Human Cytomegalovirus (CMV) is a member of the family Herpesviridae, also known as Human Herpesvirus 5 (HHV-5). It is the largest (220 nm in diameter) and most complex herpesvirus, with a 235,000 double-stranded DNA genome. CMV seroprevalence in immunocompetent adults varies from 40-100% globally.[1]
Signs and symptoms
CMV usually causes an asymptomatic infection or produces mild flulike symptoms; afterwards, it remains latent throughout life and may reactivate.
Most patients with CMV infection exhibit few clinical findings on physical examination.
Primary CMV infection may be a cause of fever of unknown origin.
Symptoms, when apparent, develop 9-60 days after primary infection.
Pharyngitis may be present.
Examination of the lungs may reveal fine crackles.
The lymph nodes and spleen may be enlarged, so CMV should be included in the differential diagnoses of infections that produce lymphadenopathy.
In immunocompromised individuals, symptomatic disease usually manifests as a mononucleosis syndrome. Symptomatic CMV disease can affect almost every organ of the body, resulting in fever of unknown origin, pneumonia, hepatitis, encephalitis, myelitis, colitis, uveitis, retinitis, and neuropathy. Rarer manifestations of CMV infections in immunocompetent individuals include Guillain-Barré syndrome, meningoencephalitis, pericarditis, myocarditis, thrombocytopenia, and hemolytic anemia.
CMV is an opportunistic infection in patients with advanced HIV/AIDS and can effect multiorgan systems. The most common sites of CMV related gastrointestinal infection are the esophagus and the colon. These patients may have concurrent CMV reitinitis and should have formal opthalmologic screening.
See Clinical Presentation for more detail.
Diagnosis
Lab studies
CMV has been detected via culture, serologies, antigen assays, polymerase chain reaction (PCR), and cytopathology. In the transplant population, antigen assays or PCR is used (sometimes in conjunction with cytopathology) for diagnosis and treatment determinations.
Imaging studies
The diagnosis of CMV pneumonia can be suggested by chest radiography findings, but these findings cannot be used to differentiate between other common causes of pneumonia in immunocompromised hosts. A chest radiograph finding consistent with pneumonia and a bronchoalveolar lavage (BAL) result that is CMV positive is a common method for diagnosis.
See Workup for more details.
Management
Healthy people who are infected with CMV but who have no symptoms usually do not require medical treatment.
Antiviral treatment is used for immunocompromised individuals who have eye infections or life-threatening illnesses due to CMV. The drug of choice for prevention of CMV disease in solid-organ transplant patients is valganciclovir.[2] Other than CMV retinitis, however, ganciclovir remains the mainstay of treatment, at least initially.
Second-line treatments include foscarnet, cidofovir, or maribavir.
Cytomegalovirus (CMV) is a double-stranded DNA virus and is a member of the Herpesviridae family. The other family members include herpes simplex virus type 1 (HSV-1 or HHV-1) and herpes simplex virus type 2 (HSV-2 or HHV-2), varicella zoster virus (VZV), human herpes virus (HHV)–6, HHV-7, and HHV-8. CMV shares many attributes with other herpes viruses, including genome, virion structure, and the ability to cause latent and persistent infections. CMV has the largest genome of the herpes viruses. Replication may be categorized into immediate early, delayed early, and late gene expression based on time of synthesis after infection. The DNA is replicated by rolling circles. Human CMV grows only in human cells and replicates best in human fibroblasts.
At least 50-60% of the US population has been exposed to CMV,[3] with a prevalence of more than 90% in high-risk groups (eg, male homosexuals), and outside of the US prevalence can be more than 90%.[4, 5, 6] The prevailing age of infection varies worldwide. In developing countries, most infections are acquired during childhood, whereas in developed countries, up to 50% of young adults are CMV seronegative. The incidence of CMV seropositivity rises with age and in a US-based study was reported to increase from 36% in children aged 6-11 years to 91% in individuals older than 80 years.[7] Other factors associated with CMV seropositivity include ethnicity (77% in Mexican Americans and 71% in Blacks),[8] female sex, foreign-born status, and low socioeconomic status.[8]
CMV usually causes an asymptomatic infection; afterward, it remains latent throughout life and may reactivate. Infection is defined as isolation of CMV, its viral proteins, or its nucleic acid from any tissue sample or body fluid.[9] In immunocompetent individuals, symptomatic disease usually manifests as a mononucleosis syndrome, which was first described in adults in 1965.[10]
Clinically significant CMV disease (reactivation of previously latent infection or newly acquired infection) frequently develops in patients immunocompromised by HIV infection, solid-organ transplantation, or bone marrow transplantation, as well as in those receiving high-dose steroids, tumor necrosis antagonists, or other immunosuppressing medications for conditions such as systemic lupus erythematosus (SLE), rheumatoid arthritis, Crohn disease, or psoriasis, among others. In patients coinfected with HIV, CMV infection leads to progression to AIDS and eventually death, even in those receiving antiretroviral therapy (ART).[11]
Symptomatic CMV disease in immunocompromised individuals can affect almost every organ of the body, resulting in fever of unknown origin, pneumonia, hepatitis, encephalitis, myelitis, colitis, uveitis, retinitis, and neuropathy.
Individuals at an increased risk for CMV infection include individuals who attend or work at daycare centers, patients who undergo blood transfusions, persons who have multiple sex partners, and recipients of CMV mismatched organ or bone marrow transplants.
CMV is transmitted from person to person via close contact with an individual who is excreting the virus. It can be spread through the placenta, blood transfusions, organ transplantation, and breast milk. It also can be spread through sexual transmission.
In the United States, congenital CMV transmission from a mother with acute infection during pregnancy is a significant cause of neurologic abnormalities and deafness in approximately 8000 newborns annually.[12, 13]
Multiple genetically distinct strains of CMV exist. Differences in genotypes may be associated with differences in virulence. Infection with more than one strain of CMV is possible and has been observed in organ transplant recipients. Dual infection is a possible explanation for congenital CMV infection in children of CMV-seropositive mothers.
CMV is a lytic virus that causes a cytopathic effect in vitro and in vivo. The pathologic hallmark of CMV infection is an enlarged cell with viral inclusion bodies. Cells that exhibit cytomegaly also are seen in infections caused by other Betaherpesvirinae. The microscopic description given to these cells is most commonly an "owl's eye," depicted in the image below. Although considered diagnostic, such histologic findings may be minimal or absent in infected organs.
View Image
Hematoxylin-eosin–stained lung section showing typical owl-eye inclusions (480X). Courtesy of Danny L Wiedbrauk, PhD, Scientific Director, Virology & ....
When the host is infected, CMV DNA can be detected with polymerase chain reaction (PCR) in all the different cell lineages and organ systems in the body. Upon initial infection, CMV infects the epithelial cells of the salivary gland, resulting in a persistent infection and viral shedding. Infection of the genitourinary system leads to clinically inconsequential viruria. Despite ongoing viral replication in the kidney, renal dysfunction is rare except in renal transplant recipients, in whom CMV is associated with rare cases of glomerulopathy and possible graft rejection.
Immunology
Primary CMV infection is defined as infection in an individual who was previously CMV seronegative.[9] In these patients, CMV immunoglobulin M (IgM) antibodies may be found as early as 4-7 weeks after initial infection and may persist as long as 16-20 weeks. Most neutralizing antibodies are directed against an envelope glycoprotein gB. Studies have shown that more than 50% of neutralizing activity in convalescent serum is attributable to glycoprotein gB. However, virion tegument proteins such as pp150, pp28, and pp65 evoke strong and durable antibody responses.
CMV is an immunomodulatory virus and may aggravate underlying immune disorders (eg, SLE).
