Sandrijn van Schaik

Increased production of IFN-γ and cysteinyl leukotrienes in virus-induced wheezing

Abstract Background: An imbalance of production of T-helper lymphocyte cytokines, favoring overproduction of IL-4, is believed to be important in the pathogenesis of allergic asthma. However, less is known about the cytokine response in virus-induced wheezing, which is a major cause of morbidity in asthma. Objective: We undertook this study to determine the magnitude of IFN-γ, IL-4 and IL-10, and leukotriene (LT) responses in infants and children with virus-induced wheezing. Methods: We measured the concentrations of IFN-γ, IL-4 and IL-10, and cysteinyl LTs in respiratory secretions of 82 infants and young children during acute episodes of virus-induced wheezing. Control subjects were 47 infants and children with uncomplicated upper respiratory infections and 18 normal healthy infants. Results: Ratios of IFN-γ to IL-4 were higher (due to increased quantities of IFN-γ) in subjects with wheezing than in those with upper respiratory infection alone ( P = .003). Quantities of LTs were also increased in wheezing subjects in comparison with those with upper respiratory infections ( P = .009). There was a significant correlation between measured concentrations of IFN-γ and LTs (correlation coefficient=.451, P = .007). Quantities of IL-4 were slightly suppressed in the wheezing groups. Conclusions: An imbalance favoring overproduction of IFN-γ appears to be associated temporarily with virus-induced wheezing. A possible mechanism is the enhanced release of LTs from eosinophils or mast cells after sensitization by IFN-γ. (J Allergy Clin Immunol 1999;103:630-6.)

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 (IFNγ) 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 IFNγ 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 (IFNγ) and the presence of inflammatory cells, and lung tissue sections were examined for histopathologic changes. The role of IFNγ was further addressed in studies of IFNγ knock‐out mice (IFNγ−/−) and of mice depleted of IFNγ 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‐γ. Both IFN‐γ−/− mice and mice treated with anti‐IFNγ developed more extensive inflammation of the airways than control mice. However mice lacking IFNγ exhibited less severe signs of airway obstruction. Together these data suggest a protective role of IFNγ in RSV infection in terms of limiting viral replication and inflammatory responses but also a pathogenic role in causing airway obstruction. J. Med. Virol. 62:257–266, 2000.

Respiratory Syncytial Virus Affects Pulmonary Function in BALB/c Mice

BALB/c mice inoculated intranasally with respiratory syncytial virus (RSV) were studied in a whole-body plethysmograph to determine if signs of respiratory illness similar to those observed in human infants could be detected. Also, responsiveness to methacholine was assessed. RSV-infected mice showed significantly higher respiratory rates than did controls (409.2 vs. 305.2 breaths/min, P < .0001). Significantly increased airway responsiveness to methacholine was noted, infected mice responding to a 100-fold lower dose than controls (P = .003). Together, these data provide the first objective evidence of respiratory illness in the mouse model of RSV infection, which enhances the value of this model for evaluating effects of vaccines, antivirals, and other drugs acting on respiratory tract disease caused by RSV.

Interprofessional Team Training in Pediatric Resuscitation: A Low-Cost, In Situ Simulation Program That Enhances Self-Efficacy Among Participants

Introduction. Simulation-based interprofessional team training is important to ensure high-quality, safe patient care, but several barriers exist, including diverging learning needs and schedules as well as limited available resources. Methods. The authors developed an in situ, simulation-based interprofessional team training program around pediatric emergencies for physicians, nurses, respiratory therapists, and pharmacists at their institution and performed an analysis of the program’s impact on self-efficacy in resuscitation skills among pediatric residents and nurses. Results. The results showed that with a design based in best principles of team training and simulation education, interprofessional team training is feasible and sustainable. The program had a beneficial effect on self-efficacy in resuscitation skills among both residents and nurses at the authors’ institution and received widespread acceptance. Conclusions. A collaborative approach to design and implementation of interprofessional team training can lead to a sustainable program that serves both patient safety and training requirements set forth by professional organizations.

Surfactant Dysfunction Develops in BALB/c Mice Infected with Respiratory Syncytial Virus

Recent reports suggest an important role for pulmonary surfactant in maintaining the patency of narrow conducting airways. The hypothesis that surfactant dysfunction is an important factor in respiratory syncytial virus(RSV) infection was tested in a mouse model. Mice, inoculated with either a low or a high dose of RSV, were subjected to bronchoalveolar lavage (BAL), and the fluids were analyzed for percentage of inflammatory cells and concentrations of proteins and phospholipids. After concentration of the surfactant by centrifugation, its function was analyzed with a capillary surfactometer. RSV infection resulted in a dose-dependent disruption of surfactant function (p < 0.0001). BAL fluid supernatants were added to calf lung surfactant extract (CLSE) to examine whether surfactant inhibiting agents were present. Indeed, BAL fluid supernatants of RSV-infected mice disrupted the normal function of calf lung surfactant extract in a dose dependent way (p < 0.0001), indicating the presence of inhibitors. Protein concentrations were increased in BAL fluids of RSV-infected mice versus control mice (p < 0.0001), and were inversely related to surfactant function (r = -0.44,p = 0.0004), suggesting an inhibitory effect of proteins. Protein concentration also correlated with the percentage of inflammatory cells(r = 0.51, p = 0.004). Phospholipid concentrations were not affected by the RSV infection. The results of these studies strongly suggest that a disruption of pulmonary surfactant function, most likely due to inhibition from inflammatory proteins, is important for the pathophysiology of RSV infection.

