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PubMed2003

Recent isolates of bovine respiratory syncytial virus from Britain are more closely related to isolates from USA than to earlier British and current mainland European isolates.

Eight isolates of Bovine respiratory syncytial virus (BRSV) were made from calves with severe respiratory disease on seven farms in one region of Britain. Genetic analysis of the viruses showed that seven, which were isolated between 1997 and 1999 were almost identical and were distinguishable from an earlier 1991 isolate. When compared with the available sequences of BRSVs from other countries, the recent British isolates were more closely related to US isolates than to earlier British and current mainland European isolates.

Amino Acid Sequence↗
PubMed2002

Prevention of respiratory syncytial virus infections in high-risk infants by monoclonal antibody (palivizumab).

Respiratory syncytial virus (RSV) is a major viral pathogen which causes serious respiratory illness in infants and children worldwide. Palivizumab (Synagis) is an anti-RSV monoclonal antibody administered intramuscularly for the prevention of severe RSV respiratory disease in high-risk infants and young children. The IMpact-RSV trial, the pivotal multicenter, randomized, placebo-controlled trial performed in the USA, Canada and the United Kingdom demonstrated an overall 55% reduction in hospitalization rate due to RSV infection in preterm infants (< or = 35 weeks gestation) with and without chronic lung disease (CLD). Subgroup analysis in premature infants without CLD revealed an even greater reduction in RSV hospitalization rates (78%). Adverse events were infrequent and did not differ between placebo and palivizumab groups. Injection site reactions were infrequent and mild; no differences were observed between palivizumab and placebo subjects. Palivizumab does not interfere with administration of other pediatric vaccines. Comprehensive parent education programs regarding prevention of infection, avoidance of risk factors for infection, careful adherence to infection control policies, and recognition of early symptoms of RSV infection remain important components of RSV prevention strategies. In light of the lack of effective vaccines for this serious health risk, palivizumab offers the only option for prophylaxis against RSV disease in high-risk infants.

Animals↗
PubMed2002

Current respiratory syncytial virus prevention strategies in high-risk infants.

Respiratory syncytial virus (RSV) was initially isolated in 1956. Since then it has become recognized as a major pathogen worldwide. It is a ubiquitous pathogen that produces seasonal epidemics. Primary infection occurs in children before 2 years of age. In older children and adults, RSV usually manifests itself as an upper respiratory tract infection. In immunecompromised patients, those with underlying cardiopulmonary disorders, premature infants, and other vulnerable individuals, RSV infection can produce severe bronchiolitis or pneumonia. In recent years we have observed exciting new information about the prevention of serious RSV infection in high-risk infants including infection control practices, active immunity and passive immunity. Two immunoprophylaxis products (RSV i.v. immune globulin and palivzumab) have been developed for clinical use in the prevention of serious RSV infection. Many other agents including vaccines, super monoclonal antibodies, and antivirals are under development. Although clinicians now have the ability to provide their most vulnerable patients with meaningful prevention strategies, much more needs to be done before we can regard RSV as a preventable disease.

Antibodies, Monoclonal↗
PubMed2004

Role of serum neutralizing antibody in reinfection of respiratory syncytial virus.

BACKGROUND: To clarify the role of serum antibody in respiratory syncytial virus (RSV) reinfection, the authors conducted a follow-up study of patients with primary RSV infection. METHODS: From 1994 to 1995, 256 patients were a diagnosed with primary RSV infection based on the antigen detection in nasopharyngeal secretions using enzyme linked immunoassay method. One hundred and sixty-five patients were followed-up for 1 year, and 87 of the 165 patients showed respiratory symptoms in winter. When a patient had a symptom such as cough, wheezing, rhinorrhea or fever, the nasopharyngial secretion was examined for the presence of RSV. Forty-one patients (group 1) were diagnosed with reinfection with RSV and the other 46 patients (group 2) were not diagnosed with reinfection. The authors compared clinical features between primary infection and reinfection of group 1 and serum neutralization test (NT) antibody titers to RSV between group 1 and 2. RESULTS: The mean age was 6.0 +/- 3.6 months at RSV primary infection and 14.6 +/- 8.2 months at RSV reinfection. Hospitalization, oxygen supplementation, and use of respirator were required by 71%, 39%, 2%, respectively, in primary infection, and by 22%, 0%, 0%, respectively, in reinfection. All children in group 1 had titers of 1 : 16 or lower, while 39.1% of children in group 2 had titers of 1 : 16 or lower (P < 0.05). No patient with the titers of 1 : 32 or higher had symptomatic reinfection. Serum NT antibodies to RSV of outpatients were higher than those of inpatients at reinfection. CONCLUSIONS: The severity of illness in RSV reinfection is generally milder than that in primary infection. Our findings suggest that NT antibodies play an important role in reducing the severity of illness as well as in protection from RSV reinfection.