The presence of CMV DNA in the blood and viruria are commonly found in healthy CMV seropositive women. Naturally acquired immunity to the virus does not seem to prevent reinfection or the duration of viral shedding.[14]
Cell-mediated immunity is considered the most important factor in controlling CMV infection. Patients deficient in cell-mediated immunity are at greatest risk for CMV disease. CMV-specific CD4+ and CD8+ lymphocytes play an important role in immune protection after primary infection or reactivation of latent disease. Studies of bone marrow transplant recipients have revealed that those who do not develop CMV-specific CD4+ or CD8+ cells are at higher risk for CMV pneumonitis. Additionally, no cases of CMV pneumonia have been reported in allogeneic marrow transplant recipients receiving infusions of CMV-specific CD8+ cells.[15]
Primary cytomegalovirus infection and viremia
Both replication of CMV DNA and morphogenesis of the virion capsid take place in the nucleus. Following maturation of the capsid, newly synthesized viral DNA is cleaved by an enzyme that results in packaging of linear genomic DNA. Subsequently, viral DNA-containing capsids acquire an inner layer of tegument proteins during their egress from the nucleus, including essential interactions between proteins and capsid protein, that stabilize the interaction between the capsid and the inner tegument layer of the virion. This then is transported along the cytoskeleton until the particle is enveloped. After this, the virus is released from the cell.[1]
Congenital cytomegalovirus disease
CMV is the leading cause of congenital infection worldwide (0.2-6.1% of live births), as well as the most common congenital viral infection in the United States (20000 to 30000 infants/year, mostly Black infants) and the leading cause of sensorineural hearing loss and neurodevelopmental delay in children. Congenital CMV-related sequelae affect over 5000 children per year and add significant cost in direct medical care in the United States. The transplacental transmission rate after maternal primary infection is around 32%. The risk for transmission is low following maternal infection occurring more than 11 weeks before conception.[16, 17, 18, 19]
Most infants are asymptomatic, however, symptomatic infants are seen in about 10% of the patients with a broad range of disease manifestations. These include thrombocytopenia, petechiae, hepatomegaly, splenomegaly, hepatitis, intrauterine growth restriction, CNS involvement (microcephaly, ventriculomegaly, intracerebral calcifications, white matter changes with seizures, and abnormal tone), ophthalmologic abnormalities (chorioretinitis, optic atrophy), and sensorineural hearing loss. Mortality due to congenital CMV infection is low (approximately 4% of infants). Symptomatic disease can be classified as moderate to severe (multiple manifestations with or without CNS involvement) or mild disease (1-2 manifestations with no CNS involvement).[16, 19]
In the pediatric population, congenital CMV infection is the most common cause of non-genetic sensorineural hearing loss (SNHL); this also is the most common permanent sequelae of congenital CMV infection. Around 40-60% of these neonates are at risk for permanent sequelae.[20] Other complications include cognitive impairment, chorioretinitis, and cerebral palsy. Other manifestations include motor deficits and seizures as well in 23% and 19%, respectively. CMV screening approaches could lead to the identification of many more infants with congenital CMV infection than are identified because of clinical signs. Trials are ongoing to formulate a vaccine for pregnant individuals.[16, 21, 22]
Increased rates of reactivation and cervical shedding are seen in advanced stages of gestation, and congenital infection is associated with sequelae previously described. Prevention includes hand hygiene to minimize occupationally acquired CMV (such as daycare centers), as well as limiting the number of sexual partners (during pregnancy).[23]
Cytomegalovirus pneumonia
This can be seen in an immunocompetent as well as an immunocompromised host, including hematopoietic stem cell transplantation (HSCT) recipients and solid organ transplant recipients. Pneumonitis is the most common manifestation of CMV infection in HSCT recipients and has a high mortality. Especially in neonates, it can lead to chronic lung disease and fibrosis. Symptoms include dry cough, shortness of breath, and fever. Imaging abnormalities include abnormal chest Xray with interstitial infiltrates as well as ground-glass opacities seen in computed tomography (CT) scans that could be nonspecific for CMV infections and should be correlated with serologic testing, viral load, respiratory samples, and histopathology.[24]
Cytomegalovirus hepatitis
CMV hepatitis is defined as elevated bilirubin and/or liver enzymes levels in combination with the detection of CMV in the absence of other causes for hepatitis.[9] CMV may be detected via culture, histopathology, immunohistochemistry, or in situ hybridization. CMV PCR alone is not satisfactory for diagnosis, as a positive result may reflect transient viral shedding.[9] The first described case of CMV hepatitis involved a child with chorioretinitis, hepatosplenomegaly, and cerebral calcifications.
Hepatitis has been commonly observed in patients with primary CMV infection and mononucleosis. Levels of hepatocellular enzymes may be mildly and transiently increased, and, in rare cases, jaundice may develop. The prognosis of CMV hepatitis in immunocompetent hosts typically is favorable, but death has been reported in immunosuppressed patients. Histology typically reveals mononuclear cell infiltration of the portal areas but also may reveal granulomatous inflammation.[25]
Cytomegalovirus gastritis and colitis
CMV GI disease is defined as the combination of symptoms of the upper and lower GI tract, mucosal lesions visible on endoscopy, and detection of CMV via culture, histopathology, immunohistochemistry, or in situ hybridization.[9] CMV colitis first was described in 1985 in 2 homosexual men who presented with abdominal pain, diarrhea, and hematochezia.[26] CMV PCR alone is insufficient for diagnosis, as a positive result may simply reflect transient viral shedding.
CMV may infect the GI tract from the oral cavity through the colon. The typical manifestation of disease is ulcerative lesions. In the oral cavity, these may be indistinguishable from ulcers caused by HSV or aphthous ulceration. Gastritis may present as abdominal pain and even hematemesis, whereas colitis more frequently presents as a diarrheal illness. CMV disease of the GI tract often is shorter-lived than that of other organ systems because of the frequent sloughing of infected cells of the GI mucosa.
Cytomegalovirus CNS disease
CMV CNS disease is defined as CNS symptoms in combination with CMV detection in CSF (culture, PCR) or brain biopsy tissue (culture, histopathology, immunohistochemistry, in situ hybridization).[9] The association between CMV and Guillain-Barré Syndrome involves 2 groups. Younger patients (typically < 35 y) present with sensory defects and facial palsy, antiganglioside (GM2) IgM response, and milder long-term sequelae.[27] A second group includes women older than 50 years. These observations were made in France and thus may not be applicable to other populations due to different ages of primary CMV exposure.
Cytomegalovirus retinitis
CMV retinitis is one of the most common opportunistic infections in persons with AIDS, typically those with CD4+ lymphocyte counts below 50 cells/µL. Although the number of cases has decreased with the use of antiretroviral therapy (ART), new cases continue to be reported. Individuals with CMV retinitis typically exhibit a progressive decrease in visual acuity, which may progress to blindness if untreated. Unilateral and bilateral disease may exist. Long-term CMV treatment is necessary to prevent retinitis relapse. All lesions suspected to be CMV retinitis must be confirmed by an ophthalmologist.
Immune reconstitution syndrome (IRIS) is reported in 16-63% of HIV-infected patients with CMV retinitis following the initiation of ART.[28, 29, 30] In one study, the median time to IRIS following ART initiation was 43 weeks but has been reported as early as 4 weeks or as late as 4 years.[31, 29] CMV IRIS may manifest as painless floaters, blurred vision, photopia, decreased visual acuity, or ocular pain. Some patients may develop macular edema leading to vision loss or proliferative vitreoretinopathy, spontaneous vitreal hemorrhage, and retinal detachment.
Cytomegalovirus nephritis
CMV nephritis is defined as CMV detection in combination with a renal biopsy showing CMV-associated changes in the setting of renal failure.[9] CMV PCR alone is inadequate for diagnosis. Of note, detection of CMV in the urine of a patient with renal failure does not meet diagnostic criteria for CMV nephritis.[9] CMV viremia has been associated with acute glomerular injury.[32]
Cytomegalovirus syndrome
In general, it is better to avoid this term in stem cell transplant recipients, as other viruses (eg, HHV-6) also can cause fever and bone marrow suppression.[9] However, in solid organ transplant recipients, CMV syndrome is better defined: fever (>38°C) for at least 2 days within a 4-day period, CMV detection in blood, and either neutropenia or thrombocytopenia.[9]
Graft versus host disease
CMV infection has been associated with acute graft verus host disease in bone marrow transplant recipients. Multiple genotypes (gB 1-4) of CMV exist, each with variations in the gene encoding envelope glycoprotein gB. The association of gB types with acute graft versus host disease and death related to myelosuppression has been examined. Taking into account disease type, donor-recipient HLA matching, donor CMV serostatus, and age, Torok-Storb et al (1997) found that gB3 and gB4 were linked to a higher degree of myelosuppression and death.[33] Interestingly, no specific CMV genotypes were linked to worse outcome in solid organ transplant recipients, although mixed gB genotype infections were associated with higher viral loads and delayed viral clearance.[34]
CMV infection is thought to be specific to humans. The age at presentation, clinical manifestations, and route of infection may vary from person to person, but very few people escape infection during their lifetime.
International
Serologic surveys conducted worldwide demonstrate CMV to be a ubiquitous infection of humans. Depending on the population surveyed, CMV may be found in more than 90% of people, depending on socioeconomic conditions.
CMV seldom is associated with mortality in nonimmunocompromised hosts (< 1%). Substantial morbidity may occur in patients with a mononucleosis syndrome, as described in Adult Cytomegalovirus Infection in the Immunocompetent Host.
In both solid organ and marrow transplant recipients, CMV causes substantial morbidity and mortality. For example, even with antiviral therapy, the mortality rate in allogeneic marrow transplant recipients with interstitial pneumonia varies from 15-75%.
CMV RNA can be detected in 15% of fetal tissues or placentae, indicating that CMV infection during pregnancy contributes to stillbirths.[35]
Age
CMV prevalence increases with age. Age also has been found to be a risk factor for CMV disease in certain transplant populations.
The prognosis of CMV hepatitis generally is good. Most patients recover completely. Symptoms can persist, usually in the form of fatigue, for several months after primary infection.
CMV pneumonia in marrow transplant recipients once carried a mortality rate higher than 85%. The use of ganciclovir plus high-dose immune globulin for the treatment of CMV pneumonia in allogeneic marrow transplant recipients has lowered the mortality rate to 30-60%.
