein-Barr virus–associated mononucleosis. Immunocompetent hosts may rarely have infection compartmentalized to a single organ system and only in exceptional cases suffer multiorgan involvement.

Neurologic complications of cytomegalovirus are uncommon but include several different syndromes (Table 1). One of the more common neurologic complications is Guillain-Barré syndrome. The incidence of Guillain-Barré syndrome is estimated at 0.6 to 2.2 cases per 1000 cases of primary cytomegalovirus infection, similar to the incidence of Guillain-Barré syndrome secondary to Campylobacter jejuni infection (25). Neurologic symptoms generally present approximately 1 to 3 weeks after symptomatic infection. A key distinguishing characteristic of Guillain-Barré syndrome secondary to cytomegalovirus is the higher frequency of sensory signs and symptoms and cranial nerve palsies, particularly facial palsies, as opposed to the predominance of weakness in Guillain-Barré syndrome secondary to C jejuni (40).

Other clinical presentations of cytomegalovirus disease include encephalitis, ventriculitis, radiculomyelitis, and peripheral neuropathies, which are far more common in immunocompromised individuals (27). Risk is increased in the setting of HIV/AIDS, with CD4 below 100 and most patients being profoundly immunosuppressed with CD4 below 50. Clinical manifestations of cytomegalovirus encephalitis include subacute, progressive cognitive changes, delirium, and focal neurologic deficits with cranial neuropathies occurring in up to 40% of the patients. Ventriculoencephalitis has also been associated with cranial neuropathies and ataxia but is more often associated with acute mental status changes and with involvement of other organ systems, such as the adrenal glands (03). Radiculomyelitis is rare and typically presents as a subacute cauda equina syndrome that progresses over days to weeks. Patients present with progressive leg weakness and sensory loss with early bowl retention and can evolve to frank paraplegia. Early recognition and treatment of cytomegalovirus radiculomyelitis may result in stabilization of the disease; otherwise, disability or death may ensue. Cytomegalovirus-related neuropathies are less common than encephalitis or radiculomyelitis. Cytomegalovirus has been implicated in other cranial neuropathies, including oculomotor, facial, and vestibulocochlear neuropathies. Involvement of peripheral nerves may result in an asymmetric multifocal motor and sensory axonal neuropathy, often involving the radial, ulnar, or peroneal nerves and constituting a mononeuritis multiplex (38).

Cytomegalovirus retinitis is the most common ocular infection among patients with AIDS, often due to reactivation of latent infection. Cytomegalovirus retinitis presents with blurred or loss of central vision, photopsia, or scotomata. Although incidence has decreased substantially with the advent of combined antiretroviral therapy (cART), individuals with CD4 counts below 50 cells/µL are at the highest risk for cytomegalovirus retinitis, which may lead to retinal detachment or necrosis (13). The CD4 cell count is the most important predictor for the recurrence of cytomegalovirus retinitis (01). Immune reconstitution inflammatory syndrome (IRIS) after initiation of cART is associated with inflammatory responses to either current or prior cytomegalovirus disease. In HIV patients with treated cytomegalovirus retinitis, the initiation of cART may be associated with immune recovery uveitis in approximately 38% of the cases. The risk of developing immune recovery uveitis seems higher in patients with greater immune dysfunction prior to the initiation of cART (15). Initiation of cART for HIV is commonly started around 2 weeks after induction therapy for cytomegalovirus retinitis to reduce the risk of IRIS. A detailed review of cytomegalovirus disease in HIV/AIDS can be found at clinicalinfo.hiv.gov/en/guidelines.