Adolescent↗
PubMed2003

Binding and entry of respiratory syncytial virus into host cells and initiation of the innate immune response.

Respiratory syncytial virus (RSV) is the most common cause of severe lower respiratory tract infection in infants and the elderly. There is currently no effective antiviral treatment for the infection, but advances in our understanding of RSV uptake, especially the role of surfactant proteins, the attachment protein G and the fusion protein F, as well as the post-binding events, have revealed potential targets for new therapies and vaccine development. RSV infection triggers an intense inflammatory response, mediated initially by the infected airway epithelial cells and antigen-presenting cells. Humoral and cell-mediated immune responses are important in controlling the extent of infection and promoting viral clearance. The initial innate immune response may play a critical role by influencing the subsequent adaptive response generated. This review summarizes our current understanding of RSV binding and uptake in mammalian cells and how these initial interactions influence the subsequent innate immune response generated.

Humans↗
PubMed2003

Otitis and respiratory distress episodes following a respiratory syncytial virus infection.

OBJECTIVE: To document, over two consecutive respiratory syncytial virus (RSV) seasons, the occurrence of acute otitis media (AOM) and recurrence of respiratory distress in children < 2 years of age hospitalized for respiratory distress. METHODS: Patients were examined during hospitalization and at 6 weeks and 6 months after discharge. RSV testing was performed on all patients, and hospitalized patients were evaluated daily for the occurrence of AOM. RESULTS: In total, 347 children were enrolled; 54.8% were RSV positive, and 45.2% were RSV negative. Children were most frequently diagnosed as having bronchiolitis (71.9%) or asthmatic bronchitis (17.9%); other diagnoses included pneumonia, laryngitis, and rhinitis. During hospitalization, AOM was diagnosed in 16.8% of RSV-positive versus 8.3% of RSV-negative children (P < 0.05). Six weeks after discharge, AOM was reported in 10.4% of RSV-positive as compared with 5.8% of RSV-negative patients. Six months later, AOM was reported in 2.9% of the RSV-positive and 7.6% of the RSV-negative patients. A second episode of acute respiratory distress, which either required (9) or did not require (35) hospitalization, occurred in 18.4% of the total population, with similar proportions of RSV-positive and RSV-negative children (17% versus 18.6%). CONCLUSION: We conclude that RSV appears to be an important contributing factor for the occurrence of AOM in young children hospitalized with respiratory distress. The occurrence of a second episode of acute respiratory distress did not appear to correlate with the previous RSV infection, but longer-term follow-up is required.

Child, Preschool↗
PubMedDate not supplied

Bovine respiratory syncytial virus: first serological evidence in Uruguay.

Bovine respiratory syncytial virus (BRSV) is a major cause of respiratory disease in calves resulting in a substantial economic loss for the cattle industry worldwide. In order to determine the presence of BRSV in Uruguay, an immunoenzymatic test was set up, using a recombinant BRSV nucleocapsid (N) protein as the antigen. The N protein was produced in Sf9 insect cells by a recombinant baculovirus expressing the N protein. Serum samples collected from one hundred cattle from four different geographic regions of Uruguay were analyzed. Antibodies against the N protein of BRSV were detected in 95% of the serum samples analyzed. These results show for the first time the presence of BRSV antibodies and suggest a widespread BRSV infection in the cattle population of Uruguay.