Because patients who develop CMV disease are immunocompromised, their prognosis may be determined by their underlying disease. The need for mechanical ventilation is a poor prognostic sign.
History varies depending on whether the host is immunocompetent or immunocompromised.
Adult cytomegalovirus infection in the immunocompetent host
Cytomegalovirus (CMV) can cause a wide spectrum of infection in immunocompetent hosts. Sites most often involved include the lung (severe community-acquired viral pneumonia), liver (transaminitis), spleen (splenomegaly), GI tract (colitis), CNS (encephalitis), hematologic system (cytopenias), and multisystem involvement (fever of unknown origin). Uncommon sites of CMV infections in immunocompetent individuals include the kidneys, adrenals, salivary glands, pancreas, and esophagus.[10]
In most cases, primary CMV infection is asymptomatic or produces mild flulike symptoms. Symptoms, when apparent, develop 9-60 days after primary infection. The lymph nodes and spleen may be enlarged, so CMV infection should be included in the differential diagnoses of infections that produce lymphadenopathy. Extreme fatigue may persist after normalization of laboratory values.
CMV may produce a mononucleosis syndrome similar to that caused by Epstein-Barr virus (EBV), primary toxoplasmosis, or acute HIV seroconversion. In a large study of 494 patients with infectious mononucleosis, 79% of cases were due to EBV, and, in the 73 heterophile antibody–negative patients, approximately half of these were CMV positive (rising complement-fixing antibodies).[36] In about a third of patients with CMV mononucleosis, a rash also may be present (macular, papular, maculopapular, rubelliform, morbilliform, or scarlatiniform).[37]
Both CMV and EBV may result in atypical lymphocytes in the blood. Other pertinent test results include negative findings on heterophil antibody studies, mildly or moderately elevated levels of aspartate aminotransferases, and evidence of subclinical hemolysis.[38] Hepatitis and atypical lymphocytes usually disappear after 6 weeks. Despite its great sensitivity, the CMV IgM test is limited by a one-way cross-reaction of acute EBV infectious mononucleosis sera. False-positive reactions have resulted from the presence of rheumatoid factors.[38]
CMV infection should be suspected in patients with clinical mononucleosis or fever of unknown origin. Most cases have a paucity of physical examination findings. Some studies have shown that, as a group, patients infected with CMV have less hepatomegaly, splenomegaly, and pharyngitis than those infected with EBV. Patients with CMV mononucleosis may be older, have a longer duration of fever, and have less cervical lymphadenopathy. However, such clinical findings are inadequate to differentiate between the 2 viruses.
Transfusion of multiple blood units is a risk factor for CMV mononucleosis and has been implicated in postoperative fever or fever in patients following trauma. Traditionally, CMV antibody tests were performed using complement fixation and showed peak viral titers 4-7 weeks after infection. Multiple tests for CMV antibody are available, some of which are sensitive enough to detect anti-CMV IgM antibody early in the course of the illness and during CMV reactivation. Reactivation of the virus is not uncommon, sometimes occurring with viremia and a positive IgM result in the presence of IgG antibody. This usually is observed during intercurrent infections or at times of patient stress. The clinical significance, time course, and natural history of reactivation in immunocompetent patients are not known for either virus.
In rare cases, CMV can cause community-acquired pneumonia in immunocompetent hosts[10] and should be considered a possible etiology (along with influenza [human, swine, avian] and adenovirus) in cases of severe viral community-acquired pneumonia.[10] Case reports describe prolonged fever, lack of cough or other respiratory symptoms, bilateral interstitial or patchy infiltrates on chest radiography, relative lymphopenia, atypical lymphocytes, and mild transaminitis.[39] Of note, some patients had negative CMV IgM findings initially but subsequently developed elevated levels of both IgM and IgG, with resolution of the infiltrates over 6 weeks.[39] There are varying degrees of hypoxemia. The prognosis of CMV pneumonia in immunocompetent hosts, even severe cases, usually is good, rarely requires a full course of antiviral treatment, and usually resolves during CMV induction therapy.[10]
Rarer manifestations of CMV infections in immunocompetent individuals include Guillain-Barré syndrome, meningoencephalitis, pericarditis, myocarditis, thrombocytopenia, and hemolytic anemia. Rubelliform or maculopapular rashes are observed with and without administration of ampicillin. GI ulceration may result from acute CMV infection in immunocompetent persons, although this finding is much more likely in immunocompromised individuals.
CMV frequently reactivates in critically ill patients and may be linked to increased length of hospital and/or intensive care stay,[40, 41, 42] duration of mechanical ventilation,[40, 41] morbidity,[42] and mortality.[40, 42, 43] However, an opposing retrospective study looking at the impact of CMV serostatus on outcomes in immunocompetent ICU patients found no association between CMV seropositivity, ICU mortality, in-hospital mortality, time to hospital discharge, duration of mechanical ventilation, or the need for renal replacement therapy.[44]
Further data are required to ascertain if CMV prophylaxis/treatment of critically ill seropositive patients leads to better clinical outcomes.
Adult cytomegalovirus infection in the immunocompromised host
In patients with a history of allogeneic HSCT, CMV infection is a known severe complication, associated with multiorgan disease. Of note, CMV seroposivity is a poor prognostic factor of non-relapse mortality in HSCT recipients. Advanced age is associated with a higher incidence of CMV antigenemia after HSCT. IgG positive recipients from CMV seronegative donors have the worst outcomes. On the other hand, CMV IgG negative recipients from CMV seronegative donors rarely develop severe CMV-related complications. Based on this, patients with hematologic diseases who are going to receive allo-HSCT need to have their CMV sero-status checked prior to the procedure.[45]
Of note, about 30% of the seronegative allo-HSCT recipients of sero-positive donor grafts develop reactivation, but more than 80% of sero-positive recipients are likely to develop CMV reactivation regardless of donor CMV status.[45]
Organ transplantation and cytomegalovirus
CMV is an important pathogen isolated in organ transplant recipients, as primary CMV infection in an organ transplant recipient may be quite severe. CMV disease occurs with the highest frequency in donor-positive/recipient-negative transplant recipients. This relationship is true for all organ transplant recipients except those who receive bone marrow, in whom the highest incidence of CMV disease is in donor-negative/recipient-positive individuals. The reason for this is unknown but may be related to the level of immunosuppression observed in patients who have received marrow transplants compared with those who have received other transplants.
Patients who have received marrow transplants undergo ablative chemotherapy and/or radiation. A period of neutropenia and a loss of specific antigen reactivity follow. All transplant recipients have a period of decreased CMV-specific cell-mediated immunity. The next step is unknown; however, patients at greatest risk for CMV disease develop viremia. The role viremia plays in the pathophysiology of CMV disease is unknown.
Life-threatening CMV pneumonia may develop in immunocompromised patients, with the incidence varying based on the type of transplant received. Patients who receive marrow, lung, heart, heart-lung, liver, pancreas-kidney, and kidney transplants have different levels of immunosuppression. Those most at risk include bone-marrow transplant recipients and recipients of lung transplants. In patients who have received marrow transplants, CMV disease is most likely 30-60 days after transplant. Fatal CMV pneumonia is much less common in patients who have received solid organ transplants than in those who have received marrow transplants. Patients initially may present with an asymptomatic infiltrate on chest radiograph.
The most common clinical presentation of CMV pneumonia is fever and shortness of breath, accompanied by an interstitial infiltrate. The differential diagnoses of CMV pneumonia in immunocompromised patients include Pneumocystis pneumonia, viral respiratory infections, pulmonary hemorrhage, drug toxicity, recurrent lymphoma, and other infections. CMV frequently is detected in the lungs of patients with HIV/AIDS but usually represents viral shedding and does not frequently cause clinically significant disease.
CMV pneumonia is difficult to treat, even with the antivirals now available. The mortality rate among bone marrow transplant recipients with CMV pneumonia was approximately 85% prior to the introduction of ganciclovir and CMV-specific immune globulin. The addition of these drugs has decreased the CMV pneumonia mortality rate to 15-75%. The mortality rate of CMV pneumonia in marrow transplants that requires mechanical ventilation is high, despite treatment with ganciclovir and immune globulin. Poor clinical outcomes also are observed in patients who are also infected with community respiratory viruses (eg, parainfluenza, influenza, respiratory syncytial virus) and those who have received allogeneic marrow transplants. This suggests that the severity of CMV pneumonia is not exclusively secondary to viral characteristics.
The use of immune globulin is based on studies of marrow transplant recipients, which noted improved survival rates in those with CMV pneumonia who received combination therapy (ganciclovir plus immune globulin).[46] This has not been studied in patients with CMV pneumonia who have received solid organ transplants. Some experts believe that the mechanism of CMV pneumonia in patients who have received solid organ transplants may differ from that in marrow transplant recipients, making the addition of immune globulin unnecessary in the former. CMV pneumonia in marrow transplant recipients does not appear to involve a simple and direct viral cytopathic effect on pneumocytes. The addition of CMV-specific immune globulin has not been shown to affect the mortality and morbidity of CMV infection of other organ systems.
