Pathogenesis
Once infected, one probably carries the virus for life. Generally, such infections remain dormant, but reactivation occurs during periods of immune compromise. Reactivation is particularly common in patients with compromised T cell function (e.g., transplant recipients or patients with lymphoid neoplasms or AIDS). Reinfections with new strains of CMV can also occur in immunosuppressed patients.
In the fetus, primary infection may result in disseminated cy-tomegalic inclusion disease with numerous congenital abnormalities, in localized disease affecting the auditory system or the CNS, or in subclinical involvement. Perinatal infection is usually asymptomatic, although protracted interstitial pneumonitis, hepatitis, and failure to thrive may result.
Symptomatic disease is more likely to be produced by primary CMV infection than by viral reactivation. The sites of latent infection are poorly defined, although it appears likely that CMV persists in numerous cell types in many organs. If host immune responses become compromised, virus reactivation and increased replication can occur and result in various syndromes. CMV replication can further suppress immune responses, leading to profound lymphocyte hyporesponsiveness and severe opportunistic infections with protozoa (e.g., Pneumocystis carinii and Toxoplasma gondii), fungi, or bacteria. The mechanisms by which CMV replication inhibits host responses are complex and involve virus interactions with both host lymphocytes and mono-cyte-macrophages.
Clinical Syndromes
CMV Mononucleosis
Clinical features CMV mononucleosis occurs in patients of any age but is most common in sexually active young adults. A vigorous host T cell response may contribute to the syndrome, which is characterized by fever, malaise, fatigue, and myalgia. Headache and splenomegaly are also often present. Mild liver enzyme abnormalities are common, and atypical lymphocytes are present in the peripheral blood. Heterophile antibodies are not formed in response to CMV infection; however, mild im-munologic abnormalities, including the presence of rheumatoid factor and antinuclear antibodies, are common.
Complications Occasionally, hemolytic anemia, thrombo-cytopenia, neurologic complications (e.g., Guillain-Barre syndrome), or other organ involvement (liver, lung) occurs and is severe.43 Acute infections generally resolve in 2 to 4 weeks, but postviral asthenia and viral excretion often persist for months.
CMV Infection in the Immunocompromised Host
CMV appears to be the most frequent and important viral pathogen in patients who have had organ transplants. Most commonly, such patients with CMV syndromes present with fever and leukopenia, which may progress to pneumonitis or, in rare instances, to disseminated disease. The period of highest risk is 1 to 4 months after transplantation and appears to relate to the degree of host immunosuppression. CMV may also increase the risk of graft loss after organ transplantation.44 CMV pneumonia occurs in nearly 20% of marrow transplant recipients; mortality in such patients, if they remain untreated, is about 90%.
CMV is recognized as an important pathogen in patients with AIDS. The virus often contributes to the immunosuppression observed in such patients and may cause disseminated disease affecting the eyes, GI tract, or CNS. At least 50% of patients with AIDS have CMV viremia, and 90% or more have evidence of CMV infection at autopsy.45 Ulcers of the esophagus, stomach, small intestine, or colon may be present and may lead to bleeding or perforation.46 It is critical to recognize CMV polyradicu-lopathy or encephalitis in this setting because this disorder is potentially reversible with therapy.47,48 Similarly, CMV retinitis is an important treatable cause of blindness in patients with AIDS.
Figure 6 Cytomegalovirus retinitis may result in hemorrhage exudates and, eventually, blindness.
Early lesions consist of small white areas of retinal necrosis that progress in a centrifugal manner and are subsequently accompanied by hemorrhage, vessel sheathing, and retinal edema [see Figure 6]. CMV and HIV have been shown to potentiate each other’s replication in vitro, and it is possible that such interactions occur in dually infected organs (e.g., the retina and brain of an AIDS patient who has CMV infection).
