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.

Immunologic studies in asymptomatic hemophilia patients. Relationship to acquired immune deficiency syndrome (AIDS).

Asymptomatic hemophilia patients receiving Factor VIII concentrate were found to have normal natural killer (NK) cells and B cells, and an inverted T helper/suppressor ratio due to an increase in cells of T suppressor phenotype. In contrast, a hemophilia patient with acquired immune deficiency syndrome (AIDS) exhibited nonfunctional NK cells, low B cells, and an inverted T helper/suppressor ratio due to very low numbers of T helper cells. Hemophilia patients on cryoprecipitate therapy exhibited normal immune parameters. A high percentage of hemophilia patients on both treatments had antibody to hepatitis B virus. The isolated finding of elevated levels of T suppressor cells in hemophilia patients receiving Factor VIII concentrate has not been recognized as an early indicator of impending AIDS, and longitudinal studies will be required to determine its clinical significance.

Circulating immune complexes in childhood malignancies: a Pediatric Oncology Group study.

Pretreatment serum samples obtained at diagnosis from 89 children with various pediatric malignancies were examined for circulating immune complexes (CIC) using the [125I]Clq binding assay. The study population consisted of 35 children with acute lymphocytic leukemia (ALL), 22 children with acute non-lymphocytic leukemia (ALL), 24 with neuroblastoma (NB), and eight with osteosarcoma (OS). Concomitant quantitation of immunoglobulins was performed in 55 patients, revealing normal values for age. Increased levels of CIC at diagnosis were found in 9%, 22%, 42%, and 50% of children with ALL, AML, NB, and OS, respectively. Except for a higher proportion of CIC-positive patients observed in stage IV NB (nine of 17) compared to stage I-III NB (one of seven), no correlation was observed between initial CIC level and presenting clinical features, response to treatment, prognosis, or presence of infection. Longitudinal sampling of six NB and two OS patients did not reveal a clear relationship between disease activity and quantity of CIC. For the pediatric malignancies studied, these data demonstrate minimal value in quantitating CIC as a means of assessing disease activity or predicting response to treatment and are in contrast to the apparently adverse effect of elevated pretreatment CIC on response to therapy and survival observed in adults with ALL, AML, and OS.

Linear single-dose pharmacokinetics of ganciclovir in newborns with congenital cytomegalovirus infections. NIAID Collaborative Antiviral Study Group.

The pharmacokinetic characteristics of ganciclovir were determined in neonates (age range, 2 to 49 days) after an 1-hour intravenous infusion of a single dose of either 4 mg/kg (n = 14) or 6 mg/kg (n = 13). Twenty-seven newborns with symptomatic cytomegalovirus inclusion disease were enrolled in this open phase I-II pharmacokinetics, safety, and tolerance trial of ganciclovir at one of two doses. Ganciclovir disposition was best described by a one-compartment open model with zero-order input and first-order elimination. The mean elimination half-life (t1/2) for both dose groups was 2.4 hours. The mean apparent volume of distribution (Vd) was 669 +/- 70 ml/kg for the 4 mg/kg group and 749 +/- 59 ml/kg for the 6 mg/kg group. The mean total body clearance (CL) for the 4 mg/kg and 6 mg/kg groups was 189 +/- 28 ml/hr/kg and 213 +/- 21 ml/hr/kg, respectively. No significant differences were observed in Vd or CL between the two groups. The Vd, expressed in milliliters, increased with increasing patient weight (r = 0.689; p = 0.0001). The CL, expressed in milliliters per hour per kilogram, increased with increasing age (r = 0.413; p = 0.032). No significant differences were observed between the two dose groups for the area under the curve normalized for dose (AUC/Dose) or the maximum plasma concentration normalized for dose (Cmax/Dose), indicating that ganciclovir exhibited linear pharmacokinetics in these neonates.

Buspirone augmentation of fluoxetine in obsessive-compulsive disorder.

Eleven obsessive-compulsive patients underwent a prospective open-label trial of fluoxetine monotherapy followed by buspirone augmentation. The combination therapy was statistically superior to fluoxetine monotherapy. The results point to the importance of the 5-HT1a receptor in obsessive-compulsive disorder.

Postictal psychiatric events during prolonged video-electroencephalographic monitoring studies.

