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PubMed2003

Hospitalization for respiratory syncytial virus in the paediatric population in Spain.

The aim of this population-based retrospective study was to determine the incidence of hospitalization for community-acquired, laboratory-confirmed respiratory syncytial virus (RSV) infection in an unselected paediatric population from southern Europe. The study was performed in an area with 15,700 children aged less than 5 years attended by a single hospital. The presence of RSV in nasopharyngeal aspirates from children with acute respiratory infection treated in the hospital was investigated in four seasons (July 1996-June 2000). A total of 390 episodes of hospitalization for RSV infection were detected and 83.3% of the children were aged less than 1 year old. The annual hospitalization rate was 37/1000 for infants aged less than 6 months and 25/1000 for those aged less than 1 year. During the study period, 2.5% of the infants younger than 1 year and approximately 5% of those younger than 3 months were hospitalized for RSV infection. The mean length of hospital stay was 5.9 days. Seven per cent of the patients required admission to the intensive care unit and more than half of these children were aged less than 1 month. In Spain, community-acquired RSV infection is a highly frequent cause of hospitalization in young children, especially in those aged less than 1 year. Prevention of RSV infection, through the development of vaccines and/or other strategies, should be a public health priority.

Child, Preschool↗
PubMed2005

The transmission dynamics of groups A and B human respiratory syncytial virus (hRSV) in England & Wales and Finland: seasonality and cross-protection.

Human respiratory syncytial virus (hRSV) transmission dynamics are inherently cyclical, and the observed genetic diversity (between groups A and B) also appears to have a repeating pattern. A key unknown is the extent to which genetic variants interact immunologically, and thus impact on epidemiology. We developed a novel mathematical model for hRSV transmission including seasonal forcing of incidence and temporary intra- and inter-group partial immunity. Simultaneous model fits to data from two locations (England & Wales, UK, and Turku, Finland) successfully reproduced the contrasting infection dynamics and group A/B dominance patterns. Parameter estimates are consistent with direct estimates. Differences in the magnitude and seasonal variation in contact rate between the two populations alone could account for the variation in dynamics between these populations. The A/B group dominance patterns are explained by reductions in susceptibility to and infectiousness of secondary homologous and heterologous infections. The consequences of the observed dynamic complexity are discussed.

Adolescent↗
PubMed1999

Molecular epidemiology of respiratory syncytial virus in The Gambia.

Respiratory syncytial virus (RSV) infection in The Gambia occurs seasonally in association with the rainy season. This study examined the genetic variability of RSV isolates from four consecutive epidemics from 1993-6. Each epidemic was made up of a number of variants which were replaced in subsequent epidemics. Analysis of attachment (G) protein gene sequences showed that isolates were closely related to those observed in the rest of the world. However, many isolates from 1993 and 1994 were unlike other isolates observed in the developed world during this period and were more similar to isolates from 1984 in Europe. In addition, the most commonly observed genotype in the UK in the 1990s was not detected in The Gambia during this period.

Amino Acid Sequence↗
PubMed1998

Respiratory syncytial virus infection in children with acute respiratory infections in Zambia.

Epidemiological research on respiratory syncytial virus (RSV) infections in children was carried out at the Virology Laboratory, University Teaching Hospital (UTH), in Lusaka, Zambia, from January-December 1996. Specimens including 736 nasal washings and 2424 throat swabs were collected from children with acute respiratory infections (ARI) and tested for RSV by enzyme immunoassay and by virus isolation. RSV was isolated in 62 (4.1%) of 1496 throat swabs collected from March to September and was detected in 99 (16.3%) of 609 nasal washings from March to November. The average RSV isolation rate was 2.6% and the average RSV detection rate was 13.5%. The highest RSV isolation (8.1%) and detection (30.5%) rates were in June 1996. RSV antibody in the 278 serum specimens collected from Zambian children, who were hospitalized in the paediatric ward, UTH, was detected using a standard neutralization test. The antibody positive rate was 60-80% in children > 4 years. It is evident that RSV is one of the main causal agents of ARI in children in Zambia.

