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Biomedical subjects

R C Welliver

Publications and source records attributed to R C Welliver.

At least 19 recordsLinked to original sources
PubMed1999

Increased production of IFN-gamma and cysteinyl leukotrienes in virus-induced wheezing.

BACKGROUND: An imbalance of production of T-helper lymphocyte cytokines, favoring overproduction of IL-4, is believed to be important in the pathogenesis of allergic asthma. However, less is known about the cytokine response in virus-induced wheezing, which is a major cause of morbidity in asthma. OBJECTIVE: We undertook this study to determine the magnitude of IFN-gamma, IL-4 and IL-10, and leukotriene (LT) responses in infants and children with virus-induced wheezing. METHODS: We measured the concentrations of IFN-gamma, IL-4 and IL-10, and cysteinyl LTs in respiratory secretions of 82 infants and young children during acute episodes of virus-induced wheezing. Control subjects were 47 infants and children with uncomplicated upper respiratory infections and 18 normal healthy infants. RESULTS: Ratios of IFN-gamma to IL-4 were higher (due to increased quantities of IFN-gamma) in subjects with wheezing than in those with upper respiratory infection alone (P =. 003). Quantities of LTs were also increased in wheezing subjects in comparison with those with upper respiratory infections (P =.009). There was a significant correlation between measured concentrations of IFN-gamma and LTs (correlation coefficient =.451, P =.007). Quantities of IL-4 were slightly suppressed in the wheezing groups. CONCLUSIONS: An imbalance favoring overproduction of IFN-gamma appears to be associated temporarily with virus-induced wheezing. A possible mechanism is the enhanced release of LTs from eosinophils or mast cells after sensitization by IFN-gamma.

Asthma↗
PubMed1999

Safety and pharmacokinetics of an intramuscular monoclonal antibody (SB 209763) against respiratory syncytial virus (RSV) in infants and young children at risk for severe RSV disease.

We conducted a multicenter, double-blind, placebo-controlled, randomized trial of a humanized monoclonal antibody against a respiratory syncytial virus (RSV) fusion protein (SB 209763) to evaluate its safety, pharmacokinetics, and fusion inhibition and neutralization titers. Forty-three infants who were either delivered prematurely (</=35 weeks' gestation) or exhibited bronchopulmonary dysplasia were administered either single or repeat (two doses, 8 weeks apart) intramuscular injections of SB 209763 at a concentration of 0.25, 1.25, 5.0, or 10.0 mg/kg or of a placebo. Four of 229 adverse events were considered related to the study drug, including purpura (n = 3) and thrombocytosis (n = 1). No subject developed a detectable level of anti-SB 209763 antibody. Approximately 1 week after administration of the second dose of SB 209763 at 10 mg/kg, the mean plasma concentration (n = 9) was 68.5 micrograms/ml. The terminal half-life (T1/2) determined by noncompartmental analysis ranged from 22 to 50 days. The population pharmacokinetics for SB 209763 following intramuscular administration was appropriately described by a one-compartment model with first-order input and elimination. Higher values for clearance and volume of distribution at steady state were observed for younger patients, with values decreasing to 0.143 (ml/h)/kg and 161 mL/kg, respectively, by a mean age of 298 days (approximately 10 months). The mean T1/2 of SB 209763 for the study population was 32.5 days. No other factor (dose, weight, gender, race, premature birth, or bronchopulmonary dysplasia) was observed to alter the population pharmacokinetics of SB 209763 in this study of infants and young children. The mean neutralization titer on day 6 was 286, and the mean fusion inhibition titer was 36. At least 57% of subjects dosed at 1.25 to 10.0 mg of SB 209763 per kg of body weight who were seronegative at baseline experienced a fourfold or greater increase in fusion inhibition titer. Nine RSV infections were documented during the 16-week course of the study; the numbers of RSV infections were similar for the different regimens, including the placebo. The doses of SB 209763 studied may have been insufficient to confer protection against RSV lower respiratory tract disease; these results suggest that additional trials using higher doses of monoclonal antibody for immunoprophylaxis should be considered.

Antibodies, Monoclonal↗
PubMed1998

Respiratory syncytial virus immune globulin for prophylaxis against respiratory syncytial virus disease in infants and children with congenital heart disease. The Cardiac Study Group.

