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Background: Streptococcus pneumoniae is a leading cause of morbidity and mortality globally, causing bacteremic pneumonia, meningitis, sepsis, and other invasive pneumococcal diseases. Evidence supports nasopharyngeal pneumococcal carriage as a reservoir for transmission and precursor of pneumococcal disease. Objectives: To estimate the pneumococcal nasopharyngeal burden in all age groups in Latin America and the Caribbean (LAC) before, during, and after the introduction of pneumococcal vaccine conjugate (PVC). Methods: Systematic literature review of international, regional, and country-published and unpublished data, together with reports including data from serotype distribution in nasopharyngeal carriage in children and adults from LAC countries following Cochrane methods. The protocol was registered in PROSPERO database (ID: CRD42023392097). Results: We included 54 studies with data on nasopharyngeal pneumococcal carriage and serotypes from 31,803 patients. In children under five years old, carriage was found in 41% and in adults over 65, it was 26%. During the study period, children under five showed a colonization proportion of 34% with PCV10 serotypes and 45% with PCV13 serotypes. When we analyze the carriage prevalence of PCV serotypes in all age groups between 1995 and 2019, serotypes included in PCV10 and those included in PCV13, both showed a decreasing trend along analysis by lustrum. Conclusion: The data presented in this study highlights the need to establish national surveillance programs to monitor pneumococcal nasopharyngeal carriage to monitor serotype prevalence and replacement before and after including new pneumococcal vaccines in the region. In addition, to analyze differences in the prevalence of serotypes between countries, emphasize the importance of approaches to local realities to reduce IPD effectively. [ABSTRACT FROM AUTHOR]

Background: Limited data exists regarding risk factors for adverse outcomes in older adults hospitalized with Community-Acquired Pneumonia (CAP) in low- and middle-income countries such as India. This multisite study aimed to assess outcomes and associated risk factors among adults aged ≥60 years hospitalized with pneumonia. Methods: Between December 2018 and March 2020, we enrolled ≥60-year-old adults admitted within 48 hours for CAP treatment across 16 public and private facilities in four sites. Clinical data and nasal/oropharyngeal specimens were collected by trained nurses and tested for influenza, respiratory syncytial virus (RSV), and other respiratory viruses (ORV) using the qPCR. Participants were evaluated regularly until discharge, as well as on the 7th and 30th days post-discharge. Outcomes included ICU admission and in-hospital or 30-day post-discharge mortality. A hierarchical framework for multivariable logistic regression and Cox proportional hazard models identified risk factors (e.g., demographics, clinical features, etiologic agents) associated with critical care or death. Findings: Of 1,090 CAP patients, the median age was 69 years; 38.4% were female. Influenza viruses were detected in 12.3%, RSV in 2.2%, and ORV in 6.3% of participants. Critical care was required for 39.4%, with 9.9% in-hospital mortality and 5% 30-day post-discharge mortality. Only 41% of influenza CAP patients received antiviral treatment. Admission factors independently associated with ICU admission included respiratory rate >30/min, blood urea nitrogen>19mg/dl, altered sensorium, anemia, oxygen saturation <90%, prior cardiovascular diseases, chronic respiratory diseases, and private hospital admission. Diabetes, anemia, low oxygen saturation at admission, ICU admission, and mechanical ventilation were associated with 30-day mortality. Conclusion: High ICU admission and 30-day mortality rates were observed among older adults with pneumonia, with a significant proportion linked to influenza and RSV infections. Comprehensive guidelines for CAP prevention and management in older adults are needed, especially with the co-circulation of SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Pneumococcal disease is a major cause of clinical and economic burden worldwide. This study investigated the burden of pneumococcal disease in Swedish adults. A retrospective population-based study was conducted using Swedish national registers, including all adults aged ≥18 years with a diagnosis of pneumococcal disease (defined as pneumococcal pneumonia, meningitis, or septicemia) in inpatient or outpatient specialist care between 2015–2019. Incidence and 30-day case fatality rates, healthcare resource utilization, and costs were estimated. Results were stratified by age (18–64, 65–74, and ≥75 years) and the presence of medical risk factors. A total of 10,391 infections among 9,619 adults were identified. Medical factors associated with higher risk for pneumococcal disease were present in 53% of patients. These factors were associated with increased pneumococcal disease incidence in the youngest cohort. In the cohort aged 65–74 years, having a very high risk for pneumococcal disease was not associated with an increased incidence. Pneumococcal disease incidence was estimated at 12.3 (18–64), 52.1 (64–74), and 85.3 (≥75) per 100,000 population. The 30-day case fatality rate increased with age (18–64: 2.2%, 65–74: 5.4%, ≥75: 11.7%), and was highest among septicemia patients aged ≥75 (21.4%). The 30-day average number of hospitalizations was 1.13 (18–64), 1.24 (64–74) and 1.31 (≥75). The average 30-day cost/infection was estimated at €4,467 (18–64), €5,278 (65–74), and €5,898 (≥75). The 30-day total direct cost of pneumococcal disease between 2015–2019 was €54.2 million, with 95% of costs from hospitalizations. The clinical and economic burden of pneumococcal disease in adults was found to increase with age, with nearly all costs associated with pneumococcal disease from hospitalizations. The 30-day case fatality rate was highest in the oldest age group, though not negligible in the younger age groups. The findings of this study can inform the prioritization of pneumococcal disease prevention in adult and elderly populations. [ABSTRACT FROM AUTHOR]