BACKGROUND: Postictal psychiatric events presenting as postictal psychotic events and postictal nonpsychotic events are known to occur following seizure clusters. Accordingly, patients undergoing prolonged video-electroencephalographic (EEG) monitoring studies may be at increased risk of experiencing postictal psychiatric event, as they often have flurries of seizures during these studies. OBJECTIVES: To determine the annual incidence and clinical characteristics of postictal psychotic events and postictal nonpsychotic events in video-EEG monitoring studies in patients with partial seizure disorders and to identify potential pathogenic factors. RESULTS: Thirteen patients met the criteria for a postictal psychiatric event during the 18-month study period, 10 presenting as postictal psychotic events and three as postictal nonpsychotic events. The annual incidence of postictal psychiatric events at our monitoring unit for 1988 was 7.8%, 6.4% presenting as postictal psychotic events and 1.4% as postictal nonpsychotic events. Seven patients had their first-ever postictal psychiatric event during the monitoring study. In 12 of the 13 patients, the postictal psychiatric events mimicked well-defined psychiatric entities of shorter duration (mean, 66.5 hours); they appeared 12 to 72 hours after the last seizure and remitted spontaneously or with the use of low-dose psychotropic medication. No significant differences in EEG, neuroradiologic, psychiatric, medical, or psychosocial data were found between the patients with postictal psychiatric events and a group of 13 age-matched control patients. Follow-up data of comparable duration were available in nine patients with postictal psychiatric events and nine controls. Psychiatric events were reported more frequently by patients with postictal psychiatric events than by control patients (P=.03). In three patients, postictal psychiatric events converted to interictal events. CONCLUSION: These findings suggest that monitoring studies increase the risk for postictal psychiatric events, which neurologists need to be familiar with, as they represent important morbidity associated with these studies.

Bioethics: communication and decision-making in advanced disease.

Effective communication is the cornerstone of excellence in patient care, and breakdown in communication is a common problem leading to requests for bioethics consultation. In palliative medicine, issues involving end-of-life decisions inherently involve many potential ethical concerns. Ensuring good communication among the physician, health care professionals, patient, and family will facilitate care, and avoid ethical problems. This chapter will address communication with patients, families, and health care professionals. Common ethical concerns such as withholding and withdrawing treatment modalities, medical futility, euthanasia, and assisted suicide will be discussed.

Psychosocial care in advanced cancer.

In palliative care, the focus is management of major symptoms and complications, and psychosocial support of the patient and family. Approaching the end of life, the patient's needs move beyond physical care to include the psychological, social, and spiritual dimensions. The main psychosocial interventions are counseling, education, and practical services directed at the needs identified by the multidimensional/multidisciplinary assessments. We will present the roles of the various team members and methods of psychosocial assessment.

Restriction endonuclease analysis of cytomegalovirus deoxyribonucleic acid as an epidemiologic tool.

The possibility of transmission of cytomegalovirus (CMV) from congenitally infected infants to susceptible medical personnel produces anxiety because the risks have not been defined. A physician conceived her first child while caring for an infant in the intensive care nursery who died with congenital CMV infection. The physician had serologic evidence of active CMV infection confirmed by isolation of virus from multiple sites. She elected to have her pregnancy interrupted. CMV was isolated from the placenta and fetal brain. Restriction enzyme analysis was employed to test all the CMV isolated for genetic relatedness. Virus isolated from the physician and her fetus was identical. The virus from the index nursery infant was different from the strain infecting the physician and her fetus. These data indicate that the physician acquired her virus from a source other than the index infant.

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.

Cytomegalovirus infection of breast milk and transmission in infancy.

Of unselected postpartum women, 39% reactivated cytomegalovirus in breast milk, vaginal secretions, urine, and/or saliva. Consumption of infected breast milk led to infection of 69% of the infants. Although there was some milk secretory immune response to this virus, it prevented neither viral shedding nor viral transmission. All infected infants chronically shed cytomegalovirus. However, no infants have yet demonstrated chronic sequelae. Two preterm infants did develop a significantly acute problem, pneumonitis, which did resolve. The possibility that an unnecessary and perhaps more severe illness might occur in low-birth-weight seronegative infants fed banked human milk from sources other than the mother is disturbing and needs resolution.

