Cytomegalovirus

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Practice Essentials

Cytomegalovirus (CMV) is a double-stranded DNA virus and is a member of the Herpesviridae family. At least 60% of the US population has been exposed to CMV,[1] with a prevalence of more than 90% in high-risk groups (eg, unborn babies whose mothers become infected with CMV during the pregnancy or people with HIV).[2, 3]

Essential update: Cidofovir may be effective for resistant CMV infections in transplant patients

Results from a retrospective study of patients undergoing solid organ transplantation who tested positive for CMV infection show that treatment with cidofovir might be superior to treatment with foscarnet.

Cidofovir, which is used to treat HIV patients with CMV retinitis, was used to treat 14 of the 20 study patients with resistance mutations. Of these 14 patients, 13 achieved cytomegalovirus clearance at a median of 4.5 months and remained free of detectable virus during a median follow-up of 10 months, and 1 patient died. The remaining 6 patients were treated with foscarnet. Of these 6 patients, 2 responded to treatment but relapsed after discontinuation, 1 had low-level viremia until cidofovir was added, 1 remained on foscarnet, and 2 died.[4]

Signs and symptoms

CMV usually causes an asymptomatic infection or produces mild flulike symptoms; afterward, it remains latent throughout life and may reactivate.

Most patients with CMV infection exhibit few clinical findings on physical examination.

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.

In patients with HIV infection, CMV involves the entire GI tract. Retinitis is the most common manifestation of CMV disease in patients who are HIV positive.

See Clinical Presentation for more detail.

Diagnosis

Lab studies

Cytomegalovirus (CMV) has been detected via culture (human fibroblast), serologies, antigen assays, 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 BAL result that is CMV positive is a common method for diagnosis.

See Workup for more detail.

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.[5] Other than CMV retinitis, however, ganciclovir remains the mainstay of treatment, at least initially.

Second-line treatments include foscarnet, cidofovir, or maribavir.

Currently, there is no vaccine to prevent CMV infection.

See Treatment and Medication for more detail.

Background

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 60% of the US population has been exposed to CMV,[1] with a prevalence of more than 90% in high-risk groups (eg, male homosexuals).[2, 3] 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.[6] Other factors associated with CMV seropositivity include ethnicity (77% in Mexican Americans and 71% in blacks),[7] female sex, foreign-born status, and low socioeconomic status.[7]

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.[8] In immunocompetent individuals, symptomatic disease usually manifests as a mononucleosis syndrome, which was first described in adults in 1965.[9]

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 highly active antiretroviral therapy (HAART).[10]

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 can also 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 neurological abnormalities and deafness in approximately 8000 newborns annually.[11, 12]

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.

Pathophysiology

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 are also 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 histological 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.[8] 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).

CMV DNAemia 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.[13]

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.[14]

Primary cytomegalovirus infection and viremia

In most hosts, primary CMV infection is clinically silent. The presentation of symptomatic primary infection is addressed in Adult Cytomegalovirus Infection in the Immunocompetent Host. Primary CMV infection of the immunocompromised host carries the greatest risk for CMV disease.

Viremia is diagnosed by isolation of CMV in culture (either via standard or shell vial culture; see Laboratory studies).[8] CMV excretion in the saliva and urine is common in immunocompromised patients and is generally of little consequence. In contrast, viremia in organ transplant recipients identifies those at greatest risk for CMV disease. The sensitivity of CMV viremia as a marker for CMV pneumonia is 60%-70% in allogeneic marrow transplant recipients. Having no evidence of virus in the bloodstream has a high negative predictive value for CMV disease. Prophylactic or preemptive antiviral therapy against CMV disease in transplant recipients typically relies on the detection of CMV in the blood by shell vial cultures, CMV antigenemia, and PCR amplification.

Congenital cytomegalovirus disease

Congenital CMV infection is one of the TORCH infections (toxoplasmosis, other infections including syphilis, rubella, CMV, and HSV), which carry a risk of significant symptomatic disease and developmental defects in newborns. The clinical syndrome of congenital cytomegalic inclusion disease includes jaundice, splenomegaly, thrombocytopenia, intrauterine growth retardation, microcephaly, and retinitis.

The most common clinical findings of congenital CMV infection include petechiae (71%), jaundice (67%), microcephaly (53%), and small size for gestational age (50%). Common laboratory abnormalities include hyperbilirubinemia (81%), increased levels of hepatocellular enzymes (83%), thrombocytopenia (77%), and increased CSF protein levels (77%). Studies have shown that asymptomatic children with neurological findings are more likely to have CMV IgM antibody. Many cases of hearing loss in children may be caused by CMV infection. CMV excretion is common in children with congenital infection and may represent a reservoir for infection in other children and daycare workers.

The CMV immune status of the woman is important in determining the risk of placental infection and subsequent symptomatic disease in the child or fetus. Symptomatic CMV congenital disease is less likely to occur in women with pre-existing immune responses to CMV than in CMV-naïve individuals. One in ten cases of acute CMV infection during pregnancy is estimated to result in congenital CMV disease.

Cytomegalovirus pneumonia

CMV pneumonia is defined as signs and symptoms of pulmonary disease in combination with detection of CMV in bronchoalveolar fluid or lung tissue.[8] CMV detection should be performed via culture, histopathology, immunohistochemical analysis, or in situ hybridization, as CMV DNA PCR testing alone is too sensitive for diagnosing CMV pneumonia.[8]

Approximately 0%-6% of adults who present with CMV infection as a mononucleosis syndrome develop pneumonia. One study found that the incidence of CMV pneumonia in immunocompetent patients was 19%. In most cases, CMV pneumonia is found on chest radiography and is of no clinical significance, rapidly resolving with the disappearance of the primary infection.

