eMedicine Specialties > Infectious Diseases > Viral Infections

Cytomegalovirus

Todd S Wills, MD, Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases, University of South Florida College of Medicine

Updated: Apr 28, 2009

Introduction

Background

Cytomegalovirus (CMV) is a member of Betaherpesvirinae in the subfamily Herpesviridae. The other Betaherpesvirinae species include human herpesvirus (HHV)–6 and HHV-7, which share common clinical characteristics with CMV. Most people are infected with CMV at some point in life, although the 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 seronegative.

CMV is usually an asymptomatic infection. In immunocompetent individuals, symptomatic disease usually manifests as a mononucleosis syndrome.

Clinically significant CMV disease frequently develops in patients immunocompromised by HIV, solid-organ transplantation, and bone-marrow transplantation. Additionally, congenital transmission from a mother with acute infection during pregnancy is a significant cause of neurological abnormalities and deafness in newborns. Symptomatic 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. As with other herpesviruses, CMV establishes a latent infection in the host. CMV may reactivate during a period of immunosuppression secondary to drugs or intercurrent infection (eg, HIV).

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 patients. Dual infection is a possible explanation for the cases of congenital CMV in children of CMV seropositive mothers.

CMV shares many attributes with other herpes viruses, including genome, virion structure, and the ability to cause latent and persistent infections. CMV is a double-stranded linear DNA virus with 162 hexagonal protein capsomeres surrounded by a lipid membrane. CMV has the largest genome of the herpes viruses, ranging from 230-240 kilobase pairs. Of the betaherpesviruses, CMV is the only class E genome, making it similar to herpes simplex 1. Human CMV is composed of unique and inverted repeats that include the existence of 4 genome isomers caused by inversion of L-S genome components (class E). Replication may be divided into immediate early, delayed early, and late gene expression based on time of synthesis after infection. The DNA is replicated by rolling circles. In vitro, CMV replicates in human fibroblasts.

Pathophysiology

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 rarely associated with glomerulopathy and possible graft rejection.

Immunology

In primary infection, CMV immunoglobulin (Ig) M antibodies may be found as early as 4-7 weeks and may persist as long as 16-20 weeks after initial infection. The majority of neutralizing antibody is 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.

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 patients have revealed that patients 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 patients receiving infusions of CMV-specific CD8⁺ cells.

Primary infection and viremia

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

CMV excretion in the saliva and urine is common in patients who are immunocompromised and is generally of little consequence. In contrast, viremia in organ transplant patients 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 patients. Having no evidence of virus in the bloodstream has a high negative predictive value for disease. Prophylactic or presymptomatic antiviral therapy against CMV disease in transplant recipients typically relies on the detection of CMV in the blood by shell vial cultures, CMV antigenemia, CMV pp65 or pp67 antigen assays, and PCR amplification.

Primary CMV infection is usually asymptomatic or produces mild flulike symptoms. CMV may produce a mononucleosis syndrome similar to Epstein-Barr virus (EBV), primary toxoplasmosis, or acute HIV seroconversion. Both CMV and EBV may cause mild hepatitis and may result in atypical lymphocytes in the blood. Some studies have shown that, as a group, patients infected with CMV have less hepatomegaly, splenomegaly, and pharyngitis than patients infected with EBV. Patients with CMV mononucleosis may be older, have a longer duration of fever, and less cervical lymphadenopathy. However, such clinical findings are inadequate to differentiate between the two viruses.

CMV may be suspected in patients with clinical mononucleosis or fever of unknown origin. Patients typically have a negative result on monospot or other heterophile-agglutinin tests. Most patients have a paucity of physical examination findings. Symptoms are present 9-60 days after primary infection. Hepatitis and atypical lymphocytes usually disappear after 6 weeks. Enlargement of the lymph nodes and spleen may be present. Extreme fatigue may persist after normalization of laboratory values.

A risk factor for CMV mononucleosis is transfusion of multiple units of blood. This 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 tests 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 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 of the viruses.

