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Cytomegalovirus infections.

Cytomegalovirus infections are common throughout the world. Certain populations, including pregnant women and their fetuses, immunosuppressed patients, and recipients of large amounts of transfused blood, are at increased risk. Although the majority of infections in all groups of patients are clinically inapparent, variable symptoms, including fever, rash, pneumonitis, and hepatitis, can occur. The infected host develops antibodies against CMF, but frequently, despite this appropriate immune response, infection becomes chronic with prolonged excretion of virus. In some instances, a latent infection, with disappearance of virus, develops and under a variety of circumstances, including immunosuppression, infection can later be reactivated with reappearance of viral excretion. The human consequences of latent infection with CMV are not yet fully appreciated, and future research on this virus with multifaceted potential will need to focus on this issue.

Adult

Perforation of the colon associated with cytomegalovirus infection.

Cytomegalovirus (CMV) inclusions were found at colonic perforation sites in three patients with clinical settings suggesting a compromised immunologic status. This could be interpreted as: (1) CMV was an etiologic agent in these perforations; or (2) CMV was an opportunistic superinfection in areas of preexisting inflammation. To determine which interpretation was more likely, we examined material from these three and ten similar patients with colonic perforations, identifying any potential causative factors present. Eleven of the 13 patients had an identifiable cause of perforation, either tumor, diverticulitis, arteritis, or pancreatic pseudocyst, while two remained unexplained. If the presence of CMV merely represented an opportunistic superinfection, then all 13 should have been at equal risk of infection. However, CMV was present in only one of the 11 cases with another identifiable cause of perforation but was present in both of the cases without another cause. This is consistent with the hypothesis that CMV was in fact an etiologic or contributing factor in those cases where it was present. Other cases of CMV infection of the gastrointestinal tract were studied to determine the mechanism by which this infection could lead to perforation of a viscus. In our three cases with perforation, four additional cases of CMV infection of the colon which we have studied, and 30 other cases in the literature, CMV inclusions were found only in areas of ulceration or perforation, never in undamaged mucosa. Thus there is as yet no evidence that CMV can be a primary cause of colonic mucosal injury. It remains likely, however, that a mucosal injury due to another cause may be followed by CMV infection of the granulation tissue which then may lead to further injury and perforation.

Adult

Pathogenesis of murine cytomegalovirus infection: the macrophage as a permissive cell for cytomegalovirus infection, replication and latency.

Macrophages harvested from the peritoneal cavities of mice of several strains were permissive to infection with murine cytomegalovirus (MCMV). Macrophages from six mouse strains released equivalent amounts of plaque-forming virus into the culture fluids and cells from mouse strains scored similarly in numbers of infectious centres. Twenty to 50% of the infected macrophages obtained after thioglycollate activation formed infectious centres. When studied by in situ hybridization, more than 82% of infected macrophages (with or without thioglycollate activation) contained MCMV DNA. Macrophages obtained from latently infected mice were examined for their content of MCMV. Using co-cultivation assays, MCMV was frequently recovered from thioglycollate activated macrophages harvested from latently infected mice but only rarely recovered from non-activated macrophages. MCMV DNA--mouse DNA hybridization assays revealed four to seven virus genome DNA copies per 100 cells. These studies indicate that macrophages harvested from mice susceptible (BALB/cSt) or resistant (C3H) to MCMV infection replicated virus equivalently and that macrophages are a reservoir of MCMV during latent and chronic infections. Activation of macrophages may be one of the important steps leading to the exacerbation of in vivo latent infections.

Animals

Effect of cytosine arabinoside and 5-iodo-2'-deoxyuridine on a cytomegalovirus infection in newborn mice.

Murine cytomegalovirus was inhibited by 0.6 to 1.2 mug of cytosine arabinoside per ml and by 0.3 to 0.6 mug of 5-iodo-2'-deoxyuridine in mouse embryo fibroblast cells. Human cytomegalovirus was inhibited by similar concentrations of the two drugs in WI-38 cells. Intraperitoneal inoculation of suckling mice with 10(4.5) plaque-forming units of murine cytomegalovirus provides a model for disseminated human cytomegalovirus infection in human newborn infants and is characterized by a widespread infection involving the liver, spleen, lung, kidney, and brain with a 70 to 90% mortality in 7 to 9 days. Treatment with 12.5 mg of cytosine arabinoside per kg or 25 mg of 5-iodo-2'-deoxyuridine per kg twice daily for 8 days had no effect on final mortality or the pathogenesis of the infection with the exception of reduced viral titers in the spleen of 5-iodo-2'-deoxyuridine-treated animals. These data indicate that neither cytosine arabinoside nor 5-iodo-2'-deoxyuridine are effective in the treatment of murine cytomegalovirus infections in suckling mice and suggest that they may be of limited value in the treatment of severe cytomegalovirus infections in human neonates.