Table 1. Clinical Manifestations of Acquired Human Cytomegalovirus Infection

Population	Systemic manifestations	Neurologic manifestations
Immunocompetent host	• Usually asymptomatic • Mononucleosis with fever, myalgia, adenopathy, splenomegaly, arthralgia, and arthritis. • GI: Colitis, hepatitis • Pneumonitis • Myocarditis • Hemolytic anemia • Thrombocytopenia • Venous and arterial thrombosis • Uveitis • Hemolytic anemia	• Aseptic meningitis • Guillain-Barré syndrome • Cranial neuropathy (CN VII) • Encephalitis or meningoencephalitis (rare) • Myelitis and transverse myelitis (rare) • Rasmussen chronic encephalitis (rare) • Brachial plexopathy • Cerebrovascular disease
HIV/AIDS	• Retinitis (85% of all cases) • GI: Enterocolitis, esophagitis, hepatitis, or gastritis • Pneumonitis • Immune recovery vitreitis-posterior segment inflammation	• Ventriculoencephalitis • Encephalitis or encephalopathy • Polyradiculomyelitis • Mononeuritis multiplex • Peripheral neuropathy
Solid organ transplant	• Febrile illness • Leukopenia and malaise • Pneumonitis • GI: Enterocolitis, esophagitis, gastritis, hepatitis • Retinitis • Other tissue-invasive disease (nephritis, cystitis, myocarditis, pancreatitis)	• Encephalitis
Hematopoietic stem cell transplant	• Pneumonitis • GI: enterocolitis, esophagitis, gastritis, hepatitis • Retinitis (less common)	• Encephalitis
Immunosuppressive drugs	• Pneumonitis • Pancytopenia • GI: pancolitis, hepatitis • Retinitis • Skin ulceration • Fever	• Encephalitis (uncommon)

Table 2. Overview of Antivirals Used Against Human Cytomegalovirus Infection*

Ganciclovir (GCV)
	Mechanism of action:	• Slows viral DNA polymerization. It requires phosphorylation by pUL97 and then conversion to triphosphate analogue by cellular kinase.
	Indication:	• First-line therapy for human cytomegalovirus infection • Intravenous use in human cytomegalovirus infection • Intravenous use for prophylaxis and preemptive therapy after transplant when oral route is contraindicated
	Dosage (adults)**:	Retinitis, radiculomyelitis, encephalitis: - Induction therapy: 5 mg/kg intravenously every 12 hours for 14 to 21 days. - Maintenance therapy: 5 mg/kg daily for 5 days per week Prevention of cytomegalovirus infection in transplant patients: Use of ganciclovir prophylaxis varies with organ (14).
	Common side effects:	• Bone marrow hypoplasia (more common in stem cell transplant recipients) • Neutropenia • Rash • Diarrhea • Nephrotoxicity
Valganciclovir (ValGCV)
	Mechanism of action:	• L-valyl ester of ganciclovir (ie, an oral prodrug)
	Indication	• Cytomegalovirus retinitis • Prevention of cytomegalovirus infection in immunosuppressed patients • Preferred over ganciclovir for oral administration due to higher bioavailability
	Dosage (adults)**:	Retinitis: - Induction: 900 mg twice daily for 21 days - Maintenance (retinitis or radiculomyelitis): 900 mg once daily Prevention of cytomegalovirus infection in heart, kidney, and kidney-pancreas transplants: 900 mg once daily with food within 10 days of transplant until 100 days post-transplant.
	Common side effects:	• Hypertension • Fever • Anemia • Tremor • Nausea, vomiting • Retinal detachment
Foscarnet
	Mechanism of action:	• Binds pyrophosphate binding site of viral DNA polymerase, blocking DNA polymerization. Does not require activation.
	Indication:	• Second-line drug for treatment of human cytomegalovirus infections, especially pUL97-associated ganciclovir-resistant strains • Cytomegalovirus retinitis
	Dosage (adults)**:	Retinitis or encephalitis (with ganciclovir): - Induction treatment: 60 mg/kg every 8 hours for 14 to 21 days or 90 mg/kg every 12 hours for 14 to 21 days - Maintenance therapy: 90 to 120 mg/kg daily
	Common side effects:	• Electrolyte abnormalities (hypokalemia, hypocalcemia, hypomagnesemia, hypophosphatemia, and renal impairment) • Urogenital ulcers • Anemia • Fever • Granulocytopenia • Requires adequate hydration
Cidofovir
	Mechanism of action:	Phosphorylated cytosine analog that is activated by cellular kinases (not by the viral pUL97 kinase). Terminates the replicating viral DNA chain.
	Indication:	• Second-line agent when ganciclovir fails due to resistant strains or when ganciclovir is contraindicated. • Cytomegalovirus retinitis
	Dosage (adults)**:	Cytomegalovirus retinitis: Induction treatment: 5 mg/kg weekly for 2 weeks Maintenance treatment: 5 mg/kg administered once every 2 weeks with probenecid.
Letermovir
	Mechanism of action:	Exerts its antiviral effect by interfering with the viral pUL56 gene product and in the process disrupting the viral terminase complex.
	Indication:	• Prophylaxis of cytomegalovirus infection and disease in adult cytomegalovirus-seropositive recipients of an allogeneic hematopoietic stem cell transplant (HSCT).
	Dosage (adults)**:	• 480 mg oral or intravenous once daily; initiate between day 0 and day 28 post-transplantation (before or after engraftment) and continue through day 100
	Common side effects	• Nausea, emesis, diarrhea • Peripheral edema • Less commonly tachycardia and atrial fibrillation
Maribavir
	Mechanism of action:	Exerts its antiviral effect as a viral pUL97 kinase inhibitor, inhibiting protein phosphorylation and viral replication
	Indication:	• Treatment of post-transplant cytomegalovirus infection that is refractory to treatment (with or without genotype resistance) with ganciclovir, valganciclovir, cidofovir, or foscarnet in adults and pediatric patients (> 12 years of age and > 35 kg)
	Dosage (adults and pediatrics)**:	• 400 mg orally twice daily with or without food
	Common side effects	• Dysgeusia • Nausea, diarrhea, vomiting • Fatigue
* Consult current, detailed prescribing information provided by the manufacturer before prescribing any drug. ** All antivirals need to be adjusted to renal function and are contraindicated in cases of allergy to any of the components. References: (23; 14; 32)

