Search

Abstract Motavizumab (MEDI-524) is a monoclonal antibody with enhanced neutralizing activity against RSV. In mice, motavizumab suppressed RSV replication which resulted in significant reduction of clinical parameters of disease severity. We evaluated the effect of motavizumab on the local and systemic immune response induced by RSV in the mouse model. Balb/c mice were intranasally inoculated with 106.5 PFU RSV A2 or medium. Motavizumab was given once intraperitoneally (1.25 mg/mouse) as prophylaxis, 24 h before virus inoculation. Bronchoalveolar lavage (BAL) and serum samples were obtained at days 1, 5 (acute) and 28 (long-term) post inoculation and analyzed with a multiplex assay (Beadlyte Upstate, NY) for simultaneous quantitation of 18 cytokines: IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, KC (similar to human IL-8), IL-10, IL-12p40, IL-12p70, IL-13, IL-17, TNF-α, MCP-1, RANTES, IFN-γ and GM-CSF. Overall, cytokine concentrations were lower in serum than in BAL samples. By day 28, only KC was detected in BAL specimens at low concentrations in all groups. Administration of motavizumab significantly reduced (p < 0.05) BAL concentrations of IL-1α, IL-12p70 and TNF-α on day 1, and concentrations of IFN-γ on days 1 and 5 compared with RSV-infected untreated controls. In the systemic compartment, the concentrations of IL-10, IFN-γ and KC were significantly reduced in the motavizumab-treated mice compared with the untreated controls. In summary, prophylactic administration of motavizumab was associated with significant reductions on RSV replication and concentrations of cytokine and chemokines, which are likely related to the improvement observed in clinical markers of disease severity.

Abstract Background Respiratory syncytial virus (RSV) is the leading respiratory viral pathogen in young children worldwide. RSV disease is associated with acute airway obstruction (AO), long-term airway hyperresponsiveness (AHR), and chronic lung inflammation. Using two different mouse strains, this study was designed to determine whether RSV disease patterns are host-dependent. C57BL/6 and BALB/c mice were inoculated with RSV and followed for 77 days. RSV loads were measured by plaque assay and polymerase chain reaction (PCR) in bronchoalveolar lavage (BAL) and whole lung samples; cytokines were measured in BAL samples. Lung inflammation was evaluated with a histopathologic score (HPS), and AO and AHR were determined by plethysmography. Results Viral load dynamics, histopathologic score (HPS), cytokine concentrations, AO and long-term AHR were similar in both strains of RSV-infected mice, although RSV-infected C57BL/6 mice developed significantly greater AO compared with RSV-infected BALB/c mice on day 5. PCR detected RSV RNA in BAL samples of RSV infected mice until day 42, and in whole lung samples through day 77. BAL concentrations of cytokines TNF-α, IFN-γ, and chemokines MIG, RANTES and MIP-1α were significantly elevated in both strains of RSV-infected mice compared with their respective controls. Viral load measured by PCR significantly correlated with disease severity on days 14 and 21. Conclusion RSV-induced acute and chronic airway disease is independent of genetic background.

Vaccines have saved the lives of millions of children and continue to be essential interventions to control infectious diseases among people of all ages. The list of recommended vaccines for children has expanded in recent years; however, many viral, bacterial and parasitic infections remain a major cause of morbidity and mortality in children. Improved vaccines to prevent Streptococcus pneumoniae and Neisseria meningitidis infections in children will soon be available. Recent scientific advances are being applied to design new childhood vaccines affording enhanced efficacy, safety and tolerability. Financial barriers and other obstacles to adequate vaccine access need to be eliminated to assure coverage for all children and adolescents.

