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Use of extracorporeal membrane oxygenation in the treatment of respiratory syncytial virus bronchiolitis: the national experience, 1983 to 1988.

In an effort to obtain data to provide the basis for the design of controlled clinical trials, we contacted all U.S. participants in the National ECMO Registry to assemble the national experience on the use of extracorporeal membrane oxygenation in respiratory syncytial virus bronchiolitis during the past 5 years. Twelve infants were treated at nine centers between 1983 and 1988. Eight had been born prematurely, and five had bronchopulmonary dysplasia. The mean age at onset of infection with respiratory syncytial virus was 108 +/- 102 days. The mean length of ventilator management before extracorporeal membrane oxygenation was 7.8 +/- 7.1 days. All infants had persistent hypoxemia with a mean arterial oxygen pressure of 39.2 +/- 11.7 torr (5.3 +/- 1.6 kPa) despite high ventilator pressures (mean airway pressure 19.7 +/- 6.4 cm H2O) and 100% inspired oxygen; six had air leak syndrome. Seven infants survived (58%). The mean duration of extracorporeal membrane oxygenation for survivors was 233 +/- 139 hours. Preexisting chronic lung disease did not predict a poor outcome: four of the five infants with bronchopulmonary dysplasia survived. Six of the survivors have subsequently achieved expected developmental milestones and one has slight motor delay. We conclude that, for infants with severe respiratory syncytial virus bronchiolitis whose condition deteriorates despite maximal ventilator management, extracorporeal membrane oxygenation may provide lifesaving support. The duration of successful treatment with this therapy may be longer than that for conventional neonatal indications, but excellent neurologic outcome may be expected in survivors.

Bronchiolitis, Viral↗

Early ribavirin treatment of respiratory syncytial viral infection in high-risk children.

A 3-year prospective, blinded, multicenter study was done to assess the efficacy of early ribavirin intervention in mild respiratory syncytial virus illness in children with bronchopulmonary dysplasia or with congenital heart disease. A cohort of 178 children younger than 36 months of age with bronchopulmonary dysplasia or congenital heart disease were followed. Forty-seven infants whose respiratory syncytial virus infection resulted in mild symptoms of less than or equal to 72 hours' duration received ribavirin (n = 20) or water placebo aerosol (n = 27) either in a hospital or at home. Outcome measures included respiratory and analog score, room air oxygen, saturation, and oxygen flow needed to maintain saturation at greater than or equal to 91%. No difference in age, gender, family size, passive smoking, baseline oxygen saturations in room air, or duration of symptoms before treatment was found between groups. After 3 days of therapy, ribavirin produced a greater rate of improvement of analog scores (p = less than or equal to 0.001), lower oxygen requirements (p = 0.01), and higher oxygen saturation (p = 0.01). Respiratory scores and total hospital days did not differ significantly between the groups. Treatment failure occurred in 2 of 20 children (10%) in the ribavirin group versus 5 of 27 children (18%) in the placebo group, a nonsignificant difference. No child required assisted ventilation or had an adverse reaction. We conclude that early ribavirin therapy may help to reduce morbidity from respiratory syncytial virus infection in high-risk young children.

Bronchopulmonary Dysplasia↗

A simultaneous outbreak of respiratory syncytial virus and parainfluenza virus type 3 in a newborn nursery.

Over a 3-week period, 20 of 34 (59%) infants in a newborn nursery developed nosocomial viral respiratory tract disease. Either respiratory syncytial virus (seven infants) or parainfluenza virus type 3 (five) or both (two) were demonstrated in respiratory secretions from 14 of the 20 symptomatic patients. Symptoms in the 20 infants included rhinitis (15 infants), cough (14), apnea (eight), pulmonary infiltrates (seven), and fever (six). There were no differences in symptoms between children infected with respiratory syncytial virus alone, with parainfluenza virus alone, or with both viruses concurrently. Patients were clustered in the nursery by agent: infants with the same virus tended to share contiguous bed spaces, supporting the concept that parainfluenza virus as well as respiratory syncytial virus can be transmitted from patient to patient. In addition to this risk for contiguous bed spaces, the presence of a nasogastric tube was associated with risk of illness (P less than 0.05). In the presence of a nursery outbreak of respiratory tract disease, more than one virus may circulate concurrently, and an individual patient may be infected simultaneously by more than one virus.

Boston↗

Serum vitamin A levels in respiratory syncytial virus infection.