Prognosis and complications

Most symptomatic neurologic human cytomegalovirus infections in immunocompetent hosts have a good prognosis, with multiorgan system involvement being an important predictor of mortality. Studies investigating long-term outcomes on individuals with Guillain-Barré syndrome show conflicting findings, with one suggesting a lower risk of long-term disability among cases related to cytomegalovirus, whereas another suggests slower recovery among those with cytomegalovirus or C jejuni infections (11). Patients with cytomegalovirus-associated Guillain-Barré syndrome are typically treated with either intravenous immunoglobulin or plasma exchange, in accordance with published society guidelines.

Symptomatic infections in immunocompromised hosts are more likely to result in significant morbidity and mortality. Most of the following data are derived from the HIV/AIDS population, as transplant recipients tend to have disease affecting other organ systems. Median survival with cytomegalovirus ventriculoencephalitis is estimated at 1 month despite treatment (17). Cytomegalovirus radiculomyelitis or progressive polyradiculopathy is a neurologic emergency that if untreated may lead to death within approximately 3 weeks (38). Treatment with ganciclovir therapy has been associated with an increased chance of surviving acute infection and an increase in mean survival time of 11 weeks (19). Given such poor outcomes, in some cases patients with cytomegalovirus disease affecting the nervous system may be treated with foscarnet in combination with ganciclovir. Untreated cytomegalovirus retinitis also has a poor prognosis, progressing to blindness among a majority of patients over the course of 1 month (01). Patients are particularly at risk during the early months of cART, prior to full reconstitution of cellular immunity.

Clinical vignette

A 37-year-old female with a longstanding history of HIV/AIDS (CD4 count 50 cells/µL) but not on cART presented to the emergency department with altered mental status. Family described a 3-week course of episodic disorientation, gait instability, fever, and malaise. She was noted to be febrile on presentation with her physical exam, demonstrating lethargy, left sixth nerve palsy, and loss of patellar reflex in the right leg. Brain MRI showed diffuse periventricular hyperintensities without edema. Cerebrospinal fluid analysis showed elevated neutrophils, low protein, and normal glucose with negative bacterial and fungal cultures.

This vignette identifies an immunocompromised patient with a clinical syndrome suggestive of widespread CNS involvement with encephalopathy, cranial neuropathies, and loss of deep tendon reflexes suggestive of ventriculitis and radiculomyelitis. The CSF findings supported a viral etiology, having ruled out bacterial and fungal infections. In this context, cytomegalovirus diagnosis should be actively pursued, and treatment should be started rapidly.

