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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
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↗
PubMed1994

Peripheral blood eosinophil counts and eosinophil cationic protein content of respiratory secretions in bronchiolitis: relationship to severity of disease.

Infants and young children with acute viral respiratory illness were studied to determine the association of peripheral blood eosinophil counts and concentrations of eosinophil cationic protein (ECP) in nasopharyngeal secretions with the development and severity of bronchiolitis. Subjects included those with upper respiratory illness (URI) alone, pneumonia or bronchiolitis. Controls consisted of healthy infants, and those hospitalized with non-respiratory illnesses. While peripheral blood eosinophil counts were suppressed in all infected infants greater than two months of age, eosinophil counts in patients with bronchiolitis were significantly greater than in those with URI alone. ECP concentrations were significantly greater among individuals with bronchiolitis than other infected infants. For bronchiolitis cases with detectable peripheral blood eosinophils, eosinophil counts correlated weakly and inversely with oxygen saturations. In contrast, ECP concentrations were strongly inversely correlated with initial oxygen saturation. ECP concentrations were also significantly correlated with peripheral blood eosinophil counts. Viral infections suppress peripheral blood eosinophil counts in infants greater than two months of age, although the effect is somewhat overcome in patients with bronchiolitis. The form and severity of bronchiolitis is much more strongly related to degranulation of eosinophils in the respiratory tract than to peripheral blood eosinophil counts.

Blood Proteins↗
PubMed1993

Prophylactic administration of respiratory syncytial virus immune globulin to high-risk infants and young children. The Respiratory Syncytial Virus Immune Globulin Study Group.

BACKGROUND: Infants with cardiac disease or prematurity are at risk for severe illness caused by respiratory syncytial virus. Immune globulin with a high titer of antibodies against respiratory syncytial virus may offer infants and young children at risk protection from this serious, common respiratory illness. METHODS: We studied 249 infants and young children (mean age, eight months) who had bronchopulmonary dysplasia due to prematurity (n = 102), congenital heart disease (n = 87), or prematurity alone (n = 60). Respiratory syncytial virus immune globulin was given monthly to some of these children in either a high dose (750 mg per kilogram of body weight; n = 81) or low dose (150 mg per kilogram; n = 79); 89 controls received no immune globulin. Group assignments were random. Assessments of respiratory illness and management were conducted without knowledge of the children's group assignments. RESULTS: There were 64 episodes of respiratory syncytial virus infection: 19 in the high-dose group, 16 in the low-dose group, and 29 in the control group. In the high-dose group there were fewer lower respiratory tract infections (7, vs. 20 in the control group; P = 0.01), fewer hospitalizations (6, vs. 18 in the control group; P = 0.02), fewer hospital days (43, vs. 128 in the control group; P = 0.02), fewer days in the intensive care unit (P = 0.05), and less use of ribavirin (P = 0.05). In the low-dose group there was a significant reduction only in the number of days in the intensive care unit (P = 0.03). Adverse events during the 580 infusions were generally mild and included fluid overload (in five children), oxygen desaturation (eight), and fever (six). Six children died: three in the high-dose group, three in the low-dose group, and none in the control group (P = 0.15), but no death was attributed to the use of immune globulin or to illness caused by respiratory syncytial virus. CONCLUSIONS: Administration of high doses of respiratory syncytial virus immune globulin is a safe and effective means of preventing lower respiratory tract infection in infants and young children at high risk for this disease.

Antibodies, Viral↗
PubMed1993

The relationship of RSV-specific immunoglobulin E antibody responses in infancy, recurrent wheezing, and pulmonary function at age 7-8 years.

In order to determine if respiratory syncytial virus (RSV)-specific IgE responses at the time of bronchiolitis in infancy are related to recurrent wheezing and pulmonary function at 7-8 years of age, a cohort of 43 infants was identified at the time of their initial RSV bronchiolitis episode. RSV-specific IgE responses in nasopharyngeal secretions were determined, and patients were then followed prospectively with notation of the number of wheezing episodes and exposure to cigarette smoke at home. At 7-8 years of age the patients underwent skin testing to 7 environmental allergens and pulmonary function testing, including pulse oximetry and methacholine challenge. Pulmonary function following inhalation of bronchodilating agents was compared to baseline pulmonary function results in order to determine if abnormalities of pulmonary function were reversible. Recurrent wheezing following bronchiolitis was associated with the initial RSV-IgE response, as well as with a family history of asthma. Current wheezing at age 7-8 years was associated with 2 or more positive skin tests (P < 0.01), a history of exercise-induced wheezing (P = 0.01), and increased sensitivity to methacholine (P < 0.01). Pulmonary function test results were similar for groups with and without recurrent wheezing following bronchiolitis. For the entire study group, RSV-IgE specific responses were unrelated to pulmonary function, but small airway dysfunction was associated with passive smoking (P < 0.025), and both large airway dysfunction and increased airway reactivity were associated with the number of positive skin tests (P < 0.025). Reduced small airway function improved following bronchodilator inhalation.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Viral↗
PubMed1993

Immunogenicity and safety of respiratory syncytial virus subunit vaccine in seropositive children 18-36 months old.