Despite the reduction of death from pneumonia over recent years, pneumonia has still been the leading infectious cause of death in under-five children for the last several decades. Unconsciousness is a critical condition in any child resulting from any illness. Once it occurs during a pneumonia episode, the outcome is perceived to be fatal. However, data on children under five with pneumonia having unconsciousness are scarce. We've retrospectively analyzed the data of under-five children admitted at the in-patient ward of Dhaka Hospital of icddr,b during 1 January 2014 and 31 December 2017 with World Health Organization classified pneumonia or severe pneumonia. Children presented with or without unconsciousness were considered as cases and controls respectively. Among a total of 3,876 children fulfilling the inclusion criteria, 325 and 3,551 were the cases and the controls respectively. A multivariable logistic regression analysis revealed older children (8 months vs. 7.9 months) (adjusted odds ratio, aOR 1.02, 95% CI: 1.004–1.04, p = 0.015), hypoxemia (aOR 3.22, 95% CI: 2.39–4.34, p<0.001), severe sepsis (aOR 4.46, 95% CI: 3.28–6.06, p<0.001), convulsion (aOR 8.90, 95% CI: 6.72–11.79, p<0.001), and dehydration (aOR 2.08, 95% CI: 1.56–2.76, p<0.001) were found to be independently associated with the cases. The cases more often had a fatal outcome than the controls (23% vs. 3%, OR 9.56, 95% CI: 6.95–13.19, p<0.001). If the simple predicting factors of unconsciousness in children under five hospitalized for pneumonia with different severity can be initially identified and adequately treated with prompt response, pneumonia-related deaths can be reduced more effectively, especially in resource-limited settings. [ABSTRACT FROM AUTHOR]

Objective: To estimate healthcare resource utilisation (HCRU) and costs associated with pneumococcal disease (PD) in children aged ≤17 years in England from 2003–2019. Methods: A retrospective study in children aged ≤17 years was conducted using the Clinical Practice Research Datalink Gold primary care database and Hospital Episodes Statistics Admitted Patient Care database from 2003–2019. Episodes of invasive pneumococcal disease (IPD) were identified in hospital, pneumococcal pneumonia (PP) and all-cause pneumonia (ACP) episodes in primary care and in hospital, and acute otitis media (AOM) episodes in primary care. General practitioner (GP) visits and inpatient admission yearly rates were calculated per 1,000 persons. The average inpatient and primary care cost per episode were calculated. The Mann-Kendall test was used to assess monotonic time trends. Results: 1,500,686 children were followed from 2003–2019. The highest average inpatient cost per episode [£34,255 (95%CI 27,222–41,288)] was in IPD, followed by ACP [£3,549 (95%CI 3,405–3,693)] and PP [£1,498 (95%CI 1,153–1,843)]. The highest primary care costs per episode were in AOM [£48.7 (95%CI 48.7–48.7)], followed by PP [£38.4 (95%CI 37.0–39.7)] and ACP [£28.6 (95%CI 28.2–29.1)]. The highest inpatient admission and GP visits yearly rates were observed in children aged <2 years. Across years, a significant decrease in GP visits yearly rates was observed for PP, ACP and AOM in children overall (p-value<0.001). A decrease in primary care costs was observed for ACP (p-value<0.001). There was an increasing trend in AOM primary care costs (p-value<0.001). No significant trends were observed in inpatient admission yearly rates in PP, ACP or IPD and inpatient costs per episode in PP, ACP and IPD. Conclusion: From 2003–2019, primary care HCRU and costs decreased (except for PP cost), but no trends in inpatient HCRU and costs were observed. The economic burden of pneumonia, IPD and AOM remains substantial in children aged ≤17 years in England. [ABSTRACT FROM AUTHOR]

PspA and pneumolysin are two important vaccine candidates, able to elicit protection in different models of pneumococcal infection. The high immunogenic potential of PspA, combined with a possible adjuvant effect of pneumolysin derivatives (due to their ability to interact with TLR-4) could greatly improve the immunogenicity and coverage of a protein-based pneumococcal vaccine. A chimeric protein including the N-terminal region of PspA in fusion with the pneumolysin derivative, PlD1, has been shown to induce high antibody levels against each protein, and protect mice against invasive challenge. The aim of the present study was to investigate the cellular response induced by such vaccine, and to evaluate protection in a murine model of lobar pneumococcal pneumonia. Pneumococcal pneumonia was induced in BALB/c mice by nasal instillation of a high dose of a serotype 14 strain with low virulence. Airway inflammation was confirmed by total and differential cell counts in BAL and by histological analysis of the lungs, and bacterial loads were measured 7 days after challenge. Cytokine levels were determined in the bronchoalveolar fluid (BALF) of mice immunized with rPspA-PlD1 fusion after challenge, by flow cytometry and ELISA. After challenge, the mice developed lung inflammation with no invasion of other sites, as demonstrated by histological analysis. We detected significant production of TNF-α and IL-6 in the BALF, which correlated with protection against pneumonia in the group immunized with rPspA-PlD1. In conclusion, we found that the rPspA-PlD1fusion is protective against pneumococcal pneumonia in mice, and protection is correlated with an early and controlled local inflammatory response. These results are in agreement with previous data demonstrating the efficacy of the fusion protein against pneumococcal sepsis and reinforce the potential of the rPspA-PlD1 protein chimera as a promising vaccine strategy to prevent pneumococcal disease. [ABSTRACT FROM AUTHOR]