Life-threatening CMV pneumonia may develop in immunocompromised patients (see Adult Cytomegalovirus Infection in the Immunocompromised Host). The highest rate of CMV pneumonia, as well as the greatest severity, occurs among lung transplant recipients, who are at an overall 50% risk of developing CMV illness (infection or disease).

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.[8] 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.[8] 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 is typically favorable, but death has been reported in immunosuppressed patients. Histology typically reveals mononuclear cell infiltration of the portal areas but may also reveal granulomatous inflammation.[15]

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.[8] CMV colitis was first described in 1985 in two homosexual men who presented with abdominal pain, diarrhea, and hematochezia.[16] 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 is often 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).[8] 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.[17] 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 infection 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 HAART, 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 HAART.[18, 19, 20] In one study, the median time to IRIS following HAART initiation was 43 weeks but has been reported as early as 4 weeks or as late as 4 years in some cases.[21, 19] 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.[8] 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.[8] CMV viremia has been associated with acute glomerular injury.[22]

Cytomegalovirus syndrome

In general, it is better to avoid this term in stem cell transplant recipients, as other viruses (eg, HHV-6) can also cause fever and bone marrow suppression.[8] 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.[8]

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.[23] 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.[24]

Frequency

United States

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 40%-100% of people, depending on socioeconomic conditions. Infection earlier in life is typical in developing countries, whereas up to 50% of young adults are seronegative in many developed nations.

Mortality/Morbidity

CMV is seldom 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.[25]

Age

CMV prevalence increases with age. Age has also been found to be a risk factor for CMV disease in certain transplant populations.

History

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.[9]

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).[26] In about a third of patients with CMV mononucleosis, a rash may also be present (macular, papular, maculopapular, rubelliform, morbilliform, or scarlatiniform).[27]

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.[28] 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.[28]

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 two 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 now 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 is usually 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[9] and should be considered a possible etiology (along with influenza [human, swine, avian] and adenovirus) in cases of severe viral community-acquired pneumonia.[9] 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.[29] 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.[29] There are varying degrees of hypoxemia. The prognosis of CMV pneumonia in immunocompetent hosts, even severe cases, is usually good, rarely requires a full course of antiviral treatment, and usually resolves during CMV induction therapy.[9]

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,[30, 31, 32] duration of mechanical ventilation,[30, 31] morbidity[32] , and mortality.[33, 30, 32] 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.[34]

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

CMV infection in transplant recipients may be primary or recurrent. Again, the former refers to CMV detection in an individual who was previously seronegative,[8] while recurrent infection includes both reinfection and reactivation. Reinfection refers to detection of a CMV strain different from the one that caused the patient's original infection.[8] Reactivation is defined as infection by the same CMV strain as was previously involved.[8]

A study by Kim et al examined CMV infections in patients after liver transplantation.[35] The study determined that the occurrence of CMV disease, and not CMV infection, was a risk factor for mortality and graft failure in adult liver transplant recipients.

CMV infection may cause direct or indirect effects.[36] Direct effects include bone marrow suppression, pneumonia, myocarditis, GI disease, hepatitis, pancreatitis, nephritis, retinitis, and encephalitis, among others.[37, 38] The main indirect effects include acute and chronic graft rejection, accelerated atherosclerosis (heart transplants), secondary bacterial or fungal infections, EBV-associated posttransplant lymphoproliferative disease (PTLD), and decreased graft and patient survival.[36, 37, 38]

CMV infection may affect the same organ systems in HIV-positive patients with low CD4 counts as those in organ transplant recipients. Retinitis has been the major reported CMV disease in patients with HIV infection, followed by CNS involvement.

Not surprisingly, CMV disease has been associated with decreased survival in transplant recipients. As an example, in a group of 187 lung transplant recipients in Sweden between 1990 and 2002, the 10-year survival rate was only 32% in patients with CMV disease, compared with 53% among those with asymptomatic CMV infection and 57% in those without CMV infection.[39]

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 may initially 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 is frequently 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 are also 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).[40] 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 is likely 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 is often not required in the absence of clinical apparent disease.

Primary GI CMV disease in solid organ transplant recipients is difficult to treat and may relapse. The relapse rate was recently 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 of CMV relapse.[41]

Human immunodeficiency virus disease and cytomegalovirus

CMV is often 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.[9] The 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 is not typically warranted in most cases.

For unknown reasons, CMV pneumonia without a co-infecting pathogen is uncommon.

In patients with HIV infection, CMV involves 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.[42] 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 are HIV positive. 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 is often 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. Unfortunately, it only slows the progression of the disease. 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.[43]

Physical

Most patients with CMV infection exhibit few clinical findings on physical examination.

Causes

See Adult Cytomegalovirus Infection in the Immunocompetent Host and Adult Cytomegalovirus Infection in the Immunocompromised Host.

Laboratory Studies

Cytomegalovirus (CMV) has been detected via culture (human fibroblast), serologies, antigen assays, PCR, and cytopathology. The IgM level is elevated in patients with recent CMV infection, or there is a 4-fold increase in IgG titers. False-positive CMV IgM results may be seen in patients with EBV or HHV-6 infections, as well as in patients with increased rheumatoid factor levels.[9]

Some tests are sensitive enough to detect anti-CMV IgM antibody early in the course of the illness (CMV early [nuclear] antigen, CMV viral capsid antigen) and during CMV reactivation. As with EBV infection, observing reactivation of the virus with a positive IgM result in the presence of IgG antibody is not uncommon. This is most commonly observed during intercurrent infection in immunocompromised patients.