Two forms of CMV encephalitis are clinically and pathologically distinguishable in patients with AIDS: multifocal micron-odular encephalitis, which resembles HIV encephalitis and presents with progressive dementia, and ventriculoencephalitis, which is characterized by acute cranial nerve deficits, ventricu-lomegaly, nystagmus, lethargy, and disorientation.48,50
Diagnosis
CMV infection cannot be reliably diagnosed on clinical grounds alone. Virus can be isolated from a variety of secretions or infected tissues, but definitive identification can take several weeks. Use of shell vial centrifugation and immunocytochemical analysis for CMV early antigens can facilitate rapid diagnosis and help monitor outcome, as can the application of immunoflu-orescence or PCR-based assays to plasma or peripheral blood leukocytes.51-53 Demonstration of viremia is a better indicator of acute infection than the detection of virus in urine or saliva. The use of PCR to detect CMV DNA in CSF is helpful in the diagnosis of CMV encephalitis and polyradiculopathy.48,50
Prevention
Several specific and nonspecific prophylactic measures to prevent CMV syndromes are under investigation. Matching of seronegative transplant or transfusion recipients with seronega-tive organ or blood donors may reduce the likelihood of transmission. Use of blood that has been frozen and thawed, washed with saline, or filtered through cotton wool can prevent transfusion-associated CMV infection. CMV immune globulin may be useful in certain seronegative bone marrow transplant recipients. Experimental CMV vaccines are under investigation.
Treatment
Management of CMV Mononucleosis
CMV mononucleosis is generally self-limited and requires only supportive care. Specific antiviral therapy is not indicated.
Management of CMV in the Immunocompromised Host
Intravenous ganciclovir, an analogue of deoxyguanosine, and oral valganciclovir, a prodrug for ganciclovir, are effective treatments for CMV infections (e.g., retinitis) in immunocompromised hosts [see Table 4]. Both ganciclovir administered intravenously (5 mg/kg twice daily for 21 days followed by 5 mg/kg daily maintenance) and oral valganciclovir (900 mg twice daily for 21 days followed by 900 mg daily maintenance) result in stabilization or improvement in 70% to 90% of patients with CMV retinitis.54 If the immunocompromised state persists, prolonged maintenance therapy may be required to maintain improvement of retinitis.55 Maintenance therapy can be safely discontinued in patients with AIDS whose CD4 cell counts increase substantially with antiretroviral therapy, but relapses occur if CD4 cell counts fall below 50/mm3.
Foscarnet (90 mg/kg twice daily for 2 to 3 weeks, followed by 90 to 120 mg/kg daily) is effective in treatment of CMV retinitis and GI disease, and cidofovir (5 mg/kg weekly for 2 weeks, followed by 5 mg/kg every 2 weeks) may be useful in CMV retini-tis. Ganciclovir ocular implants in combination with oral ganci-clovir (1.5 g three times daily) is effective for long-term treatment of CMV retinitis in persistently immunocompromised patients with HIV infection.57 The combination of ganciclovir and foscar-net may be necessary for severe CNS infections in patients with AIDS.58 Resistance to ganciclovir and other anti-CMV drugs may complicate prolonged therapy.