Animals↗
PubMed2002

Impact of respiratory syncytial virus infection as a cause of lower respiratory tract infection in children younger than 3 years of age in Japan.

BACKGROUND: Respiratory syncytial virus (RSV) is the most important viral pathogen for lower respiratory tract infection (LRI) in infants and children. An RSV-specific monoclonal antibody has been developed to provide prophylaxis against RSV associated LRI (RSV-LRI). The objective of this study was to determine the impact of RSV as a cause of LRI in children younger than 3 years of age to provide data to aide in the implementation of forthcoming prophylaxis against RSV. METHODS: We analyzed the viral etiology of LRI in hospitalized Japanese children younger than 3 years of age admitted to Shizuoka Red Cross Hospital from July, 1997 to June, 2000. RESULTS: A total of 535 patients younger than 3 years of age were hospitalized with LRI at Shizuoka Red Cross Hospital from July 1, 1997 to June 30, 2000. Of these, a positive diagnosis of RSV infection was made in 168 patients (31.4%). Most of the patients with RSV infection had been well and had had no underlying disease that was defined as risk factor of RSV infection (94.0%). The peak incidence of LRI was observed in the winter each year and the number of LRI was strongly associated with the epidemic of RSV (r=0.700, P<0.0001). The number of patients with LRI younger than 6 months of age was 116 (21.7%). Of these 116 patients younger than 6 months with LRI, 55 patients (47.4%) were confirmed to have RSV infection. The proportions of RSV infection to total LRI was greatest in early infants younger than 6 months (P<0.0001). The number of patients with which RSV infection was detected in LRI patients younger than 3 years was highest during the first five months of life and there was a dramatic decrease in incidence of RSV infection with increasing age thereafter. CONCLUSIONS: The incidence of LRI hospitalization is highly affected by RSV infection epidemic. The proportion of RSV infections among early infants younger than 6 months is greater than that of older patients. The prophylaxis against RSV will be needed to be toward early infants.

Age Factors↗
PubMed2002

Respiratory syncytial virus--viral biology and the host response.

Respiratory syncytial virus (RSV) is the most important cause of respiratory tract infection in infants. We have an incomplete understanding of the reasons why some infants are more severely affected by RSV than others. There is no effective antiviral treatment for the infection. Advances in our understanding of the biology of RSV, particularly in relation to the attachment protein G and the fusion protein F, have revealed potential targets for new antiviral therapies and vaccine development. In response to RSV infection an intense inflammatory response is triggered, mediated initially by the infected airway epithelial cells. Cell mediated responses are important in controlling the extent of infection and in viral clearance. Humoral responses are important in protection. There is early evidence that genetic variation of the host response can influence the outcome of RSV-induced bronchiolitis.

Epithelial Cells↗
PubMed2000

Long-term consequences of respiratory syncytial virus (RSV) bronchiolitis.

Despite differences in study design, follow-up studies consistently show that approximately half of the infants with respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) go on to have recurrent wheezing episodes during childhood. Respiratory symptoms are associated with abnormal lung function, including bronchial hyper-responsiveness. Wheezing symptoms following RSV LRTI gradually decrease, and it appears that during school age airway morbidity is no longer related to RSV LRTI during infancy. Mechanisms underlying the association between RSV LRTI and long-term airway morbidity are poorly understood. On the one hand, abnormal airway function that is congenitally present or acquired before RSV LRTI occurs could be the cause of both RSV LRTI and subsequent recurrent wheezing. On the other hand, it is possible that RSV LRTI causes changes in the lower airways or the immune system that result in long-term airway morbidity. Animal models suggest that RSV infection can promote the development of allergic sensitization, but most studies in humans do not indicate a role for atopy in the development of recurrent wheezing following RSV LRTI.