OBJECTIVE: To examine the effectiveness of respiratory syncytial virus immune globulin administered intravenously (RSV-IGIV) in reducing hospitalization for treatment of RSV in children with congenital heart disease (CHD). METHODS: Children younger than 4 years of age were randomly assigned to a treatment group receiving RSV-IGIV, 750 mg/kg, monthly or to a control group not receiving infusions. Surveillance for respiratory tract infections was carried out and management decisions were made by physicians blinded to treatment group. RESULTS: Hospitalization for treatment of an RSV infection occurred in 32 of 214 (15%) of control children and 21 of 202 (10%) of the children receiving RSV-IGIV, a 31% reduction (P = .16). However, in infants younger than 6 months of age at study entry, 20 of 82 (24%) in the control group and 10 of 96 (10%) in the RSV-IGIV group had RSV hospitalizations (58% reduction, P = .01). The incidence of hospitalization for any respiratory tract symptomatology was lower in the RSV-IGIV group (34 of 202, 17%) than in the control group (57 of 214, 27%; P = .02). There was a significantly higher frequency of unanticipated cyanotic episodes and of poor outcomes after surgery among children with cyanotic CHD in the RSV-IGIV group (22 of 78, 28%) than in the control group (4 of 47, 8.5%; P = .009). CONCLUSION: RSV-IGIV should not be used for prophylaxis of RSV disease in children with cyanotic CHD. RSV-IGIV did not reduce RSV hospitalization in all children with CHD, but it was effective in preventing RSV hospitalization in infants younger than 6 months of age. Further studies in these children are indicated.

Age Factors↗
PubMed1998

Respiratory syncytial virus immunoglobulin and monoclonal antibodies in the prevention and treatment of respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) infection is particularly severe in infants with bronchopulmonary dysplasia (BPD) and in premature infants without BPD. Attempts to develop a vaccine against RSV have been unsuccessful. Passive immunoprophylaxis of premature infants with or without BPD using a hyperimmune human globulin against RSV (RSVIg) decreases the severity of RSV infection such that the rate of hospitalization following infection is reduced by 40%. The severity of illness among hospitalized infants is also reduced. To avoid the difficulties associated with intravenous infusion of immunoglobulins, monoclonal IgG antibodies against the fusion protein of RSV have been developed. In one trial, the antibodies were ineffective, although subsequent trials using higher doses of the antibody show more promising results. Studies of IgA monoclonal antibodies directed against RSV, which are administered in the form of nose drops, are also in progress. None of these preparations appear to be effective in the treatment of established RSV infection. Each of the preparations appeared to be safe, with one exception. Infants with cyanotic heart disease who received RSVIg had an increased risk of surgical complications, perhaps related to increases in serum viscosity as a result of receiving the hyperimmunoglobulin monthly in doses of 750 mg/kg. While definitive cost/benefit analyses are pending, RSVIg may be useful in infants and children with BPD who have current or recent oxygen requirements, as well as in certain premature infants without BPD. Recommendations on the use of RSVIg are provided.

Antibodies, Monoclonal↗
PubMed1998

Respiratory syncytial virus affects pulmonary function in BALB/c mice.

BALB/c mice inoculated intranasally with respiratory syncytial virus (RSV) were studied in a whole-body plethysmograph to determine if signs of respiratory illness similar to those observed in human infants could be detected. Also, responsiveness to methacholine was assessed. RSV-infected mice showed significantly higher respiratory rates than did controls (409.2 vs. 305.2 breaths/min, P < .0001). Significantly increased airway responsiveness to methacholine was noted, infected mice responding to a 100-fold lower dose than controls (P = .003). Together, these data provide the first objective evidence of respiratory illness in the mouse model of RSV infection, which enhances the value of this model for evaluating effects of vaccines, antivirals, and other drugs acting on respiratory tract disease caused by RSV.

Animals↗
PubMed1997

Surfactant dysfunction develops in BALB/c mice infected with respiratory syncytial virus.