Rarer manifestations of CMV in immunocompetent individuals include Guillain-Barré syndrome, meningoencephalitis, pericarditis, myocarditis, thrombocytopenia, and hemolytic anemia. Rubelliform or maculopapular rashes are observed with and without the administration of ampicillin. Gastrointestinal ulceration may be found in acute CMV infection in immunocompetent patients, although this finding is much more likely in immunocompromised patients.

Congenital cytomegalovirus disease

Congenital CMV infection is one of the TORCH infections (toxoplasmosis, other infections including syphilis, rubella, CMV, and herpes simplex virus), 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 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. This 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 during pregnancy are estimated to result in congenital CMV disease.

Hepatitis

CMV hepatitis was found in the original case description of a child with chorioretinitis, hepatosplenomegaly, and cerebral calcifications. Hepatitis is commonly observed in patients with primary CMV infection and mononucleosis. Mild transient increases in hepatocellular enzymes may be present, and, rarely, jaundice may develop. The disease typically has a favorable prognosis, but death has been reported in immunosuppressed patients. Pathology typically shows mononuclear cell infiltration of the portal areas but may also reveal granulomatous inflammation.

Pneumonia

Adults manifesting CMV infection as a mononucleosis syndrome may occasionally have pneumonia. Pneumonia occurs at a rate of approximately 0-6%. One study found that the incidence of CMV pneumonia in immunocompetent patients was 19%. Most of the time, pneumonia is found on chest radiograph and is of no clinical significance. It rapidly resolves with the disappearance of the primary infection.

Clinically significant and life-threatening CMV pneumonia may develop in immunocompromised patients. Those most at risk are bone-marrow transplant patients and recipients of lung transplants. In patients who have received marrow transplants, CMV disease is most likely 30-60 days after transplant. Patients may initially present with an asymptomatic infiltrate on chest radiograph. The most common clinical presentation is fever and shortness of breath, accompanied by an interstitial infiltrate. The differential diagnoses in patients who are immunocompromised include Pneumocystis pneumonia, respiratory viruses, pulmonary hemorrhage, drug toxicity, recurrent lymphoma, and other infections. Notably, CMV is frequently detected in the lungs of patients with HIV/AIDS but does not frequently cause clinically significant disease.

Gastritis and Colitis

CMV may infect the gastrointestinal 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 gastrointestinal tract is often shorter-lived than that of other organ systems because of the frequent sloughing of infected cells of the gastrointestinal mucosa.

Retinitis

CMV retinitis is a common opportunistic infection in late-stage AIDS, typically with CD4⁺ lymphocyte counts of less than 50 cells/µL. Typically, patients exhibit a progressive decrease in visual acuity, which may progress to blindness if untreated. Unilateral and bilateral disease may exist.

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 and is described in Pathophysiology.

In both solid organ and marrow transplant patients, CMV causes substantial morbidity and mortality. For example, even with antiviral therapy, the mortality rate in allogeneic marrow transplant patients with interstitial pneumonia varies from 15-75%.

Age

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

Clinical

History

Adult infection in the immunocompetent host

Patients with primary cytomegalovirus (CMV) infection are usually asymptomatic, or they have only mild flulike symptoms. CMV may produce a mononucleosis syndrome similar to EBV, but no clinical differences exist between CMV and EBV mononucleosis. Patients may present with a febrile illness of varying duration and extreme fatigue. The history may be very nonspecific.

Patients may report swelling of their glands, and CMV should be included in the differential diagnosis of infectious agents that cause lymphadenopathy. Some studies have suggested that, as a group, patients with CMV infection have less hepatomegaly, splenomegaly, and pharyngitis than patients infected with EBV. This should not be relied upon to differentiate CMV from EBV mononucleosis. CMV should be suspected in patients with a negative finding on Monospot or other heterophile-agglutinin tests. Risk factors for CMV infection include patients who attend or work at daycare centers, patients who have blood transfusions, and patients who have multiple sex partners.

Physical

The most common presentation is a patient showing very few clinical findings on physical examination. Primary CMV infection can be a cause for fever of unknown origin. Symptoms are present 9-60 days after primary infection. Pharyngitis may be present. Fine crackles may be present on examination of the lungs. The lymph nodes and spleen may be enlarged. Extreme fatigue may persist after normalization of laboratory values. Many physicians believe that, in comparison to EBV infectious mononucleosis, CMV mononucleosis has a lower incidence of pharyngitis and cervical adenopathy. A recent 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% vs 75%). Although statistically significant, relying on this sign for the differentiation between CMV and EBV mononucleosis is difficult.