Respiratory syncytial virus causes worldwide epidemics of respiratory disease. Of 23 children infected with respiratory syncytial virus, 65% had low serum concentrations of vitamin A during acute illness; these low values were associated with more severe illness. Vitamin A supplementation may have a role in the management of infection with respiratory syncytial virus.

Case-Control Studies↗

Acute and long-term effects of infection by the respiratory syncytial virus in children with congenital cardiac malformations.

All newborn infants have limited pulmonary reserve compared with older children. This puts them at increased risk of respiratory complications, such as those associated with infection by the respiratory syncytial virus. Young children with congenital cardiac disease are particularly likely to suffer severe disease related to infection by the virus. In these children, the extreme vulnerability of the lung to pulmonary oedema is compounded by the additional burden caused by the respiratory syncytial virus. In addition to the well-documented acute pulmonary effects of infection with the respiratory syncytial virus, there may also be consequent long-term respiratory morbidity. Clinical studies have shown that infection by the virus in infancy is associated with a higher risk of developing subsequent bronchial obstructive disease. Much debate surrounds the mechanisms underlying this association. It is thought that a combined immunological and neurogenic response mechanism is likely. Prevention of severe respiratory disease in infants and young children with congenital heart disease due to infection by the virus may, therefore, offer both immediate and long-term benefits. Indeed, an increasing body of evidence supports this hypothesis, indicating a clinical rationale for prophylaxis against the virus in infancy, in order to reduce the chance of developing reactive airways disease and asthma in later life.

Heart Defects, Congenital↗

Adhesion molecule expression on epithelial cells infected with respiratory syncytial virus.

Respiratory epithelium is both a target and an effector of airway inflammation. Adhesion molecules on epithelium play an important role in a variety of airway diseases. Respiratory syncytial virus (RSV) is the most important pathogen for airway diseases in infants. The expression of adhesion molecules on epithelium in RSV infection, however, is unclear. The expression of selected adhesion molecules and major histocompatibility complex (MHC) class I and II antigens on a human alveolar type II epithelial cell line (A549) infected with RSV was investigated by means of flow cytometry and immunocytochemistry. The results showed that intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were expressed on A549 cells at a low level. E-cadherin and MHC class I antigen were constitutively expressed on the cells. RSV infection of A549 cells significantly upregulated the expression of ICAM-1, VCAM-1 and MHC class I and II antigens on these cells. RSV infection also altered the expression of E-cadherin on A549 cells. Immunostaining showed that E-cadherin was mainly upregulated around or in RSV-induced giant cells. These data suggest that respiratory syncytial virus infection of respiratory epithelial cells enhances the expression of adhesion molecules and major histocompatibility complex antigens. These changes may play an important role in the pathophysiology of respiratory syncytial virus disease.

Cell Adhesion Molecules↗

Outcome of respiratory syncytial virus infection and a cost-benefit analysis of prophylaxis.

OBJECTIVES: To determine outcome and length of stay (LOS) for infants younger than 2 years of age admitted to hospital for respiratory syncytial virus (RSV) infection and to perform a cost-benefit analysis of prophylaxis with RSV gamma-globulin (Respigam; CSL Laboratories, Melbourne, Victoria, Australia) and monoclonal antibody (Synagis; Abbott Australasia, Kurnell, NSW, Australia) in the Australian context. METHODS: Retrospective outcome study using data from an Australian hospital and intensive care databases over a 30 month period encompassing three RSV seasons (1 May 1997-31 October 1999). RESULTS: The mortality for RSV infection was very low, being 0.29% of all patients admitted to hospital and 0% in infants without co-existing disease. Only 11.4% of infants required admission to the intensive care unit (ICU). Respiratory syncytial virus infection was not associated with prolonged hospitalization; patients managed in the general wards had a mean length of stay (LOS) of 4.13 days with a median of 3.0 days, while those requiring intensive care had a mean LOS of 9.8 days (including 5.1 days in the ICU). Use of RSV prophylaxis would be expected to reduce the requirement for hospital admission; however, the cost of prophylaxis is conservatively estimated to be between 7.2- and 65.3-fold the money saved in hospital care, depending on the weight of the patient and choice of drug. CONCLUSIONS: Respiratory syncytial virus is a major cause of morbidity, but not mortality, in infants. In infants requiring hospitalization for this disease, the LOS is relatively short and the mortality extremely low. Use of prophylactic agents, which reduce the probability of hospital admission but have no effect on mortality, cannot be justified in the Australian context on cost-benefit grounds.