Table 4 Drug Treatment for Cytomegalovirus Infection
|
Drug |
Dose |
Efficacy Rating |
Comment |
|
Ganciclovir |
5 mg/kg I.V. b.i.d. for 21 days, then 5 mg/kg I.V. q.d. for maintenance |
First choice |
For CMV retinitis and other advanced CMV infections in immuno-compromised patients |
|
Ganciclovir + ocular implants |
1.5 g p.o., t.i.d. |
— |
For long-term therapy of CMV retinitis in patients with HIV infection |
|
Valganciclovir |
900 mg p.o., b.i.d., for 21 days, then 900 mg p.o., q.d., for maintenance |
First choice |
For CMV retinitis and other advanced CMV infections in immuno-compromised patients |
|
Foscarnet |
90 mg/kg I.V. b.i.d. for 2-3 wk, then 90-120 mg/kg I.V. q.d. |
Alternative |
For CMV retinitis or GI disease; combine with ganciclovir for severe CNS infections in patients with AIDS |
|
Cidofovir |
5 mg/kg I.V. once a week for 2 wk, then 5 mg/kg I.V. every 2 wk |
Alternative |
For CMV retinitis |
CMV—cytomegalovirus
CNS—central nervous system
GI—gastrointestinal
NA—not available
Prophylactic or suppressive ganciclovir may be useful in other high-risk patients, such as CMV-seropositive bone marrow or solid-organ transplant recipients. Several preventive or preemptive regimens of ganciclovir or valganciclovir are under study in both susceptible transplant recipients and patients with AIDS.61-63
Epstein-Barr Virus
EBV has a very limited cell tropism; its host range is generally restricted to human B cells and epithelial cells of the nasopharynx and uterine cervix. It is the cause of heterophile antibody-positive infectious mononucleosis and has been implicated in a variety of other disorders, including Burkitt lymphoma, na-sopharyngeal carcinoma, oral hairy leukoplakia, and a variety of B cell and possibly T cell lymphoproliferative disorders.64-66
Epidemiology and Etiology
In developing countries, most of the population is exposed to EBV at an early age. In the United States, approximately 50% of the population seroconvert by 5 years of age; there is also a high rate of seroconversion in adolescence and young adulthood. Clinical infectious mononucleosis develops primarily in persons who contract primary EBV infection when they are between 10 and 20 years of age; in younger persons, primary EBV infection is usually clinically inapparent. Thus, most cases of infectious mononu-cleosis occur in members of higher socioeconomic groups in developed countries, where viral transmission is often delayed until the patients are older than 10 years. Approximately 12% of susceptible college-age young adults seroconvert each year; about 50% of them acquire infectious mononucleosis. As a result, EBV infection has important public health implications for young adult populations, including students and military personnel.
EBV is shed from the oropharynx in approximately 15% of the adult seropositive population at any given time, and all EBV-seropositive individuals may shed virus in their saliva at some time.67 Shedding occurs much more frequently in patients with infectious mononucleosis and in immunocompromised persons, such as renal transplant recipients and patients with AIDS. Transmission requires close contact, usually oral to oral, with a person shedding EBV. On rare occasions, virus can be transmitted by other routes, including blood transfusion. EBV infection of the uterine cervix has been documented, genital ulcerations have been observed in patients with infectious mononucleosis, and sexual activity is a highly significant risk factor for EBV seropositivity,68 suggesting the possibility of genital transmission of EBV to sexual partners and newborns.
Pathogenesis
Infection is initiated by the binding of EBV envelope proteins gp350/120 to the cell surface molecule CD21. After initial replication in nasopharyngeal cells or B cells, B cells apparently carry the virus to other parts of the body. In the nasopharynx, infectious virus is actively replicated. In contrast, in B cells, the viral genome is present, but mature infectious virus particles are not produced. In B cells in which EBV remains latent, its DNA exists as a circular episome; in cells in which infectious virus is produced, EBV DNA exists in a linear form. Infected B cells are referred to as immortalized (i.e., capable of continuous proliferation) and may produce a variety of antibodies as a consequence of polyclonal B cell activation. One of the antibodies they produce, the heterophile antibody, is a useful diagnostic marker of infection. Once infection is initiated, the host mounts a T cell response against new antigens on infected cells and a B cell antibody response against several EBV-associated antigens, including viral capsid antigen, early antigen, and Epstein-Barr nuclear antigen.64 Antibody patterns vary according to the stage of infection and the syndrome expressed (see below).
Clinical Syndromes
Age and immunocompetence greatly influence the expression of EBV infection. Young children usually have asymptomatic or trivial infections and often do not produce heterophile antibodies. In the elderly, EBV infection may present as a persistent febrile syndrome in which the patient tests negative for het-erophile antibodies. The most common clinical manifestation of primary EBV infection is infectious mononucleosis.