Animals

Congenital cytomegalovirus infection.

The overall prevalence of congenital cytomegalovirus infection among the offspring of a highly immune young female population was 2.4 per cent (23 of 939). To ascertain whether the presence of anticytomegalovirus antibodies protects the developing fetus, we examined the offspring of 239 prospectively studied women. Despite substantial levels of preconceptional antibodies, intrauterine cytomegalovirus infection occured in seven of 208 (3.4 per cent) seroimmune women. Three neonates with congenital infection were born to 31 initially seronegative women. All the congenitally infected infants had subclinical involvement. Maternal humoral immunity may not protect the fetus against congenital cytomegalovirus infection. Neutralization kinetics and restriction enzyme analysis with endonucleases (EcoR-1 and HinD 111) demonstrated antigenic and genetic homology between viral strains isolated from two siblings consecutively infected in utero, indicating that repeat maternal infection with the same virus is transmissible to sequential products of conception.

Adolescent

[Various aspects of cytomegalovirus infection in the adult].

Cytomegalovirus infection was sought as a routine over a period of two year in 100 patients of which 34 had a suitable constitutional background [corrected] for this type infection (multiple transfusions, malignant disease, immunodepression). The authors attempt to circumscibe the main clinical aspects encountered in adults. They consider the repective diagnostic values of isolation of the virus and serological reactions. They discuss their interpretation during the course of an infection.

Adult

Effective antiviral chemotherapy in cytomegalovirus infection of mice.

Both murine and human strains of cytomegalovirus were shown to be sensitive to the antiviral effects of adenine arabinoside and phosphonoacetic acid in tissue culture. In mice with lethal cytomegalovirus infections, treatment with adenine arabinoside (either 500 mg/kg intraperitoneally once daily or 250 mg/kg intraperitoneally twice daily for seven days) failed to reduce the mortality rate or to decrease the mean number of days until death. In contrast, treatment with the same dosage regimen of phosphonoacetic acid significantly reduced the mortality rate and decreased the mean number of days until death even when therapy was delayed for 24 hr. Although early treatment with phosphonoacetic acid resulted in a marked reduction in viral titers in the brains and lungs of infected mice, the major reason for efficacy appeared to be complete inhibition of viral replication in the liver. The observation that titers of complement-requiring neutralizing antibody were significantly lower in treated animals than in untreated controls is further evidence of successful therapy. Treatment of a nonlethal cytomegalovirus infection with phosphonoacetic acid beginning 48 hr after viral challenge resulted in elimination of clinical signs of illness and reduction in viral titers in tissues. These results indicate that phosphonoacetic acid is successful in the treatment of murine infections with cytomegalovirus; they suggest that this drug should be considered for potential use in serious cytomegalovirus infections in humans.

Acetates

An IgG-Fc receptor induced in cytomegalovirus-infected human fibroblasts.

Cytomegalovirus- (CMV) infected cultured human fibroblasts incubated with normal human serum were shown to react with IgG by direct and indirect fluorescent antibody tests. The binding of IgG to infected cells was unrelated to the presence of anti-CMV complement fixing (CF) antibodies and was not observed with uninfected cells. The reaction was first observed 36 hours after infection as diffuse cytoplasmic staining which by 72 hr became localized into a dense perinuclear structure. The cytoplasmic fluorescence was not detected with anti-IgA or anti-IgM fluorescent conjugates. The reaction was seen with purified IgG and Fc fragments but was only minimally detectable with Fab fragments. It occurred in fibroblasts infected with three standard laboratory strains of CMV and seven recent CMV isolates from patients and was observed in six separate lots of human foreskin fibroblast cultures as well as in WI-38 cells. We conclude that CMV infection induces the formation of a IgG receptor in human fibroblasts.

Adult

The transplanted kidney as a source of cytomegalovirus infection.

To determine the incidence of cytomegalovirus infection in renal-transplant recipients we followed 32 prospectively for six months after operation. As judged by serologic change and virus isolation the infection rate for the entire group was 66 per cent (21 of 32 patients) - 59 per cent (13 of 22) for seronegative patients and 80 per cent (eight of 10) for seropositive patients. Of 10 seronegative patients who received kidneys from seronegative donors, only three became infected. However, of 12 seronegative patients who received kidneys from seropositive donors, 10 became infected. Thus, there was a significant correlation between development of infection and seropositivity of the donor (P = 0.03), particularly when the recipient was seronegative (P = 0.02). Five possible and four definite recognizable clinical illnesses were associated with cytomegalovirus infection; all except two were in initially seronegative subjects who received kidneys from seropositive donors. Primary infection and disease in nonimmune recipients may be caused by cytomegalovirus transmitted by the kidneys of latently infected seropositive donors.