Background: The 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended for UK older adults, but how age moderates effectiveness is unclear. Methods: Three annual cohorts of primary-care patients aged≥65y from the Clinical Practice Research Datalink selected from 2003–5 created a natural experiment (n = 324,804), reflecting the staged introduction of the vaccine. The outcome was symptoms consistent with community-acquired pneumococcal pneumonia (CAP) requiring antibiotics or hospitalisation. We used the prior event rate ratio (PERR) approach to address bias from unmeasured confounders. Results: Vaccinated patients had higher rates of CAP in the year before vaccination than their controls, indicating the potential for confounding bias. After adjustment for confounding using the prior event rate ratio (PERR) method, PPV23 was estimated to be effective against CAP for two years after vaccination in all age sub-groups with hazard ratios (95% confidence intervals) of 0.86 (0.80 to 0.93), 0.74 (0.65 to 0.85) and 0.65 (0.57 to 0.74) in patients aged 65–74, 75–79 and 80+ respectively in the 2005 cohort. Age moderated the effect of vaccination with predicted risk reductions of 8% at 65y and 29% at 80y. Conclusions: PPV23 is moderately effective at reducing CAP among UK patients aged≥65y, in the two years after vaccination. Vaccine effectiveness is maintained, and may increase, in the oldest age groups in step with increasing susceptibility to CAP. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae is a human pathogenic bacterium able to cause invasive pneumococcal diseases. Some studies have reported medicinal plants having antibacterial activity against pathogenic bacteria. However, antibacterial studies of medicinal plants against S. pneumoniae remains limited. Therefore, this study aims to describe the antibacterial activity of medicinal plants in Indonesia against S. pneumoniae. Medicinal plants were extracted by maceration with n-hexane, ethanol, ethyl acetate and water. Antibacterial activity was defined by inhibition zone and minimum inhibitory concentration (MIC). Bactericidal activity was measured by culture and time-killing measurement. Methods used to describe the mechanism of action of the strongest extract were done by absorbance at 595 nm, broth culture combined with 1% crystal violet, qRT-PCR targeting lytA, peZT and peZA, and transmission electron microscope to measure bacterial lysis, antibiofilm, LytA and peZAT gene expression, and ultrastructure changes respectively. Among 13 medicinal plants, L. inermis Linn. ethyl acetate extract showed the strongest antibacterial activity against S. pneumoniae with an MIC value of 0,16 mg/ml. Bactericidal activity was observed at 0,16 mg/ml for 1 hour incubation. Lawsonia inermis extract showed some mechanism of actions including bacterial lysis, antibiofilm, and ultrastructure changes such as cell wall disruption, decreasing cell membrane integrity and morphological disorder. Increasing of lytA and decreasing of peZA and peZT expression were also observed after incubation with the extract. In addition, liquid chromatography mass spectrophotometer showed phenolic compounds as the commonest compound in L. inermis ethyl acetate extract. This study describes the strong antibacterial activity of L. inermis with various mechanism of action including ultrastructure changes. [ABSTRACT FROM AUTHOR]

Objectives: To explore barriers and facilitators to COVID-19, influenza, and pneumococcal vaccine uptake in immunosuppressed adults with immune-mediated inflammatory diseases (IMIDs). Methods: Recruiting through national patient charities and a local hospital, participants were invited to take part in an in-depth, one-to-one, semi-structured interview with a trained qualitative researcher between November 2021 and January 2022. Data were analysed thematically in NVivo, cross-validated by a second coder and mapped to the SAGE vaccine hesitancy matrix. Results: Twenty participants (75% female, 20% non-white) were recruited. Barriers and facilitators spanned contextual, individual/group and vaccine/vaccination-specific factors. Key facilitators to all vaccines were higher perceived infection risk and belief that vaccination is beneficial. Key barriers to all vaccines were belief that vaccination could trigger IMID flare, and active IMID. Key facilitators specific to COVID-19 vaccines included media focus, high incidence, mass-vaccination programme with visible impact, social responsibility, and healthcare professionals' (HCP) confirmation of the new vaccines' suitability for their IMID. Novel vaccine technology was a concern, not a barrier. Key facilitators of influenza/pneumococcal vaccines were awareness of eligibility, direct invitation, and, clear recommendation from trusted HCP. Key barriers of influenza/pneumococcal vaccines were unaware of eligibility, no direct invitation or recommendation from HCP, low perceived infection risk, and no perceived benefit from vaccination. Conclusions: Numerous barriers and facilitators to vaccination, varying by vaccine-type, exist for immunosuppressed-IMID patients. Addressing vaccine benefits and safety for IMID-patients in clinical practice, direct invitation, and public-health messaging highlighting immunosuppression as key vaccination-eligibility criteria may optimise uptake, although further research should assess this. [ABSTRACT FROM AUTHOR]

Background: The World Health Organization (WHO)-defined radiological pneumonia is a preferred endpoint in pneumococcal vaccine efficacy and effectiveness studies in children. Automating the WHO methodology may support more widespread application of this endpoint. Methods: We trained a deep learning model to classify pneumonia CXRs in children using the World Health Organization (WHO)'s standardized methodology. The model was pretrained on CheXpert, a dataset containing 224,316 adult CXRs, and fine-tuned on PERCH, a pediatric dataset containing 4,172 CXRs. The model was then tested on two pediatric CXR datasets released by WHO. We also compared the model's performance to that of radiologists and pediatricians. Results: The average area under the receiver operating characteristic curve (AUC) for primary endpoint pneumonia (PEP) across 10-fold validation of PERCH images was 0.928; average AUC after testing on WHO images was 0.977. The model's classification performance was better on test images with high inter-observer agreement; however, the model still outperformed human assessments in AUC and precision-recall spaces on low agreement images. Conclusion: A deep learning model can classify pneumonia CXR images in children at a performance comparable to human readers. Our method lays a strong foundation for the potential inclusion of computer-aided readings of pediatric CXRs in vaccine trials and epidemiology studies. [ABSTRACT FROM AUTHOR]

