103 CYTOMEGALOVIRUS AND EPSTEIN-BARR VIRUS INFECTIONS
Harrison’s Manual of Medicine
CYTOMEGALOVIRUS AND EPSTEIN-BARR VIRUS INFECTIONS
Cytomegalovirus (CMV) Infections
Epstein-Barr Virus (EBV) Infections
CYTOMEGALOVIRUS (CMV) INFECTIONS
CMV, a member of the b-herpesvirus group, has double-stranded DNA, a protein capsid, and a lipoprotein envelope.
EPIDEMIOLOGY CMV has a worldwide distribution, with infection common in the perinatal and childhood periods. In the U.S., ~1% of newborns are infected. Spread does not occur casually but rather takes place through repeated or prolonged intimate exposure. Transmission occurs in day-care centers, through sexual contact, and after transfusion of blood products (at a frequency of 0.14–10% per unit transfused). When an infected child introduces CMV into a household, the seroconversion rate is 50% among susceptible household contacts within 6 months.
PATHOGENESIS Once acquired during asymptomatic or symptomatic primary infection, CMV persists indefinitely in latent form in tissues. If T cell function of the host becomes compromised, the virus can be reactivated to cause a variety of syndromes.
CLINICAL MANIFESTATIONS Congenital CMV Infection Most congenital CMV infections are not apparent at birth; 5–25% of asymptomatically infected infants develop psychomotor, hearing, ocular, or dental abnormalities over the next several years. Cytomegalic inclusion disease develops in ~5% of infected fetuses, almost exclusively in those whose mothers have acquired primary infection during pregnancy. Petechiae, hepatosplenomegaly, and jaundice are the most common signs (60–80% of cases). Microcephaly (with or without cerebral calcifications), intrauterine growth retardation, and prematurity are seen in 30–50% of cases. Mortality rates are as high as 20–30% among the most severely affected infants.
Perinatal Infection The majority of infants infected at or after delivery remain asymptomatic. Infection is contracted by passage through an infected birth canal or, after birth, via maternal milk. CMV causes rare cases of protracted interstitial pneumonia in premature infants.
CMV Mononucleosis Heterophile-negative mononucleosis is the most common manifestation of CMV infection in normal hosts beyond the neonatal period. The incubation period is 20–60 d, with clinical illness generally lasting 2–6 weeks. CMV mononucleosis is characterized by prolonged high fevers, sometimes with chills, fatigue, and malaise. While myalgias, headache, and splenomegaly are frequent, exudative pharyngitis and cervical lymphadenopathy are rare (in contrast to Epstein-Barr virus mononucleosis, in which these findings are prominent). The major laboratory finding is relative peripheral lymphocytosis with >10% atypical lymphocytes. Moderately elevated serum levels of aminotransferases and alkaline phosphatase are common; jaundice is rare.
CMV Infection in the Immunocompromised Host CMV is the most common and important viral pathogen affecting organ transplant recipients. Infections in these hosts include fever and leukopenia, hepatitis, pneumonitis, esophagitis, gastritis, colitis, and retinitis. The period of maximal risk is 1–4 months after transplantation. The greatest risk of disease appears to follow primary infection. The transplanted organ seems to be particularly susceptible, with CMV hepatitis common among liver transplant recipients and CMV pneumonitis among lung transplant recipients. CMV pneumonitis also occurs in 15– 20% of bone marrow transplant recipients, most frequently 5–13 weeks after transplantation; the case-fatality rate is 84–88%. CMV is a significant pathogen in pts with advanced HIV infection, generally causing clinical syndromes at CD4 cell counts of <100/µL. Retinitis, esophagitis, colitis, encephalitis, and polyradiculopathy are the most common manifestations of CMV infection in this group. Successful treatment of HIV has decreased the incidence of CMV infection in HIV-positive pts.
DIAGNOSIS Diagnosis requires the isolation of CMV in culture or the detection of CMV antigens or DNA in clinical specimens, together with the documentation of a rise in or persistently elevated antibody titer. Recovery of CMV in culture may take only a few days if the titer of virus is high (e.g., congenital infection or AIDS) but may also take several weeks (e.g., CMV mononucleosis). To expedite this process, many laboratories use a shell-vial technique on overnight tissue cultures, which employs monoclonal antibodies and immunocytochemical detection of early antigens. Viral isolation from urine or saliva does not confirm infection, since shedding may continue for months or even years after infection; detection of CMV viremia by pp65 antigen testing of peripheral blood leukocytes is a good predictor of subsequent culture-positive CMV infection. PCR of CSF is useful in the diagnosis of CMV-related neurologic disease. While a fourfold rise in antibody titer can confirm a primary infection, antibody rises may take up to 4 weeks, and titers may remain high for years.
Ganciclovir has produced response rates of 70–90% among AIDS pts treated for CMV retinitis or colitis. The induction dose of ganciclovir (5 mg/kg bid IV for 14–21 d) is followed by maintenance therapy (5 mg/kg qd IV, 6 mg/ kg IV 5 d/week, or 3 g/d PO). Neutropenia, the major toxic effect, develops in 16–29% of pts; its severity can be lessened by the use of colony-stimulating factors. Oral ganciclovir is inferior to IV ganciclovir for induction therapy. The use of oral ganciclovir in HIV-infected pts for prophylaxis of CMV infection is controversial. A ganciclovir intraocular implant in combination with systemic therapy is another treatment alternative. In bone marrow transplant recipients, ganciclovir plus CMV immune globulin have elicited a favorable clinical response in 50–70% of episodes of CMV pneumonitis. For ganciclovir-resistant strains, foscarnet is active and compares favorably with ganciclovir in the treatment of CMV retinitis in AIDS. The induction dose of foscarnet (60 mg/kg q8h or 90 mg/kg q12h for 14 d) is followed by maintenance infusions of 90–120 mg/kg qd. Foscarnet exerts considerable toxicity: renal dysfunction, hypomagnesemia, hypokalemia, hypocalcemia, seizures, fever, and rash are each seen in >5% of pts. Cidofovir is an alternative that allows intermittent IV administration. Induction doses of 5 mg/kg weekly for 2 weeks are followed by 3–5 mg/kg every 2 weeks. Renal toxicity is the major adverse effect.