Severe CMV disease likely is secondary to synergism between the virus and other factors, such as radiation, chemotherapy, conditioning regimens, a nonimmune inflammatory response, or other infections. The diagnosis of CMV pneumonia depends on recovering CMV from patients with a positive finding on chest radiograph and appropriate clinical signs. CMV may be isolated from the lung with bronchoalveolar lavage (BAL) or open lung biopsy.
In support of the diagnosis, CMV antigen or inclusions are found with histological examination. CMV isolated from clinical samples in the absence of clinical symptoms may represent viral colonization or subclinical replication. In many cases, the detection of subclinical replication in transplant recipients warrants antiviral suppressive therapy. In patients infected with HIV, antiviral therapy often is not required in the absence of clinically apparent disease.
Primary GI CMV disease in solid organ transplant recipients is difficult to treat and may relapse. The relapse rate was studied in solid organ transplant recipients following treatment for CMV infection at the Mayo clinic. The investigators found that extensive involvement of the GI tract was significantly associated with CMV relapse but that endoscopic resolution of GI disease did not necessarily translate into a reduced risk for CMV relapse.[47]
Human immunodeficiency virus disease and cytomegalovirus
CMV often is isolated from patients who are co-infected with other bacterial, parasitic, and fungal pathogens. In fact, CMV may be found in the lungs of approximately 75% of individuals infected by both HIV and Pneumocystis.[10] The etiology of CMV infection in Pneumocystis pneumonia is unclear, and treatment of the latter usually leads to resolution of the pneumonia and hypoxemia, meaning that CMV treatment typically is not warranted in most cases.
For unknown reasons, CMV pneumonia without a co-infecting pathogen is uncommon.
In patients with HIV infection, CMV can involve parths of the entire GI tract. In the upper GI tract, CMV has been isolated from esophageal ulcers, gastric ulcers, and duodenal ulcers. Patients with upper GI tract esophageal disease can present with painful dysphagia. Patients with CMV disease of the lower GI tract may present with diarrhea (colitis). CMV colitis frequently affects only the right colon, necessitating full colonoscopy and multiple biopsies for accurate diagnosis.[48] Diagnosis of CMV GI disease depends on a biopsy specimen demonstrating the typical CMV intranuclear inclusions.
Recovery of CMV in tissue culture may be helpful but is difficult to interpret because of CMV shedding. CMV may be isolated from many different sites and is not necessarily associated with disease, reinforcing the need for histopathologic examination.
Retinitis is the most common manifestation of CMV disease in patients who have advanced HIV/AIDS. It occurs most commonly in patients with CD4 counts below 50 cells/µL, with rates of up to 40% in this population. Affected patients report decreased visual acuity, floaters, and loss of visual fields on one side. In many cases, it progresses to bilateral involvement that may be accompanied by systemic CMV disease. Ophthalmologic examination shows yellow-white areas with perivascular exudates. Hemorrhage is present and often is referred to as having a "cottage cheese and ketchup" appearance. Lesions may appear at the periphery of the fundus, but they progress centrally.
Ganciclovir has been used to treat CMV retinitis. Many clinicians switch to foscarnet after ganciclovir fails. Ganciclovir implants have emerged as an important therapy in the management of CMV retinitis. The optimal treatment consists of ganciclovir implants in the vitreous, accompanied by systemic ganciclovir therapy. Oral ganciclovir may be used for prophylaxis of CMV retinitis but should not be used for treatment. The incidence of CMV retinitis has dropped since the widespread use of highly active antiretroviral therapy. During reconstitution of the immune response in patients who are HIV positive and on antiviral therapy, retinitis may worsen for a period. If severe inflammation is present, corticosteroid treatment may be necessary.
In patients who are HIV positive, CMV may cause disease in the peripheral and central nervous system.[49]
Most patients with CMV infection exhibit few clinical findings on physical examination.
Primary CMV infection may be a cause of fever of unknown origin.
Symptoms, when apparent, develop 9-60 days after primary infection.
Pharyngitis may be present.
Examination of the lungs may reveal fine crackles.
The lymph nodes and spleen may be enlarged, so CMV should be included in the differential diagnoses of infections that produce lymphadenopathy.
Many physicians believe that CMV mononucleosis is less associated with pharyngitis and cervical adenopathy than EBV infectious mononucleosis. A study in young children questioned the accuracy of this clinical pearl. The study found that cervical adenopathy was more common in patients infected with EBV than in patients infected with CMV (83% versus 75%). Although statistically significant, relying on this sign for the differentiation between CMV and EBV mononucleosis is difficult.
Despite long treatment courses with valganciclovir and documented clearance of CMV viremia, CMV relapse remains common among solid organ transplant recipients.[50] A better understanding of the epidemiology of CMV infection among solid organ transplant recipients and risk factors for disease relapse is warranted.
In congenital CMV disease, laboratory abnormalities may include abnormal transaminases, bilirubin and platelet levels. To diagnose congenital CMV infection, testing should be performed within the first 3 weeks of life, because testing past this period does not differentiate intrauterine from perinatal acquisition of CMV infection. Saliva CMV PCR is the preferred diagnostic test for newborn congenital CMV screening, because high viral loads are shed in both urine and saliva in infants with congenital CMV. Due to some false-positive results in breastfeeding patients, obtaining a sample of saliva at least 1 hour after could avoid potential contamination with CMV from human milk. Other recommended tests include polymerase chain reaction (PCR) in blood and urine as well.[16, 22]
The prognostic value of CMV viral load in neonatal samples, especially with asymptomatic infection, is unclear. The role of virus burden in the peripheral blood, urine, and saliva in disease and outcome needs further study.[16]
Antigen testing
Antigenemia is defined as the detection of the CMV pp65 antigen in leukocytes.[9]
The pp65 assay is used to detect messenger matrix proteins on the CMV virus, with either immunofluorescence assay or messenger RNA amplification. These proteins typically are expressed only during viral replication.
Antigen tests often are the basis for institution of antiviral therapy in transplant recipients and may allow for the detection of subclinical disease in high-risk patients. The assay is sensitive and specific and yields results quickly.
Antigen assays cannot be used in patients with leukopenia, as these tests detect antigen within neutrophils.
In immunocompromised patients, low or moderate CMV antigenemia may indicate reactivation or infection.[10]
It has been reported that the pp65 antigen assay and quantitative CMV PCR (COBAS Amplicor Monitor Test; see Quantitative polymerase chain reaction) yield similar effectiveness in diagnosing and monitoring patients with active CMV infection.[51]
Qualitative polymerase chain reaction
Qualitative PCR is used to detect CMV in blood and tissue samples.
PCR depends on the multiplication of primers specific for a portion of a CMV gene. The primers usually bind to the area of virus that codes for early antigen.
Qualitative PCR is extremely sensitive, but, because CMV DNA can be detected in patients with or without active disease, the clinical utility of qualitative PCR is limited.[52, 53, 54] Serial PCR may be more helpful clinically.
It yields a positive result before the antigenemia test in transplant recipients with viremia.
Results typically are negative in patients without CMV viremia.
In transplant recipients, a negative CMV PCR result goes against reactivation, but not infection.[55]
Commercially available qualitative PCR testing can be performed using the NucliSens CMV Test, a nucleic acid sequence-based amplification assay (NASBA, Organon Teknika Corporation, Durham, North Carolina).
Quantitative polymerase chain reaction
Quantitative PCR has been used to detect plasma CMV. The advantage of quantitative PCR over regular PCR is unknown. Ideally, quantitative PCR is as sensitive as qualitative PCR and provides an estimate of the number of CMV genomes present in plasma.
A study of newborns compared real-time PCR assays of liquid-saliva and dried-saliva specimens with rapid culture of saliva specimens obtained at birth. Both PCR assays showed high sensitivity and specificity for detecting CMV infection.[56]
A study of more than 3400 blood specimens from organ transplant recipients tested with CMV PCR and pp65 antigenemia found that quantitative real-time PCR for CMV DNA could be used in lieu of antigenemia for monitoring CMV infection and determining when to initiate preemptive treatment.[57]
In theory, the CMV viral load would indicate whether therapy is necessary because patients whose viral load is below a certain cutoff would not develop CMV disease. However, the level of viremia necessary for CMV disease to occur may vary depending on host factors and the type of organ transplant, and this may need to be determined empirically. For example, in CMV retinitis, the viral load has a poor positive predictive value, meaning its clinical utility is limited. A detectable CMV viral load at the time of CMV retinitis diagnosis was shown in one study to correlate with increased mortality (P = 0.007).[58] CMV involvement of the GI tract also has a poor correlation with CMV viremia.