Infectious Mononucleosis
Clinical features Patients usually present with fever, pharyngitis, and lymphadenopathy. Hepatosplenomegaly, a palatal enanthema, periorbital edema, and jaundice are less common features. A maculopapular diffuse rash occurs in 10% of patients, particularly in patients who have been given ampicillin. Hematologic abnormalities include a peripheral blood lymphocytosis; usually more than 10% of the leukocytes in the peripheral blood consist of atypical lymphocytes. The total leukocyte count may be normal, low, or high; a relative and absolute neu-tropenia is observed in 60% to 90% of patients. Thrombocytope-nia is also common, and hepatocellular enzymes are abnormal in about 90% of patients. Cryoproteins and antigranulocyte antibodies are frequently present but are usually of little clinical significance. Most cases of infectious mononucleosis resolve in 1 to 3 weeks, although malaise and fatigue occasionally persist for several weeks to months.
Complications Complications of infectious mononucleosis can affect most organ systems. Tonsillar enlargement can be extreme, causing respiratory embarrassment. Splenic rupture is rare but must be considered when abdominal pain develops, particularly during the second and third weeks of illness. Patients with splenic rupture usually have left upper quadrant pain and tenderness, often accompanied by signs of peritoneal irritation and laboratory evidence of a falling hematocrit. Splenectomy may be required when a diagnosis of splenic rupture is confirmed, although splenic preservation is sometimes possible with intensive supportive care.
Neurologic complications occur in fewer than 1% of patients with infectious mononucleosis; these complications include encephalitis, aseptic meningitis, transverse myelitis, Guillain-Barre syndrome, optic neuritis, and peripheral neuropathies. EBV encephalitis often presents as a cerebellitis, but it may mimic the temporal lobe presentation of herpes encephalitis [see 11:XVI Acute Viral Central Nervous System Diseases]. Despite the severity of the neurologic complications, most patients with such complications recover completely.
Autoimmune hemolytic anemia mediated by cold agglu-tinins directed against antigens may occur, usually during the second or third week of illness. Aplastic anemia, thrombocy-topenia with bleeding, and severe granulocytopenia with su-perinfection are rare but potentially fatal complications. EBV has been detected in bone marrow specimens by in situ hybridization. Cardiac and pulmonary complications are rare. A rare chronic syndrome of fever, persistent hepatitis, extensive lymphadenopathy, hepatosplenomegaly, pancytopenia, uveitis, and interstitial pneumonia has been associated with persistent EBV infection.69
EBV Infection in the Immunocompromised Host
Immunocompromised hosts are susceptible to overwhelming EBV lymphoproliferative syndromes. A familial X-linked disorder, Duncan disease, has been associated with fatal infectious mononucleosis, as well as agammaglobulinemia and lymphoma. All of these disorders are apparently related to EBV infection in genetically predisposed persons. The gene involved encodes for a 128 amino acid protein that may be involved in T cell signal transduction.70 Occasionally, in transplant recipients receiving cyclo-sporine and in patients with AIDS, overwhelming EBV infections develop that culminate in B cell lymphoproliferative syndromes.
Oral hairy leukoplakia is a nonmalignant hyperplastic lesion of epithelial cells that occurs in immunocompromised patients, particularly those with HIV infection, and presents as raised, white, corrugated lesions on the lateral aspect of the tongue. It is associated with active EBV replication and expression of lytic viral proteins.71
EBV Infections and Cancer
The nature of the association of EBV with Burkitt lymphoma and nasopharyngeal carcinoma remains unresolved. Nearly all African patients with Burkitt lymphoma and East Asian patients with nasopharyngeal carcinoma have elevated EBV antibody titers, and EBV DNA is found in the tumors themselves. A single clonal form of EBV has been associated with nasopharyngeal carcinoma and with preinvasive lesions, although it is not clear whether or how the virus is involved in the etiology of these neoplasms. EBV has also been associated with some cases of primary CNS B cell lymphoma, T cell lymphoma, smooth muscle tumors, lymphomatoid granulomatosis, and Hodgkin disease.64-66
Diagnosis
In most cases of infectious mononucleosis, the diagnosis is confirmed by detection of heterophile antibodies and abnormalities in the blood, characterized by the presence of atypical lymphocytes that frequently account for more than 10% of the leukocytes in the peripheral blood. Heterophile antibodies, often detected with monospot or slide tests, are not directed against viral antigens but rather against erythrocyte antigens of a variety of species, including sheep, horses, and goats. These acute-phase reac-tants, present in about 90% of patients at some point during the illness, must be distinguished from naturally occurring Forssman antibodies and the antibodies present in patients with serum sickness; differentiation can be accomplished by proper absorption tests. Heterophile antibodies may be present at the onset of clinical illness or may appear later in the course of disease; they usually disappear 3 to 4 months after the onset of illness but may persist for longer periods. False positive reactions are rare.
