Alteration of the growth of cytomegalovirus and herpes simplex virus type 1 by epidermal growth factor, a contaminant of crude human chorionic gonadotropin preparations.

Pretreatment (12-48 h) of human fibroblasts with crude, human chorionic gonadotropin (HCG) was found to suppress cytomegalovirus infection and enhance productive herpes simplex type 1 (HSV) infection in vitro. Maximal effect on virus replication occurred at the time of maximal infectivity of control cultures (48 h and 6 days after viral innoculation for HSV and cytomegalovirus, respectively). The alteration in viral growth was not due to the HCG itself, but rather to epidermal growth factor, a contaminant of crude HCG. The effect of epidermal growth factor on viral infectivity was shown to be a cell-mediated event requiring protein synthesis.

Immune complexes in congenital and natal cytomegalovirus infections of man.

The occurrence of circulating immune complexes was investigated in 31 patients with cytomegalovirus infection (29 infected in utero and 2 with natal infection) and 34 uninfected controls. Anti-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.

Plasma levels and urinary excretion of vidarabine after repeated dosing.

Vidarabine (Vira-A) was given intravenously for 5 days to 5 immunosuppressed patients with herpes zoster. The daily dose, 10 mg/kg, was given by slow infusion over 12 hr. Blood samples were taken at 0, 1, 2, 4, 8, and 12 hr on days 1, 3, and 5. Twenty-four-hour urine specimens were collected before treatment and on days 1, 3, and 5. Blood and urine specimens were assayed for vidarabine and its principal metabolite, hypoxanthine arabinoside (ara-Hx), by high pressure liquid chromatography. The results showed that vidarabine is quickly deaminated; virtually all of the drug present in the plasma and urine was in the form of ara-Hx. The highest plasma level, approximately 3 microgram/ml, was at the end of the infusion period. The urinary excretion of ara-Hx accounted for between 40% and 50% of the dose. The renal clearance values varied, but were close to the expected glomerular filtration rate of 125 ml/min. The plasma levels and the excretion levels were much the same on days 1, 3, and 5, indicating that drug did not cumulate. The results of the study were consistent with those observed in single-dose studies. The results indicated that the infusion of vidarabine is clinically appropriate, since therapeutic plasma levels are reached promptly, drug is rapidly excreted, and there is no cumulation.

Acyclovir treatment of herpes simplex virus infections in immunocompromised humans. An overview.

As reflected in the preclinical and early clinical data, acyclovir seems destined to have a very useful role in the treatment and/or prophylaxis of herpes virus (HSV) infections in immunosuppressed humans. If the preclinical predictions can be extrapolated to varicella-zoster (V-Z) infections, acyclovir could well also play a meaningful role in therapy of V-Z infections in the immunosuppressed host; however, this conjecture awaits proof of controlled studies in humans. Clearly the usefulness of acyclovir for treatment of V-Z infections should be compared with that of adenine arabinoside (ara-A) to put into proper perspective the relative efficacies of the two drugs for future therapeutic regimens. The need for comparative studies is most important at this early stage of antiviral drug development, to avoid ethical problems that will cloud the knowledge needed to move forward in a positive way. In any event, the development of acyclovir, with its targeted approach, represents a real fundamental advance in antiviral drug development. Together with the development and deployment of ara-A, it should provide the needed impetus for a surge in the creation of new antiviral compounds for tomorrow.

Effect of primary and recurrent cytomegalovirus infections upon graft and patient survival after renal transplantation.

One hundred sixty-four patients were prospectively studied for evidence of cytomegalovirus (CMV) infection after renal transplantation to determine the effect of primary and recurrent CMV infection on early graft and patient survival. Primary infections occurred in 62% (21 of 34) of pretransplant seronegative recipients and recurrent infection infection in 93% (121 of 130) of seropositive recipients. Symptomatic infections occurred in 81% (17 of 21) of primarily infected and 31% (37 of 121) of recurrently infected recipients. CMV infections (determined by initial virus excretion) occurred in 86% of the primarily infected and 96% of the recurrently infected symptomatic recipients by the 9th post-transplant week. In contrast, only 53% of nonsymptomatic recipients excrete virus by the 9th week. Primarily infected recipients experienced a significantly lower graft survival at 6 months than uninfected seronegative or recurrently infected patients. However, there was no significant difference in patient or graft survival at 1 year. Recipients who developed recurrent symptomatic infections had a significantly lower graft and patient survival than those recipients who developed nonsymptomatic recurrent infections (P less than 0.0002 patient survival and P less than 0.001 graft survival at 12 months).

Outcome of symptomatic congenital cytomegalovirus infection: results of long-term longitudinal follow-up.

