Respiratory syncytial virus increases the virulence of streptococcus pneumoniae by binding to penicillin binding protein 1a. A new paradigm in respiratory infection. (Fortenberry)

Smith CM, Sandrini S, Datta S, et al. Respiratory syncytial virus increases the virulence of streptococcus pneumoniae by binding to penicillin binding protein 1a. A new paradigm in respiratory infection. Am J Respir Crit Care Med. 2014 Jul 15;190(2):196-207.

Full-text for Children’s and Emory users.

Rationale: Respiratory syncytial virus (RSV) and Streptococcus pneumoniae are major respiratory pathogens. Coinfection with RSV and S. pneumoniae is associated with severe and often fatal pneumonia but the molecular basis for this remains unclear.

Objectives: To determine if interaction between RSV and pneumococci enhances pneumococcal virulence.

Methods: We used confocal microscopy and Western blot to identify the receptors involved in direct binding of RSV and pneumococci, the effects of which were studied in both in vivo and in vitro models of infection. Human ciliated respiratory epithelial cell cultures were infected with RSV for 72 hours and then challenged with pneumococci. Pneumococci were collected after 2 hours exposure and changes in gene expression determined using quantitative real-time polymerase chain reaction.

Measurements and Main Results: Following incubation with RSV or purified G protein, pneumococci demonstrated a significant increase in the inflammatory response and bacterial adherence to human ciliated epithelial cultures and markedly increased virulence in a pneumonia model in mice. This was associated with extensive changes in the pneumococcal transcriptome and significant up-regulation in the expression of key pneumococcal virulence genes, including the gene for the pneumococcal toxin, pneumolysin. We show that mechanistically this is caused by RSV G glycoprotein binding penicillin binding protein 1a.

Conclusions: The direct interaction between a respiratory virus protein and the pneumococcus resulting in increased bacterial virulence and worsening disease outcome is a new paradigm in respiratory infection.

Corticosteroids are associated with repression of adaptive immunity gene programs in pediatric septic shock. (Fortenberry)

Wong HR, Cvijanovich NZ, Allen GL, et al. Corticosteroids are associated with repression of adaptive immunity gene programs in pediatric septic shock. Am J Respir Crit Care Med. 2014 Apr 15;189(8):940-6.

RATIONALE: Corticosteroids are prescribed commonly for patients with septic shock, but their use remains controversial and concerns remain regarding side effects.

OBJECTIVES: To determine the effect of adjunctive corticosteroids on the genomic response of pediatric septic shock.

METHODS: We retrospectively analyzed an existing transcriptomic database of pediatric septic shock. Subjects receiving any formulation of systemic corticosteroids at the time of blood draw for microarray analysis were classified in the septic shock corticosteroid group. We compared normal control subjects (n = 52), a septic shock no corticosteroid group (n = 110), and a septic shock corticosteroid group (n = 70) using analysis of variance. Genes differentially regulated between the no corticosteroid group and the corticosteroid group were analyzed using Ingenuity Pathway Analysis.

MEASUREMENTS AND MAIN RESULTS: The two study groups did not differ with respect to illness severity, organ failure burden, mortality, or mortality risk. There were 319 gene probes differentially regulated between the no corticosteroid group and the corticosteroid group. These genes corresponded predominately to adaptive immunity-related signaling pathways, and were down-regulated relative to control subjects. Notably, the degree of down-regulation was significantly greater in the corticosteroid group, compared with the no corticosteroid group. A similar pattern was observed for genes corresponding to the glucocorticoid receptor signaling pathway.

CONCLUSIONS: Administration of corticosteroids in pediatric septic shock is associated with additional repression of genes corresponding to adaptive immunity. These data should be taken into account when considering the benefit to risk ratio of adjunctive corticosteroids for septic shock.

Full-text for Children’s and Emory users.

Beneficial hemodynamic effects of prone positioning in patients with acute respiratory distress syndrome. (Fortenberry)

Jozwiak M, Teboul JL, Anguel N, Persichini R, Silva S, Chemla D, Richard C, Monnet X. Beneficial hemodynamic effects of prone positioning in patients with acute respiratory distress syndrome. Am J Respir Crit Care Med. 2013 Dec 15;188(12):1428-33.

Rationale: The effects of prone positioning during acute respiratory distress syndrome on all the components of cardiac function have not been investigated under protective ventilation and maximal alveolar recruitment.

Objectives: To investigate the hemodynamic effects of prone positioning.

Methods: We included 18 patients with acute respiratory distress syndrome ventilated with protective ventilation and an end-expiratory positive pressure titrated to a plateau pressure of 28-30 cm H2O. Before and within 20 minutes of starting prone positioning, hemodynamic, respiratory, intraabdominal pressure, and echocardiographic data were collected. Before prone positioning, preload reserve was assessed by a passive leg raising test.

Measurements and Main Results: In all patients, prone positioning increased the ratio of arterial oxygen partial pressure over inspired oxygen fraction, the intraabdominal pressure, and the right and left cardiac preload. The pulmonary vascular resistance decreased along with the ratio of the right/left ventricular end-diastolic areas suggesting a decrease of the right ventricular afterload. In the nine patients with preload reserve, prone positioning significantly increased cardiac index (3.0 [2.3-3.5] to 3.6 [3.2-4.4] L/min/m(2)). In the remaining patients, cardiac index did not change despite a significant decrease in the pulmonary vascular resistance.

Conclusions: In patients with acute respiratory distress syndrome under protective ventilation and maximal alveolar recruitment, prone positioning increased the cardiac index only in patients with preload reserve, emphasizing the important role of preload in the hemodynamic effects of prone positioning.

Full-text for Children’s and Emory users

Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates. (Fortenberry)

Vissing NH, Chawes BL, Bisgaard H. Increased risk of pneumonia and bronchiolitis after bacterial colonization of the airways as neonates. Am J Respir Crit Care Med. 2013 Oct 3.

Rationale: The frequency of pneumonia and bronchiolitis exhibits considerable variation in otherwise healthy children, and suspected risk factors explain only a minor proportion of the variation. We hypothesized that alterations in the airway microbiome in early life may be associated with susceptibility to pneumonia and bronchiolitis in young children.

Objectives: To investigate the relation between neonatal airway colonization and pneumonia and bronchiolitis during the first three years of life.

Methods: Participants comprised children of the COPSAC2000 cohort; a prospective birth cohort study of 411 children born to asthmatic mothers. Aspirates from the hypopharynx at age four weeks were cultured for S.pneumoniae, H.influenzae, M.catarrhalis, and S.aureus. Clinical information on pneumonia and bronchiolitis within the first three years of life was prospectively collected by the research physicians at the center. Analyses were adjusted for covariates associated pneumonia and bronchiolitisand bacterial airway colonization.

Measurements and Main Results: Hypopharyngeal aspirates and full clinical follow-up until three years of age were available for 265 children. Of these, 56 (21%) neonates were colonized with S.pneumoniae, H.influenzae and/or M.catarrhalis at four weeks of age. Colonization with at least one of these microorganisms, (but not S.aureus), was significantly associated with increased incidence of pneumonia and bronchiolitis (adjusted Incidence Rate Ratio=1.79[1.29-2.48], p-value <0.005) independently of concurrent or later asthma.

Conclusion: Neonatal airway colonization with S.pneumoniae, H.influenzae or M.catarrhalis is associated with increased risk of pneumonia and bronchiolitis in early life independently of asthma. This suggests a role of pathogenic bacterial colonization of the airways in neonates for subsequent susceptibly to pneumonia and bronchiolitis.

Full-text for Children’s and Emory users.