Respiratory syncytial virus infections in hospitalized Canadian children: regional differences in patient populations and management practices. The Pediatric Investigators Collaborative Network on Infections in Canada

Respiratory syncytial virus (RSV) is the most frequent cause of hospitalization for respiratory tract infection during the first 2 years of life. The optimal approach to management remains controversial. During the 1991 to 1992 RSV season RSV-infected children admitted to eight Canadian tertiary care pediatric centers were followed to: (1) assess the morbidity and mortality attributable to RSV infection among hospitalized patients with and without known risk factors for severe disease; and (2) assess regional variation in the management of RSV infection. Of 529 RSV-infected patients 69% (363) had one or more of the risk factors for severe disease and the remaining 31% (166) had none. There were significant differences (P < or = 0.01) between the high and low risk groups, respectively, for: intensive care unit admission (27%, 2%), assisted ventilation (14%, 0.6%), ribavirin therapy (20%, 2%), supplemental oxygen (75%, 34%), antibiotic therapy (69%, 58%) and length of hospital stay > or = 7 days (39%, 6%). Among low risk patients, centers varied significantly (P < or = 0.01) in the use of systemic corticosteroids (from 3 to 69% of patients), supplemental oxygen (13 to 74%), bronchodilators (68 to 93%) and ribavirin (0 to 10%). The observed regional variation in management of hospitalized children with RSV infection has implications for both the costs of hospital care and the conduct of multicenter trials of ribavirin and other therapies for RSV infection.     

Proteolytic cleavage of MHC class I by complement C1-esterases--an overlooked mechanism?

This paper reviews recent changes in morbidity and mortality of respiratory syncytial virus (RSV) infection in infants with congenital heart disease. Mortality since the late 1970s has declined substantially, from approximately 37% to 3%. Although the frequency of admission to intensive care units has declined from approximately 60% to 30%, the frequency for mechanical ventilatory support has not changed significantly. Because mortality dropped prior to the widespread use of ribavirin, it is difficult to ascribe the improvement to this therapy. In infants with congenital heart disease (CHD), nosocomial infection remains a significant problem, accounting for approximately 33% of the RSV cases. Some authors report significant reductions in hospital-acquired RSV by use of gloves and gowns for contacts with infectious cases. Efforts at primary prevention have encountered problems with development of an RSV vaccine. Preliminary data from studies of passive immunization using immune globulins with high RSV antibody titers suggest that this therapy may reduce the severity of RSV infection in infants with serious heart disease.     

Immune responses of infants to infection with respiratory viruses and live attenuated respiratory virus candidate vaccines

Respiratory viruses such as respiratory syncytial virus (RSV), the parainfluenza viruses (PIV), and the influenza viruses cause severe lower respiratory tract diseases in infants and children throughout the world. Experimental live attenuated vaccines for each of these viruses are being developed for intranasal administration in the first weeks or months of life. A variety of promising RSV, PIV-3, and influenza virus vaccine strains have been developed by classical biological methods, evaluated extensively in preclinical and clinical studies, and shown to be attenuated and genetically stable. The ongoing clinical evaluation of these vaccine candidates, coupled with recent major advances in the ability to develop genetically engineered viruses with specified mutations, may allow the rapid development of respiratory virus strains that possess ideal levels of replicative capacity and genetic stability in vivo. A major remaining obstacle to successful immunization of infants against respiratory virus associated disease may be the relatively poor immune response of very young infants to primary virus infection. This paper reviews the immune correlates of protection against disease caused by these viruses, immune responses of infants to naturally-acquired infection, and immune responses of infants to experimental infection with candidate vaccine viruses.     