Antibodies, Monoclonal↗

Risk factors for severe respiratory syncytial virus-associated lower respiratory tract infection in children.

BACKGROUND: Respiratory syncytial virus (RSV) is the most important cause of viral lower respiratory tract infection that can be a life-threatening disease in infants and children. This study was conducted to look for independent risk factors for severe respiratory syncytial virus-associated lower respiratory tract infection (RSV-LRI) that required oxygen supplementation or mechanical ventilation. METHODS: Medical records of patients younger than 4 years hospitalized with RSV-LRI at Shizuoka Red Cross Hospital from July 1, 1995 to June 30, 1999 were reviewed. The patients were compared using univariate and multivariate logistic regression analysis. RESULTS: A total of 157 patients were hospitalized with RSV-LRI at Shizuoka Red Cross Hospital from the study time period. Of these, 20 patients (12.7%) were diagnosed with severe RSV-LRI. Subjects younger than 3 months of age had an odds ratio (OR) of 59.9 (95% confidence interval (CI) 14.7_244.0) for the dependent variable of severe RSV-LRI (P<0.0001). Subjects with a history of congenital heart disease also had an OR of 99.2 (95% C1 8.5-1160.1) (P<0.0005). CONCLUSIONS: Infants younger than 3 months without any underlying diseases may be at high risk for severe RSV-LRI. Respiratory syncytial virus prophylaxis is needed not only for high-risk patients, but for healthy early infants.

Age Factors↗

Nucleotide sequences for the gene junctions of human respiratory syncytial virus reveal distinctive features of intergenic structure and gene order.

Complete sequences for the intergenic regions of the genome of human respiratory syncytial virus were obtained by dideoxynucleotide sequencing using synthetic oligonucleotides. These experiments established that the 10 respiratory syncytial viral genes are arranged, without additional intervening genes, in the order 3' 1C-1B-N-P-M-1A-G-F-22K-L 5'. For the first nine genes, the exact gene boundaries were identified by comparison of the genomic sequences with previously determined mRNA sequences. The intergenic regions varied in length from 1 to 52 nucleotides and lacked any obvious conserved features of primary or secondary structure except that each sequence ended (3' to 5') with an adenosine residue. The exact start site of the 10th gene, the L gene, was not determined. However, RNA blot hybridization using a synthetic oligonucleotide designed from the genomic sequence mapped the L gene to within 54 nucleotides of the end of the penultimate 22K gene. The lack of conservation of chain length and nucleotide sequence for the respiratory syncytial viral intergenic regions, together with the complexity of the genetic map, contrasts with previous observations for other nonsegmented negative-strand viruses.

Base Sequence↗

Human and bovine respiratory syncytial virus: immunopathologic mechanisms.

Human respiratory syncytial virus (HRSV) is the major respiratory tract pathogen of infants and young children. Bovine respiratory syncytial virus (BRSV) is recognised as an important cause of respiratory tract disease in calves. Both of these viruses and their respective diseases share many similarities. Immunopathologic mechanisms have been proposed to be involved in the pathogenesis of respiratory syncytial virus (RSV) infections. This review examines the current understanding of the role of immunopathologic mechanisms in RSV infections. The role of vaccines in inducing hypersensitivity is also examined. Additionally, non-immunopathogenic mechanisms involved in RSV infections are discussed.

Animals↗

Activation of ERK2 by respiratory syncytial virus in A549 cells is linked to the production of interleukin 8.

The airway inflammation that results from respiratory syncytial virus infection is associated with a marked increase in interleukin 8 and neutrophils in the infected sites of the lung. In this study, the relationship between production of interleukin 8, infection of A549 cells by the virus, and activation of mitogen-activated protein kinases (MAPKs) was investigated. Infection of A549 cells by the virus caused an increase on the activity of extracellular signal-regulated kinase 2 (ERK2) by about 10-fold compared with the noninfected cells. The increase in the activity of ERK2 during the viral infection was an immediate event and occurred prior to the viral replication process. PD98059, which blocks the activation of MAPK/ERK kinase 1 (MEK1), inhibited the increase in the activity of ERK2 by infection of respiratory syncytial virus by about 50% at 10 microM. Pretreatment of A549 cells with PD98059 before the viral infection also inhibited the increase in the production of interleukin 8 by 50%, but had little effect on the mRNA level. The viral infection had no effect on the activities of p38 and c-jun N-terminal kinase (JNK). These observations suggest that activation of ERK2 by respiratory syncytial virus infection may be one of the mechanisms that result in the increase of the production of interleukin 8.

