Cytomegalovirus Infections of Man

complementary activity above 1:20 occurred in 34% (29/86) of the sera tested from the infected group in contrast to 7.5% (3/40) in the controls (P < 0.005). When assayed by means of a lymphoblastoid cell line (Raji cell test), the reactivity in these groups was 45 (39/86) and 2.7% (1/36), respectively (P < 0.001). Correlation of results between these two complement-dependent assays occurred in 75% of samples collected from the infected group. Frequency of reactivity was higher in severe intrauterine infection and during the 1st yr of life paralleling the patterns of viral excretion and humoral immune responses. Physicochemical characterization demonstrated that reactive substances in sera were acid-dissociable and, in one sample tested, contained 7S IgG antibodies with cytomegalovirus (CMV) specificity. Circulating immune complexes were heavier (18-22S) in sick, as opposed to subclinically CMV-infected patients, in whom intermediate size complexes (12-16S) were found. In three of four symptomatic patients whose demise was due to severe congenital infection, granular deposits of immunoglobulins and C3 were detected in a pattern typical of immune complexes along the glomerular basal membrane of the glomeruli. Whether or not circulation and deposition of heavier immune complexes contributed to the adverse clinical outcome is unresolved. Because of the high incidence of both congenital and natal CMV infections, definition of the pathogenetic potentials of both heavy and intermediate size immune complexes is required to design more effective therapeutic measures. Received for publication 28 February 1977 and in revised form 16 May 1977. INTRODUCTION Cytomegaloviruses (CMV)1 are the leading cause of congenital infections ofman with rates ranging from 0.5 to 2.4% of all live-births (1-3). CMV may also be acquired by an additional 3-5% of neonates and young infants via exposure to maternal genital tract secretions, breast milk, and household contacts (4). Fortunately, disease is rare with intrauterine infection and virtually lacking with natal or early postnatal acquisitions. Overt disease, with prominent involvement of reticuloendothelium, brain, and perceptual organs leading inevitably to debilitating sequelae, occurs in <5% of infants infected in utero. However, as recently shown, significant numbers of the remaining 95% subclinically infected at birth, manifest late-appearing injury, namely sensorineural hearing defects and decreased mentation (reviewed in reference 5). Perhaps this should not be surprising because CMV, when prenatally acquired, produces a chronic infection lasting several years. Persistent viral replication occurs in salivary gland and renal parenchyma as demonstrated by excretion of infectious virus in urine and saliva (6). Likely viral replication also persists in other sites inaccessible to routine virologic examination. Congenital CMV infection, is also characterized by an apparent overstimulation of the humoral immune system as exemplified by accelerated postnatal development of serum IgM and IgG as compared to uninfected controls (7). Though immunoglobulin development only grossly gauges antigenic load, it provides an indirect means for estimating the magnitude of the persistent antigenic stimulation associated with prenatally acquired CMV infection. More importantly, the specific humoral immune responses elicited are substantial ' Abbreviations used in this paper: AC, anticomplementary; CMV, cytomegalovirus; FITC, fluorescein isothiocyanate; IF, immunofluorescence, -t. The Journal of Clinical Investigation Volume 60 October 1977-838-845 838 and prolonged, whether the infection is productive or latent. (6) The persistence of viral excretion in the face of an overstimulated host immune responses provides a setting in which immune complex formation is highly probable. In fact, preliminary evidence suggests their occurrence in congenital and natal CMV infections (8, 9). Defining the formation of immune complexes and their relative amounts, size, and physiochemical nature is important in assessing their possible role in the pathogenesis of disease, both acute and long term, especially with the intrauterine form ofCMV infection. In the present study, circulating immune complexes of intermediate size were encountered in patients with subclinical congenital CMV infection. In contrast, symptomatic patients circulated immune complexes of higher molecular size, and in three patients who died with severe disease deposits of IgG, IgM and C3 were demonstrated in the basal membrane of the glomeruli.