Biological basis

Etiology and pathogenesis

Human cytomegalovirus is an enveloped double-stranded virus in the Herpesviridae family. The immune response against primary human cytomegalovirus infection involves innate and adaptive immunity. Initial contact with the virus by antigen-presenting cells activates natural killer cells and macrophages, with production of cytokines that can function as a bridge to adaptive immunity. The adaptive response, and especially cell-mediated immunity, plays a significant role, with nearly 10% of CD4+ and CD8+ T cells dedicated to human cytomegalovirus surveillance (37). Impairment of cell-mediated immunity can result in a number of complications. After primary infection in an immunocompetent host, the virus enters into a latent phase, predominantly in myeloid lineage cells that represent an important pathway for dissemination of the virus throughout the body (06). Reactivation may occur at any time but typically in the setting of impaired cell mediated immunity, either iatrogenic or secondary to conditions such as HIV/AIDS. Recurrence can be often seen and is dependent on the level of immune competency, primarily T-cell immunity, including the presence and function of cytomegalovirus-specific cytotoxic T cells. In one study, higher recurrence rates were seen in allogenic stem cell transplant recipients (37%), solid organ transplant recipients (30%), primary immunodeficiencies (21%), and during active replication in HIV-positive patients (20%) (36).

Epidemiology

Cytomegalovirus seroprevalence among the general population is estimated at 50% to 90% worldwide, with higher rates in developing counties (16). Seroprevalence in the United States is estimated at 50% and thought to be higher among African-American and Mexican-American children compared with non-Hispanic white children, and independently associated with older age, female sex, foreign birthplace, and high household crowding (05).

Cytomegalovirus infection is more common in populations at risk for HIV infection, with an estimated seropositivity in 90% of homosexual men and 75% of injection drug users. In a cohort of patients with HIV-1 infection, the prevalence of cytomegalovirus infection as an AIDS-defining disease was approximately 6.7% (24). The introduction of cART has witnessed a nearly 97% rate reduction in cytomegalovirus retinitis and a 95% reduction in cytomegalovirus-related end organ damage (33). Nevertheless, cytomegalovirus continues to be an important opportunistic infection.

In the transplant population, risk of cytomegalovirus disease is closely related to the serological status of the graft donor as well as the serological status of the graft recipient (see Prevention). The incidence of cytomegalovirus infection after transplant varies amongst different populations, including solid organ as well as bone marrow transplant, with the highest incidence (25%) reported in kidney transplant recipients (20). Risk is highest early after the transplant, with most disease identified within the first 6 months.

Prevention

Human cytomegalovirus can be acquired through various means, including placental transfer, transfusion of blood products, sexual contact, breastfeeding, or transplant (either solid organs or hematopoietic stem cells). With regards to sexual contact, the virus may be transmitted through saliva, cervical secretions, as well as semen. The virus is not typically spread by casual contact and often requires repeated or prolonged contact for transmission (16). Preventative measures are targeted at reducing primary infection in susceptible individuals and optimizing cell-mediated immunity to prevent reactivation. For individuals with a low risk of seropositivity for cytomegalovirus IgG, attention to hand hygiene and use of condoms should be emphasized. If nonemergent transfusion of blood products is needed, cytomegalovirus-negative or leukocyte-reduced blood products are recommended.

In HIV/AIDS, it is routine to obtain serologic screening for prior cytomegalovirus at the time of diagnosis. Increased risk for disease is recognized with severe immunodeficiency, though there are no data to support primary prophylaxis with antivirals at this time (41). Given that, the primary focus is on administration of cART to suppress HIV replication and, thereby, promote reconstitution of the immune system.

A key preventive measure in the transplant population includes routine serologic screening of blood and organ donors to identify human cytomegalovirus seronegative donors, which is recommended by the current guidelines (28). In the transplant population, the highest risk for cytomegalovirus disease occurs in cytomegalovirus seronegative patients receiving a tissue or organ from a cytomegalovirus seropositive donor (06). Cytomegalovirus seropositive recipients of a graft from a seronegative donor are also at a higher risk, whereas low-risk individuals are those who are seronegative and receive grafts from a seronegative donor.

Other preventive measures may include filtration to remove human cytomegalovirus-infected white blood cells from red cell and platelet transfusions, the use of cryopreserved blood, and the prophylactic use of antivirals or anti-human cytomegalovirus-specific immune globulin.

