Info CMV

Cytomegaloviruses (CMVs) are a group of agents within the herpesvirus family known for their wide distribution among humans and other animals

CYTOMEGALOVIRUS
Sergio Stagno
 
Cytomegaloviruses (CMVs) are a group of agents within the herpesvirus family known for their wide distribution among humans and other animals. In vivo and in vitro CMV infections are highly species specific. Most CMV infections are inapparent, but the virus can cause a variety of clinical illnesses that range in severity from mild to fatal. CMV is the most common congenital viral infection, which occasionally causes the syndrome of cytomegalic inclusion disease (hepatosplenomegaly, jaundice, petechia, purpura, and microcephaly) (Chapter 96 and 97). In normal, immunocompetent adults, the infection is occasionally characterized by a mononucleosis-like syndrome. Among immunosuppressed individuals, including recipients of transplants and patients with acquired immunodeficiency syndrome (AIDS), CMV pneumonitis, retinitis, and gastrointestinal disease are common and can be fatal. The infection, which occurs in a seronegative, susceptible host, is referred to as primary infection, whereas recurrent infection represents reactivation of latent infection or reinfection in a seropositive immune host. Disease may result from primary or recurrent CMV infection, but the former is a more common cause of severe disease.

ETIOLOGY.
CMV is the largest of the herpesviruses, with a diameter of 200 nm. It contains double-stranded DNA in a 64-nm core enclosed by an icosahedral capsid composed of 162 capsomers. The core is assembled in the nucleus of the host cells. The capsid is surrounded by a poorly defined amorphous tegument, which is itself surrounded by a loosely applied, lipid-containing envelope. The envelope is acquired during the budding process through the nuclear membrane into a cytoplasmic vacuole, which contains the protein components of the envelope. Mature viruses exit the cells by reverse pinocytosis. The CMV genome encodes for at least 35 structural proteins, glycoproteins, and an undefined number of nonstructural proteins. Serologic tests do not define specific serotypes. In contrast, restriction endonuclease analysis of CMV DNA shows that, although all known human strains are genetically homologous, none are identical unless they were obtained from epidemiologically related cases.

EPIDEMIOLOGY.
Seroepidemiologic surveys demonstrate CMV infection in every population examined. The prevalence of infection, which increases with age, is higher in developing countries and among lower socioeconomic strata of the more developed nations. Sources of CMV include saliva, milk, cervical and vaginal secretions, urine, semen, stools, and blood. The spread of CMV requires very close or intimate contact because it is very labile. Transmission occurs by direct person-to-person contact, but indirect transmission is possible via contaminated fomites such as toys. The incidence of congenital infection ranges from 0.2{endash}–2.4% of all live births. The higher rates occur in populations with a lower standard of living. The fetus may become infected as a consequence of both primary and recurrent infections. The latter, which is more common in highly immune populations, is less likely to cause disease in the newborn infant or to lead to developmental sequelae.
Perinatal transmission is common, reaching 10{endash}–60% by 6 mo of age. The most important sources of virus are genital tract secretions at delivery and breast milk. Infected infants excrete virus for years in saliva and urine. After the 1st year of life, the prevalence of infection is dependent on child-rearing practices, with day-care centers contributing to the rapid spread of CMV. Infection rates of 50{endash}–80% are common. For children who are not exposed to other toddlers, the rate of infection increases very slowly throughout the 1st decade of life. A 2nd peak occurs in adolescence as a result of sexual transmission.
Seronegative child care workers and parents of young children shedding CMV have a 10{endash}–20% annual risk of acquiring CMV, which contrasts with 1{endash}–3% per year for the general population. Health care providers are not at increased risk for acquiring CMV infection from patients. Nosocomial infection is a hazard of transfusion of blood and blood products. In a population with a 50% prevalence of infection, the risk has been estimated at 2.7% per unit of whole blood. Leukocyte transfusions have a much greater risk. Infection is usually asymptomatic, but, even in well children and adults, there is a risk of disease if the patients are seronegative and receive multiple units. Immunosuppressed patients and seronegative premature infants have a much higher (10{endash}–30%) risk of disease. CMV infection is transmitted in transplanted organs (kidney, heart, and bone marrow). After transplantation, many patients excrete CMV as a result of infection acquired from the donor organ or from reactivation of latent infection caused by immunosuppression. Seronegative recipients of organs harvested from seropositive donors are at greatest risk for severe disease.