Respiratory syncytial virus infection in childhood

Respiratory syncytial virus is the most frequent cause of respiratory tract infections in infants and is responsible for annual winter epidemics of acute bronchiolitis. Over the last decades medical therapy has remained unchanged and controversial, despite intensive research. Inhaled bronchodilators are often not effective and should be discontinued if no beneficial response can be documented. Steroids and ribavirin are not indicated in previously healthy infants with acute RSV bronchiolitis. There is some evidence, however, that certain risk groups may benefit from their use. With good supportive care the mortality from RSV infection is now low. Postinfectious alterations in lung function are usually transient and reversible. High-risk infants can be protected from severe RSV infections by monthly infusions of RSV immune globulins. This treatment modality has, however, not gained wide acceptance because of the benign nature of the disease and the high costs and side effects of regular immune globulin infusions. An international consensus statement on the treatment of RSV bronchiolitis may help to reduce the wide differences in clinical practice.     

Effect of rapid viral diagnosis on the management of children hospitalized with lower respiratory tract infection

BACKGROUND: Although rapid viral tests are commonly used in children with lower respiratory tract infection, their effect on patient management has not been studied. OBJECTIVES: To examine how physicians utilize an enzyme immunoassay for respiratory syncytial virus (RSV EIA) and a centrifugation-enhanced cellular immunofluorescence assay for multiple viral pathogens [viral respiratory panel (VRP)] in children hospitalized with respiratory illness; to determine the effect of testing on length of stay, antibiotic use and costs; and to determine physician attitudes toward RSV testing. DESIGN AND SETTING: Prospective study and survey at a large children's hospital. PATIENTS: Previously healthy children < 24 months of age consecutively admitted between January 1 and February 11, 1995, with symptoms of lower respiratory tract infection. RESULTS: Of 200 patients 160 were tested by RSV EIA; 92 were positive and 68 were negative. Tested children were younger, more tachypneic and more likely to require oxygen than those not tested. Overall the length of stay was similar in RSV-positive and -negative patients. Although equal proportions of each group were given antibiotic therapy, RSV-positive children received antibiotic therapy for fewer days than RSV-negative children (median 2 vs. 3 days; P = 0.0387). However, a crude cost analysis did not support a strategy of testing all bronchiolitis patients for RSV. Sixty-five of the 68 RSV-negative children were tested for RSV and other pathogens by VRP. In 55 cases the results were not available until after patient discharge and could not have influenced their management. One hundred three physicians caring for children in the study were surveyed. Of 75 respondents almost all thought that RSV EIA results influenced their management of patients and were important to parents. CONCLUSIONS: Most children hospitalized with symptoms of lower respiratory tract infection were tested for viral pathogens. The VRP provided little clinically useful information. In contrast RSV EIA results may have been used by clinicians to make antibiotic decisions. Physicians felt that rapid testing for RSV was important.     

Antigenic and nucleic acid analysis of nosocomial isolates of respiratory syncytial virus

Monoclonal antibodies and ribonuclease protection were used to analyze antigenic and genomic diversity among 42 isolates of group A respiratory syncytial virus (RSV) from studies of nosocomial RSV carried out at the University of Rochester during the 1974-1975 and 1975-1976 RSV seasons. Three distinct subgroups or lineages and a total of 12 viral variants were present. Against this background of diversity, an outbreak was recognized that included 13 indistinguishable isolates occurring during a 2-week period. This outbreak accounted for 6 of the 8 infants with nosocomial infection. In contrast to the limited diversity of the nosocomial isolates, isolates from the 10 infants with community-acquired infection included 8 variants. Like those from community outbreaks of RSV, isolates of RSV from hospitalized patients are virologically heterogeneous. However, discrete outbreaks associated with transmission of a single strain can occur.     

Respiratory syncytial virus bronchiolitis

Respiratory syncytial virus (RSV) bronchiolitis is associated with the clinical signs and symptoms of small airway obstruction. A major public health problem throughout the world, this condition is responsible for significant morbidity and mortality. Management is primarily preventive, through strict hand washing, avoidance of exposure during the respiratory illness season and intravenously administered prophylactic anti-RSV Immune globulin, especially in selected small infants with underlying cardiopulmonary disease. Supportive measures, including fluid hydration, good nutrition, aerosolized bronchodilators and steroids, may be helpful. Ribavirin may be useful in severely ill children or those with underlying cardiopulmonary disease. A significant number of patients have recurrent episodes of bronchiolitis and wheezing, and may develop asthma later in life. Avoidance of exposure to tobacco smoke, cold air and air pollutants is also beneficial to long-term recovery from RSV bronchiolitis. A number of vaccines to prevent this infection are currently being studied.     

