The utility of saliva for the assessment of anti-pneumococcal antibodies: investigation of saliva as a marker of antibody status in serum.

CONTEXT: Salivary antibodies may act as non-invasive marker of systemic immunity enabling assessment of vaccination and protection against bacterial infections. OBJECTIVE: To assess if levels of anti-pneumococcal (Pn) antibodies in saliva reflect concentrations in serum and determine whether saliva can accurately identify protective concentrations in serum. METHODS: IgG, IgA and IgM antibody levels in paired saliva and serum samples were measured against 12 Pn polysaccharide antigens in 72 healthy adults. RESULTS: Antibody levels in saliva correlated positively with serum across immunoglobulin classes, most strongly for IgA. Individuals who had protective antibody levels in serum demonstrated significantly higher IgG and IgA salivary antibody concentrations/secretion rates. Salivary IgG and IgA Pn antibodies were able to distinguish between those with/without protective levels in serum for the majority of serotypes. Salivary IgM antibodies were not able to differentiate protective status. Median IgG and IgA Pn salivary parameters were able to identify individuals who had protective levels in serum on ≥8/12 serotypes with moderate accuracy: median IgA secretion rates provided the best sensitivity (73%) and specificity (71%). CONCLUSIONS: These findings suggest that IgG and IgA Pn specific antibodies in saliva may be useful surrogate markers of antibody status in serum.

Assessment of Postvaccine Immunity against Streptococcus pneumoniae in Patients with Asplenia, including an Analysis of Its Impact on Bacterial Flora of the Upper Respiratory Tract and Incidence of Infections.

S. pneumoniae is a microorganism that may cause a serious threat in postsplenectomy patients due to a potentially invasive course of infection. In order to assess a protective activity after vaccination with the 23-valent vaccine, we made an analysis of the level of antibodies in patients with asplenia compared to a control group of healthy donors. Additionally, colonization by potentially pathogenic microorganisms of the upper respiratory tract was analyzed to determine the carrier state by strains with vaccine serotype. No such strains were found in the research, yet three non-vaccine-serotype strains were found. Colonization of the upper respiratory tract by potentially pathogenic microorganisms may be connected with increased susceptibility observed and incidence of infections in patients with asplenia. However, colonization by S. pneumoniae may not have an effect on the level of specific antibodies with the 23-valent vaccine against S. pneumoniae (PPV23) in postsplenectomy patients and healthy people. The response to vaccination against S. pneumoniae showed a lower level of specific antibodies in patients with splenectomy performed more than 2 years before the test than in patients with a recently removed spleen, i.e., from 1 month to 2 years before the test. Vaccination against pneumococci also has positive effects on incidence of other etiology infections, which is of high significance in the prophylaxis of infectious diseases in this group of patients.

The full benefits of adult pneumococcal vaccination: A systematic review.

BACKGROUND: Pneumococcal disease causes substantial morbidity and mortality, including among adults. Adult pneumococcal vaccines help to prevent these burdens, but they are underused. Accounting for the full benefits of adult pneumococcal vaccination may promote more rational resource allocation decisions with respect to adult pneumococcal vaccines. OBJECTIVES: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic review to assess the extent to which the literature has empirically captured (e.g., through measurement or modeling) the full benefits of adult pneumococcal vaccination. METHODS: We systematically searched PubMed and Embase to identify studies published between January 1, 2010 and April 10, 2016 that examine adult pneumococcal vaccination. We included articles if they captured any health or economic benefit of an adult pneumococcal vaccine administered to adults age ≥ 50 or ≥ 18 in risk groups. Finally, we summarized the literature by categorizing the types of benefits captured, the perspective taken, and the strength of the evidence presented. Our protocol is number 42016038335 in the PROSPERO International prospective register of systematic reviews. RESULTS: We identified 5,857 papers and included 150 studies for analysis. While most capture health gains and healthcare cost savings, far fewer studies consider additional benefit categories, such as productivity gains. However, the studies with a broader approach still exhibit significant limitations; for example, many present only abstracts, while others offer no new measurements. Studies that examine the 13-valent pneumococcal conjugate vaccine focus more on broad economic benefits, but still have limitations. CONCLUSIONS: This review highlights the need for more robust empirical accounting of the full benefits of adult pneumococcal vaccination. Literature outside this realm indicates that these broad benefits may be substantial. Failing to investigate the full benefits may lead society to undervalue vaccines' contributions and therefore underinvest in their development and adoption.