In solid organ and hematopoietic stem cell transplant recipients, quantitative nucleic acid amplification tests detecting the cytomegalovirus genome are currently recommended for routine surveillance to detect subclinical viremia, which will identify patients at the highest risk of clinical disease (29). Systemic surveillance employed in the months after transplant may be used to determine which patients are appropriate for prophylactic antiviral therapy and preemptive therapy, as well as when such therapy can be stopped (28). Immune monitoring through quantitative assays that detect cytomegalovirus-specific immune responses (such as interferon gamma) or monitoring of cytomegalovirus cell-mediated immunity via enzyme-like immunospot (ELISPOT) can also be used to stratify risk prior to transplant as well as post-transplant for cytomegalovirus disease and identify patients at higher risk who may need prophylactic or preemptive therapy (07). Studies have investigated the role of prophylactic administration of antiviral treatment among transplant recipients at high risk for cytomegalovirus disease. Limaye and colleagues further discuss diagnostic and preventive strategies in the transplant population (20).

Future preventive measures for immunocompromised hosts include specific immunotherapy to restore an anti-human cytomegalovirus-specific immune response (particularly involving cytotoxic T cells and natural killer cells) and the use of a safe and effective human cytomegalovirus vaccine (31). These approaches remain in development. Recombinant technology has facilitated the design of chimeric virus with enhanced immunogenicity, as well as vaccines that use viral subunits delivered as recombinant proteins or viral vectors (eg, poxvirus and adenovirus) (08). Early clinical trials indicate that a cytomegalovirus glycoprotein B vaccine has the potential to decrease the occurrence of maternal and congenital cytomegalovirus infection as well as infection among seronegative patients (26).

Differential diagnosis

In the immunocompetent host, the differential diagnosis for human cytomegalovirus-related neurologic syndromes includes other causes of acute polyradiculoneuropathy (eg, Campylobacter jejuni), aseptic meningitis, encephalitis, and transverse myelitis. In the immunocompromised host, the differential diagnosis includes infections by other agents that are likely to arise in the setting of immune deficiency such as certain bacteria (Listeria, Nocardia, and gram negatives), fungi (Aspergillus, Candida, Cryptococcus, and Mucor), parasites (Toxoplasma), and other viruses (JC virus, herpes simplex, and varicella zoster virus). Potential noninfectious causes in this population include neoplastic and toxic-metabolic processes.

In HIV-infected patients with suspected human cytomegalovirus infection, potential causative agents to consider include the retrovirus itself (HIV-1 associated encephalopathy, meningitis, or vacuolar myelopathy), other viruses (Herpes simplex virus-2, varicella zoster virus, JC virus, human T cell lymphotropic virus), bacteria (syphilis, tuberculosis, atypical mycobacteria), fungi (Cryptococcus, Coccidioides, Histoplasma), and parasites (Toxoplasma). Noninfectious processes include neoplasms (primary CNS or metastatic lymphoma, neoplastic meningitis). The differential diagnosis of human cytomegalovirus radiculomyelitis includes other opportunistic agents and conditions that can involve spinal nerve roots and cord: herpes simplex virus-2 (Elsberg syndrome), varicella zoster virus, Toxoplasma, syphilis, tuberculosis, human T-cell lymphotropic virus, Borrelia (Lyme disease), sarcoidosis, and lymphoma.

Metabolic disturbances and drug toxicity syndromes from systemic immunosuppressants should be considered in transplant patients presenting with encephalopathy and when considering encephalitis or ventriculitis.

Diagnostic workup

The diagnosis of acute systemic cytomegalovirus infection is based on the presence of clinical signs and symptoms in conjunction with compatible ancillary testing, including qualitative and quantitative polymerase chain reaction (PCR) for cytomegalovirus DNA, serology, pp65 antigenemia, culture, or histopathology. Acute cytomegalovirus infection is probable in the presence of cytomegalovirus IgM antibodies and a 4-fold or greater elevation in virus-specific serum IgG titers. PCR can detect human cytomegalovirus DNA in blood or clinical specimens whereas quantitative antigenemia assay detects viral antigens.