Causes

CMV infects and causes disease in a wide variety of immunocompromised hosts. Patients receiving organ allografts have been severely affected by CMV disease. CMV can cause a life-threatening interstitial pneumonitis, gastrointestinal disease, retinitis, hepatitis, encephalitis, myeloradiculopathy, and CMV syndrome. In addition, patients who have low CD4 counts and are HIV positive may have the same organ systems affected as those observed in patients who have received organ transplants. Retinitis has been the major reported CMV disease in patients with HIV, followed by CNS involvement.

Transmission of CMV occurs from person to person, in the form of close contact with a patient who is excreting the virus. It can be spread through the placenta, blood transfusions, organ transplantation, and breast milk. It also may be spread through sexual transmission. After infection, CMV becomes latent in the human host. Reactivation may result in disease, most commonly in patients who have a deficiency in cell-mediated immunity. This deficiency may be transitory or permanent, caused by pregnancy, antineoplastic compounds, ionizing radiation, immunosuppression for organ transplantation, and other viral infections (eg, HIV).

• Organ transplantation
  • CMV is an important pathogen isolated in patients after organ transplantation.
  • The incidence of CMV pneumonia may vary depending on the transplant population. Patients who receive marrow, lung, heart, heart-lung, liver, pancreas-kidney, and kidney transplants have different levels of immunosuppression. Fatal CMV pneumonia is much less common in patients who have received solid organ transplants compared to patients who have received marrow transplants. Prior to the introduction of ganciclovir, CMV pneumonia had a high mortality rate in patients who received allogeneic marrow transplants (85%).
  • CMV pneumonia has been difficult to treat, even with the antivirals now available. For example, the marked mortality rate for bone marrow transplant patients with CMV pneumonia was approximately 85% prior to the introduction of ganciclovir and CMV-specific Ig. The addition of Ig to ganciclovir therapy has decreased the CMV pneumonia mortality rate to 15-75%.
  • Ig use has been extrapolated from the marrow transplant experience but has not been studied in patients with CMV pneumonia who have received solid organ transplants. Some experts think the mechanism of CMV pneumonia in patients who have received solid organ transplants may be different from the mechanism in patients who have received marrow transplantation, making the addition of Ig unnecessary. CMV pneumonia in patients who have received marrow transplants does not appear to involve a simple and direct viral cytopathic effect on pneumocytes. The addition of CMV-specific Ig has not been shown to affect the mortality and morbidity of CMV infection of other organ systems.
  • Primary infection of an organ transplant recipient may be quite severe.
  • The major risk factor for CMV disease in transplant patients is a CMV-seronegative transplant recipient receiving a CMV-seropositive organ, also known as CMV mismatch.
  • CMV disease occurs more commonly in positive-donor/negative-recipient transplants than in negative-donor/positive-recipient transplants. This is true for all organ transplants except marrow, where the incidence of CMV disease in previously positive donors is no different than primary infection. The reason for this is unknown but may be related to the level of immunosuppression observed in patients who have received marrow transplants in comparison to those who have received other transplants.
  • Patients who have received marrow transplants receive 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 not known.
  • Ganciclovir has been shown to reduce the virus titer in the lungs. However, this alone does not seem to affect the clinical course of CMV pneumonia when it is administered late or without Ig. The mortality rate of CMV pneumonia in marrow transplants that requires mechanical ventilation is high, despite treatment with ganciclovir and Ig.
  • Poor clinical outcomes are also observed in patients who are also infected with community respiratory viruses (eg, parainfluenza, influenza, respiratory syncytial virus) and who have received allogeneic marrow transplants. This suggests that the severity of CMV pneumonia is not exclusively secondary to viral characteristics.
  • Severe 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 with 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 patients warrants antiviral suppressive therapy. In patients infected with HIV, antiviral therapy is often not required in the absence of clinical apparent disease.
  • Viremia has been observed in patients treated with corticosteroids.
• Cytomegalovirus and human immunodeficiency virus disease
  • Depending on the definition of pneumonia, CMV pneumonia in patients who are HIV positive is either very rare or very common. CMV is often isolated from patients who are co-infected with other bacterial, parasitic, and fungal pathogens. The role CMV plays in the pathogenesis of these pneumonias is unclear.
  • CMV pneumonia without a co-infecting pathogen is uncommon. The reason for this is unknown.
  • In patients who are HIV positive, CMV involves the entire gastrointestinal tract. In the upper gastrointestinal tract, CMV has been isolated from esophageal ulcers, gastric ulcers, and duodenal ulcers. In the lower gastrointestinal tract, patients with CMV may present with colitis.
  • Patients with upper gastrointestinal tract esophageal disease can present with painful dysphagia.
  • Diagnosis of CMV gastrointestinal 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 secondary to CMV shedding. CMV may be isolated from many different sites and not necessarily be associated with disease. This should reinforce the need for histopathologic examination.
  • Patients with lower tract gastrointestinal disease usually present with diarrhea.
  • Retinitis is the most common manifestation of CMV disease in patients who are HIV positive. It occurs most commonly in patients whose CD4 count is less than 50 cells/µL. In this group, CMV retinitis has been observed in as many as 40% of patients. The patient reports decreased visual acuity, floaters, and loss of visual fields on one side. 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.
  • Retinitis begins as a unilateral disease, but in many cases it progresses to bilateral involvement. This may be accompanied by CMV systemic disease. Ganciclovir has been used to treat retinitis. Unfortunately, it only slows the progression of the disease. Many clinicians switch to foscarnet after the failure of ganciclovir. Ganciclovir implants have emerged as an important therapy in the management of CMV retinitis. The optimal treatment is using ganciclovir implants in the vitreous, accompanied by systemic ganciclovir therapy.
  • Oral (PO) ganciclovir may be used for prophylaxis of CMV retinitis. It 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, treating the patient with corticosteroids may be necessary.
• In patients who are HIV positive, CMV may cause disease in the peripheral and central nervous system.

