Jeffrey B. Rubins

Immunogenicity and safety of pneumococcal vaccination in patients with rheumatoid arthritis or systemic lupus erythematosus.

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.

Magnitude, Duration, Quality, and Function of Pneumococcal Vaccine Responses in Elderly Adults

The suboptimal efficacy of the currently available 23-valent pneumococcal vaccine in the growing population of adults >65 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 (approximately 20%) 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.

Killing of Streptococcus pneumoniae by capsular polysaccharide–specific polymeric IgA, complement, and phagocytes

The role of IgA in the control of invasive mucosal pathogens such as Streptococcus pneumoniae is poorly understood. We demonstrate that human pneumococcal capsular polysaccharide-specific IgA initiated dose-dependent killing of S. pneumoniae with complement and phagocytes. The majority of specific IgA in serum was of the polymeric form (pIgA), and the efficiency of pIgA-initiated killing exceeded that of monomeric IgA-initiated killing. In the absence of complement, specific IgA induced minimal bacterial adherence, uptake, and killing. Killing of S. pneumoniae by resting phagocytes with immune IgA required complement, predominantly via the C2-independent alternative pathway, which requires factor B, but not calcium. Both S. pneumoniae-bound IgA and complement were involved, as demonstrated by a 50% decrease in killing with blocking of Fcalpha receptor (CD89) and CR1/CR3 (CD35/CD11b). However, IgA-mediated killing by phagocytes could be reproduced in the absence of opsonic complement by pre-activating phagocytes with the inflammatory products C5a and TNF-alpha. Thus, S. pneumoniae capsule-specific IgA may show distinct roles in effecting clearance of S. pneumoniae in the presence or absence of inflammation. These data suggest mechanisms whereby pIgA may serve to control pneumococcal infections locally and upon the pathogens entry into the bloodstream.

Dual function of pneumolysin in the early pathogenesis of murine pneumococcal pneumonia.

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 pneumolysin-deficient (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.

Pneumolysin: A multifunctional pneumococcal virulence factor

Pneumolysin (PLY) is a multifunctional pneumococcal virulence factor that appears to augment intrapulmonary growth and dissemination during the early pathogenesis of Streptococcus pneumoniae infection. Through its cytotoxicity to respiratory epithelium and endothelium, PLY disrupts pulmonary tissue barriers that serve as mechanical pulmonary defenses, thus facilitating S. pneumoniae growth and dissemination. Through direct inhibitory effects on immune and inflammatory cells and by activating complement, PLY inhibits bacterial clearance from the pulmonary interstitium and the blood. Because PLY stimulates local and systemic immune responses and enhances the immunogenicity of S. pneumoniae polysaccharide (PS), PLY-PS conjugates may form the basis for vaccines that not only induce protective and durable immune responses to pneumococcal PS but also generate neutralizing anti-PLY antibodies that can protect the respiratory mucosa from toxin-induced injury.

Serum carcinoembryonic antigen as an adjunct to preoperative staging of lung cancer

OBJECTIVE To determine whether measurement of preoperative serum carcinoembryonic antigen concentrations adds useful prognostic data to current preoperative staging of lung cancer by computed tomography, bronchoscopy, and mediastinoscopy. METHODS A prospective cohort study of 130 consecutive patients was evaluated for suspected lung cancer from July 1991 through December 1992 at a university-affiliated Veterans Affairs Medical Center. Serum concentrations of carcinoembryonic antigen were measured before diagnosis, staging, or resection of cancer. RESULTS Malignant disease was diagnosed by bronchoscopy, needle biopsy, mediastinoscopy, or resection in 111 of 130 patients. In the 50 patients undergoing resection with curative intent, multivariate analysis indicated that carcinoembryonic antigen was a significant predictor of survival independent of patient age, pathologic stage, histologic type, and tumor size (P=.0357). CONCLUSIONS Elevated preoperative serum concentrations of carcinoembryonic antigen predict a poor prognosis for lung cancer independent of other conventional staging parameters and have an adjunctive role in the staging of lung cancer.

Reimmunization with 23-Valent Pneumococcal Vaccine for Patients Infected with Human Immunodeficiency Virus Type 1: Clinical, Immunologic, and Virologic Responses

We determined the immunogenicity and safety of reimmunization with the 23-valent polysaccharide pneumococcal vaccine in patients infected with human immunodeficiency virus type 1 (HIV-1). Patients immunized >5 years earlier (initially within 1 year of HIV-1 seroconversion) were randomized to receive vaccine (n=57) or placebo (n=30). Persons with recent HIV-1 seroconversion (n=14) were immunized for the first time. Preimmunization levels of capsule-specific immunoglobulin G were similar in all groups. Reimmunized patients showed a significantly lower frequency and magnitude of antibody responses compared with persons with recent HIV-1 seroconversion. Reimmunized patients did not show adverse virologic or immunologic changes, but some reported local discomfort (15%) or fever (8%). Thus, the limited responses after reimmunization of HIV-1-infected patients with the current 23-valent vaccine mandates the need for a more effective reimmunization schedule, more immunogenic vaccines, or other behavioral and therapeutic interventions.