Commercially available quantitative PCR assays include the COBAS Amplicor CMV Monitor test (Roche Diagnostics, Indianapolis, IN) and various laboratory-developed PCR assays. The COBAS Amplicor CMV Monitor test measures viremia in the range of 600-100,000 copies/mL.[59]
In the quest to standardize viral load testing for CMV, the FDA approved marketing in July 2012 of a fully automated assay, the COBAS AmpliPrep/COBAS TaqMan CMV test (CAP/CTM CMV test, Roche Molecular Diagnostics, Pleasanton, CA), which uses an international standard to quantitate plasma CMV load. This assay is available in Europe, but not yet in the United States. It measures viremia in a range of 150-10,000,000 copies/mL.[60]
Because viral loads are not comparable among different assays, it is important to use the same test and same sample type (whole blood or plasma) when monitoring patients over time.[61]
Shell vial assay
The shell vial assay is performed by adding the clinical specimen to a vial that contains a permissive cell line for CMV. The shell vials are centrifuged at a low speed and placed in an incubator. After 24 and 48 hours, the tissue culture medium is removed and the cells are stained using a fluorescein-labeled anti-CMV antibody. The cells are read using a fluorescent microscope. Alternatively, the cells are stained with an antibody against CMV, followed by a fluorescein-labeled anti–immune globulin.
This test has been found to be as sensitive as traditional tissue culture.
Cytopathology
Intracellular inclusions surrounded by a clear halo may be demonstrated with various stains (Giemsa, Wright, hematoxylin-eosin, Papanicolaou). This gives the appearance of an "owl's eye" (see Pathophysiology).
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Hematoxylin-eosin–stained lung section showing typical owl-eye inclusions (480X). Courtesy of Danny L Wiedbrauk, PhD, Scientific Director, Virology & ....
The diagnosis of CMV pneumonia can be suggested by chest radiography findings, but these findings cannot be used to differentiate between other common causes of pneumonia in immunocompromised hosts. A chest radiograph finding consistent with pneumonia and a BAL result that is CMV positive is a common method for diagnosis.
CT scan is more sensitive for the identification of infiltrate. It has been valuable in patients who present with hypoxia and no infiltrate visible on chest roentgenography.
If resistant CMV infection is suspected (refractory to IV ganciclovir or valganciclovir therapy), an alternative therapy should be used based on genetic resistance. UL54 mutation is associated with ganciclovir resistance and a cross-resistance with cidofovir. UL97 mutation is also associated with ganciclovir resistance. If this is noted, foscarnet is the recommended therapy. Letermovir could be an alternate option due to a different mechanism of action (however this is recommended only for prophylaxis). If low levels of resistance is suspected, higher doses of ganciclovir could be used.[62]
The hallmark of CMV infection is the finding of intranuclear inclusions consistent with herpesvirus infection. CMV infection may be confirmed using in situ hybridization or direct or indirect staining of intranuclear inclusions using CMV-specific antibodies linked to an indicator system (eg, horseradish peroxidase, fluorescein).
View Image
Hematoxylin-eosin–stained lung section showing typical owl-eye inclusions (480X). Courtesy of Danny L Wiedbrauk, PhD, Scientific Director, Virology & ....
View Image
Here, using immunofluorescent technique, a specimen of human embryonic lung (25X) reveals the presence of cytomegalovirus. Courtesy of the CDC and Dr ....
There are various CMV-treatment approaches based on the patient’s CMV status and co-morbidities. Some patients receive prophylaxis whereas some receive preemptive therapy. Prophylaxis is given to a patient to prevent primary, reactivation, or recurrent infection. Preemptive therapy is given to asymptomatic CMV-infected patients with CMV detected by screening tests. Some studies have shown that high-dose acyclovir or valacyclovir prophylaxis markedly reduces CMV infection in allo-HSCT recipients. Intravenous ganciclovir also has been tested, with some reduction in CMV infection; however, this did not provide overall survival benefit and was associated with bone marrow suppression (ganciclovir-induced neutropenia).[45]
Letermovir, a novel viral terminase inhibitor, has been used for primary prevention of CMV in sero-positive allo-HSCT recipients, however, has not been approved for solid organ transplant recipients.[63, 64] A meta-analysis by Li et al, has shown only 10% CMV reactivation rate at 14 weeks after allogeneic hematopoietic stem cell transplantation in patients that received letermovir within 3 months (its effectivity decreases beyond this three-month-period).[65] This may reduce mortality by preventing or delaying clinically significant CMV infection in these patients.[21, 63, 66] It also is indicated for prevention of CMV in adult kidney transplant recipients at high risk (donor CMV seropositive/recipient CMV seronegative [D+/R-]).[67]
Ganciclovir treatment
The drug of choice for the treatment of CMV disease is intravenous ganciclovir, although valganciclovir may be used for nonsevere CMV treatment in selected cases.
Ganciclovir is a nucleoside analogue that inhibits DNA synthesis in the same manner as acyclovir. The major difference is that CMV does not contain a thymidine kinase.
Protein UL97 phosphorylates ganciclovir to ganciclovir monophosphate. One of the mechanisms of ganciclovir resistance is a change in UL97. Mutations at codon 460 and 520 and mutations or deletions around codons 590-596 in UL97 cause most ganciclovir resistance, although other resistance mechanisms may be present.
Ganciclovir has activity against CMV, HSV, VZV, and HHV-6, HHV-7, and HHV-8. However, one of the other nucleoside analogues (eg, famciclovir, penciclovir, acyclovir) is preferred to treat VZV and herpes simplex infections.
The major adverse effects of ganciclovir therapy include fever, rash, diarrhea, and hematologic effects (ie, neutropenia, anemia, thrombocytopenia). Neutropenia is managed by dose reduction and/or the addition of growth factors (ie, granulocyte colony-stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]).
Oral ganciclovir results in serum levels that are 5-10 times less than intravenous ganciclovir, making oral ganciclovir a less-than-optimal agent for the management of active disease. Valganciclovir hydrochloride, an oral version (L-valyl ester) of ganciclovir, has been approved for the treatment of CMV retinitis in HIV-positive patients.
A randomized trial of patients with CMV retinitis showed that oral valganciclovir was as effective as intravenous ganciclovir when used as an initial treatment.[68] Although no trials have compared oral valganciclovir as a maintenance treatment, pharmacokinetic studies suggest valganciclovir is approximately as effective as intravenous ganciclovir
See the Medication section for dosing.
In the treatment of CMV pneumonia, ganciclovir is administered with CMV-specific immune globulin (dosing in Medication section).[46] However, it is unknown how immune globulin facilitates ganciclovir so that it leads to a better outcome in CMV pneumonia.
The length of treatment varies. Some clinicians have administered ganciclovir for as long as 2-4 weeks from the end of the induction period, depending on the clinical status of the patient. Investigators have studied shorter courses of intravenous ganciclovir therapy for CMV infection and disease, followed by transition to oral valganciclovir.[69] If effective, this may help to improve patient quality of life and reduce the length of hospital stay.[69]
Other uses of ganciclovir include treatment of GI disease in transplant recipients and in patients who are HIV positive. Ganciclovir has been used to treat CMV esophagitis in both of these patient populations.
The drug also is used to treat diarrhea secondary to colitis or enteritis in patients positive for HIV after tissue biopsy and confirmation of CMV disease. Because of the high probability of CMV disease relapse (50%), maintenance therapy should be offered to most patients.[70]
Ganciclovir has been used to treat CNS disease, including encephalitis and neuropathy, with mixed results.
Valganciclovir
Valganciclovir is a prodrug of ganciclovir that is activated in the gut and liver to ganciclovir.
Valganciclovir has 60% bioavailability. Valganciclovir 900 mg orally once daily is equivalent to once-daily intravenous ganciclovir 5 mg/kg.
One meta-analysis showed equivalent efficacies between 900 mg of valganciclovir and 450 mg for cytomegalovirus prophylaxis in transplantation, though the 900 mg daily was associated with 3 times increased risk for leucopenia and 2 times increased risk for rejection.[71, 72]
Valganciclovir is used for treatment in selected CMV cases.[73] Most experience has been established in renal and pancreas transplant recipients and patients with AIDS who have CMV retinitis.
It is also the drug of choice now for preemptive or universal CMV prophylaxis.[2] Routine valganciclovir prophylaxis was favored over preemptive therapy in a randomized controlled trial of CMV-positive renal allograft recipients.
A glomerular filtration rate (GFR) below 10 is a contraindication to valganciclovir use.
Ganciclovir prophylaxis
A major successful use of ganciclovir has been prophylactic or preemptive treatment of CMV disease in transplant recipients. Without preventive CMV therapy, 30-75% of transplant recipients develop CMV infection, and 8-30% develop CMV disease.[73, 74]
Oral ganciclovir has been replaced by valganciclovir for prophylaxis and preemptive therapy because of bioavailability issues.