Differential Diagnoses

Workup

Laboratory Studies

Traditionally, cytomegalovirus (CMV) antibody tests were performed using complement fixation and showed peak viral titers 4-7 weeks after infection. Multiple tests are now available for measuring CMV antibody. Some tests are sensitive enough to detect anti-CMV IgM antibody early in the course of the illness and during CMV reactivation. As with EBV, observing reactivation of the virus with a positive IgM in the presence of IgG antibody is not uncommon. This is most commonly observed during intercurrent infection in patients who are immunocompromised. The clinical significance, time course, and natural history of reactivation are not known for either CMV or EBV.

• Antigen testing
  • Antigenemia is a relatively new test developed in the late 1980s. This test is based on the recognition of CMV early antigen with a mixture of 2 mouse monoclonal antibodies, C-10 and C-11. The detector system is fluorescein-labeled antimouse Ig.
  • CMV pp65 and pp67 assays: These assays are used to detect messenger matrix proteins on the CMV virus, with either immunofluorescence assay or messenger RNA amplification. These proteins are typically expressed only during viral replication.
  • Antigen tests are often the basis for institution of antiviral therapy in transplant patients and may allow for the detection of subclinical disease in patients at high risk.
• Qualitative polymerase chain reaction
  • PCR has been used to detect CMV in blood and tissue samples.
  • The PCR test 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.
  • The test is extremely sensitive.
  • It is positive before the antigenemia test in patients with viremia who have received transplants. The PCR test result is not usually positive in patients without CMV viremia.
  • Qualitative PCR has also been used to detect CMV in histological sections.
• 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.
  • Research is underway to determine if the CMV viral load present in the plasma correlates with risk of disease in different at-risk populations. In theory, the CMV viral load would indicate whether therapy is necessary because patients whose viral load is below a certain cut-off 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.
• Shell vial assay
  • The assay is performed by adding the clinical specimen to a vial containing 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-Ig.
  • This test has been found to be as sensitive as traditional tissue culture.