Gene therapy of established mesothelioma xenografts with recombinant p16INK4a adenovirus.

The absence of expression of the p16INK4a gene product is observed in virtually all mesothelioma tumors and cell lines, whereas wild-type pRB expression is maintained. We have examined the potential therapeutic role of re-expressing the p16INK4a gene product in mice with established human mesothelioma xenografts. Experiments using Adp16 treatments in mesothelioma xenografts demonstrated prolonged survival and potential cure following treatment with p16INK4a-based gene therapy. These results demonstrate that p16INK4a gene transfer may play a therapeutic role in the treatment of mesothelioma. Cancer Gene Therapy (2000) 7, 1421–1425

Pneumococcal Disease in the Elderly What is Preventing Vaccine Efficacy

The effective prevention of Streptococcus pneumoniae infection has a renewed priority in an era in which the emergence of antibacterial-resistant strains has the potential to further compromise efforts to reduce early mortality from invasive pneumococcal infection. Although the 23-valent pneumococcal polysaccharide (PPS) vaccine was approved in the US to prevent respiratory and invasive infection in the elderly and other high-risk populations, the protective efficacy of this vaccine for the growing population of adults aged >65 years remains controversial. The apparent effectiveness of pneumococcal immunisation in clinical studies of elderly adults has varied depending upon whether a reduction in pneumococcal colonisation, pneumonia, bacteraemia or death was used as an outcome.Clinical studies of vaccine efficacy to date suggest that the current pneumococcal vaccine is 56 to 81% effective at preventing invasive pneumococcal infection, and may have additive benefit to influenza vaccine in preventing community-acquired pneumonia, particularly in elderly adults with an increased risk of serious pneumonia requiring hospitalisation. Possible reasons for incomplete protection from pneumococcal infection after immunisation include infection with non-vaccine serotypes, inadequate or ineffective antibody responses, waning of antibody responses, or compromised nonhumoral host defences. Further studies are needed to determine whether: (i) elderly adults who respond poorly to the 23-valent pneumococcal vaccine can be identified prior to immunisation and targeted for study with improved pneumococcal vaccines; (ii) specific nutrient deficiencies can be identified and corrected to improve the immune responsiveness of elderly adults to the PPS vaccine; (iii) newer protein-conjugate or DNA pneumococcal vaccines may be more uniformly immunogenic for elderly adults; and (iv) whether smoking cessation reduces the risk of invasive pneumococcal infection in elderly adults.

Impact of preoperative smoking status on postoperative complication rates and pulmonary function test results 1-year following pulmonary resection for non-small cell lung cancer

There is a lack of evidence in the literature regarding the impact of preoperative smoking status on pulmonary function test (PFT) results 1 year after resection for non-small cell lung cancer (NSCLC). Furthermore, there is disagreement in the literature regarding the impact of preoperative smoking cessation on postoperative complication rates. We performed a single-institution retrospective review of all NSCLC patients who underwent resection from April 2000 through April 2006. Timing of smoking cessation was stratified as follows: smoking cessation more than a month before surgery (Distant Smokers), smoking cessation within a month before surgery (Recent Smokers), and failure to achieve smoking cessation before surgery (Current Smokers). During the study period, 213 patients underwent NSCLC resection, 121 of whom (all males; mean age, 67.4 years) completed pre- and postoperative PFTs. After adjusting for potential confounding covariates (age, type of resection, and use of radiation therapy), we noted no significant difference (p>0.40) between groups after resection with regard to either relative (-12.20+/-15.77L [Distant Smokers], -15.38+/-19.38L [Recent Smokers], -9.61+/-15.54L [Current Smokers]) or absolute changes in percent predicted forced expiratory volume in 1s (-0.14+/-0.20L [Distant Smokers], -0.18+/-0.19L [Recent Smokers], -0.12+/-0.20L [Current Smokers]). Because 92 patients did not complete postoperative PFTs, we performed a stratified analysis to assess for selection bias; as compared with those who completed PFTs, baseline PFT results did not significantly differ. We found no significant differences between the 3 groups with regard the overall rate of postoperative complications or the rate of any specific postoperative complication. In conclusion, smoking cessation immediately before NSCLC resection does not significantly impact postoperative pulmonary complication rates or 1-year postoperative PFT results and therefore should not be a reason to delay surgical resection.