Antibodies, Viral↗
PubMed2005

Infection by the respiratory syncytial virus in infants and young children at high risk.

The respiratory syncytial virus is the most common cause of infection of the lower respiratory tract in infants and young children, and is the leading cause of hospitalisation and death due to viral illness during the first year of life. In otherwise healthy infants, the virus usually causes only mild respiratory illness, but premature babies and infants with chronic lung disease, those with congenitally malformed hearts, or those who are immunodeficient, are at increased risk of serious illness, hospitalisation, and death. Recent infection with the virus is also associated with increased postoperative complications after corrective surgery for congenitally malformed hearts. No effective vaccine is currently available, and treatment is limited to supportive therapy. Prevention in groups deemed to be at high-risk, therefore, is essential. In addition to measures for control of infection, prophylactic immunotherapy is indicated in selected patients. Palivizumab (Synagis) is a monoclonal antibody indicated for the prevention of serious viral disease of the lower respiratory tract in premature infants, those with chronic lung disease, and those with haemodynamically significant congenital cardiac lesions. Palivizumab is given intramuscularly, usually as a monthly injection during the so-called "season". In a recent international, randomised, double-blind, placebo-controlled trial in 1,287 children less than or equal to 2 years old with haemodynamically significant congenital cardiac malformations, prophylaxis achieved a relative reduction of 45 per cent in the incidence of antigen-confirmed viral-related hospitalisation, and reduced the duration of hospital stay by 56 per cent. National and international guidelines, therefore, now recommend routine prophylaxis in the first year of life in children with haemodynamically significant congenital cardiac disease.

Antibodies, Monoclonal↗
PubMed2006

Interactions between respiratory syncytial virus and the host cell: opportunities for antivirus strategies?

At the start of the 21st century, respiratory syncytial virus (RSV) remains a serious global health concern. Although RSV has traditionally been acknowledged as a leading cause of morbidity and mortality in the paediatric population, the elderly and people with suppressed immune systems are now also recognised as being at risk from serious RSV infection. This problem is currently exacerbated by the lack of an effective vaccine to prevent RSV infection. Although the virus proteins play a variety of roles during the virus replication cycle, in many cases these tasks are performed via specific interactions with host-cell factors, including proteins, carbohydrates and lipids. The way in which RSV interacts with the host cell is currently being examined using a battery of different techniques, which encompass several scientific disciplines. This is providing new and interesting insights into how RSV interacts with the host cell at the molecular level, which in turn is offering the hope of new strategies to prevent RSV infection.

Host-Parasite Interactions↗
PubMed2005

Progression of respiratory syncytial virus infection monitored by fluorescent quantum dot probes.

We report the use of quantum dots (QDs) to identify the presence and monitor the progression of respiratory syncytial virus (RSV) infection over time by labeling the F and G proteins. In addition, co-localization of these viral proteins was shown using confocal microscopy. The implications of these results are that QDs may provide a method for early, rapid detection of viral infection and open the door for future studies of the intricate spatial features cell trafficking of viral proteins.

Cell Line↗
PubMed1997

Baculovirus expression of the respiratory syncytial virus fusion protein using Trichoplusia ni insect cells.

