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PubMed2000

Estimation of incidence of respiratory syncytial virus infection in schoolchildren using salivary antibodies.

An assay for respiratory syncytial virus (RSV)-specific IgG in saliva is described. The assay was used to examine the incidence of RSV infection in schoolchildren 7-10 years old during one RSV season. One hundred and twenty-one volunteer children provided saliva samples in October 1997 and March 1998; 18% of the children showed a fourfold or greater rise in anti-RSV IgG in the second sample. This prevalence of antibody increase is similar to that described in previous studies that measured CFT levels in serum samples. Overall, the children who showed rises in antibody levels, indicating that they had experienced an RSV infection, had lower levels of RSV-specific antibody in their preseason samples than those who showed no increase (P = 0.0018). These results show that saliva is an adequate substitute for serum in some antibody tests and may be useful for community studies. Such studies may provide surrogate markers for susceptibility to infection, which should benefit the planning of vaccination strategies.

Antibodies, Viral↗
PubMed2000

Respiratory syncytial virus: changes in prevalence of subgroups A and B among Argentinian children, 1990-1996.

The frequency of respiratory syncytial virus (RSV) and the distribution of subgroups A and B strains during 7 consecutive years (1990-1996) were examined in two cities of Argentina. Nasopharyngeal aspirates from 1,304 children less than 2 years of age hospitalized with acute lower respiratory infection were studied by indirect immunofluorescence. RSV was detected in 352 cases (26.9%), and the peak activity was observed in midwinter. Subgroup characterization was performed with two monoclonal antibodies against the F protein on nasopharyngeal aspirate smears. Of 195 samples, 174 (89.2%) were identified as subgroup A strains and 21 (10.8%) as subgroup B. Both strains cocirculated during 5 of 7 years studied with subgroup A predominating. Subgroup A occurred at least 8 times as often in all years except for 1994-1995. Children infected by subgroup A were younger than those infected by subgroup B (P < 0.05). The association of subgroup A infection with bronchiolitis and subgroup B with pneumonia was statistically significant (P < 0.03).

Antigens, Viral↗
PubMed1997

A monoclonal antibody pool for routine immunohistochemical detection of human respiratory syncytial virus antigens in formalin-fixed, paraffin-embedded tissue.

Four monoclonal antibodies (MAbs) with specificities for epitopes on human respiratory syncytial virus (RSV) proteins preserved after formalin fixation and paraffin embedding were identified in fixed and embedded virus-infected HEp-2 cell pellets. The MAbs bound epitopes on the fusion protein, the nucleoprotein, the phosphoprotein, and the M2 protein of the virus. Following high-temperature antigen unmasking, immunohistochemical staining revealed RSV antigens in the lungs of five of seven children who died with confirmed RSV infection and in none of nine children who died for other reasons, with no evidence of RSV infection. Staining was cytoplasmic, granular, and confined to epithelial cells. Intense staining was seen at the apex of ciliated bronchial and bronchiolar epithelial cells in all five positive cases. In one case, of pneumonitis, infected pneumocytes were present in the alveoli and in several cases, CD68-positive, cytokeratin-negative alveolar macrophages stained for viral antigens. These antibodies may prove useful in studies of the pathogenesis of RSV infection.

Antibodies, Monoclonal↗
PubMed1996

Treatment of respiratory failure due to respiratory syncytial virus pneumonia with natural surfactant.

We describe two infants suffering from severe pneumonia caused by respiratory syncytial virus (RSV) infection and needing mechanical ventilation with both high ventilator settings and a high fraction of inspired oxygen. The severity of the respiratory failure and the possibility of decreased and/or altered surfactant production led us to treat these infants with intratracheal instillation of natural surfactant. This resulted in an improvement of lung compliance and a decrease in the amount of oxygen required to maintain acceptable oxygen saturations. Intratracheal surfactant instillation might, therefore, be useful in the treatment of severe RSV pneumonia.