PATHOLOGY.
Strikingly enlarged intranuclear inclusion-bearing cells that also have cytoplasmic inclusions are pathognomonic for CMV infections. The virus induces focal mononuclear cell infiltrates, which may be present with or without cytomegalic cells. The virus may induce focal necrosis in the brain and liver, which may be extensive and accompanied by granulomatous change with calcifications. The lung, liver, kidney, gastrointestinal tract, and salivary and other exocrine glands are the most commonly infected organs, although the virus has been found in most cell types. The extent of abnormal organ function and the quantity of virus that can be recovered from affected organs are not related to the number of cytomegalic inclusion-bearing cells, which may be few or absent in each organ section examined.

CLINICAL MANIFESTATIONS.
The signs and symptoms of CMV infection vary with age, route of transmission, and immune competence of the individual. The infection is subclinical in most patients, including those with congenital infection (see Chapters 96 and 97). Infections acquired from the mother and other contacts are almost always asymptomatic and do not cause sequelae. Premature infants with transfusion-acquired infection constitute an exception. If infected, seronegative infants with birthweights of 1,500 g or less have a 40% risk of experiencing hepatosplenomegaly, pneumonitis, gray pallor, jaundice, petechia, thrombocytopenia, atypical lymphocytosis, and hemolytic anemia. In young children, the infection occasionally causes pneumonitis, hepatitis, hepatomegaly, and petechial rashes. In older children, adolescents, and adults, CMV may cause mononucleosis-like syndrome characterized by fatigue, malaise, myalgia, headache, fever, hepatosplenomegaly, abnormal liver function test results, and atypical lymphocytosis.
The course of CMV mononucleosis is generally mild, lasting 2{endash}–3 wk. An occasional patient may present with persistent fever, overt hepatitis, or morbilliform rash, or a combination. Recurrent infections are asymptomatic in the normal host. In immunocompromised individuals, the risk of CMV disease is increased with both primary and recurrent infections. Illness with a primary infection ranges from pneumonitis (most common), hepatitis, chorioretinitis, gastrointestinal disease, or fever with leukopenia as isolated entities to generalized disease, which is often fatal. The risk is greatest in patients who underwent bone marrow transplantation and in those with AIDS. Pneumonia, retinitis, and involvement of the central nervous system and gastrointestinal tract are usually severe and progressive. Submucosal ulcerations can occur anywhere in the gastrointestinal tract. Hemorrhage and perforation are known complications, as are pancreatitis and cholecystitis.

DIAGNOSIS.
Active CMV infection is best demonstrated by virus isolation from urine, saliva, bronchoalveolar washings, milk, cervical secretions, buffy coat, and tissues obtained by biopsy. Rapid (24-hr) identification is now routine with the centrifugation-enhanced rapid culture system based on the detection of CMV early antigens by monoclonal antibodies. Polymerase chain reaction and DNA hybridization techniques can be used, but their sensitivities and cost effectiveness remain to be established. Virus isolation alone cannot distinguish between primary and recurrent infections. A primary infection is confirmed by seroconversion or the simultaneous detection of immunoglobulin (Ig)G and IgM antibodies. Rising IgG antibody titers may be caused by primary and recurrent infection and must be interpreted with caution. Sensitive and specific serologic tests to measure IgG antibodies are available in diagnostic laboratories.
To define rises in antibody titers complement fixation, neutralization, anticomplement immunofluorescence, and indirect immunofluorescence, assays are preferable because they are quantitative. In contrast, radioimmunoassay (RIA) and enzyme-linked immunosorbent assay (ELISA) are less reliable for demonstrating significant changes in titers because most laboratories establish binding ratio (RIA) and absorbance units (ELISA) at a fixed serum dilution to compare the quantities of antibodies present in two sera. A simple rise in antibody titers in initially seropositive subjects must be interpreted with caution because these are occasionally seen years after primary infection. IgG antibodies persist for life. IgM antibodies can be demonstrated transiently (4{endash}–16 wk) during the acute phase of symptomatic as well as asymptomatic primary infection in adults. RIA, ELISA, and an IgM capture RIA have acceptable specificity and sensitivity to detect primary infections. IgM antibodies are rarely found with these assays (0.2{endash}–1%) in patients with recurrent infection.
A recurrent infection is defined by the reappearance of viral excretion in a patient known to have been seropositive in the past. The distinction between reactivation of endogenous virus and reinfection with a different strain of CMV requires restriction enzyme analysis of viral DNA to demonstrate homology between viral isolates.
In immunocompromised patients, excretion of CMV, rises in IgG titers, and even the presence of IgM antibodies are common, making the distinction between primary and recurrent infections more difficult. Determining pretransplantation and preimmunosuppressive treatment serologic status of the patients is helpful. Demonstrating viremia by buffy coat culture implies active disease and worse prognosis whether the type of infection is primary, recurrent, or unknown.
The definitive method for diagnosis of congenital CMV infection is virus isolation or demonstration of specific DNA sequences (see Chapters 96 and 97). Urine and saliva are the best specimens to submit to the laboratory. An IgG antibody test is of little diagnostic value because a positive result generally reflects maternal immunity, although a negative result excludes the diagnosis. Demonstration of stable or rising titers in serial specimens during the 1st year of life does not help because perinatal infection is common. In general, IgM tests lack sensitivity and specificity and are technically demanding. No reliable IgM test is commercially available.