Respiratory syncytial virus (RSV) is a major viral pathogen responsible for severe respiratory tract infections in infants, young children, and the elderly. The RSV fusion (F) protein is highly conserved among RSV subgroups A and B and is the major protective immunogen. A genetically-engineered version of the RSV F protein was produced in insect cells using the baculovirus expression system. To express a secreted form of this protein, the transmembrane domain was eliminated by removing the region of the gene encoding 48 amino acids at the C-terminus. Production of the truncated RSV F protein (RSV-Fs) was compared in two different insect cell lines, Spodoptera frugiperda (Sf9) and Trichoplusia ni (High Five). The yield of RSV-Fs secreted from High Five insect cells was over 7-fold higher than that from Sf9 insect cells. Processing of the RSV-Fs protein was also different in the two insect cell lines. N-terminal sequencing demonstrated that while most of the RSV-Fs protein secreted by High Five cells was correctly processed at the F2-F1 proteolytic cleavage site, most of the RSV-Fs protein secreted by Sf9 cells was unprocessed or incorrectly processed. Antigenicity of the major RSV F neutralization epitopes was maintained in the RSV-Fs protein secreted from High Five cells. The RSV-specific neutralizing antibody titres in the sera of cotton rats immunized with the RSV-Fs protein were equivalent to those in the sera of animals intranasally inoculated with live RSV. Animals immunized with either live RSV or the immunoaffinity purified RSV-Fs protein from High Five cells were completely protected against live virus challenge.

Animals↗
PubMed2003

Epidemiology of respiratory syncytial virus bronchiolitis in hospitalized infants in Greece.

New therapies have been introduced for the prophylaxis and treatment of respiratory syncytial virus (RSV) infection in recent years. The aim of the study was to determine the epidemiological and clinical characteristics of infants hospitalized with bronchiolitis in our area. All patients under 1 year of age admitted with acute bronchiolitis during four consecutive RSV seasons from February 1, 1997 to June 30, 2000 were enrolled in the study. The records of patients admitted during the first season were reviewed retrospectively while the rest were followed prospectively. A total of 636 infants with bronchiolitis were admitted and RSV infection was documented in 61% of those tested. Admission to intensive care unit (ICU) was required for 6.2% of them and was more common in premature infants (26%) (p < 0.001). Case fatality rate was 0.7% (overall 0.3%). RSV bronchiolitis accounted for about 12% of all infant admissions during the 5 months of the yearly outbreak. Patients with documented RSV infection had a more severe illness with a higher ICU admission rate (6 vs. 1%, p = 0.008) and longer duration of hospitalization (mean 6.3 vs. 5.3 days, p < 0.001) compared to those who tested negative. Although none of the patients had a positive blood culture on admission a considerable number of them (210/636, 33%) were treated with antibiotics. RSV infection has a significant impact on infant morbidity in our settings which is more serious among those born prematurely. Documentation of RSV infection may be a marker of more severe illness in infants hospitalized with bronchiolitis. Antibiotic use has to be restricted since the occurrence of a serious bacteraemic illness on admission is a very rare event.

Anti-Bacterial Agents↗
PubMed2003

Can respiratory syncytial virus etiology be diagnosed clinically? A hospital-based case-control study in children under two years of age.

An unmatched, hospital-based case-control study was performed, to determine, whether respiratory syncytial virus (RSV) etiology in hospitalized young children can be predicted clinically. Children under 2 years of age admitted with a lower respiratory tract infection in three hospitals in northern Germany were included (one tertiary and two secondary centers). 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. A weighted backward stepwise logistic regression model was applied for multivariate analysis. RSV-etiology could be predicted with a sensitivity of 72.8% and a specificity of 73.2%. Young age, disease entity--pneumonia or bronchiolitis, center, intercostal retractions, absence of an underlying condition, low level of C-reactive protein, short duration of symptoms (all on admission), prematurity and epidemiologic year were predictive; anatomical infiltrates and wheezing were not. Pathogen specific diagnosis is necessary for individual therapy, allocation in observational studies or treatment trials and for surveillance of airway infections in children, since the positive predictive value is too low for an accurate diagnosis and decision making. Multivariate techniques are effective tools in complex clinical research for deconfounding.

Bronchiolitis↗
PubMed2002

Structure-antigenicity relationship studies of the central conserved region of human respiratory syncytial virus protein G.