Humans↗
PubMed1998

Reduced long-term respiratory morbidity after treatment of respiratory syncytial virus bronchiolitis with ribavirin in previously healthy infants: a preliminary report.

Previously healthy infants less than 6 months of age with severe respiratory syncytial virus bronchiolitis who required hospitalization were identified from hospital records. Infants had been treated either conservatively (control group, n = 19) or with ribavirin added to conservative management (study group, n = 22). All infants underwent a 1-year follow-up after the initial illness. There was a significant reduction in the prevalence of reactive airway disease in the group treated with ribavirin (P < 0.05) compared with the control group, both in terms of the proportion of patients developing airway reactivity (59% vs. 89%) and the number of episodes of reactive airway disease (31 vs. 70). Our data suggest that ribavirin reduces the prevalence of airway reactivity.

Albuterol↗
PubMed1998

Aerosolized albuterol improves airway reactivity in infants with acute respiratory failure from respiratory syncytial virus.

The objective of this investigation was to measure the bronchodilator effect of aerosolized albuterol on infants with respiratory syncytial virus (RSV)-induced respiratory failure. Infants who required intubation and mechanical ventilator support for RSV disease were eligible for this prospective, nonrandomized study. Pulmonary function tests, including respiratory mechanics by least mean square analysis, small airway function by rapid thoraco-abdominal compression, and functional residual capacity by nitrogen washout were performed before and 20 min after inhalation of 20-40 breaths of undiluted (0.5%) albuterol solution via a small-volume nebulizer. Analysis of maximum expiratory flow at functional residual capacity (V'maxFRC) before and after albuterol administration was performed using a t-test for paired comparisons. A two-tailed P-value of less than 0.05 was considered statistically significant. Twenty-five infants (mean +/-SD postconceptional age = 45 +/- 5 weeks) were enrolled. Thirteen of the 25 infants had a prior history of prematurity and/or cardiorespiratory disease. After aerosolized albuterol, mean V'maxFRC increased significantly from 48 +/- 46 ml/sec to 65 +/- 59 ml/sec (P = 0.03); however, only three patients had an increase into the normal range. Three patients had a substantial (40-50%) decrease in V'maxFRC. These findings suggest that during the acute phase of severe RSV respiratory infection some of this group of very young infants had airway reactivity that improved in response to inhaled albuterol.

Acute Disease↗
PubMed1998

Usefulness of bronchoalveolar lavage for diagnosis of acute and persistent respiratory syncytial virus lung infections in guinea pigs.

To investigate whether bronchoalveolar lavage (BAL) fluid specimens can be used to diagnose acute and persistent respiratory syncytial virus (RSV) lung infections in guinea pigs, we tested BAL fluid and lung tissue specimens for evidence of viral infection, and compared BAL cytology between infected and uninfected animals. RSV-inoculated guinea pigs were studied during acute bronchiolitis (days 3 and 7 postinoculation), convalescence (Day 14 postinoculation), and persistent infection (Days 28 and 60 postinoculation), and were compared to the sham-infected control animals. BAL and lung tissue specimens were cultured for virus and tested by immunocytochemistry for viral protein. A reverse transcription-polymerase chain reaction (RT-PCR) method was used to test for viral nucleic acid. Total and differential BAL cell counts were compared between RSV-inoculated and control animals on each study day. In BAL specimens, replicating RSV was isolated by culture in one out of four of the animals on Day 3 postinoculation; immunocytochemistry for RSV antigens was positive in all virus-exposed animals from Days 3-14 postinoculation, and viral nucleic acid was detected by RT-PCR in one-fourth of the animals on Day 3 postinoculation. In contrast, replicating virus, viral antigens, and viral nucleic acid were documented in lung tissues obtained from the same RSV-infected animals on all study days. BAL specimens of RSV-inoculated animals contained more eosinophils on all study days (two-tailed P value < 0.01) compared to the controls. The results of this animal study demonstrate that BAL fluid is not useful for diagnosis of persistent RSV infection. However, BAL fluid may be helpful for the documentation of acute RSV lung infection when immunocytochemistry may provide a more accurate test for virus detection than RT-PCR or viral culture.