An anti-CMV immediate early antigen monoclonal antibody assay is available.[44] This reacts with an early protein and can detect CMV infection 3 hours into the infection. Intense coarse granular intranuclear inclusion staining is noted. No other nuclear staining or cytoplasmic staining is visualized.[44]

In the transplant population, antigen assays or PCR is used (sometimes in conjunction with cytopathology) for diagnosis and treatment determinations, with the choice of test varying among institutions.

Antigen testing

Qualitative polymerase chain reaction

Quantitative polymerase chain reaction

Shell vial assay

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).


View Image

Hematoxylin-eosin–stained lung section showing typical owl-eye inclusions (480X). Courtesy of Danny L Wiedbrauk, PhD, Scientific Director, Virology & ....

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 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.

Other Tests

Cytomegalovirus resistance testing

CMV infection continues to pose a major problem in transplant recipients, and antiviral resistance is encountered in all forms of transplantation. In solid-organ transplant recipients, ganciclovir resistance is found mainly among donor-positive, recipient-negative lung, kidney, and kidney/pancreas transplant recipients. Among stem cell transplant recipients, resistance primarily affects the donor-negative, recipient-positive group. Other risk factors include T-cell depletion, more than 3 months of antiviral therapy, very high viral loads, recurrent episodes of CMV disease, increased levels of immunosuppression, and suboptimal antiviral drug concentrations due to noncompliance or decreased absorption.[55] Resistance to foscarnet and cidofovir has also been reported in solid-organ and stem cell transplant recipients.

Resistance typically takes weeks to months to develop. In fact, among patients with HIV infection, a 10% ganciclovir resistance rate has been reported at 3 months.[55] Resistance should be suspected in patients who initially respond to CMV therapy but who subsequently develop an increasing viral load despite drug compliance. It should also be considered in patients who are clinically deteriorating.

Only two CMV resistance genes have been reported to date: UL-97 and UL-54. UL-97 (a phosphotransferase gene), encodes ganciclovir resistance, while UL-54 (viral DNA polymerase) mutations confer resistance to ganciclovir, foscarnet, and cidofovir. In approximately 90% of patients, ganciclovir resistance initially results from UL-97 mutations. To date, proven ganciclovir resistance mutations in UL-97 are found only in codons 460, 520, and 590-607. Mutations in codons 696-850 mediate foscarnet resistance, and mutations in these sites do not usually mediate cross-resistance to the other anti-CMV drugs. If a patient develops resistance while taking cidofovir, it is caused by a UL-54 mutation, which will encode cross-resistance to ganciclovir.[55]

Specialized assays can be used to test resistance. The most widely used of these is a genotypic assay using fluid samples (eg, CSF, blood) that contain CMV DNA or samples with cultures positive for CMV. Genotype assay results can be performed and results received in a matter of days. Unfortunately, the assay is expensive and may pick up irrelevant mutations. Hence, familiarity in interpreting the results is key.

Other resistance assays include those used to measure viral load via antigenemia or quantitative DNA, as well as a phenotypic plaque reduction assay.[56] The former is not well standardized, and interpretation may vary from one institution to the next. In addition, in certain CMV diseases (eg, retinitis), viral load testing yields a low positive predictive value.[51] The plaque reduction assay takes at least 1 month to complete, is poorly standardized, and is not routinely performed in the laboratory.[56]

Histologic Findings

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/Dr. Cra....

Medical Care

The drug of choice for prevention of cytomegalovirus (CMV) disease in solid-organ transplant patients is now valganciclovir.[5] Other than CMV retinitis, however, ganciclovir remains the mainstay of treatment, at least initially. The other options listed below are either second-line (foscarnet, cidofovir, or maribavir) or are used off-label (leflunomide). There is no consensus at this time as to whether prophylaxis versus preemptive therapy is the better approach for prevention of CMV infection in solid-organ transplant recipients. Recent data favors prophylactic therapy with either ganciclovir or valganciclovir in high risk liver transplant recipients.[57] Data also favor the use of valganciclovir prophylaxis over preemptive therapy in CMV-positive renal allograft recipients.[58]

The incidence of CMV disease has significantly dropped in solid organ transplant recipients following the development of specific antiviral therapy.[59]

For lifelong protection against CMV disease, the patient must develop a specific anti-CMV immune response.[60]

Ganciclovir treatment

Valganciclovir

Ganciclovir prophylaxis

Foscarnet

Acyclovir prophylaxis

Cidofovir prophylaxis

Maribavir

Leflunomide

Cytomegalovirus immune globulin

Consultations

Infectious diseases specialist

Hematologist

Neurologist

Ophthalmologist

Activity

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 is usually 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.

Medication Summary

The goals of pharmacotherapy are to prevent outbreaks of the disease and its complications and to reduce morbidity. Several agents are currently 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[77] ; (2) leflunomide, a pyrimidine synthesis inhibitor[78] (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.[75] ); and (3) artesunate, an antimalarial with some in vitro activity against CMV.[79, 80]

Another experimental agent, letermovir (AIC246), a member of the novel class of 3,4-dihydroquinazolinyl acetic acids, was administered to a lung transplant recipient with multidrug-resistant disseminated CMV infection (viremia, pneumonitis, colitis, retinitis) in combination with reduced immunosuppression.[81] The patient experienced rapid clinical, virologic, and radiographic resolution of disease.