Cells and mediators from pharyngeal secretions in infants with acute wheezing episodes

An acute wheezing episode is the most common feature of severe lower respiratory tract infection during infancy. Respiratory syncytial virus (RSV) is the major causative agent. In order to study inflammation during acute wheezing episodes in infants, we wanted to assess the feasibility and contribution of induction of pharyngeal secretions. We therefore compared inflammatory markers in the pharyngeal secretions of 27 infants suffering from acute wheezing episodes with an RSV infection (RSV+) and 18 infants suffering with acute wheezing episodes without RSV infection (RSV-). Pharyngeal secretions were recovered by physiotherapy using isotonic saline. The safety of the procedure was carefully checked. Pharyngeal secretions were homogenized with dithiothreitol. Total cells and eosinophils were counted and levels of eosinophil cationic protein (ECP) and histamine were measured. Induction of pharyngeal secretion was always well tolerated. Eosinophils were present in five RSV+ and seven RSV- patients. ECP levels were not significantly different between the groups. Histamine levels after protein adjustment were significantly increased in RSV+ patients (p<0.01) in comparison to RSV- patients. In this study, we have shown, that pharyngeal secretion can be safely recovered from infants suffering from acute wheezing episodes, and that it can be analysed for enumeration of inflammatory cells and measurement of inflammatory mediators.     

Diabetes mellitus and lipid metabolism (author''s transl)

Fifteen infants with pneumonia caused by respiratory syncytial virus (RSV) and 19 infants with bronchiolitis caused by RSV were studied for the influence of homologous, circulating neutralizing antibody on the severity of their illness. All infants were under nine months of age. Although maternal neutralizing antibody did not prevent infection with RSV and illness, the severity of pneumonia caused by RSV was inversely related to the level of neutralizing antibody. The severity of bronchiolitis caused by RSV was unrelated to maternal antibody levels. Chest roentgenograms showed pneumonia to be slightly more severe than bronchiolitis. Neither the severity of illness nor the presence of maternal neutralizing antibody was related to the development of complement-fixing antibody.     

Epidemiology of respiratory syncytial virus infection requiring hospitalization in East Denmark

BACKGROUND: Prophylaxis against infection caused by respiratory syncytial virus (RSV) with high titered RSV immunoglobulin or humanized antibody may soon be available in Europe. OBJECTIVE: To study the epidemiology of RSV infections requiring hospitalization in infants <6 months in East Denmark to provide a rational basis for decisions concerning prophylaxis against RSV. METHOD: Populat ion-based retrospective review of case records of infants <6 months admitted to pediatric departments with RSV infection in East Denmark from November 1, 1995, to April 30, 1996. RESULTS: Data were obtained from 459 infants. Seventy-three had predisposing conditions: prematurity, 49; pulmonary disease, 2; congenital heart disease, 7; neurologic disease, 6; others, 9. One preterm infant had bronchopulmonary dysplasia. The incidence of RSV infection requiring hospitalization in East Denmark among infants <6 months was estimated to be 34/1000/season. It was 32/1000/season among term infants and 66/ 1000/season among preterm infants (P<0.001). Infants with predisposing conditions and/or nosocomial infection (n = 24) had significantly more severe courses than otherwise healthy infants (P<0.01). One-hundred thirty infants received respiratory support by nasal continuous positive airway pressure, but only six required mechanical ventilation. No infants died. CONCLUSION: The course of RSV disease in East Denmark was milder than reported elsewhere, possibly as a result of the low prevalence of bronchopulmonary dysplasia in Denmark. However, RSV constitutes a considerable burden to the Danish pediatric health care system, and therefore prophylaxis against RSV is desirable.     