Imaging Studies

• The diagnosis of CMV pneumonia can be suggested by chest radiograph findings, but these findings cannot be used to differentiate between other common causes for pneumonia in the immunocompromised host. 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 presenting with hypoxia and no infiltrate visible on chest roentgenogram.

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).

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

Treatment

Medical Care

• Ganciclovir treatment
  • The drug of choice for treatment of cytomegalovirus (CMV) disease is ganciclovir.
  • 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.
  • The process of phosphorylating ganciclovir to ganciclovir monophosphate is performed by protein UL97. 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 the majority of ganciclovir resistance, although other resistance mechanisms may be present.
  • Ganciclovir has activity against CMV; herpes simplex virus; varicella zoster virus (VZV); and human herpesvirus 6, 7, and 8. However, for treatment of patients with VZV and herpes simplex, one of the nucleoside analogues, such as famciclovir, penciclovir, or acyclovir, is preferred.
  • The major adverse effects of ganciclovir therapy are neutropenia and 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]).
  • Intravenous (IV) ganciclovir produces serum levels of 10-12 mcg. PO ganciclovir has serum levels 5-10 times less than IV ganciclovir, making PO ganciclovir a less-than-optimal agent for the management of active CMV disease. Because of the low serum levels of the PO form, it has mainly been used for prophylaxis of CMV disease. Recently, a new preparation of ganciclovir, valganciclovir hydrochloride, has been approved for the treatment of CMV retinitis in HIV-positive patients. Valganciclovir is the L-valyl ester of ganciclovir. The dose of valganciclovir is 900 mg PO twice daily for treatment typically followed by 900 mg once as maintenance therapy. The duration of treatment is typically 21 days but is often adjusted based on the results of antigen assays or CMV PCR testing.
  • No comparative trials of valganciclovir maintenance therapy for CMV retinitis have been conducted. The drug exposure (ie, area under the curve [AUC]) of 900 mg of valganciclovir is similar to an intravenous dose of 5 mg/kg.
  • The ganciclovir induction dose is administered at 5 mg/kg twice per day. Later, the dose is decreased from twice per day to once per day and is continued as maintenance therapy.
  • For the treatment of CMV pneumonia, ganciclovir is administered with CMV-specific Ig. The dose of Ig is 500 mg/kg every other day. Ganciclovir is administered at 5 mg/kg twice per day for 14 days and then at 5 mg/kg once per day.
  • The length of treatment is variable. 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.
  • How Ig facilitates ganciclovir so that it leads to a better outcome for CMV pneumonia is not known.
  • Other uses of ganciclovir include treatment of gastrointestinal disease in patients who have received transplants and in patients who are HIV positive. Ganciclovir has also been used to treat CMV esophagitis in both of these patient populations.
  • The drug is also used to treat diarrhea secondary to colitis or enteritis in patients positive for HIV after tissue biopsy and confirmation of CMV disease.
  • Ganciclovir has also been used to treat CNS disease, including encephalitis and neuropathy, with mixed results.
• Ganciclovir prophylaxis
  • A major successful use of ganciclovir has been prophylaxis or preemptive treatment of CMV disease in patients who have received transplants.
  • Ganciclovir is administered to prevent CMV disease and is administered prior to the clinical signs and symptoms of CMV disease.
  • It may be administered prophylactically or as preemptive therapy. Prophylaxis is provided to all patients who have a positive finding on CMV serology. Preemptive therapy is provided to patients who have evidence of ongoing viral replication. Positive findings on blood cultures, antigenemia, and PCR techniques demonstrating CMV in plasma have been used as markers for the initiation of therapy. Both the prophylactic and the preemptive approaches have been used, and both were found to decrease CMV disease in patients who have received marrow or solid organ transplants. The choice of the appropriate regimen may be determined by the adverse effects of the drugs and the abilities of the microbiology laboratory.
  • In early studies, the lack of a sensitive test to detect CMV in the plasma resulted in patients developing CMV pneumonia. Culturing CMV from the blood using shell vials and starting ganciclovir was shown to result in a decrease in CMV pneumonia.
  • Another study, using antigenemia as the trigger for treatment, found prophylaxis to be more effective than preemptive therapy for preventing CMV pneumonia in patients who have received marrow transplants.
  • Preemptive therapy triggered by sensitive testing such as PCR or nucleic acid–based antigen assays has decreased the morbidity associated with CMV-related disease.
  • Preemptive therapy is attractive because it restricts the use of ganciclovir to a select population at high risk for CMV disease and eliminates toxicity in the majority that would not be diagnosed with CMV disease. Ongoing trials are investigating quantitative PCR as a method for initiating preemptive therapy.
  • Prophylactic approaches have also 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.
  • Both prophylaxis and preemptive therapy are effective but have drawbacks. Individualize the choice of strategy for the type of transplant and the individual characteristics of the transplant center.
• Foscarnet
  • Foscarnet is a DNA chain inhibitor of phosphorylation. It has been used to treat resistant herpes simplex virus and virus that is resistant to ganciclovir. It is an effective antiviral.
  • Meticulous attention must be paid to the patient's renal function. Small changes in creatinine require new calculations for renal clearance. Foscarnet is nephrotoxic. The patient must be well hydrated.
  • It 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.
  • The foscarnet dose is 60 mg/kg IV every 8 hours or 90 mg/kg IV every 12 hours for 14-21 days for the induction period for retinitis. The dose is dropped to 90-120 mg/kg/d IV for the maintenance interval.
  • 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 patients who have received organ transplants. The results have been mixed, depending 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.
  • 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 patients positive for HIV.
  • Ganciclovir resistance does not necessarily preclude the use of cidofovir.
  • Cidofovir is administered at 5 mg/kg IV every week for 2 weeks and then at 5 mg/kg every other week.
  • The patient must be hydrated, and the drug must be administered with probenecid to protect the renal tubules.