Maribavir, a benzimidazole antiviral agent, has been used as salvage therapy in a small number of patients with multidrug-resistant CMV,[69] but was unsuccessful when used as CMV prophylaxis in allogeneic stem cell transplant patients[70] or in liver transplant recipients.

Ganciclovir (Cytovene)

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.

Foscarnet (Foscavir)

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.

Cidofovir (Vistide)

Clinical Context:  Cidofovir is a pproved 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.

Valganciclovir (Valcyte)

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.

Class Summary

CMV is a double-stranded DNA virus. Drugs currently used for the treatment of DNA viral infections affect the viral DNA polymerase and affect viral DNA replication.

Cytomegalovirus immune globulin (CMV IG)

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.

Class Summary

Consists of administration of immunoglobulin pooled from serum of immunized subjects.

Leflunomide (Arava)

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.

Class Summary

These agents inhibit cell growth and proliferation.

Further Inpatient Care

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 at greater risk for bacterial and fungal infections. If possible, the patient's level of immunosuppression should be lowered.

Further Outpatient Care

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 ophthalmological examinations.

Inpatient & Outpatient Medications

See Medication section.

Deterrence/Prevention

See Treatment 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)[5] or ganciclovir. Acyclovir and valacyclovir have been used for prophylaxis and early treatment in allogeneic marrow transplant recipients. Acyclovir has also been used in recipients of other types of transplants.

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.[82] A CMV glycoprotein-B vaccine containing an MF59 adjuvant is currently in a phase 2 randomized placebo-controlled trial in transplant recipients.[83]

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, while 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.[84]

Complications

See Medication.

Despite long treatment courses with valganciclovir and documented clearance of CMV viremia, CMV relapse remains common among solid organ transplant recipients.[85] A better understanding of the epidemiology of CMV infection among solid organ transplant recipients and risk factors for disease relapse is warranted.

Prognosis

The prognosis of CMV hepatitis is generally good. Most patients recover completely. Symptoms can persist, usually in the form of fatigue, for several months after primary infection.

Author

Kauser Akhter, MD, Clinical Assistant Professor, Department of Internal Medicine, Florida State University College of Medicine; Infectious Diseases Faculty Practice, Orlando Health

Disclosure: Nothing to disclose.

Coauthor(s)

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.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

John W King, MD, Professor of Medicine, Chief, Section of Infectious Diseases, Director, Viral Therapeutics Clinics for Hepatitis, Louisiana State University Health Sciences Center; Consultant in Infectious Diseases, Overton Brooks Veterans Affairs Medical Center

Disclosure: Merck Grant/research funds Other

Chief Editor

Burke A Cunha, MD, Professor of Medicine, State University of New York School of Medicine at Stony Brook; Chief, Infectious Disease Division, Winthrop-University Hospital

Disclosure: Nothing to disclose.

Additional Contributors

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.