Primary plasmalemmal carnitine transporter defect manifested with dicarboxylic aciduria and impaired fatty acid oxidation

Respiratory syncytial virus (RSV), a common cause of both upper and lower respiratory tract infection (LRTI) in infants and children, is rarely described as an infective agent in adults. It has been reported in bone marrow transplant (BMT) recipients and patients with malignancy immunosuppressed by chemotherapy. Such reports are often associated with a high mortality. We report an outbreak of RSV infection which occurred predominantly in BMT recipients in which early investigation and institution of ribavirin therapy resulted in all patients making a full recovery.     

Respiratory syncytial virus (RSV) disease and prospects for its control

Respiratory syncytial virus (RSV) is a major virus pathogen of infants and young children, an important cause of disease in adults and is responsible for a significant amount of excess morbidity and mortality in the elderly. It also can be devastating in immunosuppressed populations. Vaccines are being developed, but none are currently licensed. Moreover, even if one or more are approved, they may not be suitable for some populations vulnerable to RSV (e.g. very young infants and the immunosuppressed). Ribavirin and immunoglobulin preparations with high titers of RSV-specific neutralizing antibodies are currently approved for use to treat and prevent RSV infection. However, neither of these is cost-effective or simple to administer. New agents are needed to reduce the impact of RSV. This review is concerned with the means currently available for controlling RSV, the search for new agents effective against this virus, and future prospects for preventing and treating RSV infections.     

Potent inhibition of respiratory syncytial virus replication using a 2-5A-antisense chimera targeted to signals within the virus genomic RNA

The 2-5A system is a recognized mechanistic component of the antiviral action of interferon. Interferon-induced 2-5A synthetase generates 2-5A, which, in turn, activates the latent constitutive RNase L that degrades viral RNA. Chemical conjugation of 2-5A to an antisense oligonucleotide can target the 2-5A-dependent RNase L to the antisense-specified RNA and effect its selective destruction. Such a 2-5A-antisense chimera (NIH351) has been developed that targets a consensus sequence within the respiratory syncytial virus (RSV) genomic RNA. NIH351 was 50- to 90-fold more potent against RSV strain A2 than was ribavirin, the presently approved drug for clinical management of RSV infection. It was similarly active against a variety of RSV strains of both A and B subgroups and possessed a cell culture selectivity index comparable to ribavirin. In addition, the anti-RSV activity of NIH351 was shown to be virus-specific and a result of a true antisense effect, because a scrambled nucleotide sequence in the antisense domain of NIH351 caused a significant decrease in antiviral activity. The 2-5A system's RNase L was implicated in the mechanism of action of NIH351 because a congener with a disabled 2-5A moiety was of greatly reduced anti-RSV effectiveness. These findings represent an innovative approach to the control of RSV replication.     

Successful treatment of severe dysrhythmias in infants with respiratory syncytial virus infections: two cases and a literature review

OBJECTIVES: To describe severe myocardial manifestations in two infants with respiratory syncytial virus infection and to review published literature reporting cardiac involvement in patients with respiratory syncytial virus disease. DESIGN: Case report and literature review. SETTING: Tertiary care pediatric intensive care unit (ICU). PATIENTS: Two infants admitted to the pediatric ICU for dysrhythmias and severe myocardial dysfunction and infected with respiratory syncytial virus. INTERVENTIONS: Conventional cardiovascular, antidysrhythmic, and respiratory support, as well as extracorporeal membrane oxygenation and high-frequency oscillatory ventilation. MEASUREMENTS AND MAIN RESULTS: Both patients had respiratory syncytial virus infections and clinical evidence of severe myocarditis, with dysrhythmias, cardiomegaly, and cardiogenic shock. Both infants survived their hospitalizations. To our knowledge, these two patients are the first reported cases of myocarditis in infants with respiratory syncytial virus infection. CONCLUSIONS: Severe myocardial dysfunction and dysrhythmias may accompany respiratory syncytial virus infection in some infants and may be reversible with aggressive supportive therapy.     