Direct and indirect impact of 10-valent pneumococcal conjugate vaccine introduction on pneumonia hospitalizations and economic burden in all age-groups in Brazil: A time-series analysis.

Background: Ten-valent pneumococcal conjugate vaccine (PCV10) was introduced in the National Immunization Program of Brazil in March/2010. Although there are recent reports of PCV10 impact on pneumonia hospitalizations, there is still uncertainty regarding the indirect impact in individuals non-targeted by vaccination. We assessed both direct and indirect effect of PCV10 on pneumonia hospitalizations and the impact on the economic burden of pneumonia hospitalizations. Methods: An interrupted time-series analysis was conducted considering monthly rates of pneumonia hospitalizations and comparison groups, in all age-groups, from January/2005-December/2015. We used records of the National Hospitalizations Information System. Observed pneumonia rates in the post-vaccination period (2011­2015) were compared to predicted rates, should PCV10 had not been introduced. Relative percent difference in rates and its 95% confidence interval were estimated. The number of pneumonia hospitalizations averted by vaccination was calculated as the difference between the predicted and observed cumulative number of pneumonia hospitalizations in the post-vaccination period. The impact of PCV10 on economic burden was presented as averted costs of pneumonia hospitalization. Results: Significant decrease in rates of pneumonia hospitalization was observed in both children targeted by vaccination (17.4%­26.5%; p<0.01), and in age-groups not targeted by vaccination (11.1%­27.1%, in individuals 10­49 years; p<0.01). In contrast, PCV10 introduction did not alter the increasing trends in pneumonia hospitalization among elderly ≥65 years. A total of 457,564 pneumonia hospitalizations was averted in Brazil for individuals aged <50 years, with a total averted costs of BRL 383.2 million (Int$ 225.2 million, and USD 147 million) for the 5 year period after PCV introduction. Conclusion: Vaccination with PCV10 5 years after its introduction in Brazil was associated with a relevant reduction in pneumonia hospitalization in the target age-groups, with an indirect effect in individuals aged 10­49 years, and significant reduction in associated economic burden. The increasing trends in pneumonia hospitalization rates in the elderly is a matter of concern for public health and should be further investigated.

Developments in the pharmacokinetic/pharmacodynamic index of linezolid: a step toward dose optimization using Monte Carlo simulation in critically ill patients.

OBJECTIVES: This study evaluated the efficacy of the pharmacokinetic/pharmacodynamic (PK/PD) index for increasing the success rate of linezolid treatment based on Monte Carlo simulation, and compared differences between the calculated PK/PD breakpoints and those defined by committee for critically ill patients with linezolid treatment. METHODS: A Monte Carlo simulation involving 10000 subjects was used to analyze the pharmacokinetic parameters and microbiological data of linezolid for an effectiveness evaluation at the corresponding AUC24/MIC values (area under the serum concentration-time curve over 24h/minimum inhibitory concentration). RESULTS: As the PK/PD index of linezolid increased from 80 to 120, the corresponding probability of target attainment (PTA) decreased from 99.91% to 18.97%, with a MIC of 2mg/l. Furthermore, the cumulative fraction of response (CFR) reached <90% for several pathogens at an AUC24/MIC of 100-120, revealing a relatively lower efficacy with recommended linezolid dosing. CONCLUSIONS: These findings reveal that the target AUC24/MIC value of 80-120 requires further classification for more accurate assessment of the linezolid dose regimen. At a MIC of ≥2mg/l, the clinical outcome varies greatly for different AUC24/MIC values when applying the same dose of linezolid. In such cases, we suggest optimized adjustment of the linezolid dosage regimen.

Rationale and design of the costs, health status and outcomes in community-acquired pneumonia (CHO-CAP) study in elderly persons hospitalized with CAP.