References

  1. Zhang LJ, Hanff P, Rutherford C, Churchill WH, Crumpacker CS. Detection of human cytomegalovirus DNA, RNA, and antibody in normal donor blood. J Infect Dis. Apr 1995;171(4):1002-6. [View Abstract]
  2. Collier AC, Meyers JD, Corey L, Murphy VL, Roberts PL, Handsfield HH. Cytomegalovirus infection in homosexual men. Relationship to sexual practices, antibody to human immunodeficiency virus, and cell-mediated immunity. Am J Med. Mar 23 1987;82(3 Spec No):593-601. [View Abstract]
  3. Guinan ME, Thomas PA, Pinsky PF, Goodrich JT, Selik RM, Jaffe HW. Heterosexual and homosexual patients with the acquired immunodeficiency syndrome. A comparison of surveillance, interview, and laboratory data. Ann Intern Med. Feb 1984;100(2):213-8. [View Abstract]
  4. Kling J. Cidofovir Showing Promise for Resistant Cytomegalovirus. Available at http://www.medscape.com/viewarticle/811494. Accessed October 7, 2013.
  5. Hodson EM, Jones CA, Webster AC, Strippoli GF, Barclay PG, Kable K. Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials. Lancet. Jun 18-24 2005;365(9477):2105-15. [View Abstract]
  6. Staras SA, Dollard SC, Radford KW, Flanders WD, Pass RF, Cannon MJ. Seroprevalence of cytomegalovirus infection in the United States, 1988-1994. Clin Infect Dis. Nov 1 2006;43(9):1143-51. [View Abstract]
  7. Bate SL, Dollard SC, Cannon MJ. Cytomegalovirus seroprevalence in the United States: the national health and nutrition examination surveys, 1988-2004. Clin Infect Dis. Jun 1 2010;50(11):1439-47. [View Abstract]
  8. Ljungman P, Griffiths P, Paya C. Definitions of cytomegalovirus infection and disease in transplant recipients. Clin Infect Dis. Apr 15 2002;34(8):1094-7. [View Abstract]
  9. Cunha BA. Cytomegalovirus pneumonia: community-acquired pneumonia in immunocompetent hosts. Infect Dis Clin North Am. Mar 2010;24(1):147-58. [View Abstract]
  10. Deayton JR, Prof Sabin CA, Johnson MA, Emery VC, Wilson P, Griffiths PD. Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet. Jun 26 2004;363(9427):2116-21. [View Abstract]
  11. Stagno S, Pass RF, Cloud G, Britt WJ, Henderson RE, Walton PD. Primary cytomegalovirus infection in pregnancy. Incidence, transmission to fetus, and clinical outcome. JAMA. Oct 10 1986;256(14):1904-8. [View Abstract]
  12. Stagno S. Cytomegalovirus. In: Remington JS, Klein JO. Infectious Diseases of the Fetus and Newborn Infant. Philadelphia: WB Saunders; 2001:389-424.
  13. Arora N, Novak Z, Fowler KB, Boppana SB, Ross SA. Cytomegalovirus viruria and DNAemia in healthy seropositive women. J Infect Dis. Dec 15 2010;202(12):1800-3. [View Abstract]
  14. Walter EA, Greenberg PD, Gilbert MJ. Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med. Oct 19 1995;333(16):1038-44. [View Abstract]
  15. Bonkowsky HL, Lee RV, Klatskin G. Acute granulomatous hepatitis. Occurrence in cytomegalovirus mononucleosis. JAMA. Sep 22 1975;233(12):1284-8. [View Abstract]
  16. Meiselman MS, Cello JP, Margaretten W. Cytomegalovirus colitis. Report of the clinical, endoscopic, and pathologic findings in two patients with the acquired immune deficiency syndrome. Gastroenterology. Jan 1985;88(1 Pt 1):171-5. [View Abstract]
  17. Orlikowski D, Porcher R, Sivadon-Tardy V, et al. Guillain-Barre Syndrome following Primary Cytomegalovirus Infection: A Prospective Cohort Study. Clin Infect Dis. Apr 2011;52(7):837-44. [View Abstract]
  18. Jabs DA, Van Natta ML, Kempen JH, Reed Pavan P, Lim JI, Murphy RL, et al. Characteristics of patients with cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Am J Ophthalmol. Jan 2002;133(1):48-61. [View Abstract]
  19. Karavellas MP, Plummer DJ, Macdonald JC, Torriani FJ, Shufelt CL, Azen SP. Incidence of immune recovery vitritis in cytomegalovirus retinitis patients following institution of successful highly active antiretroviral therapy. J Infect Dis. Mar 1999;179(3):697-700. [View Abstract]
  20. Wohl DA, Kendall MA, Owens S, Holland G, Nokta M, Spector SA. The safety of discontinuation of maintenance therapy for cytomegalovirus (CMV) retinitis and incidence of immune recovery uveitis following potent antiretroviral therapy. HIV Clin Trials. May-Jun 2005;6(3):136-46. [View Abstract]
  21. Wright ME, Suzman DL, Csaky KG, Masur H, Polis MA, Robinson MR. Extensive retinal neovascularization as a late finding in human immunodeficiency virus-infected patients with immune recovery uveitis. Clin Infect Dis. Apr 15 2003;36(8):1063-6. [View Abstract]
  22. Richardson WP, Colvin RB, Cheeseman SH. Glomerulopathy associated with cytomegalovirus viremia in renal allografts. N Engl J Med. Jul 9 1981;305(2):57-63. [View Abstract]
  23. Torok-Storb B, Boeckh M, Hoy C. Association of specific cytomegalovirus genotypes with death from myelosuppression after marrow transplantation. Blood. Sep 1 1997;90(5):2097-102. [View Abstract]
  24. Manuel O, Asberg A, Pang X, Rollag H, Emery VC, Preiksaitis JK. Impact of genetic polymorphisms in cytomegalovirus glycoprotein B on outcomes in solid-organ transplant recipients with cytomegalovirus disease. Clin Infect Dis. Oct 15 2009;49(8):1160-6. [View Abstract]
  25. Iwasenko JM, Howard J, Arbuckle S, et al. Human cytomegalovirus infection is detected frequently in stillbirths and is associated with fetal thrombotic vasculopathy. J Infect Dis. Jun 2011;203(11):1526-33. [View Abstract]