Heterophile antibody-negative infectious mononucleosis may be caused by CMV, EBV, or other viruses. For heterophile antibody-negative cases of infectious mononucleosis and for other possibly EBV-associated syndromes, measurement of EBV-specif-ic antibodies may be useful. Antibodies to viral capsid antigen appear early in the course of infection and are present in 85% of patients at the time of their initial physician visit. The presence of IgM antibodies to viral capsid antigen suggests acute infection, whereas IgG antibodies to viral capsid antigen indicate past infection. Antibodies to early antigen appear transiently during active infections and are also found in patients with the African variant of Burkitt lymphoma and in patients with nasopharyngeal carcinoma. Antibodies to Epstein-Barr nuclear antigen appear late in the course of illness and persist after recovery. Thus, the pattern of specific EBV antibody responses may indicate the stage of infection.
Cultures are usually not helpful in making a diagnosis. Although EBV can be isolated from the nasopharynx, culture techniques are cumbersome and time consuming. EBV DNA detection by PCR techniques may be useful for monitoring progression in certain diseases, such as encephalitis or lymphoproliferative syndromes.
Prevention
Experimental EBV vaccines are under study, although appropriate indications for their use are unclear.
Treatment
Management ofInfectious Mononucleosis
Treatment is supportive. The administration of corticosteroids may be helpful in certain situations, such as impending airway obstruction, severe thrombocytopenia, or hemolytic anemia.
Short-course regimens (1 to 2 weeks) are adequate. Specific antiviral agents such as acyclovir or ganciclovir are not recommended for most EBV-related disorders.75 Although intravenous acyclovir can reduce viral shedding in patients with infectious mononucleosis, clinical benefit appears to be minimal.
Management of Infection in the Immunocompromised Host
Infusion of donor leukocytes or EBV-specific cytotoxic T cells has also been useful in some EBV-related lymphoproliferative diseases after bone marrow transplantation.64,76 No antiviral agents have shown benefit in EBV-associated diseases.