Recent reports suggest an important role for pulmonary surfactant in maintaining the patency of narrow conducting airways. The hypothesis that surfactant dysfunction is an important factor in respiratory syncytial virus (RSV) infection was tested in a mouse model. Mice, inoculated with either a low or a high dose of RSV, were subjected to bronchoalveolar lavage (BAL), and the fluids were analyzed for percentage of inflammatory cells and concentrations of proteins and phospholipids. After concentration of the surfactant by centrifugation, its function was analyzed with a capillary surfactometer. RSV infection resulted in a dose-dependent disruption of surfactant function (p < 0.0001). BAL fluid supernatants were added to calf lung surfactant extract (CLSE) to examine whether surfactant inhibiting agents were present. Indeed, BAL fluid supernatants of RSV-infected mice disrupted the normal function of calf lung surfactant extract in a dose dependent way (p < 0.0001), indicating the presence of inhibitors. Protein concentrations were increased in BAL fluids of RSV-infected mice versus control mice (p < 0.0001), and were inversely related to surfactant function (r = -0.44, p = 0.0004), suggesting an inhibitory effect of proteins. Protein concentration also correlated with the percentage of inflammatory cells (r = 0.51, p = 0.004). Phospholipid concentrations were not affected by the RSV infection. The results of these studies strongly suggest that a disruption of pulmonary surfactant function, most likely due to inhibition from inflammatory proteins, is important for the pathophysiology of RSV infection.

Animals↗
PubMed1997

Respiratory syncytial virus (RSV) immune globulin intravenous therapy for RSV lower respiratory tract infection in infants and young children at high risk for severe RSV infections: Respiratory Syncytial Virus Immune Globulin Study Group.

OBJECTIVES: To evaluate the efficacy of high-titer intravenous respiratory syncytial virus immune globulin (RSVIG) in the treatment of children at high risk for severe RSV infection who were hospitalized with proven RSV. METHODS: Infants and young children younger than 2 years with bronchopulmonary dysplasia, chronic lung disease, congenital heart disease, or prematurity (<32 weeks' gestational age), hospitalized with a history of lower respiratory tract infection (LRI) of less than 4 days, were enrolled in this study. Patients were randomized in a blinded fashion to receive either 1500 mg/kg RSVIG or placebo in equal volumes. They were evaluated daily for safety and respiratory scores and for RSV nasal shedding. RESULTS: One hundred seven high-risk children were randomized--54 in the RSVIG group and 53 in the placebo group. Of these children, 51 in each group were considered evaluable. Children with pulmonary disease, congenital heart disease, or prematurity were equally distributed between the two treatment groups. However, two important differences were found in baseline variables between the two groups: there were more patients in the placebo group who had histories of previous LRI and there was a trend toward more severe disease at study entry in the RSVIG group. This was manifested by a higher entry respiratory score in the RSVIG group than in the placebo group (3.4 +/- 0.2 vs 3.1 +/- .01). A higher proportion of children in the RSVIG group (47%) than in the placebo group (28%) required intensive care at entry and mechanical ventilation at study entry (31% RSVIG-treated vs 18% placebo-treated patients). No significant difference was found between groups in the mean unadjusted duration of hospitalization (RSVIG group, 9.10 +/- 1.18 days; control group, 8.17 +/- 1.08 days). When the mean was adjusted for entry respiratory score, likewise, no difference was observed between each group (8.41 +/- 0.97 vs 8.89 +/- .99 days). The lack of efficacy observed in the study primary endpoint was observed in all diagnostic groups. No differences between the RSVIG and placebo groups were observed in the following secondary endpoints: duration of intensive care unit stay, duration of intensive care unit stay for RSV, mechanical ventilation, or supplemental oxygen. No significant differences in adverse events were reported in the RSVIG group (16 children) when compared with the control group (10 children). CONCLUSION: RSVIG treatment was safe but not efficacious in the treatment of children with bronchopulmonary dysplasia, congenital heart disease, or premature gestation who were hospitalized with RSV LRI.

Bronchiolitis↗
PubMed1996

Respiratory syncytial virus-enriched globulin for the prevention of acute otitis media in high risk children.