Twenty-six children (aged 18-36 months) previously hospitalized for respiratory syncytial virus (RSV) infection were randomized to receive 50 micrograms of an RSV subunit vaccine composed primarily of F glycoprotein or saline placebo by intramuscular injection. Serum was obtained at entry and at 1 and 6 months after vaccination for detection of antibody to F glycoprotein and G glycoprotein of subtypes A (Ga) or B (Gb) and of neutralizing antibody (nAb). At 1 month, by comparing the baseline values, vaccinees had statistically significant increases in geometric mean antibody titer (GMT) of more than fourfold to F (P = .0001), Ga (P = .0001), Gb (P = .003), and nAb (P = .009). No differences in GMT were observed between F protein vaccine and placebo recipients at entry, nor between placebo recipients at entry and 1 month. RSV infections were identified in 7 placebo recipients (4 by both viral identification and seroconversion, 3 by seroconversion alone). No vaccine recipient had RSV infection documented in the 6 months after vaccination (P = .003). There were no significant vaccine-related side effects, and no evidence of enhanced respiratory illnesses was observed. The subunit F protein vaccine appears safe and immunogenic and may prevent infection in healthy children primed by prior RSV infection.

Antibodies, Viral↗
PubMed1993

Bronchiolitis.

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Age Factors↗
PubMed1993

Respiratory syncytial virus vaccines: can we improve on nature?

Both inactivated and live RSV candidate vaccines will continue to be tested in infants and young children. Sequential vaccination, with a first dose of live attenuated vaccine followed by boosting with intramuscular subunit vaccines, also is an option. We are encouraged by the fact that influenza subunit and cold-adapted live vaccines are both safe and immunogenic in infants and children of the same age group. Testing of RSV vaccines must proceed at a slower pace because of the phenomenon of vaccine-induced enhanced disease. Curiously, this phenomenon of disease enhancement has not been demonstrated in the case of inactivated influenza or parainfluenza virus vaccines. Another important step in the development of RSV vaccines is to determine a target population. Clearly, children with underlying cardiac or pulmonary disease would benefit from an RSV vaccine. It can be expected that 1% of all infants in the general population will be hospitalized for RSV infection during their first year of life. These infants also would appear to be good candidates for an RSV vaccine, but it is unclear how they would be identified before infection occurs. Immunization of the entire population of infants to protect these 1% would be feasible only if the vaccine were inexpensive and easily administered.

Adult↗
PubMed1992

Eosinophil degranulation in the respiratory tract during naturally acquired respiratory syncytial virus infection.

Eosinophil cationic protein (ECP), a cytotoxic protein contained in the granules of eosinophils, has been suggested as having an important role in the pathogenesis of asthma. To determine whether ECP plays a similar role in bronchiolitis, we tested samples of nasopharyngeal secretions, obtained from a group of 47 children with various forms of illness related to respiratory syncytial virus (RSV) and from 26 children with non-RSV upper respiratory tract illness or bacterial pneumonia, for the presence of ECP by means of a double-antibody radioimmunoassay. Concentrations of ECP in children with RSV bronchiolitis were significantly higher (166.8 ng/ml) than the mean concentration of ECP in both groups of children with RSV upper respiratory tract illness (43.5 ng/ml, p less than 0.002) and RSV lower respiratory tract disease without wheezing (29.1 ng/ml; p less than 0.0002). Children with non-RSV upper respiratory tract illness or bacterial pneumonia had levels of ECP in nasopharyngeal secretions similar to those of children with RSV upper respiratory tract illness or RSV pneumonia. High ECP levels in nasopharyngeal secretions (greater than 50 ng/ml) were predictive of the development of bronchiolitis at the time of RSV infection (p less than 0.001), and the individual ECP levels correlated with severity of the disease as determined by the initial PaO2 concentrations (p less than 0.05). These data suggest that eosinophil degranulation in the respiratory tract occurs during RSV bronchiolitis and may play a significant role in the development of virus-induced airway obstruction.

Bacterial Infections↗