EPSTEIN-BARR VIRUS (EBV) INFECTIONS
EBV is a human herpesvirus that consists of a linear double-stranded DNA core surrounded by an icosahedral nucleocapsid and a glycoprotein-containing envelope. It is cytotropic for B lymphocytes.
EPIDEMIOLOGY EBV is transmitted primarily in saliva and occasionally by blood transfusion and is not highly contagious. Primary infection tends to occur at an early age in lower socioeconomic groups and in developing countries. Primary EBV infection among adolescents and young adults accounts for most cases of infectious mononucleosis (IM). By adulthood, >90% of individuals are seropositive for EBV. The virus is shed from the oropharynx for up to 18 months after primary infection and intermittently thereafter in the absence of clinical illness.
CLINICAL MANIFESTATIONS Infection in Infants and Young Children EBV infection in this group is generally asymptomatic or presents as mild pharyngitis with or without tonsillitis.
Infectious Mononucleosis The incubation period for IM is 4–6 weeks. Prodromal symptoms of malaise, fatigue, and myalgia frequently precede the onset of pharyngitis, fever, and lymphadenopathy by a few days. Common signs and symptoms are listed along with their frequencies in Table 103-1. After ampicillin administration, most pts with IM develop a pruritic maculopapular eruption that is not predictive of future penicillin allergy. Symptoms usually last for 2–4 weeks, but malaise and difficulty concentrating may persist for months. Complications are infrequent but may be dramatic and include autoimmune hemolytic anemia, thrombocytopenia, granulocytopenia, splenic rupture, cranial nerve palsies, encephalitis, hepatitis, pericarditis, myocarditis, coronary artery spasm, and airway obstruction from pharyngeal or paratracheal adenopathy.
Table 103-1 Signs and Symptoms of Infectious Mononucleosis
Other Diseases Associated with EBV Infection EBV-associated lymphoproliferative disease occurs in pts with congenital or acquired immunodeficiency, including AIDS, severe combined immunodeficiency, and transplantation. Pts present with fever and lymphadenopathy or GI symptoms. X-linked lymphoproliferative syndrome (Duncan’s syndrome), a disorder in immune responsiveness to EBV, permits overwhelming EBV infection in young boys. Oral hairy leukoplakia, an early feature in pts with HIV infection that is characterized by raised white corrugated tongue lesions, is caused by EBV. A rare chronic form of EBV infection (distinct from chronic fatigue syndrome) is characterized by multiple organ involvement, including hepatosplenomegaly, lymphadenopathy, and pneumonitis, uveitis, or neurologic disease.
EBV-Associated Malignancy First described in association with 90% of cases of African Burkitt’s lymphoma, EBV has been associated with American Burkitt’s lymphoma (15% of cases), anaplastic nasopharyngeal carcinoma, and B cell lymphomas, especially in pts immunosuppressed as a result of organ allografts and AIDS.
DIAGNOSIS Heterophile antibodies (antibodies to sheep, horse, or cow erythrocytes) are present in 40% of pts with IM during the first week and in 80–90% during the third week (Table 103-2). The test usually remains positive for 3 months after the illness, but positivity can persist for up to 1 year. The commercially available monospot test for heterophile antibodies is somewhat more sensitive than the classic heterophile test. While more specific EBV antibodies can be measured, these studies are rarely required for the diagnosis of IM except in heterophile-negative or atypical cases (Table 103-2). IgM antibodies to viral capsid antigen (VCA) are diagnostic of primary EBV infection and persist for only 2 months; IgG antibodies to VCA develop early in infection and persist for life. Antibodies to Epstein-Barr nuclear antigen (EBNA) appear at about 6–8 weeks and persist for life. The presence of IgM antibody to VCA and seroconversion to EBNA are diagnostic of primary EBV infection. PCR for EBV DNA in the CSF is used in the diagnosis of CNS lymphoma in AIDS pts. Culture of EBV from the throat is not diagnostic of acute infection since this virus is commonly shed from the oropharynx for the lifetime of the infected individual.
Table 103-2 Serologic Features of EBV-Associated Diseases
The treatment of IM is supportive. Excessive physical activity should be avoided for 6–8 weeks to avert splenic rupture. Glucocorticoids are indicated for airway obstruction and severe hemolytic anemia or thrombocytopenia. Occasional pts with protracted illness may also benefit from a short course of prednisone, but routine steroid use is not advised. Antiviral agents are not useful in the treatment of IM.
For a more detailed discussion, see Cohen JI: Epstein-Barr Virus Infections, Including Infectious Mononucleosis, Chap. 184, p. 1109; and Hirsch MS: Cytomegalovirus and Human Herpesvirus Types 6, 7, and 8, Chap. 185, p. 1111, in HPIM-15.