Acute otitis media (AOM) has been associated with respiratory syncytial virus (RSV) infection; AOM develops in up to one third of children with RSV illness. A masked multicenter trial used an immune globulin enriched with RSV-neutralizing antibodies (RSVIG) to prevent RSV infection of the lower respiratory tract in 249 children with either bronchopulmonary dysplasia, congenital heart disease, or prematurity. To determine whether monthly RSVIG therapy might decrease the incidence of AOM, we retrospectively analyzed the records of 109 children in two of the centers. RSVIG was administered during RSV season of a high dose of 750 mg/kg monthly or a low dose of 150 mg/kg monthly; control children received no RSVIG. Children were examined for AOM by masked observers using pneumatic otoscopy. No difference in sex, race, underlying diagnosis, number of persons in the home, exposure to smoking, or atopy was found between groups studied. In recipients of high doses of RSVIG, significantly less AOM developed per season than in control children (mean episodes, 0.15 vs 0.78; p = 0.003), and fewer episodes of RSV-related AOM occurred (0 vs 5; p = 0.047). Low doses of RSVIG did not have a clinically significant impact. High doses of RSVIG appeared to have a significant impact on preventing AOM (both RSV- and non-RSV-related AOM) in these-high risk populations. This finding may have important implications in the development of improved preventive modalities for AOM.

Acute Disease↗
PubMed1996

An ultrastructural study of the interaction of human eosinophils with respiratory syncytial virus.

It was shown previously that eosinophils are activated in vivo and in vitro by respiratory syncytial virus (RSV) (Garofalo et al., J Pediatr 1992: 120: 28-32; Kimpen et al., Pediatr Res 1992: 32: 160-4). For study of the interaction of eosinophils and RSV on the ultrastructural level, normodense eosinophils were purified from peripheral blood of healthy human volunteers. After incubation with RSV in the presence or absence of autologous serum, the eosinophils were examined with immunofluorescence microscopy employing an RSV-specific monoclonal antibody, and with transmission electron microscopy. After 2-h incubation in the presence of live RSV, 25.6 +/- 12.9% of the eosinophils demonstrated positive fluorescence. This increased to 62.8 +/- 8.9% when fresh autologous serum was added during incubation (P = 0.015). The effect was abolished when the serum was heat-treated, indicating Fc-receptor-independent enhancement of viral uptake by the cells. In transmission electron microscopy, virions were seen in phagocytic vacuoles at the periphery of the cells. Eosinophil activation characterized by piece-meal degranulation was evident. In conclusion, activation of eosinophils during RSV bronchiolitis probably occurs in part by direct interaction of the cells with the virus.

Adult↗
PubMed1995

Safety and immunogenicity of the PFP vaccine against respiratory syncytial virus (RSV): the western blot assay aids in distinguishing immune responses of the PFP vaccine from RSV infection.

PFP-1 vaccine was evaluated in a randomized, controlled study in 47 RSV seropositive children. Trivalent inactivated influenza virus (TIV) vaccine was the control. Vaccine reactions were monitored, and bloods were obtained before vaccination, 4 weeks after vaccination, and at the end of the RSV season. Respiratory illnesses were evaluated during the outbreak. Neutralizing antibody (Nt Ab) assay to RSV, IgG ELISA to RSV proteins and a Western blot assay were performed. Acute reactions with the PFP vaccine were mild. An early RSV outbreak resulted in infection of 44.4% of the TIV recipients shortly after vaccination. In the PFP vaccine groups, the Nt Ab and ELISA assays did not distinguish between Ab rises due to natural infection versus vaccine; however, the Western blot assay characterized the post-vaccine rises. Two major Western blot profiles were produced: an infection profile (antibodies that recognized the F and G surface glycoproteins and internal proteins) and a vaccine profile (antibodies that recognized only the surface glycoproteins). The PFP vaccinees who were not infected with RSV developed ELISA and Nt Ab responses to the surface glycoproteins that were similar to the TIV vaccines with natural RSV infection. None of the children developed vaccine-enhanced disease. Thus, the PFP-1 vaccine was safe and immunogenic in RSV seropositive children even when vaccine was administered during a RSV outbreak, and the Western blot assay was useful in distinguishing Ab rises caused by RSV infection versus PFP vaccine.

Antibodies, Viral↗
PubMed1995

Safety and bioequivalency of three formulations of respiratory syncytial virus-enriched immunoglobulin.