Prophylaxis is provided to all patients who have positive CMV serology results. Positive findings on blood cultures, pp65 antigenemia, and CMV PCR have been used as markers for the initiation of therapy. Both the prophylactic and the preemptive approaches have been used, and both have been found to decrease CMV disease in bone marrow or solid organ transplant recipients. The choice of the appropriate regimen may be determined by the adverse effects of the drugs and the abilities of the microbiology laboratory. Universal prophylaxis versus preemptive therapy as the best approach remains a matter of debate and varies among institutions. Recent data favor universal prophylaxis with either ganciclovir or valganciclovir in high-risk liver transplant recipients.[75]
Preemptive therapy is attractive because it restricts the use of ganciclovir to a select population at high risk for CMV disease, eliminates toxicity in most patients who would not be diagnosed with CMV disease, and decreases the cost of medical care.
A study compared 96 renal transplant recipients in Italy between May 2006 and December 2007, all of whom received preemptive therapy with ganciclovir and/or valganciclovir, with 100 controls who received CMV prophylaxis. Serial quantitative viral loads were obtained weekly during the first 4 months. Asymptomatic patients, with a viral load DNA of more than 100,000 copies/mL determined using PCR, were treated for 3 months or until resolution of viral replication. Among the 96 transplant recipients, blood CMV viral loads were elevated in 14 asymptomatic patients, who were treated with oral valganciclovir for 3 months. After a median follow-up period of 13.3 months, none of the 14 patients who received valganciclovir developed CMV disease, leading the authors to conclude that valganciclovir administered as preemptive therapy was safe and efficacious in preventing CMV disease.[76]
Conversely, a study using CMV pp65 antigenemia as the trigger for treatment found prophylaxis to be more effective than preemptive therapy for preventing CMV pneumonia in marrow transplant recipients.[77] At the same time, however, ganciclovir at engraftment was associated with more early invasive fungal infections and more late CMV disease.[77]
Some experts believe CMV prophylaxis in solid organ transplant recipients may protect against indirect CMV effects not measurable by levels, such as graft rejection, opportunistic infections, and transplant-associated vasculopathy.[73]
Prophylactic approaches have been very successful in eliminating CMV disease; however, toxicities are increased with this approach because patients without viral reactivation may be exposed to antiviral therapy. Many transplantation centers reserve prophylactic therapy for patients most at risk (CMV-positive donors/CMV-negative recipients) for disease reactivation and use antigen assays to institute preemptive therapy in other patients.
Some experts recommend extending the duration of CMV prophylaxis to the period of reduced immunosuppression. They feel this may protect patients from late-onset CMV disease.[73]
Prolonged ganciclovir use has been associated with development of resistance.
Letermovir prophylaxis
Letermovir is an anti-CMV drug that was approved by the FDA in November 2017. It inhibits the CMV DNA terminase complex (pUL51, pUL56, and pUL89), which is required for viral DNA processing and packaging by affecting the production of proper unit length genomes and interfering with virion maturation. Approval of letermovir was based on a phase 3 clinical trial (n=565). In this study, significantly fewer patients developed clinically significant CMV infection in the letermovir group (38%; n=122/325) compared to the placebo group (61%; n=103/170). In addition, fewer patients discontinued treatment or had missing data through week 24 post-HSCT (P< 0.0001), the primary efficacy endpoint.
All-cause mortality in patients receiving letermovir was lower compared with placebo, 12% vs 17% at week 24 posttransplant. The incidence of bone marrow suppression in the letermovir group was comparable to that of the placebo group. The median time to engraftment was 19 days in the letermovir group and 18 days in the placebo group.[63]
Of note, letermovir has only been approved for allogenic -HCST recipients and not for solid organ transplant recipients. Patients under letermovir prophylaxis need additional antiviral for human herpes virus coverage such as HSV and VZV since letermovir does not have activity against these mentioned viruses.[78]
Foscarnet
Foscarnet is a DNA chain inhibitor of phosphorylation and it is considered the drug of choice for ganciclovir-resistant CMV infections. The most common mutations are UL97 phosphotranferase-gene (ganciclovir and maribavir resistance) and UL 54 polymerase-gene (ganciclovir, cidofovir, and foscarnet resistance).[79]
Meticulous attention must be paid to the patient's renal function. Small changes in creatinine levels require new calculations for renal clearance. Foscarnet is nephrotoxic. The patient must be well hydrated.
Foscarnet may cause changes in calcium and phosphorus metabolism. Other adverse effects include neurological toxicities, anemia, headache, and nausea. It can cause a fixed drug reaction on the penis.
See the Medication section for dosing.
Foscarnet does not require intracellular phosphorylation. Foscarnet resistance is secondary to mutations of the viral DNA polymerase involving codons from 696-845.
Acyclovir prophylaxis
High-dose valacyclovir, penciclovir, famciclovir, and acyclovir have been used for CMV prophylaxis in organ transplant recipients. The results have been mixed and depend on the transplant population.
European transplant groups are more likely to use acyclovir or valacyclovir for CMV prophylaxis than their US counterparts.
In vitro assays have shown that some strains of CMV may be susceptible to acyclovir.
Overall, acyclovir prophylaxis is not as effective as prophylaxis with ganciclovir.
Cidofovir prophylaxis
Cidofovir is a nucleotide that inhibits DNA replication.
It is effective against a broad range of viruses. It has been used for the treatment of refractory CMV retinitis in HIV-positive patients.
Ganciclovir resistance does not necessarily preclude the use of cidofovir.
See the Medication section for dosing.
The patient must be hydrated, and the drug must be administered with probenecid to protect the renal tubules
Maribavir
Maribavir has significant activity against both human cytomegalovirus (CMV) and Epstein-Barr virus, but not other herpesviruses.
Maribavir is a benzimidazole nucleoside and prevents viral DNA synthesis, as well as capsid nuclear egress.
Unlike ganciclovir, which requires phosphorylation by UL 97 kinase to become an active inhibitor of DNA polymerase, maribavir directly inhibits UL 97 kinase.
Maribavir's bioavailability is greater than that of oral ganciclovir, but less than that of valganciclovir.
It may be useful for CMV resistant to ganciclovir, foscarnet, or cidofovir; however, the optimal dose, treatment duration, and use in combination versus monotherapy are undefined.[80]
In the phase 3 AURORA trial, a double-blinded, randomized, multicenter, double-dummy, and active control study, maribavir and valganciclovir were compared for treatment effectiveness. The recommended dose for maribavir was 400mg twice a day (BID) versus valganciclovir with a maximum dose of 900mg BID. The primary endpoint of this study was to compare the clearance of CMV viremia in 8 weeks between these two medications. It was observed that maribavir was not inferior to valganciclovir, with a margin of 7% (adjusted difference: −7.7%; 95% CI: −14.98, −.36). In regards to the second endpoint, there was no significant difference in viremia clearance and clinical findings of CMV-tissue invasive disease up to 16 weeks between maribavir and valganciclovir (52.7% vs 48.5%; adjusted difference: 4.4; 95% CI: −3.91, 12.76).[81]
By the other hand, in SOLSTICE trial, Maribavir shown to be superior in clearing CMV viremia when compared with valganciclovir/ganciclovir, foscarnet, or cidofovir. In addition, the safety of maribavir compared to valganciclovir for treatment was preferred due to less incidence of neutropenia (16.1%) when compared with valganciclovir (52.1%) and less acute kidney injury when compared with foscarnet (8.5% vs 21,3%) leading to continuation of the medication.[82]
Maribavir differs from current CMV antiviral agents in its adverse event profile. It is not associated with nephrotoxicity or hematologic toxicity but has been associated with taste disturbances.[83]
Leflunomide
Leflunomide is an antimetabolite used as a disease-modifying agent in rheumatoid arthritis. It has also been successfully used off-label in both CMV disease treatment and prophylaxis.[84, 85, 86]
Leflunomide failure has been reported in hematopoietic stem cell transplant recipients.[87]
See the Medication section for dosing.
Cytomegalovirus immune globulin
CMV immune globulin has been approved by the US Food and Drug Administration for the prophylaxis of CMV disease in high-risk lung transplant recipients when given in conjunction with ganciclovir. In a retrospective study of cardiothoracic transplant recipients, those who received CMV immune globulin plus ganciclovir had a higher disease-free incidence of CMV, less rejection, higher survival rate, and reduced coronary intimal thickening compared with patients who received ganciclovir alone.[88] A prospective randomized study is required to confirm these observations.
CMV immune globulin is used in combination with ganciclovir to treat CMV pneumonia.
Obtaining a consultation with an infectious disease specialist in patients with CMV viremia or pneumonia is prudent. This is particularly true in patients who are HIV positive, patients who have received organ transplants, and individuals who are immunocompromised in any other way (eg, heavy steroid use, tumor necrosis antagonists)
Antiviral medications have many adverse effects that are best managed by a physician who has experience using these drugs.
Cidofovir and foscarnet have significant toxicity, including acute permanent renal failure. These drugs should be administered in conjunction with a clinician experienced in their usage.
Hematologist
CMV infection may cause hemolytic anemia and thrombocytopenia.
A hematologist may be consulted in severe cases.
Neurologist
CMV may cause aseptic meningitis, encephalitis, polyneuritis, and Guillain-Barré syndrome.
A neurologist may be helpful in the management of these diseases.