Thirty-four patients with congenital cytomegalovirus infection who were symptomatic as newborns were followed in a special clinic providing periodic medical and visual examinations as well as psychometric testing and audiometry. All patients had symptoms of congenital infection by 2 weeks of age, and 31 of 34 had virus isolated from urine within the first month of life. Age at latest follow-up varied from 9 months to 14 years with a mean of about 4 years. Ten patients died and 23 surviving patients had adequate follow-up examinations; all but two had evidence of central nervous system or auditory handicaps. Microcephaly was present in 16 (70%), mental retardation in 14 (61%), hearing loss in seven (30%), neuromuscular disorders in eight (35%), and chorioretinitis or optic atrophy in five (22%). Children with symptomatic congenital cytomegalovirus infection are at very high risk for handicaps that will significantly impair development.

The natural history of herpes simplex virus infection of mother and newborn.

The controlled evaluation of vidarabine as therapy of neonatal herpes implex virus (HSV) infection provided an opportunity to collect data to further assess the natural history of maternal and newborn infections. Women delivering infected babies were young, nulliprous, and infrequent aborters. Nearly 50% of the gestations ended in premature labor. Maternal infection was asymptomatic in 39 of 56 (70%) of the mothers, at the time of delivery. However, risk factors included a past history of genital herpes at any time and exposure to a sexual partner with presumed HSV lesions. Associated diseases in children born to these women were common. Premature infants had an incidence of respiratory distress of 52% (14 of 27). Eight of 29 (28%) term newborns had a bacterial infection, antedating the onset of neonatal HSV infection. Virologic studies on infected newborns confirmed that skin lesions were the most frequent site for virus retrieval. Progression of disease from isolated skin lesions was common, occurring in 70% of babies whose presenting sign was skin vesicles. CSF was virus-positive from 14 babies and more frequently in those with localized CNS disease. Importantly, brain biopsy was necessary for diagnosis in four cases. Finally, neither the presence or absence of antibodies to HSV was useful in predicting either presentation or outcome of infection. These studies further emphasize the complex nature of HSV infections of the newborn and need for tertiary care.

Congenital cytomegalovirus infection: diagnostic and prognostic significance of the detection of specific immunoglobulin M antibodies in cord serum.

Specific immunoglobulin M antibodies were detected by radioimmunoassay (RIA-IgM) in cord sera from 83/93 (89%) babies congenitally infected with cytomegalovirus (CMV) but in 0/104 cord sera from uninfected control subjects. The type of maternal infection did not affect the ability of the assay to identify congenital infections, but increased RIA-IgM titers were found more frequently in cord sera from babies infected following primary CMV infections (9/18; 50%) than following recurrent CMV infections (1/12; 8%) (P less than .05). The magnitude of the fetal immune response was related to disease inasmuch as 14/40 (35%) babies with increased RIA-IgM titers were symptomatic at birth compared with 1/43 (2%) with lower titers (P less than .001). When combined with the results of testing for rheumatoid factor and total IgM, the RIA-IgM assay defined subgroups of babies with generally poor (7/15; 47% symptomatic at any stage) or generally good (0/21 symptomatic) prognoses. Prospective studies currently identifying cases of congenital CMV infection may wish to use these three serologic techniques as the results obtained appear to have prognostic significance for those babies who are initially asymptomatic.

Comparative study of diagnostic procedures for congenital cytomegalovirus infection.

In a prospective study the incidence of congenital cytomegalovirus (CMV) infection was 2.2% (31 OF 1,412) as evidenced by viruria during the first week of life. Among immunoserologic methods used to screen these neonates, the rheumatoid factor test, although non-specific, proved to be the most convenient; its sensitivity for identifying infants with CMV infection was 35% to 45% with no false-positives. The rates for correct and incorrect identification of neonates at risk was, respectively, 33% and 3.1% when testing for increased levels of IgM; 5% and 10% when testing for increased levels of IgA; 76% and 21% when testing for IgM anti-CMV (IgM immunofluorescent test) antibody, and 0% when testing for IgA anti-CMV antibody. Rapid virologic diagnosis was achieved by assessing urine specimens. Confirmation by electron microscopy was possible in less than one hour in 92% of cases. The detection of early induced CMV-specific nuclear antigens by anticomplement immunofluorescence was diagnostic in 91% of cases within one day of inoculation of specimens in tissue culture. Infectivity of CMV in urine was well preserved for a least seven days at 4 C. Thus, in order to achieve a rapid diagnosis of congenital CMV infection, in sick as well as asymptomatic neonates, urine specimens may, if necessary, be transported at 4 C to distant laboratories.

Vidarabine therapy of neonatal herpes simplex virus infection.