Development of adverse sequelae in children born with subclinical congenital Toxoplasma infection.

Most infants born with congenital Toxoplasma infection are asymptomatic in the newborn period, and therefore their infection is not recognized. We performed follow-up evaluations on 24 such children. The mean age of these children at least examination was 8.5 years. In group I (13 children), the diagnosis was made prospectively. In group II (11 children), no symptoms or signs were noted in the newborn period and the diagnosis was made only after the first sign developed. Eighty-five percent of the children in group I and all of the children in group II have developed chorioretinitis. In group I, three children (23%) have unilateral blindness; in group II, three children (27%) and five children (45%) have unilateral and bilateral blindness, respectively. One child (8%) in group I and two children (18%) in group II developed severe, permanent neurologic sequelae after they initially presented with eye disease. Two of the children in each group are now retarded (IQ score range, 36 to 62). Six of the children in group I who were tested sequentially have had lower IQ scores (mean change from 97 to 74) on repeat tests performed an average of 5.5 years later. Less severe neurologic, intellectual, and audiologic deficits were observed in other children in each group. Treatment of some children may have had a beneficial effect on their outcome.

Pneumocystis carinii infection: evidence for high prevalence in normal and immunosuppressed children.

Using Pneumocystis carinii organisms propagated through three passages in embryonic chick epithelial lung cultures, specific antigens and antisera were prepared for use in counterimmunoelectrophoresis and indirect immunofluorescent antibody techniques. These methods proved to be specific and sensitive for the detection of P. carinii antigen and antibody, respectively, in sera, and were applied to the study of cancer patients with P. carinii pneumonitis (PCP), cancer patients without pneumonitis, and normal children. Antigenemia was detected in 95% of patients with PCP, in 15% of cancer patients without pneumonitis, and in none of the normal children tested. In cross-sectional and longitudinal studies of normal infants and children, acquisition of serum antibody to P. carinii was demonstrated to occur progressively with increase in age. By 4 years of age two thirds of the normal children were found to have antibody to P. carinii in titers of 1:16 or greater. These studies indicate that subclinical P. carinii infection is highly prevalent in normal children, analogous to other opportunistic infections where active disease is manifest predominantly in the compromised host.

Pneumocystis carinii pneumonitis in young immunocompetent infants.

Of 67 infants enrolled in a prospective study of infant pneumonia ten (14%) had evidence of Pneumocystis carinii infection. Diagnosis was achieved by demonstrating circulating P carinii antigens by counterimmunoelectrophoresis in all ten cases and by histopathology in the only infant who underwent an open lung biopsy. Antigenemia did not occur in 64 control infants (P = .003), nor in 57 patients of similar age who were hospitalized with pneumonitis due to Chlamydia trachomatis, respiratory syncytial virus, cytomegalovirus, adenovirus, and influenza A and influenza B viruses. None of the ten infants with P carinii pneumonitis had evidence of a primary immunodeficiency nor had any received immunosuppressive medication. These patients were hospitalized at a mean age of 6 weeks (range 2 to 12) and their illness was characterized by its afebrile course, presentation in crisis with severe respiratory distress, apnea, tachypnea, cough, increased IgM, and bilateral pulmonary infiltrates with hyperaeration. The clinical features of P carinii pneumonitis were indistinguishable from those of C trachomatis and cytomegalovirus pneumonia. Treatment with trimethoprim-sulfamethoxazole was associated wtih rapid disappearance of circulating antigens; however, the small number of patients studied did not permit an analysis of its clinical efficacy. These results indicate that P carinii singly or in combination with other infectious agents may be an important cause of pneumonitis in young, immunocompetent infants with no underlying illnesses.

An outbreak of toxoplasmosis linked to cats.