BACKGROUND: Vaccine effectiveness is usually determined in randomized controlled trials (RCT) and if effective, additional information, e.g. on cost-effectiveness, is required to allow evidence-based decision making. A prerequisite for proper health economic modelling is the availability of good quality data on health care resources use, health outcomes and quality-of-life (QoL) data. The "Collecting health outcomes and economic data on hospitalized Community Acquired Pneumonia (CHO-CAP)--a prospective cohort study" is executed alongside the Community Acquired Pneumonia Immunization Trial with Adults (CAPiTA trial) to capture health outcomes and economic data of elderly hospitalized with CAP and matched controls without CAP. METHODS/DESIGN: CAPiTA is a placebo-controlled double-blind RCT evaluating the effectiveness of a 13-valent conjugated pneumococcal vaccine in preventing vaccine-type pneumococcal CAP in 84,496 elderly in the Netherlands. Participants of CAPiTA, who consented and provided information on health status (EQ-5D) and socio-demographic background at the time of vaccination, constitute the source population of CHO-CAP and are eligible for the nested matched cohort study. CHO-CAP patients hospitalized with CAP form the "diseased" cohort and the "non-diseased" cohort consists of unaffected persons (i.e. no CAP). Observations in the diseased cohort and in matched controls from the non-diseased cohort are used to determine excess costs and QoL changes attributable to CAP.Based on an estimated 2,000 CAPiTA participants being hospitalized with CAP and an assumed CHO-CAP participation rate of 30% of all CAPiTA participants (±25,000), 600 CAP episodes are expected among CHO-CAP participants (the "diseased" cohort). For each patient with CAP, two non-diseased CHO-CAP subjects will be selected from the CHO-CAP cohort, with matching for age, gender and EQ-5D baseline-score. Data on healthcare and non-healthcare resources use, quality-of-life (using EQ-5D and SF-36 questionnaires) and selected health outcomes will be collected at 0, 1, 6 and 12 months after hospitalization for CAP.The CHO-CAP study was approved by the Central Committee on Research involving Human Subjects in the Netherlands. DISCUSSION: With an expected 600 CAP episodes this study will be one of the biggest prospectively studied cohorts of hospitalized elderly with CAP with regard to resources use and Qol data. Strengths of this study further include collection of out-of-pocket costs of patients and productivity losses of both patients and their caregivers and the follow-up period of up to one year post-discharge. This study is therefore expected to add more in-depth knowledge on the short and longer term outcomes of pneumonia in elderly. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00812084.

Aging population and future burden of pneumococcal pneumonia in the United States.

Pneumococcal pneumonia is concentrated among the elderly. Using a decision analytic model, we projected the future incidence of pneumococcal pneumonia and associated healthcare utilization and costs accounting for an aging US population. Between 2004 and 2040, as the population increases by 38%, pneumococcal pneumonia hospitalizations will increase by 96% (from 401 000 to 790 000), because population growth is fastest in older age groups experiencing the highest rates of pneumococcal disease. Absent intervention, the total cost of pneumococcal pneumonia will increase by $2.5 billion annually, and the demand for healthcare services for pneumococcal pneumonia, especially inpatient capacity, will double in coming decades.

Estimating rates of carriage acquisition and clearance and competitive ability for pneumococcal serotypes in Kenya with a Markov transition model.

BACKGROUND: There are more than 90 serotypes of Streptococcus pneumoniae, with varying biologic and epidemiologic properties. Animal studies suggest that carriage induces an acquired immune response that reduces duration of colonization in a nonserotype-specific fashion. METHODS: We studied pneumococcal nasopharyngeal carriage longitudinally in Kenyan children 3-59 months of age, following up positive swabs at days 2, 4, 8, 16, and 32 and then monthly thereafter until 2 swabs were negative for the original serotype. As previously reported, 1868/2840 (66%) of children swabbed at baseline were positive. We estimated acquisition, clearance, and competition parameters for 27 serotypes using a Markov transition model. RESULTS: Point estimates of type-specific acquisition rates ranged from 0.00025/d (type 1) to 0.0031/d (type 19F). Point estimates of time to clearance (inverse of type-specific immune clearance rate) ranged from 28 days (type 20) to 124 days (type 6A). For the serotype most resistant to competition (type 19F), acquisition of other serotypes was 52% less likely (95% confidence interval = 37%-63%) than in an uncolonized host. Fitness components (carriage duration, acquisition rate, lack of susceptibility to competition) were positively correlated with each other and with baseline prevalence, and were associated with biologic properties previously shown to associate with serotype. Duration of carriage declined with age for most serotypes. CONCLUSIONS: Common S. pneumoniae serotypes appear superior in many dimensions of fitness. Differences in rate of immune clearance are attenuated as children age and become capable of more rapid clearance of the longest-lived serotypes. These findings provide information for comparison after introduction of pneumococcal conjugate vaccine.