Several studies have described a clear association between respiratory syncytial virus (RSV) lower respiratory tract infection in infancy and the subsequent development of persistent wheezing in children. Using the mouse model we demonstrated that RSV induces long-term airway disease characterized by chronic airway inflammation and airway hyperreactivity (AHR). The RSV murine model offers great advantages to study the immunopathogenesis of RSV-induced long-term airway disease. Mice can be challenged with aerosolized methylcholine to determine the presence of AHR. We can apply the reverse transcription-polymerase chain reaction assay (RT-PCR) to detect RSV RNA in the respiratory tract and we can perform lung gene expression analysis to further characterize the chronic changes induced by RSV infection. Compared with sham-inoculated controls, RSV-infected mice developed chronic airway disease characterized by AHR and persistent airway inflammation. Forty-two days after RSV infection, a time point when RSV could no longer be isolated, RT-PCR demonstrated, quite unexpectedly, the presence of RSV RNA in the lower respiratory tract of mice. The presence of genomic RNA persisted for months after inoculation. Furthermore, preliminary studies also demonstrated that on day 42 there were a number of genes differentially expressed in RSV-infected mice compared with controls. RSV-infected mice with persistent AHR exhibited presence of abnormal chronic inflammatory changes, altered gene expression profiles, and persistence of RSV RNA, which may contribute to long-term airway disease induced by RSV. Future studies are needed to define the significance of persistent RSV RNA in the mouse model, and its potential role in the pathogenesis of RSV-induced persistent wheezing in children.

Background: Risk factors for severe respiratory syncytial virus (RSV) disease include prematurity, congenital heart disease, chronic lung disease, and immunocompromised states. There is no consensus concerning the most effective therapy for severe RSV infection in high-risk patients. Palivizumab is approved for prevention of RSV disease, and ribavirin is approved for treatment of RSV infections but its efficacy in high-risk patients has not been conclusively established., Methods: Retrospective chart review of RSV infected children treated with intravenous palivizumab and ribavirin in a pediatric hospital from 2001 to 2005., Results: : Twenty male and 11 female patients with a median age of 23.4 months, hospitalized for RSV infection were treated with intravenous palivizumab from October 2001 through July 2005. Mean dose was 14.93 (SD = 0.68) mg/kg. Twenty-five patients (80%) also received ribavirin, 22 of whom by aerosolization. Common baseline diagnoses were malignancy (n = 15), congenital heart disease (n = 5), and prematurity (n = 5). Included above are 1 cardiac and 6 hematopoietic stem cell transplant recipients. Eighteen (58%) patients had signs of lower respiratory tract infection, 17 were hypoxemic, 10 required intensive care unit (ICU) admission, and 5 were intubated. Twenty-nine (93.6%) patients survived and 2 died. No adverse events attributed to intravenous palivizumab or ribavirin administration were observed., Conclusions: Treatment of RSV-infected high-risk children with intravenous palivizumab alone or in combination with ribavirin was well tolerated and associated with decreased mortality compared with previous reports.

Motavizumab (MEDI-524) is a monoclonal antibody with enhanced neutralizing activity against RSV. In mice, motavizumab suppressed RSV replication which resulted in significant reduction of clinical parameters of disease severity. We evaluated the effect of motavizumab on the local and systemic immune response induced by RSV in the mouse model. Balb/c mice were intranasally inoculated with 106.5 PFU RSV A2 or medium. Motavizumab was given once intraperitoneally (1.25 mg/mouse) as prophylaxis, 24 h before virus inoculation. Bronchoalveolar lavage (BAL) and serum samples were obtained at days 1, 5 (acute) and 28 (long-term) post inoculation and analyzed with a multiplex assay (Beadlyte Upstate, NY) for simultaneous quantitation of 18 cytokines: IL-1alpha, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, KC (similar to human IL-8), IL-10, IL-12p40, IL-12p70, IL-13, IL-17, TNF-alpha, MCP-1, RANTES, IFN-gamma and GM-CSF. Overall, cytokine concentrations were lower in serum than in BAL samples. By day 28, only KC was detected in BAL specimens at low concentrations in all groups. Administration of motavizumab significantly reduced (p < 0.05) BAL concentrations of IL-1alpha, IL-12p70 and TNF-alpha on day 1, and concentrations of IFN-gamma on days 1 and 5 compared with RSV-infected untreated controls. In the systemic compartment, the concentrations of IL-10, IFN-gamma and KC were significantly reduced in the motavizumab-treated mice compared with the untreated controls. In summary, prophylactic administration of motavizumab was associated with significant reductions on RSV replication and concentrations of cytokine and chemokines, which are likely related to the improvement observed in clinical markers of disease severity.