Animals↗
PubMed2002

Respiratory syncytial virus infections in children.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory disease in young children in both developing and developed countries. By age 2, nearly all children have been infected by RSV.The clinical manifestations range from mild upper respiratory symptoms to bronchiolitis and pneumonia. First infections are nearly always symptomatic and frequently cause lower respiratory tract disease, whereas subsequent infections are generally milder. Although children with underlying conditions such as prematurity, chronic lung disease, congenital heart disease, and immuno-suppression are at high risk for severe disease, many children without underlying conditions require hospitalization. Treatment is supportive. Immunoprophylaxis with palivizumab or RSV immune globulin may benefit children born prematurely, especially those with bronchopulmonary dysplasia. To date, the development of an effective vaccine has been unsuccessful.

Antibodies, Monoclonal↗
PubMedDate not supplied

Variables explaining the duration of hospitalization in children under two years of age admitted with acute airway infections: does respiratory syncytial virus have a direct impact?

BACKGROUND: Duration of hospitalization is influenced by many factors. It is an important parameter for quality of care. So far it is unknown, whether respiratory syncytial virus (RSV) etiology itself contributes to the time in hospital. METHOD: Children under 2 years of age admitted with a lower respiratory tract infection in 3 hospitals (1 tertiary and 2 secondary centers) in northern Germany were included in an unmatched, hospital-based case-control study. Cases were children tested positive for RSV by multiplex RT-PCR. One control group consisted of children tested negative for RSV in the multiplex-RT-PCR and a second control group consisted of patients in whom no PCR was done. Since only 4 to 5% in the latter group and thus 2% of the study population were misclassified, this group could be involved in the analysis. RESULTS: The median days of hospitalization was 7 days; 9 days in the RSV-positive group, 8 and 6 days in the RSV-negative and non-PCR group, respectively. The time in hospital was diminishing over the 4 year observation period. Duration of hospitalization was best predicted by--young age, presence of an underlying condition, disease entity--being pneumonia or bronchiolitis, prematurity, earlier epidemiologic year and intercostal retractions. Not predictive were: RSV-etiology, center, duration of illness, wheezing, C-reactive protein level and consolidation on the chest x-ray (all on admission). CONCLUSIONS: RSV-etiology is influencing the duration of hospitalization only indirectly via its predilection for the very young age and certain underlying conditions--not by RSV itself. In spite of considerable variation of patient populations between secondary and tertiary care facilities and locally different care practices, the treatment center pre se did not influence the duration of hospitalization significantly. Further rationalization of treatment is, however, possible.

Acute Disease↗
PubMedDate not supplied

[Prophylaxis of respiratory syncytial virus (RSV) in preterm infants with/without bronchopulmonary dysplasia: hyperimmune globulin (RSV-IGIV) and palivizumab (MEDI-493)].

Respiratory syncytial virus (RSV) causes seasonal epidemics between December and March (April) and remains the main agent that causes severe lower respiratory tract infections in young infants. Children with bronchopulmonary dysplasia up to 24 months of age and preterm infants with a gestational age of 32 weeks and below, who are less than six months of age, are at highest risk for severe RSV infection. RSV-IGIV has been demonstrated to reduce significantly RSV associated hospitalizations, RSV associated hospital days and the incidence of severe RSV lower respiratory tract infections. Monthly infusions during RSV season were safe and well tolerated. Adverse events related to the hyperimmune globulin infusion were generally mild (< 3%) including fluid overload, decreased oxygen saturation and fever. Palivizumab, an intramuscularly administered humanized monoclonal antibody (RSV-glycoprotein-F antibody), will be preferable for the future because of ease of administration and comparable reduction in the risk of hospitalization. RSV-IGIV and palivizumab are both cost expansive and prophylaxis should be limited to high-risk infants.

Antibodies, Monoclonal↗
PubMed2005

Respiratory syncytial virus infection in elderly and high-risk adults.

