Streptococcus pneumoniae is one of the most common etiologic agents of community-acquired pneumonia, particularly bacteremic pneumonia. Pneumolysin, a multifunctional cytotoxin, is a putative virulence factor for S. pneumoniae; however, a direct role for pneumolysin in the early pathogenesis of pneumococcal pneumonia has not been confirmed in vivo. We compared the growth of a pneumolysindeficient (PLY[ -]) type 2 S. pneumoniae strain with its isogenic wild-type strain (PLY [ + ]) after direct endotracheal instillation of bacteria into murine lungs. Compared with PLY(-) bacteria, infection with PLY( +) bacteria produced greater injury to the alveolar-capillary barrier, as assayed by albumin concentrations in alveolar lavage, and substantially greater numbers of PLY( +) bacteria were recovered in alveolar lavages and lung homogenates at 3 and 6 h after infection. The presence of pneumolysin also contributed to the development of bacteremia, which was detected at 3 h after intratracheal instillation of PLY( +) bacteria.The direct effects of pneumolysin on lung injury and on the ability of pneumococci to evade local lung defenses was confirmed by addition of purified recombinant pneumolysin to inocula of PLY( -) pneumococci, which promoted growth of PLY( -) bacteria in the lung to levels comparable to those seen with the PLY( +) strain. We further demonstrated the contributions of both the cytolytic and the complement-activating properties of pneumolysin on enhanced bacterial growth in murine lungs using genetically modified pneumolysin congeners and genetically complement-deficient mice.Thus, pneumolysin facilitates intraalveolar replication of pneumococci, penetration of bacteria from alveoli into the interstitium of the lung, and dissemination of pneumococci into the bloodstream during experimental pneumonia. Moreover, both the cytotoxic and the complement-activating activities of pneumolysin may contribute independently to the acute pulmonary injury and the high rates of bacteremia which characterize pneumococcal pneumonia. (J. Clin. In-

Prevention of bacterial infection, which is a leading cause of morbidity in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), is a priority. However, the safety and immunogenicity of the pneumococcal vaccine in such patients remain controversial. We evaluated the currently available pneumococcal vaccine in patients with RA or SLE. Pneumococcal vaccination was not associated with an appreciable deterioration in any clinical or laboratory measure of disease activity in either group. One month after vaccination, patients in both groups had significant increases in geometric mean concentrations of pneumococcal polysaccharide-specific IgG to all 7 serotypes tested, as did control subjects. However, 14 (33.3%) of 42 patients with RA and 5 (20.8%) of 24 patients with SLE responded either to none or to only 1 of the 7 polysaccharides. Pneumococcal vaccination is generally safe and immunogenic in patients with RA or SLE, but a subset of patients may remain unprotected by the currently available vaccine.

The suboptimal efficacy of the currently available 23-valent pneumococcal vaccine in the growing population of adults ú65 years old may be related to the limited immunogenicity of the vaccine polysaccharides in this group. In this study, the majority of elderly outpatients with stable chronic illnesses generated a vigorous IgG response to seven vaccine serotypes comparable to that of healthy young adults at 1, 3, and 16 months after immunization. Moreover, the quality and function of anticapsular antibodies, measured as avidity and in vitro opsonization, were comparable between elderly and young subjects over time. However, a subset (Ç20%) of elderly outpatients responded to fewer than two of seven serotypes tested 1 and 3 months after immunization, whereas none of the healthy young adults were such poor responders. Thus, despite the adequate mean immune responses of the elderly as a group, a substantial proportion of elderly persons may have poor responses to the currently available pneumococcal vaccine.Effective prevention of Streptococcus pneumoniae infection control studies. These studies have indicated variable and incomplete protection (60% -81%) from lethal disease among has renewed priority in an era in which the emergence of antibiotic-resistant strains has further compromised efforts to immunized elderly adults [6 -11].The variable efficacy of the pneumococcal vaccine in the reduce early mortality from invasive pneumococcal infection [1 -3]. Although the 23-valent pneumococcal polysaccharide elderly presumably reflects the poor immunogenicity of polysaccharide-based vaccines in this population. Measurements of (PPS) vaccine was formulated to prevent invasive infection in the elderly and other high-risk populations, the protective effi-PPS-specific serum antibodies after pneumococcal immunization of the elderly have produced conflicting results, possibly cacy of this vaccine for the growing population of adults ú65 years old remains uncertain. Doubts regarding the vaccine's because of differences in the selection of subjects (e.g., chronically ill or unusually healthy elderly) or controls (e.g., historical ability to prevent pneumococcal infection in this group were first raised by prospective randomized trials that did not detect controls or cohort) and in methods for assaying antibody concentrations [12 -20]. More importantly, measures of the quality significant reductions in the incidence of pneumococcal bronchitis, pneumonia, or bacteremia in immunized elderly adults of immune responses to pneumococcal vaccine in the elderly have been assayed in only a single report [19], and the func- [4,5]. However, these studies may have lacked sufficient statistical power to exclude the possibility of vaccine efficacy, due tional response to pneumococcal immunization has not been previously assessed. to the unexpectedly low frequency of pneumococcal infection during these trials. Because further clinical trials were not feasiTherefore, in order to establish the effectiveness of pneumococcal vaccination in elderl...

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Pneumolysin, the major Streptococcus pneumoniae cytotoxin, contributes to the early pathogenesis of invasive pneumococcal pneumonia by facilitating intrapulmonary bacterial growth and invasion into the blood. Pneumolysin is a multifunctional toxin, with distinct cytolytic ("hemolytic") and complement-activation ("complement") activities that have been mapped to several regions of the molecule. To characterize the specific contributions of pneumolysin's hemolytic and complement properties to the pathogenesis of pneumococcal pneumonia, we compared the in vivo effects of type 2 S. pneumoniae mutant strains, which produce pneumolysins deficient in these activities. The absence of either pneumolysin's hemolytic or complement activities rendered mutant strains less virulent than the wild-type strain during pulmonary infection. Pneumolysin's hemolytic activity correlated with acute lung injury and bacterial growth at 3 and 6 h after endotracheal instillation. In contrast, pneumolysin's complement activity correlated with bacterial growth and bacteremia at 24 h after pulmonary infection. Pneumolysin's complement activity was not associated with the degree of alveolar-capillary injury or recruitment of leukocytes during initial pulmonary infection. However, pneumolysin's complement activity inhibited killing of mutant bacteria in an in vitro complement-dependent neutrophil killing assay. Thus, both pneumolysin's hemolytic and complement activities made specific contributions to the early pathogenesis of pneumococcal pneumonia at different stages of infection and by different mechanisms.