Respiratory syncytial virus (RSV) is the most important cause of viral lower respiratory tract illness in infants and children worldwide and is responsible for over 120 000 annual hospitalizations in infants in the US alone. RSV is also recognized as a major respiratory viral pathogen in the elderly and other high-risk populations. Bronchiolitis, pneumonia, apnea, respiratory failure, and death are well known manifestations of severe acute RSV disease. RSV infection has also been associated with recurrent wheezing in children, but the mechanisms involved in this association are not completely understood. The host immune response plays a significant role in controlling the infection but is likely also involved in augmenting the disease through pathways that have not been completely identified. The treatment options for RSV infection are very limited. Ribavirin, corticosteroids, and bronchodilators are not used routinely because they have not proven to be sufficiently effective. Education of caregivers, strict handwashing, and avoidance of exposure to environmental factors associated with severe forms of RSV infection are among the most effective preventive means. Passive immunization with monoclonal antibodies provides protection against severe RSV disease in high-risk children. Clinical trials to evaluate the safety and efficacy of a second-generation monoclonal antibody are underway. Efforts to develop a safe and effective RSV vaccine have continued despite the poor outcomes observed following the administration of formalin-inactivated formulations in the 1960s. In the last decade, live attenuated vaccines (including those developed by recombinant techniques) and purified subunit vaccines have all been evaluated in humans. Results of clinical trials have been encouraging, but the availability of a safe and effective RSV vaccine is not a reality yet. Better prevention strategies will have an impact, not only on acute morbidity caused by RSV, but will also likely have an effect on ameliorating the chronic consequences of this disease.

Respiratory syncytial virus (RSV) is the leading viral pathogen responsible for bronchiolitis and pneumonia in infants and young children worldwide. We have previously shown in the mouse model that treatment with an anti-RSV neutralizing monoclonal antibody (MAb) against the F glycoprotein of RSV, palivizumab, decreased lung inflammation, airway obstruction, and postmethacholine airway hyperresponsiveness. MEDI-524, or Numax, is a new MAb derived from palivizumab with enhanced neutralizing activity against RSV. We compared the effects of these two MAbs on different markers of disease severity using the murine model of RSV infection. BALB/c mice were intranasally inoculated with RSV A2. Palivizumab or MEDI-524 was administered once at either 24 h before or 48 h after RSV inoculation. Regardless of the time of administration, all treated mice showed significantly decreased RSV loads in bronchoalveolar lavage samples measured by plaque assay. Only MEDI-524 given at -24 h significantly decreased lung RSV RNA loads on days 5 and 28 after RSV inoculation. Pulmonary histopathologic scores, airway obstruction, and postmethacholine airway hyperresponsiveness were significantly reduced in mice treated with MEDI-524 at 24 h before inoculation, compared with untreated controls and the other regimens evaluated. MEDI-524 was superior to palivizumab on several outcome variables of RSV disease assessed in the mouse model: viral replication, inflammatory and clinical markers of acute disease severity, and long-term pulmonary abnormalities.

Background: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and pneumonia among children aged < 1 year. The majority of children hospitalized for RSV infection are younger than 6 months of age. RSV also causes repeated infections including severe lower respiratory tract disease, which may occur at any age, especially among the elderly or those with compromised cardiac, pulmonary, or immune systems., Methods: Using the mouse model of RSV infection, this article examines the immunopathogenesis during acute and chronic phases of the disease. This model allows for measurement of basal enhanced pause, which reflects airway obstruction in the acute phase, and the response to methacholine challenge to assess airway hyperresponsiveness during the chronic phase. This article also summarizes some recent studies focusing on novel perspectives and strategies for treatment and prevention of RSV infections., Results: Compared with the lungs of sham-inoculated control mice, mice inoculated with live RSV showed a persistent progression of the severity of pneumonia as determined by an increasing histopathologic score. Mucus production of RSV-infected mice in the acute phase illustrated increased periodic acid-Schiff-positive hypertrophic cells in central and peripheral airways., Conclusions: RSV-infected mice with persistent airway hyperresponsiveness exhibited the presence of abnormal chronic inflammatory changes and mucus overproduction, which likely contributed to long term airway disease induced by RSV infection. These findings provide a histologic correlation to the abnormal pulmonary responses documented by plethysmography. Current trials have demonstrated positive results in continuing to target different alternatives for a new RSV vaccine.