Consultations

• Infectious diseases specialist
  • Obtaining an infectious disease consultation in patients with CMV viremia or pneumonia is wise. This is particularly true in patients who are immunocompromised and in patients who have received organ transplants.
  • Current 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 neurology consultation may be helpful in the management of these diseases.
• Ophthalmologist
  • Chorioretinitis may be observed in immunocompromised hosts.
  • In addition, an ophthalmology consultation is important in monitoring patients with HIV for opportunistic infections, especially those patients with a CD4 cell count of fewer than 100 cells/µL.

Activity

Patients commonly ask when they can resume their usual activities. The most common symptom after resolution of the acute phase of the infection is fatigue. This may be present for as long as 18 months after the primary infection but usually is much shorter in patients. 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

The goals of pharmacotherapy are to prevent outbreaks of the disease and its complications and to reduce morbidity.

Antivirals

Cytomegalovirus (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.

Ganciclovir (Cytovene)

Synthetic guanine derivative active against CMV. An acyclic nucleoside analog of 2'-deoxyguanosine that inhibits replication of herpes viruses both in vitro and in vivo.
Levels of ganciclovir-triphosphate are as much as 100-fold greater in CMV-infected cells than in uninfected cells, possibly because of preferential phosphorylation of ganciclovir in virus-infected cells.
In patients who are HIV positive, resistance is manifested by progressive disease. A PO formulation exists and is used for prophylaxis of CMV infection, but it should not be used for treatment of acute infection. A new PO preparation is available called valganciclovir. It achieves serum levels comparable to IV administration. The length of treatment is variable and depends on the disease and the host.

Dosing

Adult

CMV retinitis
Induction: 5 mg/kg IV over 1 h q12h for 14-21 d (do not use PO ganciclovir for induction treatment)
Maintenance: 1 g PO tid
5 mg/kg IV qd for 5-7 d/wk
CMV pneumonia
Induction: 5 mg/kg IV bid plus Ig 500 mg/kg 3 times per wk for the first 2 wk
Maintenance: 5 mg/kg/d IV for 1 mo plus Ig 500 mg/kg qwk for 1 mo

