Cytomegalovirus infection (cytomegalic inclusion disease; salivary gland virus disease) is manifest clinically in a number of guises, depending upon the age and physical condition of the host and whether the disease is associated with primary (initial) or reactivated infection. The disease was originally recognized as a pathologic entity associated with the postmortem finding of enlarged epithelial cells bearing intranuclear and cytoplasmic inclusions in salivary glands, liver, spleen, lungs, and other viscera. The disease has emerged to prominence in recent years as a legacy of iatrogenic impairment of host defenses in the course of surgery requiring extensive transfusion or immunosuppressive therapy. The cardinal manifestation x)f such cases is a mononucleosis without heterophil antibody (posttransfusion or post-perfusion mononucleosis.
Etiology.
Human cytomegalovirus is less thoroughly characterized than other human herpesviruses but, like other members of the group, has a capsid with icosahedral symmetry containing 162 elongated hollow capsomers. The virion is 960 A in diameter and contains double-stranded DNA with a molecular weight of 32 x 106 daltons. The capsid is enclosed in a lipid-containing envelope. The virus is relatively unstable, having a half-life of less than an hour at 37° C. Cytomegalovirus is highly specific in its cultural requirements so that viral replication and cytopathic effects occur only in human fibroblast cultures. For this reason, and because of the slow growth rate and low yield of virus in culture, some have suggested that cytomegalovirus be categorized as a subgroup separate from herpes simplex and herpes zoster-aricella viruses. At present, these minor biologic differences are outweighed by the chemical and structural similarities of the viruses.
Incidence, Prevalence, and Epidemiology.
Cytomegalovirus infection is common. Incidence increases cumulatively with advancing age so that more than 80 per cent of those over 35 have serum-neutralizing antibodies as evidence of previous infection. As with herpes simplex, the presence of neutralizing antibody may be equated with persistence of the virus, although direct demonstration of infective virus or cytomegaly has been rare in asymptomatic “carriers” of the virus.
With rubella and toxoplasmosis, cytomegalovirus infection is one of the few proved congenital infections of man. As with rubella, virus may be excreted for months after birth. Postnatal infection occurs less frequently in infancy and early childhood than is the case with herpes simplex. The frequency of infection varies widely (7 to 50 per cent i with increased prevalence noted in lower socioeconomic groups or in institutionalized populations of children.
The mechanism of virus spread is unknown in the case of the naturally occurring disease. In some cases, transmission of infection has been plausibly associated with the transfusion of fresh blood — usually in large amounts. These observations are not surprising in view of the presumably persistent carriage of virus in most of the population of blood donor age.
The source of infection, whether exogenous or endogenous, is not easy to establish in many cases, as initial antibody titers may be low or equivocally positive, and because parenteral reinfection in the presence of antibody has been observed.
Pathogenesis and Pathology.
The slow replication of cytomegalovirus in tissue culture is paralleled by a lag of a month or more from introduction of virus (probably by maternal contact in newborns or by transfusion in adults) and the appearance of disease. Intrauterine infection leads to hepato-splenomegaly with jaundice, microcephaly, mental retardation, and death. Postnatally acquired infection of the newborn is also serious and is characterized by generalized visceral involvement. Even the more common asymptomatic infections in infants and young children are attended by viremia and protracted excretion of virus in urine and sputum.
The characteristic cytopathology of the disease is denoted explicitly by the name cytomegalic inclusion disease. Infected cells may be greatly enlarged and contain eosinophilic, intranuclear, and basophilic cytoplasmic inclusion. These cells may be seen as part of a mononuclear cell infiltration in almost all viscera, but predominantly in salivary glands, lymph nodes, liver, spleen, and lungs. The interstitial “transplantation” pneumonia that follows renal allografting commonly causes death through respiratory insufficiency.
Clinical Manifestations of Cytomegalovirus Infection.
Clinical manifestations have been considered in part in previous sections of this article. In summary, the acute, initial (primary) stage of infection is more often than not asymptomatic in the infant or child, with hepator splenomegaly (with hepatitis) more common in the neonatally or congenitally infected.
A maculo papular erythematous rash is an inconstant occurrence in childhood infections. Primary infection in previously healthy young adults resembles the febrile or typhoidal type of infectious mononucleosis without exudative pharyngitis or lymphadenopathy. Fever in such cases usually lasts for three weeks, and is the principal clinical sign. Recovery is usually uneventful in such patients.
Post-transfusion mononucleosis related to cytomegalovirus infection may be either primary or reactivated. The febrile disease evoked may be very severe in the debilitated or immunosup-pressed patients who require transfusion or extra-corporeal circulation in the course of cardiac surgery or renal allotransplantation. As one would expect, the prior presence of specific antibody has a better prognostic augury. It is now clear that cytomegalovirus infections account for many cases of cryptic postoperative febrile syndromes. Infections associated with surgery and transfusion can be asymptomatic like the naturally occurring disease.
Cytomegalovirus Infection Diagnosis.
Protracted fever with minimal clinical findings save for evidence of low-grade hepatitis and the presence of abnormal mononuclear cells in the blood in the absence of heterophil antibody suggest the diagnosis of cytomegalovirus infection. The demonstration of large inclusion-containing mononuclear cells in urinary sediment is strongly presumptive evidence of cytomegalovirus infection. Definitive diagnosis demands (1) recovery of virus from blood, urine, or biopsy material by inoculation of human fibroblast cultures, or (2) increase in specific complement fixing or neutralizing antibody during illness.
Other human herpesviruses, including the Epstein-Barr virus (EBV) and, rarely, herpes simplex virus, have been associated with mononucleosis. Current evidence favors the EBV as the cause of heterophil antibody-positive infectious mononucleosis.
Cytomegalovirus Infection Treatment.
As with most virus diseases, treatment is supportive with an emphasis on antipyretics. The severe disease that may occur in leukemic children has been reported to respond to the DNA (thymidine) ‘antagonist 2′-deoxy-5-fiuorouridine (FUDR).
Prognosis.
Except with congenital or neonat?! infections the prognosis for complete recovery appears to be excellent. However, reactivated or primary infections as complications of cardiac or transplantation surgery may contribute to a fatal outcome, especially if interstitial pneumonia results. The full potential of this persistent latent virus is yet to be determined.