Acute Disease↗
PubMed1999

Combining DNA and protein vaccines for early life immunization against respiratory syncytial virus in mice.

Early life responses to respiratory syncytial virus (RSV)-F DNA and RSV-F protein immunization were studied in murine models of neonatal immunization. RSV-F DNA induced similar antibody (Ab) responses, antigen-specific IFN-gamma production and cytotoxic T lymphocyte (CTL) responses in 1-week-old and adult BALB / c mice. In contrast, RSV-F protein induced much higher IL-5 responses in early life. Both vaccines elicited Ab and CTL responses in spite of maternal Ab, but with distinctive kinetics. Sequential RSV-F DNA priming / protein boosting primed 1-week-old mice for RSV-F-specific CTL responses, reduced IL-5 production and enhanced Ab responses. In contrast, IL-5 exceeded IFN-gamma responses when young mice were primed with protein and boosted with DNA. Last, when protein and DNA immunization were combined, a single vaccine dose induced early Ab responses, preferential IL-5 responses but strong CTL responses. Sequential or combined DNA / protein immunization thus represent interesting strategies for early life immunization.

Animals↗
PubMed2000

Role of interferon gamma in the pathogenesis of primary respiratory syncytial virus infection in BALB/c mice.

Immunologic mechanisms are thought to contribute to the pathogenesis of respiratory syncytial virus (RSV) bronchiolitis in humans. RSV-infected BALB/c mice exhibit tachypnea and signs of outflow obstruction, similar to symptoms in humans. Interferon gamma (IFNgamma) has been found to be the predominant cytokine produced in humans and mice with RSV infection. We therefore undertook this study to evaluate the role of IFNgamma in the development of respiratory illness in RSV-infected mice. BALB/c mice were infected with RSV, and lung function was assessed by plethysmography. Bronchoalveolar lavage (BAL) fluids were analyzed for the concentration of interferon gamma (IFNgamma) and the presence of inflammatory cells, and lung tissue sections were examined for histopathologic changes. The role of IFNgamma was further addressed in studies of IFNgamma knock-out mice (IFNgamma(-/-)) and of mice depleted of IFNgamma by in vivo administration of a neutralizing antibody. After infection, mice developed respiratory symptoms that were strongly associated with the number of inflammatory cells in BAL, as well as with the concentrations of IFN-gamma. Both IFN-gamma(-/-) mice and mice treated with anti-IFNgamma developed more extensive inflammation of the airways than control mice. However mice lacking IFNgamma exhibited less severe signs of airway obstruction. Together these data suggest a protective role of IFNgamma in RSV infection in terms of limiting viral replication and inflammatory responses but also a pathogenic role in causing airway obstruction.

Animals↗
PubMed2000

Novel pathways in the pathogenesis of respiratory syncytial virus disease.

Respiratory syncytial virus (RSV) is a leading cause of severe respiratory infections in infants and children. Extensive research in past decades has expanded our knowledge regarding the specific mechanisms involved in the pathogenesis of RSV bronchiolitis and subsequent chronic obstructive airway disease. Studies of RSV infection are performed in humans, cell culture models, and animal models, each with their own specific limitations. A recently developed murine model in which pulmonary dysfunction can be monitored and quantified appears to add a powerful tool for the study of specific pathogenic mechanisms of experimental RSV infections. Both immunologic and nonimmunologic factors have been implicated in the pathogenesis of RSV-induced diseases. Recently, a hypothesis that RSV bronchiolitis may be the result of production of Th2-type cytokines has become popular. There are, however, studies in human infants with RSV as well as in RSV-infected mice that suggest this theory is incorrect, or at least an oversimplification. There is compelling evidence that cells producing interferon gamma may contribute to RSV-induced wheezing, possibly through induction of leukotriene release. Among the nonimmunologic factors, pulmonary surfactant has recently attracted attention, especially because of the therapeutic implications for infants with severe bronchiolitis. A better understanding of the pathogenesis of RSV-induced diseases will be of considerable help in developing specific therapeutic strategies and in vaccine development.