  26. Klemola E, Von Essen R, Henle G, Henle W. Infectious-mononucleosis-like disease with negative heterophil agglutination test. Clinical features in relation to Epstein-Barr virus and cytomegalovirus antibodies. J Infect Dis. Jun 1970;121(6):608-14. [View Abstract]
  27. Cohen JI, Corey GR. Cytomegalovirus infection in the normal host. Medicine (Baltimore). Mar 1985;64(2):100-14. [View Abstract]
  28. Horwitz CA, Henle W, Henle G. Clinical and laboratory evaluation of cytomegalovirus-induced mononucleosis in previously healthy individuals. Report of 82 cases. Medicine (Baltimore). Mar 1986;65(2):124-34. [View Abstract]
  29. Klemola E, Stenström R, von Essen R. Pneumonia as a clinical manifestation of cytomegalovirus infection in previously healthy adults. Scand J Infect Dis. 1972;4(1):7-10. [View Abstract]
  30. Jaber S, Chanques G, Borry J, Souche B, Verdier R, Perrigault PF. Cytomegalovirus infection in critically ill patients: associated factors and consequences. Chest. Jan 2005;127(1):233-41. [View Abstract]
  31. von Müller L, Klemm A, Weiss M, et al. Active cytomegalovirus infection in patients with septic shock. Emerg Infect Dis. Oct 2006;12(10):1517-22. [View Abstract]
  32. Kalil AC, Florescu DF. Prevalence and mortality associated with cytomegalovirus infection in nonimmunosuppressed patients in the intensive care unit. Crit Care Med. Aug 2009;37(8):2350-8. [View Abstract]
  33. Cook CH, Yenchar JK, Kraner TO, Davies EA, Ferguson RM. Occult herpes family viruses may increase mortality in critically ill surgical patients. Am J Surg. Oct 1998;176(4):357-60. [View Abstract]
  34. De Vlieger G, Meersseman W, Lagrou K, et al. Cytomegalovirus serostatus and outcome in nonimmunocompromised critically ill patients. Crit Care Med. Jan 2012;40(1):36-42. [View Abstract]
  35. Kim JM, Kim SJ, Joh JW, et al. Is cytomegalovirus infection dangerous in cytomegalovirus-seropositive recipients after liver transplantation?. Liver Transpl. Apr 2011;17(4):446-55. [View Abstract]
  36. Rubin RH. The indirect effects of cytomegalovirus infection on the outcome of organ transplantation. JAMA. Jun 23-30 1989;261(24):3607-9. [View Abstract]
  37. Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med. Jun 11 1998;338(24):1741-51. [View Abstract]
  38. Snydman DR. Infection in solid organ transplantation. Transpl Infect Dis. Mar 1999;1(1):21-8. [View Abstract]
  39. Johanssson I, Mårtensson G, Andersson R. Cytomegalovirus and long-term outcome after lung transplantation in Gothenburg, Sweden. Scand J Infect Dis. 2010;42(2):129-36. [View Abstract]
  40. Reed EC, Bowden RA, Dandliker PS. Treatment of cytomegalovirus pneumonia with ganciclovir and intravenous cytomegalovirus immunoglobulin in patients with bone marrow transplants. Ann Intern Med. Nov 15 1988;109(10):783-8. [View Abstract]
  41. Eid AJ, Arthurs SK, Deziel PJ, Wilhelm MP, Razonable RR. Clinical predictors of relapse after treatment of primary gastrointestinal cytomegalovirus disease in solid organ transplant recipients. Am J Transplant. Jan 2010;10(1):157-61. [View Abstract]
  42. Dieterich DT, Rahmin M. Cytomegalovirus colitis in AIDS: presentation in 44 patients and a review of the literature. J Acquir Immune Defic Syndr. 1991;4 Suppl 1:S29-35. [View Abstract]
  43. McCutchan JA. Cytomegalovirus infections of the nervous system in patients with AIDS. Clin Infect Dis. Apr 1995;20(4):747-54. [View Abstract]
  44. Anti-Cytomegalovirus (CMV) Immediate Early Antigen Monoclonal Antibody, Unconjugated, Clone 3G9.2 from CHEMICON. www.chemicon.com. Available at http://www.bio-medicine.org/biology-products/Anti-Cytomegalovirus--28CMV-29-Immediate-Early-Antigen-Monoclonal-Antibody--Unconjugated--Clone-3G9-2-from-CHEMICON-2132-1/. Accessed March 17, 2010.
  45. Martín-Dávila P, Fortún J, Gutiérrez C, Martí-Belda P, Candelas A, Honrubia A, et al. Analysis of a quantitative PCR assay for CMV infection in liver transplant recipients: an intent to find the optimal cut-off value. J Clin Virol. Jun 2005;33(2):138-44. [View Abstract]
  46. Aitken C, Barrett-Muir W, Millar C, Templeton K, Thomas J, Sheridan F. Use of molecular assays in diagnosis and monitoring of cytomegalovirus disease following renal transplantation. J Clin Microbiol. Sep 1999;37(9):2804-7. [View Abstract]
  47. Gerna G, Zipeto D, Parea M, Revello MG, Silini E, Percivalle E. Monitoring of human cytomegalovirus infections and ganciclovir treatment in heart transplant recipients by determination of viremia, antigenemia, and DNAemia. J Infect Dis. Sep 1991;164(3):488-98. [View Abstract]
  48. Tanabe K, Tokumoto T, Ishikawa N, Koyama I, Takahashi K, Fuchinoue S. Comparative study of cytomegalovirus (CMV) antigenemia assay, polymerase chain reaction, serology, and shell vial assay in the early diagnosis and monitoring of CMV infection after renal transplantation. Transplantation. Dec 27 1997;64(12):1721-5. [View Abstract]
  49. Boppana SB, Ross SA, Shimamura M, Palmer AL, Ahmed A, Michaels MG, et al. Saliva polymerase-chain-reaction assay for cytomegalovirus screening in newborns. N Engl J Med. Jun 2 2011;364(22):2111-8. [View Abstract]