BACKGROUND: Respiratory syncytial virus (RSV) is an increasingly recognized cause of illness in adults. Data on the epidemiology and clinical effects in community-dwelling elderly persons and high-risk adults can help in assessing the need for vaccine development. METHODS: During four consecutive winters, we evaluated all respiratory illnesses in prospective cohorts of healthy elderly patients (> or =65 years of age) and high-risk adults (those with chronic heart or lung disease) and in patients hospitalized with acute cardiopulmonary conditions. RSV infection and influenza A were diagnosed on the basis of culture, reverse-transcriptase polymerase chain reaction, and serologic studies. RESULTS: A total of 608 healthy elderly patients and 540 high-risk adults were enrolled in prospective surveillance, and 1388 hospitalized patients were enrolled. A total of 2514 illnesses were evaluated. RSV infection was identified in 102 patients in the prospective cohorts and 142 hospitalized patients, and influenza A was diagnosed in 44 patients in the prospective cohorts and 154 hospitalized patients. RSV infection developed annually in 3 to 7 percent of healthy elderly patients and in 4 to 10 percent of high-risk adults. Among healthy elderly patients, RSV infection generated fewer office visits than influenza; however, the use of health care services by high-risk adults was similar in the two groups. In the hospitalized cohort, RSV infection and influenza A resulted in similar lengths of stay, rates of use of intensive care (15 percent and 12 percent, respectively), and mortality (8 percent and 7 percent, respectively). On the basis of the diagnostic codes of the International Classification of Diseases, 9th Revision, Clinical Modification at discharge, RSV infection accounted for 10.6 percent of hospitalizations for pneumonia, 11.4 percent for chronic obstructive pulmonary disease, 5.4 percent for congestive heart failure, and 7.2 percent for asthma. CONCLUSIONS: RSV infection is an important illness in elderly and high-risk adults, with a disease burden similar to that of nonpandemic influenza A in a population in which the prevalence of vaccination for influenza is high. An effective RSV vaccine may offer benefits for these adults.

Adult↗
PubMed2001

Immunostimulatory DNA sequences inhibit respiratory syncytial viral load, airway inflammation, and mucus secretion.

BACKGROUND: Immunostimulatory DNA sequences (ISS) activate the innate immune system to generate antiviral cytokines, such as IFN-gamma. OBJECTIVE: This study investigated whether ISS could reduce viral load, mucus secretion, airway inflammation, and airway hyperreactivity to methacholine in a mouse model of respiratory syncytial virus (RSV) infection. METHODS: Mice were pretreated with ISS 6 days before RSV infection, and lung indices of RSV viral load (viral titer and PCR), bronchoalveolar lavage fluid cytokines (IFN-gamma), airway inflammation (peribronchial inflammation and periodic acid-Schiff-positive mucus cells), and airway hyperreactivity (methacholine responsiveness) were assessed 4 to 6 days after RSV infection. RESULTS: ISS induced the expression of the antiviral cytokine IFN-gamma in the lung, and this was associated with significantly reduced RSV viral titers, mucus secretion, and peribronchial inflammation. ISS reduced, but did not significantly inhibit, RSV-induced airway hyperreactivity to methacholine. CONCLUSION: Because ISS induced significant levels of lung IFN-gamma, an immunization strategy based solely on the administration of IFN-gamma may be insufficient to inhibit RSV-induced airway hyperreactivity to methacholine, an endpoint important in the subset of RSV-infected subjects with asthma.

Adjuvants, Immunologic↗
PubMed1997

Respiratory syncytial virus (RSV) SH and G proteins are not essential for viral replication in vitro: clinical evaluation and molecular characterization of a cold-passaged, attenuated RSV subgroup B mutant.

A live, cold-passaged (cp) candidate vaccine virus, designated respiratory syncytial virus (RSV) B1 cp-52/2B5 (cp-52), replicated efficiently in Vero cells, but was found to be overattenuated for RSV-seronegative infants and children. Sequence analysis of reverse-transcription-PCR-amplified fragments of this mutant revealed a large deletion spanning most of the coding sequences for the small hydrophobic (SH) and attachment (G) proteins. Northern blot analysis of cp-52 detected multiple unique read-through mRNAs containing SH and G sequences, consistent with a deletion mutation spanning the SH:G gene junction. Immunological studies confirmed that an intact G glycoprotein was not produced by the cp-52 virus. Nonetheless, cp-52 was infectious and replicated to high titer in tissue culture despite the absence of the viral surface SH and G glycoproteins. Thus, our characterization of this negative-strand RNA virus identified a novel replication-competent deletion mutant lacking two of its three surface glycoproteins. The requirement of SH and G for efficient replication in vivo suggests that selective deletion of one or both of these RSV genes may provide an alternative or additive strategy for developing an optimally attenuated vaccine candidate.