PREVENTION
Passive Immunoprophylaxis. The use of hyperimmune plasma or globulin for prophylaxis of infection in transplant recipients reduces the risk of symptomatic disease but does not prevent infection. The efficacy of immunoglobulin is more striking in situations in which the hazard of primary CMV infection is greatest, such as in bone marrow transplantation. One recommended regimen is 1.0 g/kg of immunoglobulin given as a single intravenous dose beginning within 72 hr of transplantation and once weekly thereafter until day 120 after transplantation.
Active Immunization. The beneficial role of immunity is substantial, as illustrated by the fact that most severe disease follows primary infections, especially in congenital infection, transfusion-acquired infection, and infection in transplant recipients. Candidates for a CMV vaccine include seronegative women of childbearing age and seronegative transplant recipients. Live, attenuated vaccines are immunogenic, but immunity wanes quickly. The investigational Towne vaccine produces self-limited asymptomatic infection, which results in the production of humoral and cell-mediated immune responses in most healthy volunteers. Vaccine virus does not seem to be transmissible. Vaccines are protected when challenged with low but not high doses of challenge virus and illness occurs from higher vaccine doses. The vaccine does not protect renal transplant recipients from CMV infection but appears to reduce the virulence of primary infection. In a study of vaccine efficacy in normal adult women, the Towne vaccine did not provide protection against naturally acquired infection. Other types of vaccines, such as subunit and recombinant vaccines, are being developed.
The use of CMV-free blood and blood products and, when possible, the use of organs from CMV-free donors represent important measures to prevent CMV infection and disease in nonimmune patients.

TREATMENT.
Ganciclovir has been used to treat life-threatening CMV infections in immunocompromised hosts (such as bone marrow, heart, and kidney transplant recipients and patients with AIDS). A regimen of 10 mg/kg/24 hr, with individual doses administered at 12-hr intervals for 2{endash}–3 wk, followed by maintenance dose of 5 mg/kg/24 hr administered until regression of clinical manifestations, has had some efficacy. CMV retinitis and gastrointestinal disease appear to be clinically responsive to therapy but, like viral excretion, often recur on cessation. Toxicity with ganciclovir is extensive, including neutropenia, thrombocytopenia, liver dysfunction, reduction in spermatogenesis, and gastrointestinal and renal abnormalities. No controlled studies of treatment of congenital CMV infection are available. One phase I-II study shows encouraging results at a dose of 12 mg/kg/24 hr for a total of 6 wk. A randomized study of symptomatic congenital CMV infection is in progress.

PROGNOSIS
Congenital Disease. See Chapters 96 and 97.
Acquired Disease. Patients with CMV mononucleosis usually recover fully, although some have a protracted illness. Many whose infections are acquired in association with immunosuppression and transplantation recover, but a significant number have severe pneumonitis, and the fatality rate is high if hypoxemia develops. CMV infection and disease may be terminal events in individuals with increased susceptibility to infections such as those with AIDS.

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