Assessment of Streptococcus pneumoniae capsule in conjunctivitis and keratitis in vivo neuraminidase activity increases in nonencapsulated pneumococci following conjunctival infection.

PURPOSE: The pneumococcal capsule is required for pathogenesis in systemic infections, yet reports show most conjunctivitis outbreaks are caused by nonencapsulated pneumococci, while keratitis infections are caused by encapsulated strains. This study aims to determine the effect of capsule in pneumococcal keratitis and conjunctivitis in rabbit models of infection. METHODS: A capsule-deficient isogenic mutant was created using homologous transformation. Parent and mutant strains were injected within the upper bulbar conjunctiva (conjunctivitis) or into the corneal stroma (keratitis) of New Zealand white rabbits. Clinical examinations were performed 24 and 48 hr post-infection at which time corneas or conjunctivae were removed, homogenized, and plated to determine the recovered bacterial load. Whole eyes were removed for histological examination. The neuraminidase activity was determined following in vitro and in vivo growth. RESULTS: There were no significant differences in clinical scores between the eyes infected with the parent or mutant for either infection, nor was there a difference in the amount of bacteria recovered from the cornea. In the conjunctivae, however, the mutant strain was cleared by the host faster than the parent strain. Histological examination showed slightly more infiltrating polymorphonuclear leukocytes (PMN) and macrophages in the conjunctivae infected with the parent strain. The neuraminidase activity of both strains was not significantly different when the strains were grown in vitro. However, the neuraminidase activity of the parent was significantly less than that of the mutant at 3 and 12 hr post conjunctival infection. CONCLUSIONS: Although more outbreaks of pneumococcal conjunctivitis are tied to nonencapsulated S. pneumoniae strains, this study showed that an encapsulated strain was capable of establishing conjunctivitis in a rabbit injection model and survive attack by the host immune system longer than its nonencapsulated isogenic mutant. Nonetheless, the nonencapsulated pneumococci had an increased neuraminidase activity level in vivo when compared to the parent strain.

Assessment of molecular typing methods to determine invasiveness and to differentiate clones of Streptococcus pneumoniae.

In the United States, Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and invasive bacterial disease. As antimicrobial resistance increases, it will become critical to determine if strains circulating in a population are likely to cause invasive pneumococcal disease (IPD). This is possible by comparison of an isolate's genotype to strains known to be invasive. In this work, we compared pulse-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST), comparative genomic hybridization (CGH) and multi-invasive-locus sequence typing (MILST) for their ability to distinguish between known IPD causing and carrier strains using phylogenetic analyses. In addition, we assess the ability of these techniques to determine true clones from highly related strains. The resulting trees suggest that despite similar overall topologies, the clearest picture of invasiveness and genetic relatedness can be viewed when typing methods are used collectively.

The burden of invasive pneumococcal disease and the potential for reduction by immunisation.

Streptococcus pneumoniae causes invasive disease world-wide and in all age groups. The reported incidence varies geographically and is increased in certain population groups. The incidence is highest in children less than 2 years and is also increased in the elderly. Mortality remains substantial even in the developed world despite appropriate antimicrobial therapy. The emergence of penicillin-resistant pneumococci highlights the importance of immunisation as a means to prevent disease. This review discusses the burden of invasive pneumococcal disease, identifies high-risk patients and analyses evidence for vaccine efficacy and cost-effectiveness.