Pediatric Resident Confidence in Resuscitation Skills Relates to Mock Code Experience

To assess confidence in resuscitation skills among pediatric residents and its relationship to training and experience, all pediatric residents at one institution were surveyed regarding their confidence in technical and leadership resuscitation skills and their prior experience with real and mock codes. Respondents (61/82, 74%) reported participation in 4.9 ± 3.6 mock and 3.9 ± 5.0 real codes. Confidence score for all skills was 2.7 ± 0.6 (scale 1-5). Senior residents were more confident than interns (2.8 ± 0.5 vs 2.3 ± 0.5). Residents were more confident in basic (3.9 ± 0.6) than in advanced (2.6 ± 0.6) or expert resuscitation skills (1.6 ± 0.7). Confidence correlated with mock codes (r = 0.52) and to a lesser degree with real codes attended (r = 0.36). Performance of active roles and debriefing occurred more commonly with mock than with real codes. The data indicate that pediatric residents have limited confidence in resuscitation skills and that mock code training with active participation and debriefing may be an effective educational tool.

Ozone affects breathing and pulmonary surfactant function in mice

The effect on breathing of BALB/c mice immediately following ozone exposure (2 ppm) for 0, 2, 4, 6, and 8 h was studied with a whole body plethysmograph. Whether such exposure affected the normal function of pulmonary surfactant of maintaining airway patency was evaluated with a capillary surfactometer. Respiratory rate in mice that were not exposed was 358+/-16 (mean+/-S.E.) breaths/min and decreased to 202+/-10 after 6 h exposure. The mean pressure change caused by breathing diminished significantly, indicating a reduced tidal volume. BAL fluid from controls maintained patency for 88+/-2% of the study time, 120 s, implying a good surfactant function, but the ozone exposure caused the surfactant to lose its capability of maintaining patency (P < 0.0001). This decaying surfactant function of the BAL fluid coincided with an increasing protein concentration in the fluid of exposed animals (1.46+/-0.14 mg/ml in the 8-h group) as compared to controls (0.44+/-0.04 mg/ml, P < 0.0001). It is concluded that leakage of plasma proteins into the airway lumen was probably the main reason for the surfactant dysfunction, which may have contributed to the altered breathing pattern.

Perceptions of interprofessional teamwork in low-acuity settings: a qualitative analysis

Working effectively in interprofessional teams is a core competency for all health care professionals, yet there is a paucity of instruments with which to assess the associated skills. Published medical teamwork skills assessment tools focus primarily on high‐acuity situations, such as cardiopulmonary arrests and crisis events in operating rooms, and may not generalise to non‐high‐acuity environments, such as in‐patient wards and out‐patient clinics.

Role of T cells in a murine model of Escherichia coli sepsis

To study the role of T cells in gram‐negative sepsis, we developed a mouse model in which i.v. injection of Escherichia coli results in severe systemic illness, with high mortality rates after day 5. A large proportion of both CD4+ and CD8+ T cells are activated within 1 day after infection, as evidenced by up‐regulation of CD69 and down‐regulation of CD62L. Even more surprisingly, T cell‐deficient mice exhibit markedly decreased disease severity compared to WT mice, indicating a pathogenic role of T cells. Mice lacking IFN‐γ also show diminished disease, and exhibit reduced T cell activation. Therefore, the pathogenic role of T cells may be mediated by IFN‐γ. Both T cell‐ and IFN‐γ‐deficient mice have reduced serum IL‐6 levels compared to WT mice, suggesting that T cells may stimulate innate immune responses, resulting in enhancement of disease. These data indicate an important role for T cells in a mouse model of E. coli sepsis, and reveal an unexpected early and pathogenic T cell response to this bacterial infection.

Validation of a self-efficacy instrument and its relationship to performance of crisis resource management skills

Self-efficacy is thought to be important for resuscitation proficiency in that it influences the development of and access to the associated medical knowledge, procedural skills and crisis resource management (CRM) skills. Since performance assessment of CRM skills is challenging, self-efficacy is often used as a measure of competence in this area. While self-efficacy may influence performance, the true relationship between self-efficacy and performance in this setting has not been delineated. We developed an instrument to measure pediatric residents’ self-efficacy in CRM skills and assessed its content validity, internal structure, and relationship to other variables. After administering the instrument to 125 pediatric residents, critical care fellows and faculty, we performed an exploratory factor analysis within a confirmatory factor analysis as well as a known group comparison. The analyses specified four factors that we defined as: situation awareness, team management, environment management, and decision making. Pediatric residents reported lower self-efficacy than fellows and faculty in each factor. We also examined the correlation between self-efficacy and performance scores for a subset of 30 residents who led video recorded simulated resuscitations and had their performances rated by three observers. We found a significant, positive correlation between residents’ self-efficacy in situation awareness and environment management and their overall performance of CRM skills. Our findings suggest that in a specific context, self-efficacy as a form of self-assessment may be informative with regards to performance.