Mycoplasma pneumoniae is a major cause of community-acquired pneumonia. We evaluated the efficacy of LBM415, a novel peptide deformylase inhibitor antimicrobial agent, for the treatment of M. pneumoniae pneumonia in a mouse model. Eight-week-old BALB/c mice were intranasally inoculated once with 10(7) CFU of M. pneumoniae. Groups of mice were treated with LBM415 (50 mg/kg of body weight) or placebo subcutaneously daily for 13 days, starting 24 h after inoculation. Groups of mice were evaluated at the baseline; at days of treatment 1, 3, 6, and 13; and at 7 days after treatment. The MIC of LBM415 against M. pneumoniae was <0.005 microg/ml. LBM415-treated mice had significantly lower bronchoalveolar lavage fluid M. pneumoniae concentrations than placebo-treated mice on days 6 and 13 of treatment. Compared with placebo treatment, therapy with LBM415 significantly decreased lung histopathology scores at days 3, 6, and 13 of treatment and at 7 days after treatment. Airway obstruction was significantly lower in LBM415-treated mice than in placebo-treated mice on days 1, 3, and 6 of treatment and after 7 days of therapy, while airway hyperresponsiveness was significantly lower only on day 3 of therapy. The bronchoalveolar lavage fluid concentrations of tumor necrosis factor alpha, gamma interferon (IFN-gamma), interleukin-6 (IL-6), IL-12, KC (functional IL-8), monocyte chemotactic protein 1, macrophage inflammatory protein 1alpha, monokine induced by IFN-gamma, and IFN-inducible protein 10 were significantly reduced in LBM415-treated mice compared with the levels in placebo-treated mice. There were no differences in the bronchoalveolar lavage fluid concentrations of granulocyte-macrophage colony-stimulating factor, IL-1beta, IL-2, IL-4, IL-5, and IL-10 between the two groups of mice. LBM415 therapy had beneficial microbiologic, histologic, respiratory, and immunologic effects on acute murine M. pneumoniae pneumonia.

We evaluated the efficacy of azithromycin therapy given as a single high dose or divided over 5 days for the treatment of mild experimental Mycoplasma pneumoniae pneumonia. Although both azithromycin regimens significantly reduced quantitative cultures, lung histopathology, and pulmonary cytokines and chemokines, there were no significant differences between the two regimens.

Purpose of Review: Respiratory syncytial virus is the leading viral pathogen associated with lower respiratory tract infection in young children worldwide. The pathogenesis of acute bronchiolitis and the mechanisms by which the virus induces long-term airway disease remain to be elucidated. This review highlights new findings reported in the English-language medical literature from January 2004 to January 2005., Recent Findings: Several studies have confirmed a strong association between respiratory syncytial virus infection in infancy and an increased risk for recurrent wheezing. Evidence indicates that the exaggerated immune response and abnormal neurogenic mechanisms induced by the virus play a significant role in the pathogenesis of the disease. Different genetic and immune markers have been correlated with acute disease severity and with increased risk of long-term pulmonary abnormalities. Recently, the application of real time polymerase chain reaction has demonstrated the persistence of respiratory syncytial virus RNA in the lungs of infected mice for months after inoculation. This unexpected observation has stimulated discussions as to whether the long-term presence of the virus could contribute to the long-term airway disease observed in children after respiratory syncytial virus lower respiratory tract infection., Summary: Despite almost half a century of active research into the pathogenesis of respiratory syncytial virus-induced acute and chronic airway disease, many questions remain unresolved. Studies in animal models demonstrate that interventions reducing viral replication resulted in improvement of acute disease severity and long-term pulmonary abnormalities. The stage is ready for clinical studies to determine whether preventing or delaying the primary infection could reduce the incidence of recurrent wheezing in children.

Microbiologic causes of meningitis include bacteria, viruses, fungi, and parasites. Before routine use of pneumococcal conjugate vaccine, bacterial meningitis affected almost 6000 people every year in the United States, and about half of all cases occurred in children 18 years old or younger. Prompt and accurate diagnosis and adequate treatment of bacterial meningitis in children remains a major challenge, as reflected by the continued high morbidity and case-fatality rates of the disease worldwide. Appropriate use of antibiotics, along with adjunctive therapies, such dexamethasone, has proved helpful in the prevention of neurologic sequelae in children with bacterial meningitis. Better understanding of pathophysiologic mechanisms likely would result in more effective therapies in the future.