Animals↗
PubMed2000

Long-term effects of prednisolone in the acute phase of bronchiolitis caused by respiratory syncytial virus.

Follow-up studies have demonstrated that bronchiolitis caused by respiratory syncytial virus (RSV) is strongly associated with wheezing in the ensuing years. During the acute infection the immune response may induce long-lasting detrimental effects, thereby contributing to post-bronchiolitis wheezing (PBW). Therefore, immune-modulating drugs like corticosteroids, administered in the acute phase of RSV bronchiolitis, may prevent PBW and asthma. To evaluate this, we performed a controlled prospective follow-up study after a randomized double-blind placebo-controlled intervention in the acute phase with oral prednisolone. Fifty-four patients under 2 years of age and hospitalized for RSV bronchiolitis between 1992 and 1995 were randomly assigned to prednisolone 1 mg/kg/day for 7 days or placebo. At the mean age of 5 years, 47 patients had completed their follow-up. Patients were divided into four groups: no wheezing, transient wheezing (wheezing during the first year of life); persistent wheezing (wheezing during the first year of life and asthma at the age of 5); and late-onset wheezing (no wheezing during the first year of life but asthma at the age of 5). Prevalence of wheezing and asthma were investigated through an interview by telephone, using a standardized questionnaire. We found no significant differences between the prednisolone- and the placebo-treated group in the number of patients with transient wheezing (8% vs. 17%), persistent wheezing (42% vs. 31%), or late-onset wheezing (17% vs. 13%). We conclude that oral prednisolone during the acute phase of RSV bronchiolitis is not effective in preventing PBW or asthma at the mean age of 5 years. Pediatr Pulmonol. 2000; 30: 92-96.

Acute Disease↗
PubMed2001

Long-term persistence and reactivation of T cell memory in the lung of mice infected with respiratory syncytial virus.

In mice acutely infected with respiratory syncytial virus (RSV), more than 20% of pulmonary CD8(+) T cells, but only 2-3% of CD8(+) T cells in the draining lymph node secreted interferon-gamma in response to a single peptide. Surprisingly, the percentage of virus-specific T cells in the lung remained at these high levels long after the acute infection. Pulmonary memory T cells were further studied in a sensitive adoptive transfer system, which allows visualizing polyclonal CD4(+) and CD8(+) virus-specific memory T cell responses. Fifty days after infection, persisting RSV-specific pulmonary T cells remained CD69(hi) CD62L(lo), but had returned to a resting memory state according to functional criteria. In the absence of neutralizing antibodies reinfection first induced cell division among virus-specific memory T cells 3 days after infection predominantly in the local lymph node. However, divided cells then rapidly accumulated in the lung without significantly increasing in the lymph node. These results suggest rapid export of reactivated cells from the lymph node to the target organ. Thus, although memory T cells can be maintained in the infected organ after a localized virus infection, amplification of a recall response appears to be most effective in organized lymphoid tissue.

Adoptive Transfer↗
PubMed2002

Pulmonary T cells induced by respiratory syncytial virus are functional and can make an important contribution to long-lived protective immunity.

The contribution of T cell responses to immunity against respiratory syncytial virus (RSV) is not fully defined, but this is an important issue for vaccine design. Recent studies demonstrating RSV-induced pulmonary T cell suppression suggest that RSV may have evolved strategies to escape T cell immunity. Here we evaluated potential consequences of RSV-mediated immunosuppression for protective memory T cell responses in vivo. Surprisingly, we found strong ex vivo cytolytic activity and interferon production of pulmonary RSV-specific CD8(+) T cells both in the acute and the memory phase of primary murine RSV infection. More significantly, T cell memory made an important contribution to immunity against RSV independent of antibodies. Thus, RSV-primed mice were protected against challenge with RSV-recombinant vaccinia viruses, which can be controlled by RSV-specific T cells, but not by RSV-specific antibodies. In conclusion, RSV does not appear to impair acute and protective memory T cell responses induced by a primary infection. These findings further support that induction of T cell immunity should be a relevant goal for RSV vaccines.