Interpretive algorithms for the symptom-limited exercise test: assessing dyspnea in Persian Gulf war veterans

The mechanisms by which respiratory syncytial virus (RSV) infection induces bronchiolitis and airway disease are unclear. The presence of large numbers of polymorphonuclear leukocytes (PMN) in the airways of infants with RSV infection suggests a potential role of PMN in airway injury associated with RSV infection. To investigate the potential role of neutrophils in RSV bronchiolitis, human alveolar type II cells (A549 cells) were infected with different doses of RSV for 6-48 h. A 51Cr-releasing assay was used to measure PMN-induced damage and image analysis was used to determine PMN adhesion and detachment of epithelial cells. The results showed that RSV infection of epithelial cells enhanced PMN adherence in a dose- and time-dependent pattern, RSV infection alone could damage and detach epithelial cells to a limited extent and PMN significantly augmented RSV infection-induced damage and detachment of epithelial cells. These data suggest that respiratory syncytial virus infection of respiratory epithelial cells enhances neutrophil adhesion to the epithelium and that activated neutrophils augment the damage and detachment of epithelium infected with the virus. Polymorphonuclear leukocytes may contribute to the pathogenesis of respiratory syncytial virus airway disease by inducing epithelial damage and cell loss.     

Workshop on chronic pain, pain control, and patient outcomes in rheumatoid arthritis and osteoarthritis

OBJECTIVE: Coincident with a change in the physician staff in our pediatric intensive care unit (PICU), the frequency and duration of invasive monitoring were decreased. We examined the impact of this change on outcomes, complications, and hospital charges in infants admitted to the PICU with respiratory syncytial virus (RSV) infection. STUDY DESIGN: We reviewed medical records of all children less than 1 year of age who were admitted to the PICU from January 1989 to July 1993 with confirmed RSV infection. Patient characteristics, therapeutic interventions, outcomes, and hospital charges were extracted and compared. RESULTS: Seventy-eight patients were identified, 38 admitted from January 1989 through July 1991 (group 1) and 40 from July 1991 through July 1993 (group 2). The groups were well matched in age, preexisting disease, and cardiorespiratory status on admission. Group 1 had significantly greater use of invasive monitoring, pharmacologic paralysis, inotropes, blood products, antibiotics, and parenteral nutrition. Outcomes were not different, but group 1 patients had significantly longer stays, more complications, and higher hospital charges. CONCLUSIONS: Routine use of invasive monitoring of PICU patients with RSV disease was associated with increased laboratory testing, overtreatment, and significant increases in costs and morbidity without improvement in outcome.     

High resolution EEG

Rhinovirus is an important cause of respiratory infection among all age groups, but it is primarily thought of as being responsible for upper respiratory tract infection. Rhinovirus was isolated from the respiratory tract of 48 pediatric patients who were hospitalized (40) or seen in a pediatric emergency room (8) during the period of July, 1985, through December, 1988. Twenty-eight (58%) of the patients presented during the spring and early summer. Forty-one (86%) of the 48 patients were less than 12 months of age. All except four of the patients had viral cultures performed because of respiratory symptoms. Bronchiolitis was the single most frequent clinical diagnosis and was noted in equal proportion among children less than 3 months and 3 to 12 months of age. Nine patients were assigned a diagnosis of suspected sepsis. Rhinovirus infection was a complication of underlying illness for 17 (44%) of the 40 hospitalized patients, and those patients tended to be older than the otherwise healthy hospitalized infants with rhinovirus. Twenty-six patients (54%) were treated with antibacterial agents, although only one patient was documented to have a concomitant bacterial infection (Chlamydia trachomatis). Overall rhinovirus isolation during the study period represented 0.7% of all specimens submitted for viral isolation compared with 8.2% for respiratory syncytial virus. Rhinovirus infection leads to hospitalization less frequently than does respiratory syncytial virus infection, but the severity of illness and clinical presentation in young infants are similar.     