Ophthalmologist
Chorioretinitis may be observed in immunocompromised hosts.
In addition, consultation with an ophthalmologist is important in monitoring patients with HIV for opportunistic infections, especially patients with a CD4 cell count of fewer than 100 cells/µL.
Patients with CMV infection commonly ask when they can resume their usual activities. The most common symptom after resolution of the acute phase of CMV infection is fatigue, which may persist up to 18 months after the primary infection but usually is much shorter. Some patients resume their usual activities almost immediately, but the average time to recovery from fatigue is 1-2 months. Patients should resume activity as they can tolerate.
See Medical Care for a discussion about early treatment versus prophylaxis with ganciclovir.
Other drugs have been used for CMV prophylaxis, but none is as effective as valganciclovir (drug of choice)[2] or ganciclovir. Acyclovir and valacyclovir have been used for prophylaxis and early treatment in allogeneic marrow transplant recipients. Acyclovir also has been used in recipients of other types of transplants.
Letermovir is indicated for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Among 495 patients with undetectable CMV DNA at randomization, fewer patients in the letermovir group than in the placebo group had clinically significant CMV infection or were imputed as having a primary end-point event by week 24 after transplantation (P < 0.001).[63]
Additionally, letermovir is indicated for prophylaxis of CMV disease in adult kidney transplant recipients at high risk (donor CMV seropositive/recipient CMV seronegative [D+/R-]). Letermovir (n = 289) was noninferior to valganciclovir (n = 297) for prevention of CMV disease through week 52 (10.4% vs 11.8% of participants with committee-confirmed CMV disease).[67]
CMV remains the most common viral cause of severe disease in the transplant population, with significant associated morbidity and mortality. This, together with the issue of drug treatment toxicities and drug interactions, makes the development of a successful vaccine a high priority.[89] A CMV glycoprotein-B vaccine containing an MF59 adjuvant is in a phase 2 randomized placebo-controlled trial in transplant recipients.[90]
Congenital CMV infection is an important cause of hearing, cognitive, and motor impairments in newborns. A phase 2, placebo-controlled, randomized, double blind trial by Pass et al (2009) evaluated a recombinant CMV vaccine (envelope glycoprotein B with MF59 adjuvant). Three doses of the CMV vaccine or placebo were administered at 0, 1, and 6 months to 464 CMV-seronegative women within 1 year after they had given birth. After a minimum follow-up period of 1 year, 49 confirmed CMV infections were reported—18 in the vaccine group and 31 in the placebo group. One infant in the vaccine group was found to have congenital CMV infection, whereas 3 infants from the placebo group were infected. Ongoing research continues to evaluate the potential for a CMV vaccine to decrease maternal and congenital CMV infection.[91]
When ganciclovir is administered on an outpatient basis for the treatment of CMV retinitis, follow-up with a CBC count once per week (monitoring for hematological toxicity) is necessary. Monitoring electrolytes at the same time is prudent. Ganciclovir therapy should be stopped when neutrophil counts are less than 500 cells/µL. Starting growth factors, such as GM-CSF or G-CSF, may be necessary. A switch to foscarnet may be required at this time.
Patients with CMV retinitis should undergo regular ophthalmologic examinations.
Patients with cytomegalovirus (CMV) disease must be well hydrated.
Nutrition is an important factor because many patients are debilitated by transplant or HIV disease.
As with any patient, attention must be focused on avoiding iatrogenic infections and problems.
Patients who develop CMV disease are immunocompromised, meaning that they are at greater risk for bacterial and fungal infections. If possible, the patient's level of immunosuppression should be lowered.
The goals of pharmacotherapy are to prevent outbreaks of the disease and its complications and to reduce morbidity. Several agents are available for the treatment of cytomegalovirus (CMV) infection and disease.
In addition, multiple agents are being looked at for the treatment of CMV disease. These include (1) CMX001 (hexadecyloxypropyl-cidofovir, an ester of cidofovir), which is under development for ganciclovir-resistant CMV disease[92] ; (2) leflunomide, a pyrimidine synthesis inhibitor[93] (Leflunomide has been successfully used in solid organ transplant recipients for both CMV treatment and prophylaxis. Unfortunately, leflunomide failure has been reported in hematopoietic stem cell transplant recipients[87] ); and (3) artesunate, an antimalarial with some in vitro activity against CMV.[94, 95]
Letermovir, a member of the novel class of 3,4-dihydroquinazolinyl acetic acids, is indicated for CMV prophylaxis in adult CMV-seropositive recipients of an allogeneic HSCT and kidney transplant recipients.[63, 67]
Maribavir, a benzimidazole antiviral agent, has been used as salvage therapy in a small number of patients with multidrug-resistant CMV,[80] but was unsuccessful when used as CMV prophylaxis in allogeneic stem cell transplant patients[64] or in liver transplant recipients.
Clinical Context:
Ganciclovir is a synthetic guanine derivative nucleoside analog active against CMV. It inhibits replication of herpes viruses both in vitro and in vivo. In patients with HIV infection, resistance manifests as progressive disease.
Clinical Context:
Foscarnet inhibits viral replication of herpesviruses (CMV, HSV-1, HSV-2) at pyrophosphate-binding site on virus-specific DNA polymerases. It is used for ganciclovir-resistant CMV retinitis and herpes simplex disease.
Clinical Context:
Cidofovir is approved for the treatment of CMV retinitis in AIDS. It is a nucleotide analog, whose active metabolite inhibits herpes virus polymerases at concentrations that are 8- to 600-fold lower than those needed to inhibit human cellular DNA polymerases alpha, beta, and gamma. Incorporation of cidofovir into the growing viral DNA chain results in reductions in the rate of viral DNA synthesis.
Clinical Context:
Letermovir is part of a new class of non-nucleoside CMV inhibitors, the 3,4 dihydro-quinazoline-4-yl-acetic acid derivatives, and has activity in the late stages of viral replication rather than against the viral DNA polymerase like other anti-CMV therapies. Specifically, letermovir inhibits the viral terminase complex at pUL56 and pUL89, which leads to compromised viral replication by preventing genomes of proper unit length and the accumulation of immature viral DNA. Advantages of letermovir use include oral route and fewer side effects (no myelosupression, no nephrotoxicity).
It is indicated for prophylaxis of CMV infection and disease in adult CMV-seropositive recipients [R+] of an allogeneic hematopoietic stem cell transplant (HSCT). Additionally, it is indicated for prophylaxis of CMV disease in adult kidney transplant recipients at high risk (donor CMV seropositive/recipient CMV seronegative [D+/R-]).
Clinical Context:
Valganciclovir is an L-valyl ester prodrug of ganciclovir. It is used for CMV disease prophylaxis in various solid organ transplant recipients. It inhibits the replication of human CMV in vitro and in vivo. Valganciclovir achieves serum levels comparable to those obtained with IV ganciclovir.
There are multiple antivirals with different mechanisms of action; these include DNA polymerase inhibitors like ganciclovir (nucleoside analog), cidofovir (nucleotide analog) as well as pyrophosphate analogues such as foscarnet. Ganciclovir is considered the treatment of choice for CMV infections.
Clinical Context:
CMV immune globulin (CMV-IG) is a preparation of immunoglobulin derived from pooled healthy blood donors with high CMV titers; administration provides a passive source of antibodies against cytomegalovirus. It is used for CMV pneumonia treatment. It may also be used for CMV prophylaxis in heart, lung, kidney, liver and pancreas transplant recipients, in addition to ganciclovir.
CMVIG mainly provides passive immunity by neutralizing and assisting in the elimination of circulating CMV particles.[97] In the meta-analysis studies, when compared to the control groups, therapy with CMVIG decreased the likelihood of CMV infection. The variations seen in the combined outcomes were found to be statistically significant. The majority of research has shown that administering CMVIG to patients who have received solid organ transplantation offers better protection against CMV infection as compared to controls. Prophylactic CMVIG treatment was also typically well tolerated. These findings imply that prophylactic CMVIG may be recommended for patients receiving liver, kidney, lung, or heart transplants. CMVIG is also an excellent alternative for patients who are susceptible to antiviral-induced side effects like nephrotoxicity, neutropenia, or patient immunosuppressed.[98]
Clinical Context:
Leflunomide has been used off-label in the treatment of cytomegalovirus (CMV) disease in transplant recipients, as well as in the prevention of acute and chronic rejection in recipients of solid organ transplants. It inhibits pyrimidine synthesis (via dihydroorotate dehydrogenase inhibition), leading to immunomodulatory and antiproliferative activity.