Clinical, serologic, and epidermiologic evidence documents an outbreak of toxoplasmosis involving ten of 30 members of an extended family. The index patient had unusual clinical manifestations including brain abscesses, progressive chorioretinitis, seizures, neurologic deficits, hepatosplenomegaly, pneumonitis, and eosinophilia. Toxoplasmosis was confirmed by demonstrating the organism in brain tissue and cerebrospinal fluids; clinical and serologic evidence also indicated infection with Toxocara (viscd children. Of the 11 such children, seven (68%) were seropositive, six of whom had high acute-phase titers (greater than or equal to 1024) to Toxoplasma and a disease consistent with acute toxoplasmosis. All six of the latter group required specific chemotherapy. Geophagia was associated statistically with acute toxoplasmosis among the children; it also increased the risk of infection with Toxocara and enteroparasites. Two school-aged children and two adults had serologic evidence of acute toxoplasmosis, but only one of the group was symptomatic. Epidemiologic evidence indicates that this outbreak was probably caused by ingesting oocysts from cat feces. We suggest that the severe and unusual clinical manifestations of the index patient resulted from simultaneous infection with Toxoplasma and Toxocara.

Infant pneumonitis associated with cytomegalovirus, Chlamydia, Pneumocystis, and Ureaplasma: follow-up.

A total of 205 infants who were hospitalized when younger than 3 months of age for pneumonitis were followed longitudinally. Of these patients, 145 (70%) had evidence of infection with one or more pathogens. The most common etiologic agents were Chlamydia trachomatis 61/193 (36%), respiratory syncytial virus 33/142 (23%), cytomegalovirus 42/203 (20%), Pneumocystis carinii 30/171 (17%), and Ureaplasma urealyticum 21/125 (16%). The initial clinical presentation was characterized by cough, rales, normal temperature, and diffuse obstructive airways disease by chest roentgenogram. Regardless of etiology, significant association occurred for cough and cytomegalovirus, apnea and Pneumocystis, and conjunctivitis and Chlamydia. Longitudinal follow-up demonstrates a mortality of 7/205 (3.4%). Morbidity was manifest as recurrent wheezing episodes in 86/187 (46%) patients, persistently abnormal chest roentgenographic findings for at least 12 months in 17/109 (15%) patients, and abnormal pulmonary functions in 15/25 (60%) patients. These abnormalities occurred irrespective of prematurity, atopy, or the initial etiologic agent associated with the pneumonitis. These data add further evidence that respiratory infections during infancy may well be predecessors of obstructive airways disease in later life.

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.

Use of restriction enzymes to investigate the source of a primary cytomegalovirus infection in a pediatric nurse.

The risk of transmission of cytomegalovirus (CMV) infection from congenitally infected infants to nonimmune medical attendants is unknown. The case of a CMV-seronegative, pregnant nurse who seroconverted after caring for an infant with symptomatic CMV infection is reported. She elected to be aborted and the fetal tissue contained CMV. Isolates from the nurse, the fetal tissue, and the infant to whom the nurse was exposed were examined for genetic relatedness by restriction enzyme analysis. As expected, the isolates from the nurse and the fetal tissue were identical. However, the virus isolated from the symptomatic infant was different from the strain infecting the nurse. These data indicate that the nurse acquired her infection from a source other than the index infant, either within the hospital or within the community.

Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus.

OBJECTIVES: To determine the frequency of symptomatic congenital cytomegalovirus (CMV) infection in the offspring of women with a recurrent maternal CMV infection and to characterize the demographic and newborn findings. METHODS: Study subjects consisted of infants with symptomatic congenital CMV infection identified by a newborn virologic screening program at the University of Alabama Hospital between 1991 and 1997 and were enrolled in a long-term follow-up study. Maternal infections were categorized by an analysis of archival serum specimens collected before pregnancy and at the time of delivery. Demographic data and clinical findings at birth were collected from maternal and newborn hospital records and from parents at the time of initial evaluation. RESULTS: Of the 47 infants with symptomatic congenital CMV infection identified during the study period, 8 were born to mothers with a confirmed nonprimary or recurrent CMV infection. The type of maternal infection could be ascertained in only approximately 43% (20/47) of the children with symptomatic congenital CMV infection born at the University of Alabama Hospital during the study period. There were no significant differences in demographic characteristics of the recurrent infection group and the infants who were born to mothers with either primary CMV infection during pregnancy or unclassified maternal infection. Similarly, the range of severity of clinical abnormalities during the newborn period did not differ in the two groups of children. Furthermore, there were no significant differences in the incidence of sequelae at long-term follow-up in the two groups of children. CONCLUSIONS: Symptomatic congenital CMV infection can occur after a nonprimary or recurrent maternal infection. However, the exact incidence of symptomatic congenital CMV infection among children born to women with preexisting immunity remains to be defined.

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.