Global control of pneumococcal infections by pneumococcal vaccines.

Streptococcus pneumoniae is a major worldwide cause of morbidity and mortality. Pneumococcal carriage is considered to be an important source of horizontal spread of this pathogen within the community. Pneumococcal conjugate vaccine (PCV) is capable of inducing serotype-specific antibodies in sera of infants, and has been suggested to reduce nasopharyngeal carriage of vaccine-type pneumococci in children. PCV is generally immunogenic for pediatric patients with invasive pneumococcal disease, with an exception for the infecting serotypes. Based on evidences from the clinical trials of PCV, the health impact of childhood pneumococcal pneumonia appears to be high in developing countries where most of global childhood pneumonia deaths occur. PCV vaccination may prevent hundreds of deaths per 100,000 children vaccinated in developing countries, while PCV vaccination is expected to prevent less than 10 deaths per 100,000 children vaccinated in the developed countries. Therefore, the WHO has proposed a strategy to reduce the incidence of severe pneumonia by 75% in child less than 5 years of age compared to 2010 levels by 2025.

Hyporesponsiveness to the infecting serotype after vaccination of children with seven-valent pneumococcal conjugate vaccine following invasive pneumococcal disease.

Antibody responses to the infecting serotype in children who are vaccinated with pneumococcal conjugate vaccine (PCV) after having invasive pneumococcal diseases (IPD) have not been fully investigated. Of 56 children diagnosed with IPD between October 2009 and April 2013 in whom the infecting serotype was confirmed, 17 who were vaccinated with PCV7 following IPD were tested to determine the geometric mean concentration of serotype-specific immunoglobulin G (IgG) and the geometric mean titers of opsonization indices (OIs) using paired sera obtained at the onset of IPD and after PCV doses following the resolution of IPD. The geometric mean concentrations of serotype-specific IgG for all PCV7 serotypes other than serotype 6B were significantly increased after the last PCV7 dose compared with those at the time of IPD onset (P<0.01), as were the geometric mean titers of OIs for all PCV7 serotypes. In 14 children with IPD caused by PCV7 serotypes for whom both IgG and OI results were available, the OIs for the infecting serotype at the time of IPD onset were <8, although the IgG levels varied between from <0.2 to >5.0µg/ml. After the last PCV7 dose, the OIs for the infecting serotype remained <8 for six (43%) of 14 children. In these six children, hyporesponsiveness to PCV7 was specific for the infecting serotype. Hyporesponsiveness was found for serotypes 6B (n=5) and 23F (n=1). No difference was found between the responders (n=8) and the hyporesponders (n=6) with regard to any clinical characteristics. Our data suggest that hyporesponsiveness to the infecting serotype may occur in children vaccinated with PCV7 following IPD.

Low opsonic activity to the infecting serotype in pediatric patients with invasive pneumococcal disease.

Serotype-specific protective immunity in pediatric patients with invasive pneumococcal disease (IPD) has not been fully investigated. To determine the protective immunity to the infecting serotype, the serotype-specific immunoglobulin G (IgG) levels and opsonization indices (OIs) were examined in 24 Japanese pediatric patients whose serum was collected within one month of an IPD episode between May 2008 and June 2011. The median age (range) of IPD patients was 17 (10-108) months and 63% were boys. In all 17 patients tested, the levels of serotype-specific IgG to the infecting serotype were higher than 0.2 µg/ml, but the OIs to the infecting serotype were <8. The avidities of 19F- or 6B-specific IgG in patients with levels higher than 5.0 µg/ml, but with undetectable OIs, were confirmed to be lower than those in patients with high OIs. Our data demonstrated that although the levels of serotype-specific IgG to the infecting serotype were higher than 0.2 µg/ml in sera of pediatric patients with IPD, the OIs were low one month after the IPD episode. Low opsonic activities in these patients may, in part, be explained by the low avidity of serotype-specific IgG.

Clinical evaluation of endoscopic bronchial occlusion with silicone spigots for the management of persistent pulmonary air leaks.

OBJECTIVE: The aim of this study was to evaluate the clinical effectiveness of endoscopic bronchial occlusion (EBO) with endobronchial Watanabe spigots (EWSs), a type of silicone bronchial blocker, for managing prolonged pulmonary air leaks. PATIENTS AND METHODS: Between October 2002 and April 2010, 24 patients with surgically incurable pulmonary air leaks underwent EBO with EWSs. The spigot was grasped with forceps and inserted into the affected bronchus by using a flexible bronchoscope through an endotracheal or a tracheostomy tube. RESULTS: In each patient, at least one EWS (mean=2.8) was placed for air leaks due to pneumothorax (n=15), empyema (n=8), or postsurgical complications (n=1). Twelve patients (50%) had complete resolution of the air leaks and seven (29.2%) had a reduction in air leaks, but five (20.8%) showed no improvement. Twenty-three patients required thoracic drainage tubes, which were successfully removed after EBO in 15 patients (65.2%). Of the 24 patients, four experienced severe respiratory failure requiring mechanical ventilation but were successfully treated. Complications were spigot migration, atelectasis, pneumonia, and lung abscess, but none caused significant mortality. CONCLUSION: EBO with EWSs seems to be a reasonable and manageable treatment option for patients with prolonged pulmonary air leaks, including those with severe respiratory failure requiring mechanical ventilation.

A major influence of CYP2C19 genotype on the steady-state concentration of N-desmethylclobazam.

N-desmethylclobazam (N-CLB), the major metabolite of clobazam (CLB), exerts a large influence on therapeutic and adverse effects of CLB. A substantial inter-individual variability has been observed in the ratios of N-CLB concentration/CLB dose and of the N-CLB/CLB concentration. We document here a genotype-phenotype correlation between CYP2C19 polymorphisms and those ratios. Patients with two mutated CYP2C19 alleles show significantly higher ratios than those with the wild type genotype: patients with one mutated allele exhibited intermediate trait. That is, the degree of elevation in the ratios was dependent on the number of mutated alleles of CYP2C19 (gene-dose effect). The N-CLB concentration/CLB dose ratio of patients with two mutated alleles was more than six fold higher than that of wild type patients. Thus, the serum N-CLB/CLB concentration ratio may be a valuable parameter to screen for patients at risk for side effects. Such precautions may be clinically relevant in populations where the mutant allele frequency is high, such as in Asian populations ( approximately 35%). Patients co-medicated with CYP3A4 inducer showed lower CLB concentration/CLB dose ratios and higher N-CLB/CLB concentration ratios. The overall effect of CYP3A4 inducer on N-CLB metabolism, however, was small and, thus, we conclude that the CYP2C19 genotype is the major determinant of the N-CLB concentration. For this reason it is crucial for the better management of epilepsy and other chronic illnesses in general to establish the correlation of genotype of CYP enzymes and pharmacokinetics/dynamics of drugs.