What is cytomegalovirus (CMV)?What are the signs and symptoms of cytomegalovirus (CMV)?What are clinical manifestations of cytomegalovirus (CMV)?How is cytomegalovirus (CMV) infection detected?What is the role of imaging studies in the diagnosis of cytomegalovirus (CMV)?What are the treatment options for cytomegalovirus (CMV)?What is cytomegalovirus (CMV)?What is the prevalence of cytomegalovirus (CMV) infection?What is the progression of cytomegalovirus (CMV) infection?How is cytomegalovirus (CMV) infection transmitted?What is the pathophysiology of cytomegalovirus (CMV) infection?What is the primary cytomegalovirus (CMV) infection?What is the role of cell-mediated immunity in the control of cytomegalovirus (CMV) infection?What is the pathophysiology of primary cytomegalovirus (CMV) infection and viremia?What is the pathophysiology of congenital cytomegalovirus (CMV) infection?What is the pathophysiology of cytomegalovirus (CMV) pneumonia?What is the pathophysiology of cytomegalovirus (CMV) hepatitis?What is the pathophysiology of cytomegalovirus (CMV) gastritis and colitis?What is the pathophysiology of cytomegalovirus (CMV) CNS disease?What is the pathophysiology of cytomegalovirus (CMV) retinitis?What is the pathophysiology of cytomegalovirus (CMV) nephritis?What is cytomegalovirus (CMV) syndrome?What is the role of cytomegalovirus (CMV) infection in the pathophysiology of graft versus host disease?What is the prevalence of cytomegalovirus (CMV) infection?What is the mortality and morbidity of cytomegalovirus (CMV)?How does the prevalence of cytomegalovirus (CMV) vary by age?What is the prognosis of cytomegalovirus (CMV) infection?Where can patient education resources for cytomegalovirus (CMV) be found?Which sites are most commonly affected by cytomegalovirus (CMV) infection in the immunocompetent host?What are the signs and symptoms of cytomegalovirus (CMV) infection in the immunocompetent host?What are the signs and symptoms of cytomegalovirus (CMV) mononucleosis and how is it differentiated from Epstein-Barr virus (EBV) infectious mononucleosis?What are risk factors for cytomegalovirus (CMV) mononucleosis?What are rare manifestations of cytomegalovirus (CMV) infection in the immunocompetent host?What are the signs and symptoms of cytomegalovirus (CMV) infection in transplant recipients and how does it affect prognosis?Which organ transplant recipients are at highest risk for cytomegalovirus disease?Which organ transplant recipients are at highest risk for cytomegalovirus (CMV) pneumonia?What are the signs and symptoms of CMV pneumonia in organ transplant recipients?What are the treatment options for CMV pneumonia in organ transplant recipients?What causes severe cytomegalovirus (CMV) pneumonia in organ transplant recipients and how is it diagnosed?How is GI cytomegalovirus (CMV) disease managed in organ transplant recipients?How frequently is cytomegalovirus (CMV) pneumonia comorbid with other pathogens in patients with HIV disease?What is the manifestation of cytomegalovirus (CMV) GI disease in patients with HIV disease and how is it diagnosed?What are the clinical manifestations of cytomegalovirus (CMV) retinitis and how is it diagnosed and treated?Which physical findings are characteristic of cytomegalovirus (CMV) infection?What are the causes of cytomegalovirus (CMV)?What causes relapse of cytomegalovirus (CMV) in solid organ transplant recipients?What are the differential diagnoses for Cytomegalovirus (CMV)?What is the role of lab studies in the workup of cytomegalovirus (CMV) infection?What is the role of antigen testing in the workup of cytomegalovirus (CMV) infection?What is the role of qualitative polymerase chain reaction (PCR) in the workup of cytomegalovirus (CMV) infection?What is the role of quantitative polymerase chain reaction (PCR) in the workup of cytomegalovirus (CMV) infection?What is the role of shell vial assay in the workup of cytomegalovirus (CMV) infection?What is the role of cytopathology in the workup of cytomegalovirus (CMV infection)?What is the role of imaging studies in the workup of cytomegalovirus (CMV) infection?What is the role of cytomegalovirus antiviral resistance testing in the workup of cytomegalovirus (CMV)?Which histologic findings indicate cytomegalovirus (CMV)?What is the role of leflunomide in the treatment of cytomegalovirus (CMV)?Which medications are used in the management of cytomegalovirus (CMV) disease?What is the role of ganciclovir in the treatment of cytomegalovirus (CMV) disease?What are the adverse effects of ganciclovir therapy for treatment of cytomegalovirus (CMV) disease?What is the efficacy of oral valganciclovir in the treatment of cytomegalovirus (CMV) retinitis?What are the treatment options for cytomegalovirus (CMV) pneumonia?What is the role of ganciclovir in the treatment of GI and CNS manifestations of cytomegalovirus (CMV)?What is the role of valganciclovir in the treatment of cytomegalovirus (CMV)?What is the role of ganciclovir in prophylaxis against cytomegalovirus (CMV) disease?What is the efficacy of preemptive therapy against cytomegalovirus (CMV) disease?What is the efficacy of prophylactic approaches against cytomegalovirus (CMV) disease?What is the role of letermovir for prophylaxis against cytomegalovirus (CMV) disease?What is the role of foscarnet in the treatment of cytomegalovirus (CMV)?What is the role of acyclovir in the prophylaxis against cytomegalovirus (CMV) disease?What is the role of cidofovir in the prophylaxis against cytomegalovirus (CMV) disease?What is the role of maribavir in the treatment of cytomegalovirus (CMV)?What is the role of cytomegalovirus immune globulin in the treatment of cytomegalovirus (CMV)?What is the benefit of consultation with an infectious diseases specialist for the treatment of cytomegalovirus (CMV)?When is consultation with a hematologist indicated in the treatment of cytomegalovirus (CMV)?When is consultation with a neurologist indicated in the treatment of cytomegalovirus (CMV)?When is consultations with an ophthalmologist indicated in the treatment of cytomegalovirus (CMV)?What activity modifications are indicated in the management of cytomegalovirus (CMV) infection?How is cytomegalovirus (CMV) prevented?What is included in outpatient monitoring of patients taking ganciclovir for the treatment of cytomegalovirus (CMV)?What is included in inpatient care for cytomegalovirus (CMV) disease?What are the goals of drug treatment for cytomegalovirus (CMV) infection, and which agents are under investigation for the treatment of CMV disease?Which medications in the drug class Antimetabolite are used in the treatment of Cytomegalovirus (CMV)?Which medications in the drug class Immune Globulin are used in the treatment of Cytomegalovirus (CMV)?Which medications in the drug class Antivirals are used in the treatment of Cytomegalovirus (CMV)?
Ricardo Cedeno-Mendoza, MD, Infectious Disease Specialist, Sagebrush Health
Disclosure: Nothing to disclose.
Coauthor(s)
Elvin Alfonso Colón Martínez, MD, Resident Physician, Department of Internal Medicine, Sunrise Health GME Consortium, Mountain View Hospital
Disclosure: Nothing to disclose.
Lisa Vanchhawng Pedroza, MD, Assistant Professor of Medicine, Attending Physician, Division of Infectious Diseases, Cooper University Hospital
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
John W King, MD, Professor of Medicine, Chief, Section of Infectious Diseases, Director, Viral Therapeutics Clinics for Hepatitis, Louisiana State University School of Medicine in Shreveport; Consultant in Infectious Diseases, Overton Brooks Veterans Affairs Medical Center
Disclosure: Nothing to disclose.
Chief Editor
Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London
Disclosure: Nothing to disclose.
Additional Contributors
Kauser Akhter, MD, Assistant Professor, Department of Internal Medicine, Florida State University College of Medicine; Associate Program Director, Infectious Diseases Fellowship Program, Orlando Health
Disclosure: Nothing to disclose.
Todd S Wills, MD, Associate Professor, Department of Medicine, Division of Infectious Disease and International Medicine, Program Director, Infectious Disease Fellowship Program, University of South Florida College of Medicine
Disclosure: Nothing to disclose.
Acknowledgements
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous coauthor Todd S Wills, MD to the development and writing of this article.
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Hematoxylin-eosin–stained lung section showing typical owl-eye inclusions (480X). Courtesy of Danny L Wiedbrauk, PhD, Scientific Director, Virology & Molecular Biology, Warde Medical Laboratory, Ann Arbor, Michigan.
Hematoxylin-eosin–stained lung section showing typical owl-eye inclusions (480X). Courtesy of Danny L Wiedbrauk, PhD, Scientific Director, Virology & Molecular Biology, Warde Medical Laboratory, Ann Arbor, Michigan.
Hematoxylin-eosin–stained lung section showing typical owl-eye inclusions (480X). Courtesy of Danny L Wiedbrauk, PhD, Scientific Director, Virology & Molecular Biology, Warde Medical Laboratory, Ann Arbor, Michigan.
Here, using immunofluorescent technique, a specimen of human embryonic lung (25X) reveals the presence of cytomegalovirus. Courtesy of the CDC and Dr Craig Lyerla.
Here, using immunofluorescent technique, a specimen of human embryonic lung (25X) reveals the presence of cytomegalovirus. Courtesy of the CDC and Dr Craig Lyerla.
Hematoxylin-eosin–stained lung section showing typical owl-eye inclusions (480X). Courtesy of Danny L Wiedbrauk, PhD, Scientific Director, Virology & Molecular Biology, Warde Medical Laboratory, Ann Arbor, Michigan.
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