Introduction: Streptococcus pneumoniae is a cause of infections that range in severity from acute otitis media (AOM) to pneumonia and invasive pneumococcal disease (IPD). The 10-valent pneumococcal conjugate vaccine (PHiD-CV10) was introduced into the Icelandic paediatric immunisation programme in 2011. The aim was to estimate the population impact and cost-effectiveness of PHiD-CV10 introduction. Methods: Data on primary care visits from 2005–2015 and hospitalisations from 2005–2017 were obtained from population-based registries. A Bayesian time series analysis with synthetic controls was employed to estimate the number of cases of AOM, pneumonia and IPD that would have occurred between 2013–2017, had PHiD-CV10 not been introduced. Prevented cases were calculated by subtracting the observed number of cases from this estimate. The cost of the programme was calculated accounting for cost-savings due to prevented cases. Results: The introduction of PHiD-CV10 prevented 13,767 (95% credible interval [CI] 2,511–29,410) visits for AOM from 2013–2015, and prevented 1,814 (95%CI -523-4,512) hospitalisations for pneumonia and 53 (95%CI -17-177) admissions for IPD from 2013–2017. Visits for AOM decreased both among young children and among children 4–19 years of age, with rate ratios between 0.72–0.89. Decreases were observed in both pneumonia hospitalisations (rate ratios between 0.67–0.92) and IPD (rate ratios between 0.27–0.94). The total cost of implementing PHiD-CV10 in Iceland was -7,463,176 United States Dollars (USD) (95%CI -16,159,551–582,135) with 2.1 USD (95%CI 0.2–4.7) saved for every 1 USD spent. Conclusions: The introduction of PHiD-CV10 was associated with large decreases in visits and hospitalisations for infections commonly caused by pneumococcus and was cost-saving during the first five years of the immunisation programme. [ABSTRACT FROM AUTHOR]

Pneumonia is one of the leading causes of death worldwide. The course of the disease is often highly dynamic with unforeseen critical deterioration within hours in a relevant proportion of patients. Besides antibiotic treatment, novel adjunctive therapies are under development. Their additive value needs to be explored in preclinical and clinical studies and corresponding therapy schedules require optimization prior to introduction into clinical practice. Biomathematical modeling of the underlying disease and therapy processes might be a useful aid to support these processes. We here propose a biomathematical model of murine immune response during infection with Streptococcus pneumoniae aiming at predicting the outcome of different treatment schedules. The model consists of a number of non-linear ordinary differential equations describing the dynamics and interactions of the pulmonal pneumococcal population and relevant cells of the innate immune response, namely alveolar- and inflammatory macrophages and neutrophils. The cytokines IL-6 and IL-10 and the chemokines CCL2, CXCL1 and CXCL5 are considered as major mediators of the immune response. We also model the invasion of peripheral blood monocytes, their differentiation into macrophages and bacterial penetration through the epithelial barrier causing blood stream infections. We impose therapy effects on this system by modelling antibiotic therapy and treatment with the novel C5a-inactivator NOX-D19. All equations are derived by translating known biological mechanisms into equations and assuming appropriate response kinetics. Unknown model parameters were determined by fitting the predictions of the model to time series data derived from mice experiments with close-meshed time series of state parameters. Parameter fittings resulted in a good agreement of model and data for the experimental scenarios. The model can be used to predict the performance of alternative schedules of combined antibiotic and NOX-D19 treatment. We conclude that we established a comprehensive biomathematical model of pneumococcal lung infection, immune response and barrier function in mice allowing simulations of new treatment schedules. We aim to validate the model on the basis of further experimental data. We also plan the inclusion of further novel therapy principles and the translation of the model to the human situation in the near future. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae is often isolated from patients with community-acquired pneumonia. Antibiotics are the primary line of treatment for pneumococcal pneumonia; however, rising antimicrobial resistance is becoming more prevalent. Hinokitiol, which is isolated from trees in the cypress family, has been demonstrated to exert antibacterial activity against S. pneumoniae in vitro regardless of antimicrobial resistance. In this study, the efficacy of hinokitiol was investigated in a mouse pneumonia model. Male 8-week-old BALB/c mice were intratracheally infected with S. pneumoniae strains D39 (antimicrobial susceptible) and NU4471 (macrolide resistant). After 1 h, hinokitiol was injected via the tracheal route. Hinokitiol significantly decreased the number of S. pneumoniae in the bronchoalveolar lavage fluid (BALF) and the concentration of pneumococcal DNA in the serum, regardless of whether bacteria were resistant or susceptible to macrolides. In addition, hinokitiol decreased the infiltration of neutrophils in the lungs, as well as the concentration of inflammatory cytokines in the BALF and serum. Repeated hinokitiol injection at 18 h intervals showed downward trend in the number of S. pneumoniae in the BALF and the concentration of S. pneumoniae DNA in the serum with the number of hinokitiol administrations. These findings suggest that hinokitiol reduced bacterial load and suppressed excessive host immune response in the pneumonia mouse model. Accordingly, hinokitiol warrants further exploration as a potential candidate for the treatment of pneumococcal pneumonia. [ABSTRACT FROM AUTHOR]