Respiratory syncytial virus infection in tropical and developing countries

Little is known about the epidemiology of respiratory syncytial virus (RSV) infection in tropical and developing countries; the data currently available have been reviewed. In most studies, RSV was found to be the predominant viral cause of acute lower respiratory tract infections (ALRI) in childhood, being responsible for 27-96% of hospitalised cases (mean 65%) in which a virus was found. RSV infection is seasonal in most countries; outbreaks occur most frequently in the cold season in areas with temperate and Mediterranean climates and in the wet season in tropical countries with seasonal rainfall. The situation on islands and in areas of the inner tropics with perennial high rainfall is less clear-cut. The age group mainly affected by RSV in developing countries is children under 6 months of age (mean 39% of hospital patients with RSV). RSV-ALRI is slightly more common in boys than in girls. Very little information is available about the mortality of children infected with RSV, the frequency of bacterial co-infection, or the incidence of further wheezing after RSV. Further studies on RSV should address these questions in more detail. RSV is an important pathogen ill young children in tropical and developing countries and a frequent cause of hospital admission. Prevention of RSV infection by vaccination would have a significant impact on the incidence of ALRI in children in developing countries.     

Ultraviolet-B irradiation of leukapheresis. Products: dose-response relationship with the mixed lymphocyte reaction

Our aim was to study the influence of infection with the respiratory syncytial virus (RSV) in non-hospitalized infants on sensitization to aeroallergens and the early manifestation of atopy. Six hundred and nine infants from the prospective German Multicenter Cohort Study on Atopy were included, 38% of whom had an elevated atopic risk. RSV IgG and IgM antibodies were tested by ELISA with gradient purified RSV antigen. Specific IgE against mites, cat dandruff, birch and grass pollens and relevant nutritional antigens were tested with CAP-RAST-FEIA (Pharmacia, Sweden). Of the cord sera 99% were positive for RSV-IgG, 44.7% at one year and 64.2% (n = 265) at two years of age. The positivity rate after 12 months varied with the season of birth, the number of siblings and the degree of exposure to tobacco smoke; and correlated closely with attacks of wheezing during infancy. Twenty (2.8%) children were found to be sensitized against at least one aeroallergen at one year, and 28 (10.5%) at two years. By the first birthday, mite sensitization (n = 3) could only be seen in the RSV-infected children; grass pollen sensitization (n = 9) was associated with RSV seropositivity (logistic regression model including the confounders mentioned above: with RSV IgG < p = 0.048 > and IgM < p = 0.0006 >), as was birch sensitization (n = 5) with RSV IgM (p = 0.009). No such differences could be detected at two years. No correlation of RSV seropositivity to any allergic manifestation could be found. We conclude, that it is only in the first year of life, that RSV infection plays a significant role in promoting sensitization against aeroallergens, which do not at this time produce allergic symptoms.     

Detection of Bordetella pertussis and respiratory synctial virus in air samples from hospital rooms

OBJECTIVE: To evaluate the distribution of Bordetella pertussis and respiratory syncytial virus (RSV) in the hospital setting. DESIGN: Air samples were collected using filters in the hospital rooms of 12 children with pertussis and 27 children with RSV infection. Material eluted from these filters was subjected to RSV- and B pertussis-specific polymerase chain reaction (PCR) amplification. SETTING: Patients were hospitalized in private rooms in one of two referral centers, a university teaching hospital and a university-affiliated private children's hospital. PATIENTS: 12 children (16 days-3 years of age) with documented pertussis infection and 27 patients (10 days-7 years of age) with documented RSV infection. RESULTS: B pertussis DNA was detected in 7 (58%) of 12 rooms housing pertussis patients and in 16 (25%) of 63 total samples. B pertussis DNA was detected as far as 4 m away from the patient's bedside. The detection of B pertussis DNA in air samples did not change over the short duration of hospitalization. RSV RNA was detected in 17 (63%) of 27 rooms housing RSV-infected patients and in 32 (22%) of 143 total samples. RSV RNA was detected at distances as far as 7 m from the patient's bedside and for up to 7 days of hospitalization. CONCLUSIONS: Using PCR-based detection methods, B pertussis DNA and RSV RNA both can be detected in air samples from the hospital rooms of infected patients. Both can be detected at large distances from a patient's bedside in a minority of cases. These detection methods are suitable for further studies of control measures used to contain nosocomial infections caused by both B pertussis and RSV.