Pediatric

CMV retinitis
<3 months: Not established
>3 months: Administer as in adults

Interactions

Concomitant administration with dapsone, vinblastine, Adriamycin, pentamidine, flucytosine, vincristine, amphotericin B, and trimethoprim and sulfamethoxazole combinations or other nucleoside analogs may result in additive toxicity in bone marrow, spermatogonia, and germinal layers of skin and GI mucosa (coadminister only if potential benefits outweigh risks); coadministration with imipenem and cilastatin may cause generalized seizures (use only if potential benefits outweigh risks); serum creatinine may increase following concurrent use of ganciclovir with either cyclosporine or amphotericin B; renal clearance is reduced in the presence of probenecid; bioavailability may increase when didanosine is administered either 2 h prior to or simultaneously with ganciclovir; bioavailability may decrease in the presence of zidovudine, while the bioavailability of zidovudine is increased in the presence of ganciclovir

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Clinical toxicity includes granulocytopenia, anemia, and thrombocytopenia; because PO formulation is associated with a higher rate of CMV retinitis progression compared to IV use, use PO only when benefits outweigh risks (eg, advanced HIV disease); half-life and plasma and/or serum concentrations may be increased as a result of reduced renal clearance; dosages > 6 mg/kg IV may result in increased toxicity; rapid infusions may result in increased toxicity; initially, reconstituted solutions of IV ganciclovir have a high pH (ie, 11); phlebitis or pain may occur at the site of IV infusion despite further dilution in IV fluids; administration should be accompanied by adequate hydration; photosensitization (ie, photoallergy, phototoxicity) may occur; should not be administered if the neutrophil count is <500 cells/µL or platelet counts <25,000 cells/µL; monitor CBC count and electrolytes qwk (if stable on long-term therapy, frequency can be extended)

Foscarnet (Foscavir)

Organic analog of inorganic pyrophosphate that inhibits replication of known herpesviruses, including CMV, HSV-1, and HSV-2. Inhibits viral replication at pyrophosphate-binding site on virus-specific DNA polymerases. Used for the treatment of ganciclovir-resistant CMV retinitis and herpes simplex disease. Poor clinical response or persistent viral excretion during therapy may result from viral resistance. Patients who can tolerate foscarnet may benefit from initiation of maintenance treatment at 120 mg/kg/d early in treatment. Individualize dosing based on renal function status.

Dosing

Adult

Induction: 60 mg/kg/dose IV q8h or 90 mg/kg IV q12h for 14-21 d
Maintenance: 90-120 mg/kg/d IV as single infusion; rate not to exceed 1 mg/kg/min

Pediatric

Not established

Interactions

Coadministration with potentially nephrotoxic drugs (eg, aminoglycosides, amphotericin B, IV pentamidine) may increase nephrotoxicity (do not administer unless potential benefits outweigh risks); coadministration with IV pentamidine may cause hypocalcemia

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

May cause decline in renal function; for correct dosing, obtain 24-h serum creatinine at baseline and continue to monitor (discontinue if serum creatinine <0.4 mL/min/kg); hydration may reduce nephrotoxicity; monitor electrolytes (eg, calcium, magnesium); assess for electrolyte and mineral level abnormalities if mild perioral numbness, paresthesias symptoms, or seizures occur; granulocytopenia and anemia may occur (regularly monitor CBC count); infuse into veins with adequate blood flow to avoid local irritation; to avoid toxicity, do not administer by rapid or bolus IV injection; adverse effects include neurological toxicities, anemia, headache, and nausea; can cause a fixed drug reaction on the penis

Cidofovir (Vistide)

Currently approved for treatment of CMV retinitis in AIDS. Cidofovir is the first member of a group of antivirals known as acyclic phosphonate nucleotide analogs. Cidofovir diphosphate, the active intracellular metabolite of cidofovir, 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.