The performances of the ImmuView Streptococcus pneumoniae (Sp) and Legionella pneumophila (Lp) urinary antigen test were compared to that of the BinaxNOW Sp and Lp assays, using frozen urine from 166 patients with Legionnaires' disease (LD) and 59 patients with pneumococcal pneumonia. Thirty Sp-positive or contrived cerebrospinal fluids (CSF) were also tested. Test specimens were collected and tested at different sites, with each site testing unique specimens by technologists blinded to expected results. No significant differences in test concordances were detected for the ImmuView and BinaxNOW assays for the Sp or Lp targets for urine from patients with pneumococcal pneumonia or LD when performance from both sites were combined. At one of two test sites the ImmuView Lp assay was more sensitive than the BinaxNOW assay, with no correlation between test performance and Lp serogroup 1 monoclonal type. Urines from six of seven patients with LD caused by Legionella spp. bacteria other than Lp serogroup 1 were negative in both assays. Both tests had equivalent performance for Sp-positive CSF. The clinical sensitivities for pneumococcal pneumonia were 88.1 and 94.4% for the ImmuView and Binax assays, and 87.6 and 84.2% for the Lp assays, respectively. Test specificities for pneumococcal pneumonia were 96.2 and 97.0% for the ImmuView and Binax assays, and 99.6 and 99.1% for the Lp assays. Both assays were highly specific for Sp in pediatric urines from children with nasopharyngeal colonization by the bacterium. ImmuView and BinaxNOW assay performance was equivalent in these studies. [ABSTRACT FROM AUTHOR]

Although many influenza-related deaths are attributable to secondary bacterial infection with S. pneumoniae, vaccines that simultaneously protect against influenza and pneumococcal infection are currently not developed. The aim of our study was to evaluate the possibility to prevent post-influenza pneumococcal infection using an associated vaccine based on live influenza vaccine (LAIV) combined with recombinant polypeptides derived from superficial factors of Group B streptococcus (GBS) determining pathogenicity. We demonstrated in a model of post-influenza pneumococcal pneumonia that intranasal pneumococcal super-infection seriously complicated the course of A/Shanghai/2/2013(H7N9) CDC-RG virus infection in mice. Associated immunization using LAIV and GBS vaccine (GBSV) prevented post-influenza pneumococcal pneumonia better than mono-LAIV or GBSV immunization. At the same time, parenteral pneumococcal post-influenza infection of immune mice was more severe in the groups immunized using recombinant GBS peptides which can be explained by antibody-dependent enhancement of infection. In this case, the introduction of blockers of histamine receptors type 1 and 2 reduced the burden of secondary pneumococcal infection. [ABSTRACT FROM AUTHOR]

Enhanced surveillance of invasive pneumococcal disease (IPD) in adults was conducted during April 2013–March 2018 in 10 of 47 prefectures in Japan, and a total of 1277 IPD patients were enrolled. An emergence of IPD caused by serotype 12F was identified during May 2015–March 2018 through this surveillance. 12F isolates were composed of four related sequence types. In total, 120 patients with 12F IPD were reported during this period. To characterize the clinical features of 12F IPD, the disease characteristics of these patients were compared with those of 1157 patients with non-12F IPD. Compared with the non-12F IPD patients, a significantly lower proportion of 12F IPD patients was aged 65 years or older (55% vs. 70%), vaccinated with 23-valent pneumococcal polysaccharide (4% vs. 14%), had comorbid illness (65% vs. 77%), or were immunocompromised (19% vs. 30%; all P < 0.05). No significant difference in the proportion of case fatalities was found between the two groups. The proportions of those aged 65 years or older (53% vs. 69%) and with bacteremic pneumonia (35% vs. 69%) were significantly lower in 17 patients who died from 12F IPD than in 205 patients who died from non-12F IPD (all P < 0.05). Differences in clinical features were similarly found between 12F IPD patients and patients in low- or intermediate-level invasive potential serogroups. Our data demonstrated that serotype 12F was associated with IPD in younger adults and a lower proportion of comorbid illness, including immunocompromised conditions, in adult IPD, suggesting the high invasive potential of the serotype 12F. In addition, patients who died from 12F IPD were younger and had proportionately more bacteremia without focus. These findings may provide new insight into the pathogenesis of IPD in adults caused by 12F serotype with a high invasive potential. [ABSTRACT FROM AUTHOR]

Despite the availability of a pneumococcal National Immunization Program, which provides free PPSV23 vaccination for older adults aged ≥65 years in South Korea, pneumococcal pneumonia remains one of the most common respiratory infections, with increasing antimicrobial resistance. From January to December in 2015, all pneumococcal isolates were collected from a 1,050-bed teaching hospital in South Korea. All isolates were analyzed for serotype, genotype, and antimicrobial susceptibility. Demographic, clinical and microbiological data were compared between ceftriaxone susceptible and non-susceptible cases. Among 92 microbiologically identified pneumococcal isolates, ceftriaxone non-susceptible pneumococci (CNSP) accounted for 32 cases (34.8%). Some of these cases also showed levofloxacin resistance (25%, 8/32 isolates) and all CNSP cases were multidrug resistant. Compared to patients with ceftriaxone susceptible pneumococci (CSP), long-term care facility residents (odds ratio [OR] 7.0, 95% confidence interval [CI] 0.8–62.1) and patients with chronic lung (OR 4.1, 95% CI 1.1–15.0) and renal diseases (OR 9.1, 95% CI 1.2–70.5) were more common among those with CNSP on multivariate analysis. PPSV23-unique serotypes not included in PCV13 were more common in CNSP than in CSP (34.4% versus 13.3%, p = 0.02). Regarding genotypes, ST320 (10 cases), ST166 (7 cases) and ST8279 (3 cases) were dominant in CNSP, and ST8279 was only detected in previous long-term care facility residents. Clonal expansion and spread of CNSP strains should be monitored among patients with chronic lung/renal diseases and residents of long-term care facilities. [ABSTRACT FROM AUTHOR]