Vidarabine (adenine arabinoside) was evaluated for treatment of neonatal herpes simplex virus infection in a randomized controlled study. Of 56 infected newborns, 13 had infection of skin, eye, or mouth only, 16 had localized brain disease (CNS), and 27 had disseminated disease. Both treatment and placebo groups were comparable by disease distribution and for major population characteristics. Because of the severity of CNS and disseminated disease, these groups were combined for mortality assessment. Mortality was significantly reduced in babies with CNS and disseminated disease from 74% to 38% with drug therapy, P = .014. Outcome in babies with disseminated disease alone, although improved, was poor. Death rate was reduced from 85% to 57% with therapy. Only 14% of drug and 8% of placebo recipients were assessed as normal at 1 year of age. Outcome was better with localized CNS disease; mortality was reduced from 50% to 10%. With treatment, 50% of infected newborns were normal and without only 17%. With skin, eye, or mouth infection death did not occur; however, severe sequelae occurred in 38% of placebo and minor sequelae in 25% of drug recipients. No evidence of acute toxicity was identified in this study. Thus, a beneficial effect of vidarabine therapy on neonatal herpes simplex infection is similar to that evident with therapy of herpes simplex encephalitis occurring in older individuals. Nevertheless, improvement in the mode of therapy or the development of more potent antiviral drugs is essential.

Intellectual development in school-aged children with asymptomatic congenital cytomegalovirus infection.

Congenital cytomegalovirus infection occurs in about 1% of live births. Although symptomatic congenital infection often results in severe developmental deficits and mental retardation, about 90% have asymptomatic infection. Previous studies of the intellectual development in children with asymptomatic congenital cytomegalovirus have resulted in mixed findings. To control for the effects of hearing impairment (which occurs in about 15% of asymptomatic children) on intelligence scores, we tested 18 prospectively followed, normally hearing, school-aged children with asymptomatic congenital cytomegalovirus (15 black, ten male) and 18 controls matched for age, sex, race, school grade, and socioeconomic status. Children were tested via the Wechsler Intelligence Scale for Children-Revised, the Kaufman Assessment Battery for Children, and the Wide Range Achievement Test. Multivariate analysis revealed no differences between groups on intelligence scores or subscales, achievement scores, or incidence of learning disabilities (defined as significant discrepancy between intelligence and achievement), and mean scores for both groups were very close to national norms. It is concluded that the 25,000 children born in the United States each year with asymptomatic congenital cytomegalovirus and normal hearing are not likely to be at increased risk of mental impairment.

Auditory and visual defects resulting from symptomatic and subclinical congenital cytomegaloviral and toxoplasma infections.

Sensorineural hearing loss was present in ten of 59 (17%) patients with congenital cytomegalovirus (CMV) infection (three of eight born with symptomatic and seven of 51 born with subclinical infection). The defect was bilateral in eight, moderate to profound in eight, and of progressive nature in two. Hearing loss did not occur in 21 patients with natal CMV infection nor in seven of 12 patients with congenital toxoplasmosis. Histopathologic and immunofluorescent studies of the inner ear in two of three neonates who died with severe infection revealed that viral antigens were widely distributed in cochlear structures. Eye pathology was associated only with congenital Toxoplasma (nine of 12) and CMV (seven of 43) infections. Visual impairments were more prominent and severe in those born with symptomatic infections, exclusively so with CMV. However, ocular defects, in particular chorioretinitis, developed after birth in five of eight patients born with asymptomatic congenital toxoplasmosis. These data firmly establish clinically inapparent congenital CMV infection as a major public health problem and confirm the fact that congenital toxoplasmosis may be associated with late-appearing, debilitating chorioretinitis.

Neonatal herpes simplex virus infection: follow-up evaluation of vidarabine therapy.

An open study of vidarabine (adenine arabinoside) therapy was performed to verify the mortality from neonatal herpes simplex virus infection and to define further long-term morbidity. A total of 39 babies not previously reported were treated with either 15 mg/kg/d (16 newborns) or 30 mg/kg/d (23 newborns) of vidarabine administered intravenously for ten to 14 days. Outcome was compared with that from 56 newborns evaluated in a prior trial. Irrespective of the dose of medication, therapy decreased the mortality in babies with disseminated and CNS disease to 40%. The extent of organ involvement and, in particular, pulmonary herpes simplex infection were predictive of mortality (P = .001, for both). For these babies, 32% achieved normal developmental milestones 2 years after therapy. Disease localized to the skin, eye, and/or mouth was not associated with death. However, neurologic impairment occurred in 12% of this treated group of newborns. These findings underscore the value of vidarabine therapy of neonatal herpes simplex virus infection. However, an increase in dosage did not appear to result in significant improvement in either mortality or morbidity. Further improvement in the mode of therapy and the utilization of more potent antiviral drugs are currently being tested.

Effect of growth rate and simian adenovirus-7 transformation on in vitro 67Ga binding to hamster embryo cells.