Dosing

Adult

5 mg/kg IV qwk with probenecid (2 g PO 3 h before HPMPC, 1 g PO 2 h immediately after dose, and 1 g PO 8 h after dose)
Adequately hydrate by administering an IV infusion of 1 L 0.9% NaCl 1 h before HPMPC infusion

Pediatric

Not established

Interactions

Coadministration of aminoglycosides, amphotericin B, IV pentamidine, and foscarnet may increase nephrotoxicity

Contraindications

Documented hypersensitivity; coadministration with other nephrotoxic agents; serum creatinine >1.5 mg/dL; a CrCl <55 mL/min; urine protein >100 mg/dL

Precautions

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Monitor neutrophil counts; renal toxicity is major adverse effect; prehydrate with normal saline IV and coadminister probenecid with each infusion to minimize nephrotoxicity (monitor renal function); monitor serum creatinine and urine protein 48 h prior to treatment (adjust dose accordingly); granulocytopenia may occur

Follow-up

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 focus on avoiding iatrogenic infections and problems.
• Patients who develop CMV disease are immunocompromised and are 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 retinitis, follow-up with a CBC count once per week (monitoring for hematological toxicity) is necessary. Also, monitoring electrolytes at the same time is a good idea. Ganciclovir 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.
• If treating a patient who has CMV retinitis, regular ophthalmological examinations should be performed.

Deterrence/Prevention

• See Treatment for a discussion about early treatment versus prophylaxis with ganciclovir.
• Other drugs have been used for prophylaxis, but none are as effective as ganciclovir. Acyclovir and valacyclovir have been used for prophylaxis and early treatment in patients who have received allogeneic marrow transplants. Acyclovir has also been used in patients who have received other types of transplants.
• Congenital infection with CMV is an important cause of hearing, cognitive, and motor impairments in newborns. A phase II, 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.¹

Complications

• See Medication.

Prognosis

• The prognosis of patients with CMV hepatitis is generally good. Most patients recover completely. Symptoms can persist, usually in the form of fatigue, for several months after primary infection.
• CMV pneumonia in patients who have received marrow transplants once carried a mortality rate higher than 85%. The use of ganciclovir plus high-dose Ig for the treatment of CMV pneumonia in patients who have received allogeneic marrow transplants 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.

Patient Education

• For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center. Also, see eMedicine's patient education article Mononucleosis.

Miscellaneous

Medicolegal Pitfalls

• Because of the toxicity of the antivirals used to treat cytomegalovirus (CMV) disease, consulting a physician familiar in the use and adverse effects of these drugs is important.

Multimedia

Media file 1: Here, using immunofluorescent technique, a specimen of human embryonic lung (25X) reveals the presence of cytomegalovirus. Courtesy of the CDC/Dr. Craig Lyerla.

References

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Keywords

cytomegalovirus, CMV, Betaherpesvirinae, Herpesviridae, mononucleosis, pneumonia, hepatitis, encephalitis, colitis, uveitis, retinitis, neuropathy, HIV, CMV syndrome, fever of unknown origin, FUO, STDs, transplant infections

Contributor Information and Disclosures

Author

Todd S Wills, MD, Assistant Professor, Department of Internal Medicine, Division of Infectious Diseases, University of South Florida College of Medicine
Todd S Wills, MD is a member of the following medical societies: Infectious Diseases Society of America
Disclosure: Nothing to disclose.

Medical Editor

Douglas A Drevets, MD, Assistant Professor, Department of Medicine, Section of Infectious Disease, Oklahoma University Health Sciences Center
Douglas A Drevets, MD is a member of the following medical societies: American Association of Immunologists, American Society for Microbiology, Central Society for Clinical Research, and Christian Medical & Dental Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

John W King, MD, Professor of Medicine, Section of Infectious Diseases, Louisiana State University Health Sciences Center; Director, Viral Therapeutics Clinics for Hepatitis; Consulting Staff, Department of Infectious Diseases, Overton Brook Veterans Affairs Medical Center
John W King, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Federation for Medical Research, American Society for Microbiology, Association of Subspecialty Professors, Infectious Diseases Society of America, and Sigma Xi
Disclosure: emedicine $50.00 author of chapter

CME Editor

Eleftherios Mylonakis, MD, Clinical and Research Fellow, Department of Internal Medicine, Division of Infectious Diseases, Massachusetts General Hospital
Eleftherios Mylonakis, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Microbiology, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

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
Burke A Cunha, MD is a member of the following medical societies: American College of Chest Physicians, American College of Physicians, and Infectious Diseases Society of America
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous coauthor James M Goodrich, MD, PHD, to the development and writing of this article.

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