  50. Sanghavi SK, Abu-Elmagd K, Keightley MC, St George K, Lewandowski K, Boes SS. Relationship of cytomegalovirus load assessed by real-time PCR to pp65 antigenemia in organ transplant recipients. J Clin Virol. Aug 2008;42(4):335-42. [View Abstract]
  51. Jabs DA, Martin BK, Forman MS, Ricks MO. Cytomegalovirus (CMV) blood DNA load, CMV retinitis progression, and occurrence of resistant CMV in patients with CMV retinitis. J Infect Dis. Aug 15 2005;192(4):640-9. [View Abstract]
  52. Roche Molecular Diagnostics. COBAS AMPLICOR CMV MONITOR test. Available at http://molecular.roche.com/assays/Pages/COBASAMPLICORCMVMONITORTest.aspx. Accessed July 10, 2012.
  53. Roche Molecular Diagnostics. COBAS AmpliPrep/COBAS TaqMan CMV test. Available at http://molecular.roche.com/assays/Pages/COBASAmpliPrepCOBASTaqManCMVTest.aspx. Accessed July 10, 2012.
  54. Smith TF, Espy MJ, Mandrekar J, Jones MF, Cockerill FR, Patel R. Quantitative real-time polymerase chain reaction for evaluating DNAemia due to cytomegalovirus, Epstein-Barr virus, and BK virus in solid-organ transplant recipients. Clin Infect Dis. Oct 15 2007;45(8):1056-61. [View Abstract]
  55. [Best Evidence] Drew WL. Cytomegalovirus resistance testing: pitfalls and problems for the clinician. Clin Infect Dis. Mar 1 2010;50(5):733-6. [View Abstract]
  56. Drew WL, Miner R, Saleh E. Antiviral susceptibility testing of cytomegalovirus: criteria for detecting resistance to antivirals. Clin Diagn Virol. Aug 1993;1(3):179-85. [View Abstract]
  57. Bodro M, Sabé N, Lladó L, et al. Prophylaxis versus preemptive therapy for cytomegalovirus disease in high-risk liver transplant recipients. Liver Transpl. Sep 2012;18(9):1093-9. [View Abstract]
  58. Witzke O, Hauser IA, Bartels M, Wolf G, Wolters H, Nitschke M. Valganciclovir prophylaxis versus preemptive therapy in cytomegalovirus-positive renal allograft recipients: 1-year results of a randomized clinical trial. Transplantation. Jan 15 2012;93(1):61-8. [View Abstract]
  59. Fishman JA, Emery V, Freeman R, Pascual M, Rostaing L, Schlitt HJ. Cytomegalovirus in transplantation - challenging the status quo. Clin Transplant. Mar-Apr 2007;21(2):149-58. [View Abstract]
  60. Legendre C, Pascual M. Improving outcomes for solid-organ transplant recipients at risk from cytomegalovirus infection: late-onset disease and indirect consequences. Clin Infect Dis. Mar 1 2008;46(5):732-40. [View Abstract]
  61. No authors listed. Valganciclovir: new preparation. CMV retinitis: a simpler, oral treatment. Prescrire Int. Aug 2003;12(66):133-5. [View Abstract]
  62. Caldés A, Gil-Vernet S, Armendariz Y, Colom H, Pou L, Niubó J, et al. Sequential treatment of cytomegalovirus infection or disease with a short course of intravenous ganciclovir followed by oral valganciclovir: efficacy, safety, and pharmacokinetics. Transpl Infect Dis. Dec 9 2009;[View Abstract]
  63. Dieterich DT, Chachoua A, Lafleur F. Ganciclovir treatment of gastrointestinal infections caused by cytomegalovirus in patients with AIDS. Rev Infect Dis. Jul-Aug 1988;10 Suppl 3:S532-7. [View Abstract]
  64. Kalil AC, Mindru C, Florescu DF. Effectiveness of valganciclovir 900 mg versus 450 mg for cytomegalovirus prophylaxis in transplantation: direct and indirect treatment comparison meta-analysis. Clin Infect Dis. Feb 2011;52(3):313-21. [View Abstract]
  65. Avery RK. Low-dose valganciclovir for cytomegalovirus prophylaxis in organ transplantation: is less really more?. Clin Infect Dis. Feb 2011;52(3):322-4. [View Abstract]
  66. Cytomegalovirus. Am J Transplant. Nov 2004;4 Suppl 10:51-8. [View Abstract]
  67. Paudice N, Mehmetaj A, Zanazzi M, Moscarelli L, Piperno R, Di Maria L. Preemptive therapy for the prevention of cytomegalovirus disease in renal transplant recipients: our preliminary experience. Transplant Proc. May 2009;41(4):1204-6. [View Abstract]
  68. Boeckh M, Gooley TA, Myerson D. Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood. Nov 15 1996;88(10):4063-71. [View Abstract]
  69. Avery RK, Marty FM, Strasfeld L, Lee I, Arrieta A, Chou S. Oral maribavir for treatment of refractory or resistant cytomegalovirus infections in transplant recipients. Transpl Infect Dis. Dec 2010;12(6):489-96. [View Abstract]
  70. Marty FM, Ljungman P, Papanicolaou GA, Winston DJ, Chemaly RF, Strasfeld L. Maribavir prophylaxis for prevention of cytomegalovirus disease in recipients of allogeneic stem-cell transplants: a phase 3, double-blind, placebo-controlled, randomised trial. Lancet Infect Dis. Apr 2011;11(4):284-92. [View Abstract]
  71. Trofe J, Pote L, Wade E, Blumberg E, Bloom RD. Maribavir: a novel antiviral agent with activity against cytomegalovirus. Ann Pharmacother. Oct 2008;42(10):1447-57. [View Abstract]
  72. John GT, Manivannan J, Chandy S, Peter S, Jacob CK. Leflunomide therapy for cytomegalovirus disease in renal allograft recepients. Transplantation. May 15 2004;77(9):1460-1. [View Abstract]
  73. John GT, Manivannan J, Chandy S, Peter S, Fleming DH, Chandy SJ, et al. A prospective evaluation of leflunomide therapy for cytomegalovirus disease in renal transplant recipients. Transplant Proc. Dec 2005;37(10):4303-5. [View Abstract]
  74. Levi ME, Mandava N, Chan LK, Weinberg A, Olson JL. Treatment of multidrug-resistant cytomegalovirus retinitis with systemically administered leflunomide. Transpl Infect Dis. Mar 2006;8(1):38-43. [View Abstract]