The influence of growth rate and malignant transformation on 67Ga uptake was studied using cultured hamster embryo fibroblasts. Normalnonconfluent cells in log phase of growth bound approximately twice as much isotope as did confluent cells in a plateau phase of growth. In contrast, cells transformed by simian adenovirus-7 (SA-7), WHICH WERE ALSO UNDERGOING LOG GROWTH, BOUND ALMOST NO 67Ga. These results suggest that, although the rate of cellular proliferation may influence tissue affinity for 67Ga, other factors must also be considered when studying the effect of malignant transformation.

Symptomatic congenital cytomegalovirus infection: neonatal morbidity and mortality.

Knowledge of the natural history of symptomatic congenital cytomegalovirus (CMV) infection in the newborn is essential in order to anticipate complications and assess the potential benefit from antiviral therapy. To define the disease course we reviewed data on 106 neonates with symptomatic congenital CMV infection diagnosed and managed by the investigators. Petechiae, jaundice and hepatosplenomegaly were each noted in 70% or more patients. Microcephaly was noted in 54 of 102 (53%) at birth. Elevated alanine aminotransferase, conjugated hyperbilirubinemia and thrombocytopenia were seen in 83, 81 and 77%, respectively. Eighty-six percent had at least two of the manifestations highly suggestive of congenital infection. Platelet count fell to its nadir during the second week of life whereas elevated alanine aminotransferase and direct bilirubin persisted past the first month. In spite of the difficulty in assessing central nervous system function in the newborn, evidence of damage was present in the majority. Seventy-two had microcephaly, poor suck, lethargy/hypotonia or seizures. Abnormal computerized tomographic scan was present in 16 of 20 (80%) and decreased hearing in 20 of 39 (56%). Cerebrospinal fluid protein was greater than 120 mg/dl in 24 of 52 (46%) and this elevation was associated with neurologic abnormalities as well as hearing loss. The mean length of hospital stay was 13 and 22.4 days for term and preterm infants, relatively. Thirteen infants (12%) died during the first 6 weeks of life. Disseminated CMV infection with multiorgan involvement was evident in 7 of 9 at postmortem examination. We conclude that neonates with symptomatic congenital CMV infection have a multi-system disease with significant morbidity and mortality.

The effect of sleep and nocturnal movement on stiffness, pain, and psychomotor performance in ankylosing spondylitis.

OBJECTIVE: This study was carried out in order to assess whether AS patients are adversely affected by a "good" night's sleep accompanied by little nocturnal movement. METHODS: Objective and subjective nocturnal movement, flexibility, stiffness, pain and psychomotor performance were measured in 22 subjects, 11 with ankylosing spondylitis and 11 controls. RESULTS: A better sleep integrity with little nocturnal movement was related to a decrease in lumbar flexibility. Difficulty in awakening and feeling tired and clumsy in the morning correlated with stiffness. Pain was correlated with a subjective difficulty in getting to sleep and a worse quality of sleep, but was also correlated with less objective sleep disruption. In the control group a better sleep integrity was correlated with an overnight decrease in psychomotor performance. In the spondylitic group a significant increase in performance occurred. Stiffness and pain did not correlate with performance. CONCLUSION: Sleep in ankylosing spondylitis differs from sleep in normals.

Comparison of the effects of astemizole/pseudoephedrine and triprolidine/pseudoephedrine on CNS activity and psychomotor function.

The sedative properties of astemizole-D and triprolidine-D were compared in a double-blind, placebo-controlled, repeated-measures design study comprising three experimental treatments, each with a duration of 2 days (n = 12). Sedation was assessed by continuous electroencephalographic measurement (C-EEG), intermittent performance testing and subjective measures. C-EEG monitoring revealed that triprolidine-D produced significantly more daytime sedation and drowsiness than either astemizole-D or placebo (p < 0.05). Intermittent performance testing did not reveal consistent psychomotor deficits. There were no differences from placebo; the only significant findings showed that astemizole-D improved tracking accuracy at T + 65 h (p < 0.05) compared to baseline. Also, when scores were summed across all time points, astemizole-D improved scores significantly in contrast to triprolidine-D for the total scores (p < 0.05). It is concluded that, in contrast to triprolidine-D, astemizole-D does not produce daytime drowsiness or sedation.

Immunoglobulin determinations in the diagnosis of fetal infection.

Current indications are that the human fetus is not immunologically incompetent. An elevated IgM level may be a nonspecific indicator of a newborn at high risk for intrauterine infections--which may not be clinically apparent.

Neonatal herpes simplex virus infection.

These results suggest that Ara A, within its nontoxic dose range, may be efficacious in the treatment of neonatal HSV infection, provided the drug is given early in the course of the disease. Such studies as this have prompted a large scale multi-institutional study, which hopefully will provide a greater insight into the natural history of this usually devastating disease. The information gathered undoubtedly will lead to better and more specific antiviral agents as well as diagnostic techniques for earlier identification of neonatal HSV disease.