Background: Respiratory syncytial virus (RSV) is the leading respiratory viral pathogen in young children worldwide. RSV disease is associated with acute airway obstruction (AO), long-term airway hyperresponsiveness (AHR), and chronic lung inflammation. Using two different mouse strains, this study was designed to determine whether RSV disease patterns are host-dependent. C57BL/6 and BALB/c mice were inoculated with RSV and followed for 77 days. RSV loads were measured by plaque assay and polymerase chain reaction (PCR) in bronchoalveolar lavage (BAL) and whole lung samples; cytokines were measured in BAL samples. Lung inflammation was evaluated with a histopathologic score (HPS), and AO and AHR were determined by plethysmography., Results: Viral load dynamics, histopathologic score (HPS), cytokine concentrations, AO and long-term AHR were similar in both strains of RSV-infected mice, although RSV-infected C57BL/6 mice developed significantly greater AO compared with RSV-infected BALB/c mice on day 5. PCR detected RSV RNA in BAL samples of RSV infected mice until day 42, and in whole lung samples through day 77. BAL concentrations of cytokines TNF-alpha, IFN-gamma, and chemokines MIG, RANTES and MIP-1alpha were significantly elevated in both strains of RSV-infected mice compared with their respective controls. Viral load measured by PCR significantly correlated with disease severity on days 14 and 21., Conclusion: RSV-induced acute and chronic airway disease is independent of genetic background.

Respiratory tract infections result in wheezing in a subset of patients. Mycoplasma pneumoniae is a common etiologic agent of acute respiratory infection in children and adults that has been associated with wheezing in 20-40% of individuals. The current study was undertaken to elucidate the host-dependent pulmonary and immunologic response to M. pneumoniae respiratory infection by studying mice with different immunogenetic backgrounds (BALB/c mice versus C57BL/6 mice). After M. pneumoniae infection, only BALB/c mice developed significant airway obstruction (AO) compared with controls. M. pneumoniae-infected BALB/c mice manifested significantly elevated airway hyperresponsiveness (AHR) compared with C57BL/6 mice 4 and 7 d after inoculation as well as BALB/c control mice. Compared with C57BL/6 mice, BALB/c mice developed worse pulmonary inflammation, including greater peribronchial infiltrates. Infected BALB/c mice had significantly higher concentrations of tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-1beta, IL-6, IL-12, KC (functional IL-8), and macrophage inflammatory protein 1alpha in the bronchoalveolar lavage fluid compared with infected C57BL/6 mice. No differences in IL-2, IL-4, IL-5, IL-10, and granulocyte/macrophage colony-stimulating factor concentrations were found. The mice in this study exhibited host-dependent infection-related AO and AHR associated with chemokine and T-helper type (Th)1 pulmonary host response and not Th2 response after M. pneumoniae infection.

Better therapies and prevention strategies are needed to decrease the burden of acute RSV disease in all age populations worldwide. Furthermore, we can hypothesize that those improved measures also would likely have an effect on the chronic consequences of RSV infection in children and will reduce the incidence of recurrent wheezing and persistent pulmonary function abnormalities caused by RSV LRIs.

Numerous studies have described an association between respiratory sincticial virus (RSV) infection in infancy and the subsequent development of airway hyperresponsiveness (AHR). Besides the exaggerated immune response and the abnormal neurogenic mechanisms induced by RSV, recent studies have correlated the "persistence" of RSV in the lower respiratory tract with the development of AHR. Several investigators have evaluated whether treatment with antiviral or immunosuppressive agents could decrease the long term respiratory abnormalities induced by RSV. The RSV murine model has allowed us to study the immunopathogenesis of RSV-induced AHR. Once the airway obstruction, typical of acute disease, is resolved and no virus is longer detected by cell cultures, mice progress into a chronic phase characterized by AHR and persistent airway inflammation. The use of polymerase chain reaction assay for RSV quantitation has demonstrated, quite unexpectedly, the presence of RSV RNA in the lower respiratory tract of mice during the chronic phase of the disease. As an example of intervention, the administration of an anti-RSV neutralizing antibody (palivizumab) was associated with a significant reduction in viral replication, pulmonary inflammation and inflammatory cytokines, as well as a significant improvement in the pulmonary function both in the acute and chronic phases of the disease. Future clinical studies to determine whether therapy with palivizumab can prevent the long-term morbidity associated with RSV in children are warranted.