  75. Battiwalla M, Paplham P, Almyroudis NG, McCarthy A, Abdelhalim A, Elefante A. Leflunomide failure to control recurrent cytomegalovirus infection in the setting of renal failure after allogeneic stem cell transplantation. Transpl Infect Dis. Mar 2007;9(1):28-32. [View Abstract]
  76. Valantine HA, Luikart H, Doyle R, Theodore J, Hunt S, Oyer P. Impact of cytomegalovirus hyperimmune globulin on outcome after cardiothoracic transplantation: a comparative study of combined prophylaxis with CMV hyperimmune globulin plus ganciclovir versus ganciclovir alone. Transplantation. Nov 27 2001;72(10):1647-52. [View Abstract]
  77. Price NB, Prichard MN. Progress in the development of new therapies for herpesvirus infections. Curr Opin Virol. Dec 2011;1(6):548-54. [View Abstract]
  78. Torres-Madriz G, Boucher HW. Immunocompromised hosts: perspectives in the treatment and prophylaxis of cytomegalovirus disease in solid-organ transplant recipients. Clin Infect Dis. Sep 1 2008;47(5):702-11. [View Abstract]
  79. Wolf DG, Shimoni A, Resnick IB, Stamminger T, Neumann AU, Chou S. Human cytomegalovirus kinetics following institution of artesunate after hematopoietic stem cell transplantation. Antiviral Res. Jun 2011;90(3):183-6. [View Abstract]
  80. Shapira MY, Resnick IB, Chou S, et al. Artesunate as a potent antiviral agent in a patient with late drug-resistant cytomegalovirus infection after hematopoietic stem cell transplantation. Clin Infect Dis. May 1 2008;46(9):1455-7. [View Abstract]
  81. Kaul DR, Stoelben S, Cober E, Ojo T, Sandusky E, Lischka P. First report of successful treatment of multidrug-resistant cytomegalovirus disease with the novel anti-CMV compound AIC246. Am J Transplant. May 2011;11(5):1079-84. [View Abstract]
  82. Go V, Pollard RB. A cytomegalovirus vaccine for transplantation: are we closer?. J Infect Dis. Jun 15 2008;197(12):1631-3. [View Abstract]
  83. Schleiss MR. A cytomegalovirus vaccine tames the troll of transplantation. Lancet. Apr 9 2011;377(9773):1216-8. [View Abstract]
  84. [Best Evidence] Pass RF, Zhang C, Evans A, Simpson T, Andrews W, Huang ML, et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med. Mar 19 2009;360(12):1191-9. [View Abstract]
  85. Shanahan A, Malani PN, Kaul DR. Relapsing cytomegalovirus infection in solid organ transplant recipients. Transpl Infect Dis. Dec 2009;11(6):513-8. [View Abstract]
  86. Alexander BT, Hladnik LM, Augustin KM, Casabar E, McKinnon PS, Reichley RM. Use of cytomegalovirus intravenous immune globulin for the adjunctive treatment of cytomegalovirus in hematopoietic stem cell transplant recipients. Pharmacotherapy. Jun 2010;30(6):554-61. [View Abstract]
  87. Angela M Caliendo, MD, PhD. Viral load testing for cytomegalovirus in solid organ transplant recipients. Available at http://www.uptodate.com/online/content/topic.do?topicKey=viral_in/21207&selectedTitle=6%7E150&source=search_result#H2. Accessed July 11, 2013.
  88. Avery RK, Bolwell BJ, Yen-Lieberman B, et al. Use of leflunomide in an allogeneic bone marrow transplant recipient with refractory cytomegalovirus infection. Bone Marrow Transplant. Dec 2004;34(12):1071-5. [View Abstract]
  89. Avery RK, Mossad SB, Poggio E, Lard M, Budev M, Bolwell B. Utility of leflunomide in the treatment of complex cytomegalovirus syndromes. Transplantation. Aug 27 2010;90(4):419-26. [View Abstract]
  90. Bueno J, Ramil C, Green M. Current management strategies for the prevention and treatment of cytomegalovirus infection in pediatric transplant recipients. Paediatr Drugs. 2002;4(5):279-90. [View Abstract]
  91. Cesaro S, Zhou X, Manzardo C, Buonfrate D, Cusinato R, Tridello G. Cidofovir for cytomegalovirus reactivation in pediatric patients after hematopoietic stem cell transplantation. J Clin Virol. Oct 2005;34(2):129-32. [View Abstract]
  92. Cunha BA, Gouzhva O, Nausheen S. Severe cytomegalovirus (CMV) community-acquired pneumonia (CAP) precipitating a systemic lupus erythematosus (SLE) flare. Heart Lung. May-Jun 2009;38(3):249-52. [View Abstract]
  93. Cunha BA, Pherez F, Walls N. Severe cytomegalovirus (CMV) community-acquired pneumonia (CAP) in a nonimmunocompromised host. Heart Lung. May-Jun 2009;38(3):243-8. [View Abstract]
  94. Schleiss MR. VCL-CB01, an injectable bivalent plasmid DNA vaccine for potential protection against CMV disease and infection. Curr Opin Mol Ther. Oct 2009;11(5):572-8. [View Abstract]
  95. Thorne JE, Jabs DA, Kempen JH, Holbrook JT, Nichols C, Meinert CL. Causes of visual acuity loss among patients with AIDS and cytomegalovirus retinitis in the era of highly active antiretroviral therapy. Ophthalmology. Aug 2006;113(8):1441-5. [View Abstract]
  96. Wloch MK, Smith LR, Boutsaboualoy S, Reyes L, Han C, Kehler J. Safety and immunogenicity of a bivalent cytomegalovirus DNA vaccine in healthy adult subjects. J Infect Dis. Jun 15 2008;197(12):1634-42. [View Abstract]

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/Dr. Craig Lyerla.

Here, using immunofluorescent technique, a specimen of human embryonic lung (25X) reveals the presence of cytomegalovirus. Courtesy of the CDC/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.