Background: Pneumonia is one of the leading causes of mortality and has a high burden in morbidity. In Portugal, 7-valent pneumococcal conjugated vaccine (PCV) was used since 2001 and PCV10/13 since 2009, being the last introduced into the National Immunization Program in 2015. Methods: We conducted an ecological study to evaluate the impact of PCV7 and PCV13 on pneumococcal pneumonia (PP) hospitalizations in adults aged 65 years or more in Portugal. National hospital discharge registry data from 1998/99 to 2015/16 were used, and PP hospitalization was defined as any hospitalization coded in primary diagnosis as 481 (ICD-9-CM) or J18 (ICD-10-CM). Poisson regression models adjusted for seasonality, influenza-like illness and allowing for overdispersion was used to estimate annual average change of PP hospitalization rate. To assess PP hospitalization trends before and after PCV7 and PCV13 introduction interrupted time series analysis was performed. Results: In 1998/99 PP hospitalization rate was 7.0 per 10,000 inhabitants, varying between 3.2 (females, 65–74 years) to 20.7 (males, +85 years), and annually increasing by 16% during the pre-PCV7 period. Statistically significant reduction of 14% per year in PP hospitalization rate was observed after PCV7 introduction. Between 2004/05 and 2009/10 PP hospitalization rate decreased annually by 4% and after PCV13 introduction by 11% per year. In 2015/16 we found an overall reduction of 2.9 (CI 95%: 2.7; 3.1) PP hospitalizations per 10,000 inhabitants (598 hospitalizations) attributable to PCV13, varying from 2.2 (CI 95%: 1.3; 3.1) (female, 65–74 years) to 5.6 (CI 95%: 3.8; 7.5) (female, +85 years). Conclusions: Our results suggest that introduction of both PCV7 and PCV13 vaccines resulted in the reduction of PP hospitalizations rates among older adults. [ABSTRACT FROM AUTHOR]

Non-invasive pneumococcal pneumonia (NIPP) is a frequent cause of morbidity and mortality worldwide. The 13-valent pneumococcal conjugate vaccine (PCV13) was included in the national immunization program of children living in Portugal in 2015. Until then, PCV7 (since late 2001) and PCV13 (since early 2010) were given through the private market. We determined the serotype distribution and antimicrobial susceptibility of isolates causing adult NIPP in 2012–2015 and compared the results with previously published data (2007–2011). There were 50 serotypes among the 1435 isolates. The most common were serotypes: 3 (14%), 11A (8%), 19F (6%), 23A (5%), 6C (5%), 19A (4%), 23B (4%), 9N (4%) and non-typable isolates (4%). When considering data since the availability of PCV13 for children in the private market, the proportion of PCV13 serotypes declined from 44.0% in 2010 to 29.7% in 2015 (p < 0.001), mainly due to early decreases in the proportions of serotypes 3 and 19A. In contrast, during the same period, PCV7 serotypes (11.9% in 2012–2015) and the serotypes exclusive of the 23-valent polysaccharide vaccine (26.0% in 2012–2015), remained relatively stable, while non-vaccine types increased from 27.0% in 2010 to 41.9% in 2015 (p<0.001). According to the Clinical and Laboratory Standards Institute (CLSI) breakpoints, penicillin non-susceptible and erythromycin resistant isolates accounted for 1% and 21.7%, respectively, of the isolates recovered in 2012–2015, with no significant changes seen since 2007. Comparison of NIPP serotypes with contemporary invasive disease serotypes identified associations of 19 serotypes with either disease presentation. The introduction of PCV13 in the national immunization program for children from 2015 onwards may lead to reductions in the proportion of NIPP due to vaccine serotypes but continued NIPP surveillance is essential due to a different serotype distribution from invasive disease. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae colonization is a precursor to pneumococcal disease. Although children with a tracheostomy have an increased risk of pneumococcal pneumonia, the pneumococci colonizing their lower airways remain largely uncharacterized. We sought to compare lower respiratory tract isolates colonizing tracheostomy patients and a convenience sample of isolates from individuals intubated for acute conditions. We collected pneumococcal isolates from the lower respiratory tract of 27 patients with a tracheostomy and 42 patients intubated for acute conditions. We compared the penicillin susceptibility, rates of co-colonization, genetic background, and serotype of isolates colonizing these patient populations. Isolates from both groups showed high genetic diversity. Forty multi-locus sequence types and 20 serotypes were identified. There was no significant difference in serotype distribution, co-colonization rates, vaccine coverage, or non-susceptibility to penicillin among pneumococcal isolates from the two groups. Colonization of the lower airways with non-vaccine serotypes 15B/C, 23B and 35B was noted for the first time in patients with tracheostomies and supports recently observed increases in nasopharyngeal colonization and disease due to these serotypes. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae is an opportunistic Gram-positive pathogen that can cause invasive disease. Recent studies have shown that S. pneumoniae is able to invade the myocardium and kill cardiomyocytes, with one-in-five adults hospitalized for pneumococcal pneumonia having a pneumonia-associated adverse cardiac event. Furthermore, clinical reports have shown up to a 10-year increased risk of adverse cardiac events in patients formerly hospitalized for pneumococcal bacteremia. In this study, we investigated the ability of nine S. pneumoniae clinical isolates, representing eight unique serotypes, to cause cardiac damage in a mouse model of invasive disease. Following intraperitoneal challenge of C57BL/6 mice, four of these strains (D39, WU2, TIGR4, and 6A-10) caused high-grade bacteremia, while CDC7F:2617–97 and AMQ16 caused mid- and low-grade bacteremia, respectively. Three strains did not cause any discernible disease. Of note, only the strains capable of high-grade bacteremia caused cardiac damage, as inferred by serum levels of cardiac troponin-I. This link between bacteremia and heart damage was further corroborated by Hematoxylin & Eosin and Trichrome staining which showed cardiac cytotoxicity only in D39, WU2, TIGR4, and 6A-10 infected mice. Finally, hearts infected with these strains showed varying histopathological characteristics, such as differential lesion formation and myocytolysis, suggesting that the mechanism of heart damage varied between strains. [ABSTRACT FROM AUTHOR]