Adolescent

Early alterations in the morphology of cytomegalovirus-infected human fibroblasts.

Cytomegalovirus-infected human fibroblasts developed large numbers of fine microvilli within 90 min after addition of virus. The structure of these microvilli gradually changed as the infection proceeded, although the infected cells were easily detected by their large number of processes. These processes may be involved in the increased transport of ions and nutrients into the infected cell.

Cell Line

Pathological observations on experimental cytomegalovirus infections in pregnancy.

Cytomegalovirus injected intramuscularly or intraperitoneally into mice on the 8th day of pregnancy resulted in a significant retardation in foetal growth and a reduced number of offspring surviving until near-term. Pathological changes consisted of inflammatory cell infiltration in the liver, heart, salivary glands and adrenal cortex of affected animals. Necrotic changes were also present in the adrenal cortex in most severely affected animals following intraperitoneal injection of virus. Intraperitoneal infection led to a frank peritonitis and marked splenic necrosis with a degeneration and inflammation of visceral fatty tissue and lymphadenitis. In contrast, intramuscular injection of virus did not produce a peritonitis but the spleen was greatly enlarged with reaction centres and increased numbers of lymphocytes being identified at histology. As a consequence of cytomegalovirus infection in pregnant mice foetal growth impairment and intrauterine death was seen. This was related to the severity of pathological changes in the mothers. In those animals dying or appearing sick at near-term, most foetuses were dead and resorbing. Since murine cytomegalovirus was not identified by inclusion body formation in foetal or placental tissues in this study and virus has not been isolated from these tissues previously, it was concluded that the mechanism for the impaired foetal growth was of an indirect nature and attributable primarily to a severe generalised maternal illness.

Animals

Murine model for immunoprophylaxis of cytomegalovirus infection. I. Efficacy of immunization.

Murine cytomegalovirus was utilized as a model for human cytomegalovirus, which had no experimental animal, to study immunoprophylaxis of the cytomegalovirus infections. (1) Murine cytomegalovirus (MCMV) serially propagated in mouse embryonic fibroblasts had lost pathogenicity for weanling mice including neonatally thymectomized mice. (2) The cell culture-adapted MCMV was effective as a "live, attenuated virus vaccine" against challenge by virulent, mouse-passaged MCMV. (3) The immunization via intraperitoneal route protected mice from every parameter of MCMV infection. These included clinical signs, virus replication, histopathology and mortality. (4) The protective immunity was active against the virulent MCMV which was not neutralized by the rabbit anti-attenuated MCMV serum.

Animals

Cytomegalovirus infection in dialysis patients and personnel.

In a 12-month prospective study of cytomegalovirus infection on an acute hemodialysis unit, 10 of 80 patients (13%) and none of 26 staff developed active cytomegalovirus infection. Seven infections were coincidental with renal allograft rejection; three occurred 3 to 6 weeks after the transfusion of multiple units of conventional blood into seronegative patients. No person-to-person transmission was documented. In contrast to the effects of transfusing conventional blood, all 21 patients who entered dialysis without detectable cytomegalovirus antibody and received 2 to 10 U of frozen deglycerolyzed erythrocytes (total of 157 U) remained seronegative. Transmission of cytomegalovirus infection with transfusion with conventional blood is probably secondary to passage of leukocyte-borne virus that is lost during the freezing and deglycerolization procedure. Frozen erythrocytes prepared by cytoagglomeration procedures appear to be free of viable leukocytes and appear to carry a minimal risk of transmitting cytomegalovirus infection.

Acute Disease

Perinatal cytomegalovirus infection in man.

In a prospective study of 148 children from urbanized southern Finland 3 were found to be congenitally and 48 perinatally infected with cytomegalovirus (CMV), while 6 developed "late" infection during the first year of life. During pregnancy and the first year after delivery 23 of the mothers had no CMV antibodies; none of the children of these seronegative mothers developed any type of CMV infection. Fresh blood exchange transfusions did not increase the risk of CMV infection. The data support the hypothesis that the mother is the source of perinatal CMV infection. Children with a low birthweight not due to prematurity, and first children seem to run a greater risk of acquiring perinatal CMV infection. If the child is breast fed up to the age of 2 months the risk seems to be increased. Perinatal CMV infection gave rise to no symptoms or signs and had no effect on growth or on motor and psychosocial development during the first year of life.

Birth Order