Respiratory syncytial virus (RSV) causes serious illness (lower respiratory illness) in preterm infants. RSV antibody-enriched immunoglobulin (RSVIG) that was lyophilized (LYO) protected against RSV lower respiratory illness. The Food and Drug Administration now requires an additional viral inactivation step (VI). We compared LYO, LYO-VI, and a more convenient liquid RSVIG (LIQ-VI) in 30 preterm infants (median age, 7 months; median weight, 5.4 kg). Infants were randomized to receive LYO (n = 10), LYO-VI (n = 10), or LIQ-VI (n = 10) in monthly infusions of 750 mg/kg of body weight per dose (December to March). Children were monitored closely for adverse reactions to RSVIG and for RSV illness.

Double-Blind Method↗
PubMed1995

Pulmonary surfactant maintains patency of conducting airways in the rat.

The hypothesis was tested that after extrusion of the liquid columns that often block the lumen of conducting airways, the latter will remain open because of well-functioning pulmonary surfactant preventing the liquid columns from returning. The extirpated lungs of 22 Wistar rats were studied. Via a tracheal tube a very fine catheter (PE 10) was inserted and advanced until it pierced the pleura. It was extracted until only 2 mm remained in the lung parenchyma. A pressure transducer measured the resistance that met a steady flow of air through the series of tubes: the PE 10 tube, the conducting airway of the lung, and the tracheal tube. The airway resistance was studied for 240 s after three airway flushings, two with saline solution and one with calf lung surfactant extract (CLSE), 3 mg/ml. The pressure recording showed that a low pressure, indicating airway patency, occurred for only 31 +/- 8 s (mean +/- SEM) after the first saline flush, and for 26 +/- 8 s after the second. After the CLSE flush the airway remained open for 174 +/- 12 s, which indicated a significantly reduced resistance (p < 0.0001). The results imply that well-functioning pulmonary surfactant is required for a low airway resistance.

Airway Resistance↗
PubMed1994

Second-year surveillance of recipients of a respiratory syncytial virus (RSV) F protein subunit vaccine, PFP-1: evaluation of antibody persistence and possible disease enhancement.

In a previous study, children 18 to 36 months of age and seropositive for respiratory syncytial virus (RSV) were vaccinated with an RSV subunit vaccine (PFP-1) consisting of the viral fusion protein. Vaccines developed substantial increases in anti-fusion and neutralizing antibody and exhibited protection against RSV infection through one RSV epidemic, in comparison to controls. This present study of the same cohort was undertaken to determine the persistence of antibody responses and immunity to reinfection, as well as to monitor for enhanced disease upon subsequent RSV infection during the second RSV season after vaccination. Vaccinees continued to have greater ELISA specific anti-fusion (F) antibody responses than controls up to 18 months after vaccination. Neutralizing antibody titres were not as durable, and the attack rates for RSV in the second winter season after vaccination (25% in vaccines versus 42% in controls) were not significantly different (p = 0.23). Nevertheless, 'high-responder' subgroups may have had residual protection into the second postvaccination year. Enhanced illness did not occur. PFP-1 is immunogenic and appears safe, but yearly reimmunization may be necessary to maintain immunity to RSV infection.

Antibodies, Viral↗
PubMed1994

Respiratory syncytial virus-specific cell-mediated immune responses after vaccination with a purified fusion protein subunit vaccine.

Vaccination with a respiratory syncytial virus (RSV) fusion protein subunit vaccine (PFP-2) was done to determine if this vaccine induced evidence of cell-mediated immunity to RSV and if cell-mediated immunity prevented RSV reinfection. Healthy children 12-18 months old received 50 micrograms of PFP-2 or a saline control. Lymphocyte transformation (LTF) responses were determined before and 1 and 6 months after vaccination. PFP-2 induced positive LTF responses in 5 (83%) of 6 subjects whose prevaccination samples lacked evidence of cell-mediated immunity. Positive LTF responses in prevaccination samples were not boosted but were more persistent in vaccinees than in controls. Positive LTF responses were not associated with protection against subsequent infection. Immunization with PFP-2 induces correlates of cell-mediated immunity, but this immunity does not appear to be a critical component of protection.

Double-Blind Method↗