Background: The pneumococcal urinary antigen test (UAT) has been known to improve sensitivity and specificity for the diagnosis of pneumococcal pneumonia. Associations of UAT results with prognosis in community acquired pneumonia (CAP) are not known. We hypothesized that positive UAT is associated with a good prognosis, and incorporation of UAT into CRB65 would improve its prognostic performance. Methods: In this registry-based retrospective study, we analyzed CAP patients over a 10-year period beginning in April 2008. Patients who had UAT results were included in multivariable extended Cox-regression analyses to determine the association between UAT positivity and 30-day mortality. UAT results were incorporated for patients with a CRB65 score of 1 by subtracting 1 from the scoring system if the test was positive. The performance of the modified scoring systems was assessed with area under the receiver operating characteristic (AUROC) curves. Results: Among 5145 CAP patients, total 2280 patients had UAT results and were included in analyses. A positive UAT result was associated with a good prognosis after a week of hospitalization (aHR, 0.14; p = 0.007). After modification of CRB65 using UAT results, positive and negative predictive values for 30-day mortality were increased from 7.7 to 8.3 (p<0.001) and 98.9 to 99.1 (p = 0.010). The AUROC increased from 0.73 to 0.75 (p<0.001). Conclusions: Positive results on UAT could be considered as a good prognostic factor in CAP. UAT could be used as a useful tool in deciding whether to refer patients to the hospital, especially in moderate CAP with a CRB score of 1. [ABSTRACT FROM AUTHOR]

Background: There is only limited information on mortality over extended periods in hospitalized patients with pneumococcal community-acquired pneumonia (CAP). We aimed to evaluate the 30-day mortality and whether is changed over a 20-year period among immunocompetent adults hospitalized with pneumococcal CAP. Methods: We conducted a retrospective observational study of data that were prospectively collected at the Hospital Clinic of Barcelona of all adult patients hospitalized with diagnosis of pneumococcal CAP over a 20-year period. To aid analysis, results were divided into four periods of 5 years each (1997–2001, 2002–2006, 2007–2011, 2012–2016). The primary outcome was 30-day mortality, but secondary outcomes included intensive care unit (ICU) admission, lengths of hospital and ICU-stays, ICU-mortality, and need of mechanical ventilation. Results: From a cohort of 6,403 patients with CAP, we analyzed the data for 1,120 (17%) adults with a diagnosis of pneumococcal CAP. Over time, we observed decreases in the rates of alcohol consumption, smoking, influenza vaccination, and older patients (age ≥65 years), but increases in admissions to ICU and the need for non-invasive mechanical ventilation. The overall 30-day mortality rate was 8% (95% confidence interval, 6%–9%; 84 of 1,120 patients) and did not change significantly between periods (p = 0.33). Although, we observed a decrease in ICU-mortality comparing the first period (26%) to the second one (10%), statistical differences disappeared with adjustment (p0.38). Conclusion: Over time, 30-day mortality of hospitalized pneumococcal CAP did not change significantly. Nor did it change in the propensity-adjusted multivariable analysis. Since mortality in pneumococcal pneumonia has remained unaltered for many years despite the availability of antimicrobial agents with proven in vitro activity, other non-antibiotic strategies should be investigated. [ABSTRACT FROM AUTHOR]

Introduction: In 2012, PCV13 was introduced into the National Immunization Program in Argentina, 2+1 schedule for children <2 years. Coverage rates for 1st and 3rd doses were 69% and 41.0% in 2012, 98% and 86% in 2013; 99% and 89% in 2014, respectively. The aims of this study were to evaluate impact of PCV13 on Consolidated Pneumonia (CP) and Pneumococcal Pneumonia (PP) burden, and to describe epidemiological-clinical pattern of PP during the three-year period following vaccine introduction. Methods: Hospital-based study at 10 pediatric surveillance units in Argentina. CP and PP discharge rates per 10,000 hospital discharges were compared between the pre-vaccination period 2007–2011 (preVp), the year of intervention (2012) and the post-vaccination period 2013–2014 (postVp). Results: Significant reduction in CP and PP discharge rates was observed in patients <5 years [% reduction (95%CI)]: 10.2% (6.3; 14.0) in 2012 and 24.8% (21.3; 28.2) in postVp for CP discharge rate; 59.5% (48.0; 68.5) in 2012 and 68.8% (58.3; 76.6) in postVp for PP discharge rate. Significant changes were also observed in children ≥5 years, mainly in PP discharge rate. A total of 297 PP cases were studied; 59.3% male; 31.3% <2 years; 42.9% had received PCV13 in 2012 and 84.5% in posVp. Case fatality rate was 3.4%. PCV13 serotypes decreased from 83.0% (39/47) in 2012 to 64.2% (52/81) in postVp, p = 0.039. Conclusions: After PCV13 introduction, significant reduction in CP and PP discharge rates was observed in hospitalized children <5 years. In patients ≥5 years, PP discharge rate also decreased significantly. [ABSTRACT FROM AUTHOR]