Animals↗
PubMed2004

The role of Toll-like receptor 4 versus interleukin-12 in immunity to respiratory syncytial virus.

Toll-like receptors (TLR) and IL-12 represent key elements of innate immunity. Using C57BL/10 ScCr mice it was shown that TLR4 is important for control of infection with respiratory syncytial virus (RSV). Since these mice have an additional defect in the IL-12R, we reinvestigated immunity to RSV in several C57BL/10 and BALB/c mouse strains lacking a functional TLR4, a functional IL-12-IL-12R interaction or both. In the absence of a functional IL-12 axis, early virus control was impaired in C57BL/10 mice, but not in BALB/c mice. By contrast, TLR4 had no impact on RSV elimination. Pulmonary NK cell recruitment was impaired in IL-12 deficient BALB/c mice and NK cytotoxicity was reduced in IL-12/IL-12R-deficient mice of both genetic backgrounds. Absence of TLR4 had no impact on NK cell recruitment or NK activity nor on recruitment of other pulmonary inflammatory cells. Activation of RSV-specific T cell immunity, including T cell mediated immunopathology, was normal in all mutant strains. These findings clearly argue against a significant role for TLR4 and define a limited role for IL-12 in primary murine RSV infection.

Animals↗
PubMed2005

Respiratory syncytial virus-induced exaggeration of allergic airway disease is dependent upon CCR1-associated immune responses.

Severe respiratory syncytial virus (RSV) infection has a significant impact on airway function, and may alter subsequent development of asthma. CCR1 mRNA was significantly up-regulated during primary RSV infection in BALB/c mice, and was also up-regulated during allergen exposure in sensitized mice. Although CCR1(-/-) mice exhibited similar levels of airway hyperresponsiveness (AHR) as wild-type mice in response to cockroach allergen alone, in animals treated with RSV prior to cockroach antigen (CRA) sensitization and challenge, a significant decrease in exacerbated AHR was observed in the CCR1(-/-) mice. The reduction in AHR after RSV and allergen challenge in CCR1(-/-) mice was not associated with changes in peribronchial eosinophilia, but was accompanied by significantly decreased IL-13 levels in the lungs, as well as an absence of mucus cell staining within the airways. When T lymphocyte numbers were compared in animals receiving CRA to animals receiving a combination of RSV and allergen an increase in both CD4 and CD8 T lymphocytes could be detected in wild-type but not CCR1(-/-) animals. Thus, these data suggest that CCR1-mediated responses have a primary role for inducing severe disease during RSV infection, and may be responsible for altering the lung pathophysiological responses to subsequent allergen challenges via IL-13-mediated mechanisms.

Allergens↗
PubMed1995

Molecular epidemiology of respiratory syncytial virus: a review of the use of reverse transcription-polymerase chain reaction in the analysis of genetic variability.

Respiratory syncytial virus (RSV) is the major viral cause of lower respiratory tract disease (bronchiolitis and pneumonia) in babies and infants. Infections with the virus occur as annual winter epidemics in temperate climates, placing considerable pressure on the provision of hospital beds. The virus is unusual in that it can reinfect individuals and it can infect babies despite the presence of maternal antibody. RSV has a negative sense nonsegmented RNA genome and as such is liable to high levels of mutation. This paper describes methods developed to determine the degree of genetic variability of the virus both during individual epidemics and worldwide. It is necessary for these methods to be quick, easy and cheap so that large numbers of samples can be analysed readily. They are based on extraction of viral RNA directly from clinical samples or from viral cultures, reverse transcription of the viral RNA, and then amplification of selected regions of the genome by the polymerase chain reaction (PCR). PCR products are then analysed by restriction mapping, or, if necessary, direct nucleotide sequencing. In this way isolates of RSV have been shown to fall into a number of genotypes, with epidemics being made up of cocirculating genotypes whose relative proportions vary with each epidemic. An understanding of the molecular epidemiology of this important human pathogen will be of significance in the search for an effective vaccine.