Patients with neurologic complications, such as encephalitis, ventriculitis, or myeloradiculopathy, should have CSF analysis to detect cytomegalovirus DNA or virus-specific intrathecal antibodies (10). Histopathology can provide a definitive diagnosis, particularly in the setting of mononeuritis multiplex, though it is not commonly pursued in CNS disease given the associated morbidity of brain or spinal cord biopsy. Although systemic viremia may be present in end organ disease, it is not ubiquitous. It is important to note that blood tests to detect antigen, culture, or PCR assays are not routinely recommended for cytomegalovirus end organ disease affecting the central or peripheral nervous system as they have a poor positive predictive value for nervous system disease, and a negative test does not rule out disease. In encephalitis and ventriculitis, CSF may show a pleocytosis (lymphocytic, occasionally a mixture of lymphocytes and neutrophils), low to normal glucose, and normal to mildly elevated total protein. In myeloradiculitis, there is typically a polymorphonuclear pleocytosis (neutrophils), with low glucose and elevated total protein.

Neuroimaging findings in acute cytomegalovirus infection are often nonspecific. Cytomegalovirus encephalitis is typically characterized by patchy or confluent areas of high T2 signal intensity in the periventricular white matter, whereas cytomegalovirus ventriculitis is characterized by smooth ependymal diffusion restriction, T2 hyperintensity, or enhancement. Intramedullary spinal cord or polyradicular enhancement may suggest myeloradiculitis (09; 34). Neuroimaging can exclude other pathologic processes, such as neoplasm or vascular pathology.

Electrodiagnostic testing is an important diagnostic investigation for presentations of Guillain-Barré syndrome, suspected myeloradiculitis, and mononeuritis multiplex. In Guillain-Barré syndrome, such testing can confirm the presence of an acute acquired demyelinating polyneuropathy based on distal latencies, conduction velocities, the presence of partial or complete conduction block, late responses (H reflexes and f-response latencies), and observation of a sural-sparing sensory pattern. In myeloradiculitis, the typical electrodiagnostic pattern reveals acute lumbosacral polyradiculopathies. A mononeuritis multiplex is suggested by an acute or subacute asymmetric or non-length-dependent sensorimotor axonal polyneuropathy. Results of electrodiagnostic testing frequently impact decisions to proceed with nerve and muscle biopsy in suspected mononeuritis multiplex, recognizing that concomitant muscle biopsy increases diagnostic sensitivity. In mononeuritis multiplex, potential causes for a similar clinical picture are related to vasculitis associated with hepatitis B or hepatitis C co-infection, cryoglobulinemia, immune complex disease, or drug-induced vasculitides.

Management

Treatment of human cytomegalovirus infection had focused on four antiviral drugs until the approval of letermovir for prophylaxis of human cytomegalovirus infection in allogenic organ transplantation (summarized in Table 2). Ganciclovir, valganciclovir (an oral prodrug of ganciclovir), foscarnet, and cidofovir target the viral DNA polymerase. Letermovir is a small molecule that inhibits the packaging of DNA within the viral particle and is the first of its class to be approved (12). A phase 3 clinical trial showed that letermovir reduced the risk of clinically significant cytomegalovirus infection in patients undergoing allogeneic hematopoietic-cell transplantation (21). Maribavir is a new pUL97 kinase inhibitor that has been shown to be effective in the treatment of resistant cytomegalovirus infection with or without genotype resistance (04). It has been approved by the FDA based on results of this phase 3 study.

Different antiviral strategies may be used depending on the individual patient risk for or degree of immunosuppression, potential for antiviral drug resistance, and drug-specific side effects. In situations of iatrogenic immune suppression, reduction of immunosuppression or a change to medications proven to be less associated with human cytomegalovirus infection may be part of the treatment strategy. The mainstay of therapy with neurologic disease includes intravenous ganciclovir with or without foscarnet. In cytomegalovirus retinitis, local intravitreal ganciclovir or foscarnet is combined with systemic therapy (typically oral valganciclovir), the latter of which may be added to prevent systemic disease and disease in the contralateral eye as well as reduce mortality. The administration of human cytomegalovirus-specific hyperimmune globulin has been shown to be effective in the reduction of human cytomegalovirus infections in patients after solid organ transplant (30; 35).