BBG2Na is a recombinant protein, composed in part of carrier protein BB and of the central conserved domain of the attachment glycoprotein G of human respiratory syncytial virus (HRSV) subgroup A. This protein is a potent vaccine candidate against HRSV. G2Na contains several contiguous B-cell epitopes, occupying sequential positions in the linear sequence of the protein. One of the epitopes contains four cysteines that are completely conserved in known strains of HRSV and form a 'cysteine noose' motif. In this study, we analysed circular dichroism (CD) spectra of BBG2Na and its B-cell epitopes. We also used NMR and molecular dynamics simulations to determine the three-dimensional structure of the cysteine noose domain. We observed significant structural differences related to the length of peptides containing the cysteine noose. These differences show good correlation with the immunogenic activity of the peptides. It is shown that a single Val(171) addition induces a pronounced structure stabilization of the cysteine noose peptide G4a (1-4/2-3) (residues 172-187), which is associated with a 100-fold increase in its antigenicity vis-à-vis a G-protein specific monoclonal antibody.

Antigens, Viral↗
PubMed2003

Synthesis, refolding and protective immune responses of a potential antigen for human Respiratory Syncytial Virus vaccine.

The design of new antigens with both high immunogenic and safety properties is of particular interest to vaccine against infectious diseases. In the present study, we describe the synthesis and the refolding of peptide G20 derived from the Human Respiratory Syncytial Virus (hRSV) G-protein. G20 (MEF G140-190 G144-158) is a peptide of 69 amino acids with two disulfide bridges, which comprises multiple protective B-cell epitopes. It was deleted of the T helper cell epitope 184-198 of the RSV G-protein, which was found to induce pulmonary pathology after RSV challenge in mice. Interestingly, we showed in the present study that G20 generated a highly protective antibody response against RSV challenge in Balb/c mice. Therefore, G20 represents a new potential antigen for an RSV vaccine.

Amino Acid Sequence↗
PubMed2000

Wheezing following lower respiratory tract infections with respiratory syncytial virus and influenza A in infancy.

We examined the incidence of subsequent wheezing in 292 children, hospitalized for influenza A or respiratory syncytial virus (RSV) lower respiratory tract infection, during two consecutive seasons (November-December, 1993 and March-April, 1995). Questionnaires concerning episodes of wheezing and known risk factors for wheezy bronchitis were mailed to parents 1 year after hospitalization. Sixty per cent of parents reported two or more episodes of wheezing following either influenza A or RSV. Hospitalization as a result of wheezing was necessary in 15% of the patients. The severity of the primary infection, as indicated by the need for treatment in the intensive care unit (ICU), was correlated with later wheezing. No additional significant risk factors predicting later wheezing could be identified.

Asthma↗
PubMed2002

Interleukin-6, interleukin-8, interleukin-11, and interferon-gamma levels in nasopharyngeal aspirates from wheezing children with respiratory syncytial virus or influenza A virus infection.

The differences between respiratory syncytial virus (RSV) and influenza A virus (IFAV) in the pathogenesis of wheezing in young children have not been clearly defined. The aim of this study was to assess the contributions of RSV vs IFAV in the pathogenesis of upper airway inflammation in wheezy young children. We compared interleukin (IL)-6, IL-8, IL-11, and interferon-gamma (IFN-gamma) levels in nasopharyngeal aspirates (NPA) from non-asthmatic children with respiratory virus infections (RSV in 17 children and IFAV in 13 children), asthmatic children with viral infections (RSV in nine children, IFAV in 10 children), and 22 unaffected healthy children (controls). Levels of IL-11 in NPA from asthmatic children were significantly higher than those from non-asthmatic children with RSV infection, and RSV infection enhanced the IL-11 production in NPA significantly compared to IFAV infection. Nasopharyngeal epithelium from children with RSV infection secreted more IL-6 than that of children with IFAV infection. There was little difference in the IL-8 and IFN-gamma levels between asthmatic and non-asthmatic children with RSV or IFAV infection. In conclusion, asthma enhanced IL-11 production in RSV infection rather than IFAV infection in early childhood. There was a trend towards greater IL-6 production in RSV infection compared with IFAV infection.