Enzyme Activation↗

Aerosolized ribavirin in mechanically ventilated children with respiratory syncytial virus lower respiratory tract disease: a prospective, double-blind, randomized trial.

OBJECTIVE: To study the effect of ribavirin aerosol therapy on the immediate clinical course of mechanically ventilated children with respiratory syncytial virus lower respiratory tract disease. DESIGN: Prospective, randomized, double-blind, placebo-controlled study. SETTING: Pediatric intensive care unit (ICU) of a university teaching hospital. PATIENTS: Forty-one children requiring mechanical ventilation for respiratory syncytial virus lower respiratory tract disease. INTERVENTIONS: Patients were stratified by the presence or absence of and underlying disease and then randomized to receive aerosolized ribavirin (20 mg/mL) or saline for 18 hrs/day for 5 days or until endotracheal extubation, whichever came first. MEASUREMENTS AND MAIN RESULTS: Dependent variables included the time course of the illness and the change in FIO2, ventilatory rate, PaO2/FIO2 ratio, and ventilatory-efficiency index of patients while they received aerosol therapy. Ribavirin- and placebo-treated patient groups were not significantly different in the number of ventilator days (6.4 +/- 6.9 vs. 8.2 +/- 10.1; p = .5), oxygen days (10.8 +/- 7.7 vs. 12.2 +/- 11.8; p = .9), ICU days (7.9 +/- 7.0 vs. 10.3 +/- 11.0; p = .7), or hospital days (12.9 +/- 9.7 vs. 16.2 +/- 14.0; p = .6) after the initiation of aerosol therapy. The change in FIO2, ventilatory rate, PaO2/FIO2 ratio, or ventilatory-efficiency index did not differ between the two groups. No ventilator malfunction was observed. There were six deaths caused by intractable hypoxemia in patients with underlying cardiopulmonary disease. Four of these deaths were in the placebo group and two in the ribavirin group (p = .5). CONCLUSIONS: Ribavirin aerosol therapy can be safely administered to mechanically ventilated children with severe respiratory syncytial virus lower respiratory tract disease. However, this therapy does not appear to affect immediate clinical outcome in such patients.

Aerosols↗

Pediatric critical care physicians' attitudes about guidelines for the use of ribavirin in critically ill children with respiratory syncytial virus pneumonia.

OBJECTIVE: To determine the attitude of pediatric critical care physicians concerning the use of ribavirin in children with respiratory syncytial virus lung disease in light of the revised American Academy of Pediatrics practice guidelines. DESIGN: A questionnaire was sent to 145 pediatric critical care doctors in the United States. MEASUREMENTS AND MAIN RESULTS: Seventy-seven percent of questionnaires were returned. The vast majority (91%) of the respondents think that the available literature does not support the Academy's recommendations for the administration of ribavirin to critically ill children with respiratory syncytial virus pneumonia. The largest single group of respondents (42%) does not usually prescribe ribavirin for these patients, but may be persuaded to use it by colleagues or consultants in individual cases. Twenty-six percent of all respondents stated that they do not use ribavirin at any time, even in severely ill patients with documented infection. Twenty-two percent of the respondents say that they will prescribe ribavirin, not because they believe it is efficacious, but because they believe the Academy guidelines compel them to do so as a standard of care. The respondents reported adverse effects of the drug, most notably exacerbations of bronchospasm (92%), far more often than the Academy document asserts. When solicited for general comments, the respondents were frequently concerned that critical care physicians were not involved in the development of the guidelines, the guidelines were based on a paucity of reliable data, and that the guidelines could put them at risk of malpractice litigation should they choose to not use ribavirin. CONCLUSIONS: Practice guidelines are increasingly being incorporated into patient care and quality improvement regimens, and it is imperative both that appropriate experts be included in their development, and that they be based on valid scientific data. The pediatric critical care community currently treats most of the severely ill patients with respiratory syncytial virus pneumonia. As a group, they remain unconvinced about the efficacy and safety of this drug, and many pediatricians are concerned about the ramifications of individualizing ribavirin therapy in their patients in light of the revised Academy recommendations.

Attitude of Health Personnel↗

Duration of hospitalization in previously well infants with respiratory syncytial virus infection.