Mycoplasma pneumoniae is a major etiologic agent of acute lower respiratory infections. We evaluated the antimicrobial and immunologic effects of cethromycin (ABT-773), a ketolide antibiotic, for the treatment of M. pneumoniae pneumonia in a mouse model. Eight-week-old BALB/c mice were inoculated intranasally once with 10(6) CFU of M. pneumoniae on day 0. Treatment was started 24 h after inoculation. Groups of mice were treated subcutaneously with cethromycin at 25 mg/kg of body weight or with placebo daily until sacrifice. Five to ten mice per group were evaluated at days 1, 4, 7, and 10 after inoculation. Outcome variables included bronchoalveolar lavage (BAL) for M. pneumoniae quantitative culture and cytokine and chemokine concentration determinations by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-alpha], gamma interferon [IFN-gamma], interleukin-1beta [IL-1beta], IL-2, IL-4, IL-12, granulocyte-macrophage colony-stimulating factor, IL-8, monocyte chemoattractant protein 1 [MCP-1], and macrophage inflammatory protein 1alpha [MIP-1alpha]), histopathologic score of the lungs (HPS), and pulmonary function tests (PFT) using whole-body, unrestrained plethysmography at the baseline and post-methacholine exposure as indicators of airway obstruction (AO) and airway hyperresponsiveness (AHR), respectively. The cethromycin-treated mice had a greater reduction in M. pneumoniae culture titers than placebo-treated mice, reaching statistical significance on days 7 and 10 (P < 0.05). HPS was significantly reduced in cethromycin-treated mice compared with placebo-treated mice on days 4, 7, and 10 (P < 0.05). Cytokine concentrations in BAL samples were reduced in mice that received cethromycin, and the differences were statistically significant for 7 of the 10 cytokines measured (TNF-alpha, IFN-gamma, IL-1beta, IL-8, IL-12, MCP-1, and MIP-1alpha) on day 4 (P < 0.05). PFT values were improved in the cethromycin-treated mice, with AO and AHR significantly reduced on day 4 (P < 0.05). In this mouse model, treatment with cethromycin significantly reduced M. pneumoniae culture titers in BAL samples, cytokine and chemokine concentrations in BAL samples, histologic inflammation in the lungs, and disease severity as defined by AO and AHR.

Numerous studies have described a strong association between respiratory syncytial virus (RSV) infection in infancy and the development of recurrent wheezing and airway hyperresponsiveness. We evaluated the effect of an anti-RSV neutralizing monoclonal antibody (palivizumab) on different aspects of RSV disease by using a murine model. BALB/c mice were intranasally inoculated with RSV A2. Palivizumab or an isotype-matched control antibody was administered once at 24 h before inoculation, 1 h after inoculation, or 48 h after inoculation. Regardless of the timing of administration, all mice treated with the neutralizing antibody showed significantly decreased RSV loads in bronchoalveolar lavage (BAL) and lung specimens compared with those of infected controls. Pulmonary histopathologic scores, airway obstruction measured by plethysmography, and airway hyperresponsiveness after methacholine challenge were significantly reduced in mice treated with the anti-RSV antibody 24 h before inoculation compared with those for untreated controls. Concentrations of interferon-gamma, interleukin-10, macrophage inflammatory protein 1alpha, regulated on activation normal T-cell expressed and secreted (RANTES), and eotaxin in BAL fluids were also significantly reduced in mice treated with palivizumab 24 h before inoculation. This study demonstrates that reduced RSV replication was associated with significant modulation of inflammatory and clinical markers of acute disease severity and significant improvement of the long-term pulmonary abnormalities. Studies to determine whether strategies aimed at preventing or reducing RSV replication could decrease the long-term morbidity associated with RSV infection in children should be considered.