Asthma↗
PubMed2002

A rhesus monkey model of respiratory syncytial virus infection.

Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract disease in infants and young children worldwide. To date, there is no single animal model that adequately reproduces all human disease states. Here, we have developed a model of experimental infection with human RSV in infant Rhesus macaques. Infected animals demonstrated mild clinical disease including increased respiratory rates, fever and adventitious lung sounds. While more severe disease was not observed, preliminary virological and histopathological findings are promising. It is anticipated that with further optimization, this model will provide a useful system with which to study disease due to RSV infection and evaluate candidate vaccines.

Animals↗
PubMed2000

A RhoA-derived peptide inhibits syncytium formation induced by respiratory syncytial virus and parainfluenza virus type 3.

The fusion glycoproteins of human respiratory syncytial virus (RSV) and human parainfluenza virus type-3 (PIV-3) mediate virus entry and syncytium formation. Interaction between the fusion protein of RSV and RhoA, a small GTPase, facilitates virus-induced syncytium formation. We show here a RhoA-derived peptide inhibits RSV and syncytium formation induced by RSV and PIV-3, both in vitro by inhibition of cell-to-cell fusion and in vivo by reduction of peak titer by 2 log10 in RSV-infected mice. These findings indicate that the interaction between these two paramyxovirus fusion proteins and RhoA is an important target for new antiviral strategies.

Amino Acid Sequence↗
PubMed2000

Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus.

The innate immune system contributes to the earliest phase of the host defense against foreign organisms and has both soluble and cellular pattern recognition receptors for microbial products. Two important members of this receptor group, CD14 and the Toll-like receptor (TLR) pattern recognition receptors, are essential for the innate immune response to components of Gram-negative and Gram-positive bacteria, mycobacteria, spirochetes and yeast. We now find that these receptors function in an antiviral response as well. The innate immune response to the fusion protein of an important respiratory pathogen of humans, respiratory syncytial virus (RSV), was mediated by TLR4 and CD14. RSV persisted longer in the lungs of infected TLR4-deficient mice compared to normal mice. Thus, a common receptor activation pathway can initiate innate immune responses to both bacterial and viral pathogens.

Animals↗
PubMed2006

The histopathology of fatal untreated human respiratory syncytial virus infection.

The pathology of respiratory syncytial virus (RSV) infection was evaluated 1 day after an outpatient diagnosis of RSV in a child who died in a motor vehicle accident. We then identified 11 children with bronchiolitis from the Vanderbilt University autopsy log between 1925 and 1959 who met criteria for possible RSV infection in the preintensivist era. Their tissue was re-embedded and evaluated by routine hematoxylin and eosin and PAS staining and immunostaining with RSV-specific antibodies. Tissue from three cases was immunostain-positive for RSV antigen and was examined in detail. Small bronchiole epithelium was circumferentially infected, but basal cells were spared. Both type 1 and 2 alveolar pneumocytes were also infected. Although, not possible for archival cases, tissue from the index case was evaluated by immunostaining with antibodies to define the cellular components of the inflammatory response. Inflammatory infiltrates were centered on bronchial and pulmonary arterioles and consisted of primarily CD69+ monocytes, CD3+ double-negative T cells, CD8+ T cells, and neutrophils. The neutrophil distribution was predominantly between arterioles and airways, while the mononuclear cell distribution was in both airways and lung parenchyma. Most inflammatory cells were concentrated submuscular to the airway, but many cells traversed the smooth muscle into the airway epithelium and lumen. Airway obstruction was a prominent feature in all cases attributed to epithelial and inflammatory cell debris mixed with fibrin, mucus, and edema, and compounded by compression from hyperplastic lymphoid follicles. These findings inform our understanding of RSV pathogenesis and may facilitate the development of new approaches for prevention and treatment.

Antigens, Viral↗