To describe the typical hospital course of infection in previously well infants hospitalized with respiratory syncytial virus (RSV) infection, we reviewed the charts of 196 patients with laboratory-proved respiratory syncytial virus infection in the 1987-1988 respiratory disease season. Eighty-seven of the children had been previously well. Their mean duration of hospitalization was 3.4 days. Previously well infants younger than 6 weeks of age experienced significantly longer hospitalizations and more days of supplemental oxygen and were more likely to require intensive care than were older children. Children older than 12 weeks of age were hospitalized for a mean of 2.5 days and did not require intensive care. Oxygen saturation was measured in the emergency room for 67 of the previously well infants; in 42 oxygen saturation was at least 90% whereas in 25 saturation was less than 90% or infants were receiving supplemental oxygen at the time of measurement. Decreased initial oxygen saturation was associated with a prolonged hospitalization (5.3 vs. 3.2 days, P less than 0.01) and with more days of supplemental oxygen (4.4 vs. 1.5 days, P less than 0.01). We conclude that among previously well infants admitted to the hospital with respiratory syncytial virus infection, infants younger than 6 weeks of age are at increased risk for a prolonged and more severe hospital course than are older children.

Age Factors↗

Selected populations at increased risk from respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is the principal cause of bronchiolitis and pneumonia in infants and young children worldwide. Deficits in cellular immunity appear to promote severe RSV disease in children with malignancies, those undergoing chemotherapy and bone marrow transplant recipients. Respiratory syncytial virus infection appears to exacerbate pulmonary symptoms of cystic fibrosis. In such patients RSV disease may result in a prolonged hospital course, which is often complicated by the need for mechanical ventilation. Retrospective analyses of hospital admissions for RSV bronchiolitis among Native American and Alaskan Native children younger than 1 year of age have demonstrated rates of 62 per 1000 or higher, compared with the national average of 34 per 1000. Among these ethnic groups, specific host factors as well as environmental factors appear to contribute to these comparatively high rates of hospitalization for RSV infection. Respiratory syncytial virus has the potential to cause disease in all age groups. A 3-year observational study found that individuals who lived in a community setting, or who cared for young children on a consistent basis, experienced acute respiratory infections more commonly than those living independently or whose interaction with children was limited.

Adolescent↗

The prevalence of naturally occurring antibodies to human syncytial virus in East African populations.

A seroepidemiological study of naturally occurring antibodies to the human syncytial virus has been carried out by means of an indirect immunofluorescence test on 639 East Africans, consisting of 493 normal Ugandans, 66 Kenyan patients with nasopharyngeal carcinoma (NPC), and 80 Kenyan and Tanzanian patients with various other tumours or non-cancerous conditions. It was found that 3.4% of the normal individuals had antibodies to the virus and serial serum samples were available from 14 of these, permitting the study of antibody class in seroconversion and antibody persistence. As in an earlier survey, a significantly higher incidence of antibodies was found amongst NPC patients. Blocking and indirect immunofluorescence test with simian foamy viruses (SFV) showed some cross-reactivity between SFV 6 and the human syncytial virus, but not identity. The results are discussed in relation to the very real occurrence of natural infection by human syncytial virus in certain geographical regions.

Adolescent↗

Systemic and mucosal immunity to respiratory syncytial virus induced by recombinant Streptococcus gordonii surface-displaying a domain of viral glycoprotein G.

A conserved fragment comprising amino acid residues 130-230 of the G glycoprotein of human respiratory syncytial virus subtype A was expressed in the commensal bacterium Streptococcus gordonii. Recombinant streptococci displaying the G domain at the cell surface were used to immunize mice via both parenteral and mucosal routes. Subcutaneous immunization induced respiratory syncytial virus-specific serum immunoglobin G (IgG) capable of partially controlling virus replication in the lungs. Intranasal immunization with live bacteria stimulated the production of IgA against both the whole virus and the G domain in serum and bronchoalveolar fluid. Upon challenge, immunized animals had significantly lower virus titres in the lungs than the controls. Our results show for the first time that the G domain-expressing S. gordonii strain elicits both systemic and mucosal immunity that reduced respiratory syncytial virus replication in the lungs of mice.

Animals↗

Growth of respiratory syncytial virus in suspension cell culture.

Respiratory syncytial virus, Burnett strain, adsorbed efficiently and grew to high titers in suspension cultures of HEp-2 and MA-160 cells. Our results compared favorably with previous experience with the growth of respiratory syncytial virus in monolayer cell cultures. The use of suspension cell cultures provides a convenient and simple procedure for producing high-titering respiratory syncytial virus pools.

Adsorption↗