Animals↗
PubMed1999

Interferon gamma expressed by a recombinant respiratory syncytial virus attenuates virus replication in mice without compromising immunogenicity.

Interferon gamma (IFN-gamma) has pleiotropic biological effects, including intrinsic antiviral activity as well as stimulation and regulation of immune responses. An infectious recombinant human respiratory syncytial virus (rRSV/mIFN-gamma) was constructed that encodes murine (m) IFN-gamma as a separate gene inserted into the G-F intergenic region. Cultured cells infected with rRSV/mIFN-gamma secreted 22 microg mIFN-gamma per 10(6) cells. The replication of rRSV/mIFN-gamma, but not that of a control chimeric rRSV containing the chloramphenicol acetyl transferase (CAT) gene as an additional gene, was 63- and 20-fold lower than that of wild-type (wt) RSV in the upper and lower respiratory tract, respectively, of mice. Thus, the attenuation of rRSV/mIFN-gamma in vivo could be attributed to the activity of mIFN-gamma and not to the presence of the additional gene per se. The mice were completely resistant to subsequent challenge with wt RSV. Despite its growth restriction, infection of mice with rRSV/mIFN-gamma induced a level of RSV-specific antibodies that, on day 56, was comparable to or greater than that induced by infection with wt RSV. Mice infected with rRSV/mIFN-gamma developed a high level of IFN-gamma mRNA and an increased amount of interleukin 12 p40 mRNA in their lungs, whereas other cytokine mRNAs tested were unchanged compared with those induced by wt RSV. Because attenuation of RSV typically is accompanied by a reduction in immunogenicity, expression of IFN-gamma by an rRSV represents a method of attenuation in which immunogenicity can be maintained rather than be reduced.

Animals↗
PubMed2002

2'-5' Oligoadenylate synthetase plays a critical role in interferon-gamma inhibition of respiratory syncytial virus infection of human epithelial cells.

Respiratory syncytial virus (RSV), associated with bronchiolitis and asthma, is resistant to the antiviral effects of type-I interferons (IFN), but not IFN-gamma. However, the antiviral mechanism of IFN-gamma action against RSV infection is unknown. The molecular mechanism of IFN-gamma-induced antiviral activity was examined in this study using human epithelial cell lines HEp-2 and A549. Exposure of these cells to 100-1000 units/ml of IFN-gamma, either before or after RSV infection, results in a significant decrease in RSV infection. After 1 h of exposure, IFN-gamma induces protein expression of IFN regulatory factor-1 (IRF-1) but not IRF-2, double-stranded RNA-activated protein kinase, and inducible nitric-oxide synthase in these cells. The mRNA for IRF-1, p40, and p69 isoforms of 2'-5' oligoadenylate synthetase (2-5 AS) are detectable, respectively, at 1 and 4 h of IFN-gamma exposure. Studies using cycloheximide and antisense oligonucleotides to IRF-1 indicate a direct role of IRF-1 in activating 2-5 AS. Cells transfected with 2-5 AS antisense oligonucleotides inhibit the antiviral effect of IFN-gamma. A stable cell line of HEp-2 overexpressing RNase L inhibitor, RLI-14, which exhibits an IFN-gamma-induced gene expression pattern similar to that of the parent cell line, shows a significant reduction in RNase L activity and IFN-gamma-mediated antiviral effect, compared with HEp-2 cells. These results provide direct evidence of the involvement of 2-5 AS in IFN-gamma-mediated antiviral activity in these cells.

2',5'-Oligoadenylate Synthetase↗