A major concern is the emergence of human cytomegalovirus resistance to antiviral agents. Antiviral resistance should be suspected when stable or increasing viral loads and persistence of clinical symptoms are observed 7 to 10 days after initiation of full-dose therapy. Ganciclovir’s antiviral activity depends on phosphorylation by the cytomegalovirus protein kinase pUL97, and mutations in pUL97 can confer resistance to ganciclovir. Foscarnet has a different mechanism of action as it inhibits polymerase function through blocking the pyrophosphate binding site of pUL54. Mutations in UL54 can lead to viral resistance against ganciclovir, cidofovir, as well as foscarnet. If clinically indicated, susceptibility testing in peripheral blood using cytomegalovirus DNA PCR testing with sequencing for UL97 mutations or point mutations may be considered to guide antiviral treatment. The emergence of resistant phenotypes is related to the duration of antiviral treatment, particularly in the presence of severe immunosuppression, which allows significant virus replication in the presence of antiviral drugs. However, resistance can emerge in all populations of patients infected by the virus (32).

Maribavir was approved by the FDA in late 2021 as a treatment option for post-transplant treatment-refractory cytomegalovirus infection in adults and children over 12 years of age (and over 35 kg) (18). It can be used to treat disease resistant to ganciclovir, valganciclovir, cidofovir, or foscarnet, with or without genotype resistance.

New drugs targeting resistant phenotypes are being developed (32; 06). Leflunomide, a drug used to treat rheumatoid arthritis, has potent antiviral properties mainly involving viral replication by down-modulating cell signaling pathways in infected cells. Anecdotal data cite leflunomide as effective in renal and cardiac allograft recipients. Leflunomide is low in cost compared to ganciclovir and does not promote cross-resistance with other antivirals due to its different mechanism of action (02). However, further studies will be needed to determine if it may serve as an adjunct to therapeutic regimens against cytomegalovirus because as leflunomide is immunosuppressive, it may not be useful in the AIDS and transplant populations. Human cytomegalovirus-specific adoptive immunotherapy is a developing strategy for treating human cytomegalovirus infection (08). The process of isolating and expanding donor T cells can be enhanced by using MHC-peptide complexes to select specific anti-human cytomegalovirus T cells from whole blood. An alternative immunotherapy strategy is to use HLA-matched allogeneic virus-specific T cells.

Outcomes

Outcomes are discussed in Prognosis and complications, but it is important to recognize that cytomegalovirus disease may have indirect effects in transplant recipients, including graft rejection, secondary bacterial or fungal infection, and accelerated atherosclerosis.

Special considerations

Pregnancy

The Centers for Disease Control reports that about half of expectant mothers in the United States are seronegative and an estimated 1% to 4% of this population may develop primary cytomegalovirus infection during pregnancy. Asymptomatic or a mononucleosis-like primary cytomegalovirus infection during pregnancy can lead to fetal infection in about 30% to 50% of cases, whereas latent or reactivated cytomegalovirus infection leads to fetal infection in 1% of cases. Fetal infections range from asymptomatic to severe. An estimated 10% to 15% of infected fetuses develop congenital cytomegalovirus disease characterized by microcephaly with or without cerebral calcifications, intrauterine growth retardation, and prematurity in 30% to 50% of cases. Of those with asymptomatic infections, 5% to 25% subsequently develop serious psychomotor impairment, hearing loss, or ocular or dental abnormalities. Another study among pregnant women with early primary cytomegalovirus infection showed that treatment with cytomegalovirus hyperimmunoglobulin led to a decreased incidence of neurologic complications of infants at 1 year (39). Congenital cytomegalovirus is discussed in further detail in the MedLink article, “Congenital cytomegalovirus.”

Aging

The number of people over the age of 60 years is expected to double by 2050 according to the World Health Organization. Studies have suggested that elder persons who are seropositive for cytomegalovirus (latent infection) have an impaired humoral immune response to vaccinations, more specifically the influenza vaccine. It appears that age-related changes in T-cell-mediated immunity are augmented by cytomegalovirus infection and may be associated with more serious complications of influenza infection. This indicates that having human cytomegalovirus latent infection increases the influenza-associated morbidity and mortality with age (22).