Human Herpesvirus Type 6
In 1986, a newly recognized herpesvirus, HHV-6, was isolated from the peripheral blood leukocytes of six persons with various lymphoproliferative disorders.77 It was initially designated human B lymphotropic virus but was renamed when subsequent studies demonstrated that the virus replicated in cells of T cell origin.78 Two genetically distinct variants of HHV-6—namely, HHV-6A and HHV-6B—are recognized. Disease is most commonly associated with HHV-6B infection; however, HHV-6A may have greater neurotropism.79 An immunomodulatory protein, CD46, is a cellular receptor for HHV-6.80
HHV-6 infection typically occurs during infancy as the level of maternal antibody wanes (peak between 6 to 9 months), although intrauterine infection can also occur.81 As many as 80% of adults are seropositive for HHV-6. Infection can present as exanthema subitum (roseola infantum), a common illness characterized by fever followed by a rash or by a febrile illness without rash but often with febrile seizures.82 HHV-6 has been associated with encephalitis, and it has been suggested, though not proved, that HHV-6 is a causal agent in multiple sclerosis.83 HHV-6 may be transmitted by saliva and possibly by genital secretions, blood, or transplanted organs, and HHV-6 infection may cause a mononucleosis-like syndrome.84 After primary infection, the viral genome may persist in peripheral blood mononuclear cells and in salivary glands. Reactivation accompanies immunosup-pression, and 30% to 45% of bone marrow transplant recipients develop HHV-6 viremia in the first few weeks after grafting.85 In immunocompromised adults, HHV-6 may be associated with a rash resembling graft versus host disease and may cause pneu-monitis, encephalitis, graft rejection, or disseminated disease, although its etiologic relationship to any of these remains un-proven.8588 There is no antiviral agent with proven clinical efficacy against HHV-6, although ganciclovir and foscarnet have been suggested as possible therapies.89
Human Herpesvirus Type 7
In 1990, another lymphotropic human herpesvirus, tentatively called HHV-7, was isolated from human T cells obtained from a healthy 26-year-old man.90 Its role in human disease has not been established, although it appears frequently in the saliva of healthy adults.91 Infection generally occurs by age 5, and approximately 90% of adults are seropositive.92 The HHV-7 genome can also be detected in peripheral blood leukocytes and cervical secretions. HHV-7 may account for some cases of roseola or febrile seizures93,94 and may be associated with graft dysfunction after solid-organ transplantation.88 Although it has been suggested that both HHV-6 and HHV-7 are etiologic agents in chronic fatigue syndrome and pityriasis rosea, supportive evidence is lacking.95,96
Human Herpesvirus Type 8
Several reports in late 1994 and 1995 provided convincing evidence of unique herpesvirus-like sequences in Kaposi sarcoma (KS) and body cavity-based lymphoma tissue from patients with AIDS.97-100 Using representational difference analysis, researchers found that more than 90% of the KS tissue studied contained these sequences; appropriate control tissue tested negative, except for 15% of non-KS tissue from AIDS patients.97 The same herpesvirus-like DNA sequences were subsequently reported in KS tissue from patients who did not have AIDS98-100 and in lymph node biopsy specimens from patients with multi-centric Castleman disease.
HHV-8 has been propagated in cell cultures and closely resembles a recently identified gamma herpesvirus of rhesus monkeys. Several serologic assays have been developed.102-104 One, which detects antibody to a latency-associated nuclear antigen, finds seropositivity in 1% to 2% of HIV-negative blood donors; in 30% of HIV-positive hemophiliacs, transfusion recipients, and women; and in more than 80% of patients with HIV infection and KS.
The natural history and clinical spectrum of diseases caused by HHV-8 is not yet well characterized. Primary infection in im-munocompetent children may be associated with fever and a maculopapular rash, and a finding of HHV-8 DNA in saliva suggests salivary transmission.105 One individual developed fever, hepatosplenomegaly, angiolymphoid hyperplasia, and transient KS during seroconversion.106 Family studies suggest transmission to children via nonsexual routes and between spouses via sexual routes.107 Transmission has also been demonstrated in the intra-partum and postpartum periods, and intrauterine infection may also occur.108 Among men who have sex with men, risk factors for transmission include increased number of sex partners, amyl nitrite use, and occurrence of lymphadenopathy within the previous 6 months.109 Risk factors for transmission in North American women include HIV infection, increasing age, history of syphilis, injection drug use, and black race.
Molecular and serologic evidence strongly suggests a causal role for HHV-8 in KS and associations with body cavity-based lymphomas and multicentric Castleman disease. Although it has been suggested that HHV-8 is associated with both multiple myeloma and sarcoidosis, confirmatory evidence is lacking. Studies of HHV-8 susceptibility to antiviral drugs suggest relative resistance to acyclovir and penciclovir but susceptibility to ganciclovir, foscarnet, and cidofovir.112,113 However, one pilot trial of cidofovir showed no effect on either HHV-8 viral load or on KS lesions.114 In contrast, effective antiretroviral infection in individuals dually infected with HIV-1 and HHV-8 may reduce the HHV-8 load and may be associated with KS regression.