Genetic Variation↗
PubMed1996

Respiratory syncytial virus G-protein modulates cytokine release from human peripheral blood mononuclear cells.

Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in children and adults. In vivo the host has to cope with intact replicative virus, with non-replicative virus, and/or with viral structural proteins including the outer membrane G-protein. We analyzed the role of purified RSV G-protein with regard to its modulatory efficacy for interleukin (IL) -10, IL-12, and tumor necrosis factor-alpha (TNF-alpha) release from human peripheral blood mononuclear cells (PBMC). These cytokines seem to contribute to the deleterious effect in viral infections. Treatment of PBMC with RSV at a multiplicity of infection of 10 down to 0.001 induced the release of TNF-alpha, IL-10, and IL-12; also time kinetics and dose-responses differed markedly. Stimulation of PBMC with purified RSV G-protein (from 0.001 up to 10 microgram/10(6) PBMC) led only to a pronounced increase in IL-10 within a concentration range from 0.01 up to 0.5 microgram/10(6) PBMC with a maximum between 12 and 18 h of incubation. AT later time points (24, 48, and 72 h) G-protein concentrations above 1 microgram/10(6) PBMC suppressed IL-10, TNF-alpha, and IL-12 release from human PBMC. Coating of PBMC with RSV G-protein suppressed IL-10, TNF-alpha, and IL-12 release after subsequent stimulation with RSV. Our data indicate a regulatory role of RSV G-protein immune responses toward viral infection.

Cells, Cultured↗
PubMed1996

IL-8 release from human neutrophils by the respiratory syncytial virus is independent of viral replication.

Elevated interleukin-8 levels and a massive accumulation of neutrophils (PMN) are the hallmark of a variety of severe lung diseases. The respiratory syncytial virus (RSV), an important respiratory pathogen, induces interleukin-8 (IL-8) release from human PMN, however, the mechanism is as yet unknown. We analyzed the role of virus uptake, intracellular virus replication, virus attachment, and of virus capsid proteins for the induction of IL-8 (protein + mRNA) in human PMN. Cell supernatants were analyzed for IL-8 release via enzyme-linked immunosorbent assay; cell pellets were analyzed for IL-8-specific mRNA expression and for RSV-specific genomic and RSV-specific mRNA by reverse transcriptase-polymerase chain reaction. Stimulation of human PMN with viable, heat-inactivated, or UV-inactivated RSV [at a multiplicity of infection (m.o.i.) from 0.01 up to 10] induced IL-8 production (protein + mRNA) to a similar degree. Maximal IL-8 release was observed at a m.o.i. of 5-10 after 18-24 h. RSV-specific genomic RNA was present inside PMN up to 24 h independent of whether viable or inactivated RSV was used. Withdrawal of extracellular viable or inactivated (heat, UV) RSV after infection of PMN (2 h) abolished IL-8 mRNA expression and IL-8 release; the intracellular persistence of RSV lasted for up to 24 h. Stimulation of human PMN with purified RSV G-protein, a major capsid protein, in a concentration range from 0.1 up to 2.5 microg/5 X 10(5) PMN resulted in an increased IL-8 release from human PMN but to a significantly lesser degree compared with the intact RSV. RSV G-protein concentration above 1 microg inhibited the RSV-induced IL-8 release by up to 90%. Our data contribute to the understanding of the pathomechanisms leading to IL-8 release from human PMN.

Base Sequence↗