Background: The Belgian Superior Health Council (SHC) recently added a 13-valent pneumococcal conjugate vaccine (PCV13) to its recommendations for adult pneumococcal vaccination. This study addresses the policy question regarding whether a single dose of PCV13 should be reimbursed among Belgian adults aged 65–84 years with chronic comorbidities (“moderate-risk”) or immunosuppression (“high-risk”). Methods: A cohort model was developed to project lifetime risks, consequences, and costs of invasive pneumococcal disease (IPD) and pneumococcal community-acquired pneumonia (CAP). Parameter values were estimated using published literature and available databases, and were reviewed by Belgian experts. PCV13 effectiveness was assumed to be durable during the first 5 years following receipt, and to progressively decline thereafter with 15 years protection. The Belgian National Health Insurance perspective was employed. Results: Use of PCV13 (vs. no vaccine) in moderate/high-risk persons aged 65–84 years (n = 861,467; 58% vaccination coverage) would be expected to prevent 527 cases of IPD, 1,744 cases of pneumococcal CAP and 176 pneumococcal-related deaths, and reduce medical care costs by €20.1 million. Vaccination costs, however, would increase by €36.9 million and thus total overall costs would increase by €16.8 million. Cost per QALY gained was €17,126. In probabilistic sensitivity analyses, use of PCV13 was cost-effective in 97% of 1,000 simulations. Conclusions: Reimbursement of PCV13 in moderate/high-risk Belgian adults aged 65–84 years would be cost-effective from the Belgian healthcare perspective. [ABSTRACT FROM AUTHOR]

Background: Pneumococcal colonization is a precursor to pneumonia, and pneumococcal conjugate vaccines (PCV) can decrease vaccine-type (VT) colonization. Pneumococcal colonization studies are traditionally done among healthy children in the community; however, VT colonization prevalence may differ between these children and those with pneumonia. We assessed overall and VT pneumococcal colonization and factors associated with colonization among children with and without pneumonia after Mozambique introduced 10-valent PCV (PCV10) in 2013. Methods: We used data from ongoing pneumonia surveillance in children aged <5 years and from cross-sectional nasopharyngeal colonization surveys conducted in October 2014 –April 2015 and October 2015 –May 2016. Pneumonia was defined using WHO standard criteria for radiologically confirmed pneumonia. Children with pneumonia enrolled from January 2014 –April 2016 were compared to children without pneumonia enrolled from the cross-sectional surveys. Clinical data and nasopharyngeal (NP) swabs were collected from each child. NP specimens were cultured for pneumococci, and culture-negative specimens from children with pneumonia underwent polymerase chain reaction (PCR). Results: Of 778 and 927 children with and without pneumonia, 97.4% and 27.0% were exposed to antibiotics before swab collection, respectively. Based on culture, pneumococcal colonization was 45.1% for children with and 84.5% for children without pneumonia (P<0.001); VT pneumococcal colonization was 18.6% for children with and 23.4% for children without pneumonia (P = 0.02). The addition of PCR in children with pneumonia increased overall and VT-pneumococcal colonization to 79.2% and 31.1%, respectively. In multivariable analysis including PCR results, pneumonia was associated with VT pneumococcal colonization (adjusted OR: 1.4, 95%CI: 1.10–1.78). Conclusion: Vaccine-type pneumococcal colonization remains common among children with and without pneumonia post-PCV10 introduction in Mozambique. In a population of children with high antibiotic exposure, the use of PCR for culture-negative NP swabs can improve assessment of pneumococcal colonization and circulating serotypes. [ABSTRACT FROM AUTHOR]

Background: Pneumonia is a leading infectious cause of morbidity and mortality among adults. Pneumococcal pneumonia (PP) is the most common vaccine-preventable bacterial etiology of pneumonia. In this study, we estimated the incidence of community-acquired pneumonia (CAP) and pneumococcal diseases among Korean adults. Methods: Clinical and microbiological databases from three hospitals were retrospectively reviewed to determine the incidence and case fatality rates of CAP and pneumococcal diseases in Korean adults aged ≥19 years from 2011 to 2014. Incidence and case fatality rates of CAP, PP and invasive pneumococcal diseases (IPD) were evaluated based on the catchment population. Catchment population was calculated using national health insurance data, estimating the proportion of patients with pneumonia that were medically attended at each hospital. Results: Among 5,783 patients with medically attended CAP, 833 (14.4%) had PP. For IPD, a total of 91 culture-confirmed cases were identified. The overall incidence of CAP was 307.7 cases per 100,000 persons per year with an in-hospital mortality rate of 6.2%. The estimated annual incidence of pneumococcal pneumonia was 42.2–49.4 cases per 100,000 persons per year, increasing with age to >280 per 100,000 persons per year in older patients over 70 years. The annual incidence of IPD had a range of 4.1–6.5 cases per 100,000 persons per year. The overall case fatality rate for invasive pneumococcal diseases was 30.8% with the highest rate of 66.7% in patients over 80 years. Conclusion: Over the study period, incidences of CAP, PP and IPD were consistently high, particularly in older people. These results provide baseline data to establish healthcare strategies and estimate their impact among Korean adults. [ABSTRACT FROM AUTHOR]

The 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in The Netherlands in 2006 and was replaced by PHiD-CV10 in 2011. Data on carriage prevalence of S. pneumoniae serotypes in children and invasive pneumococcal disease (IPD) in children and older adults were collected to examine the impact of PCVs on carriage and IPD in The Netherlands. Pneumococcal carriage prevalence was determined by conventional culture of nasopharyngeal swabs in 24-month-old children in 2015/2016. Data were compared to similar carriage studies in 2005 (pre-PCV7 introduction), 2009, 2010/2011 and 2012/2013. Invasive pneumococcal disease isolates from hospitalized children <5 years and adults >65 years (2004–2016) were obtained by sentinel surveillance. All isolates were serotyped by Quellung. Serotype invasive disease potential was calculated using carriage and nationwide IPD data in children. The overall pneumococcal carriage rate was 48% in 2015/2016, lower than in 2010/2011 (64%) and pre-vaccination in 2005 (66%). Carriage of the previously dominant non-vaccine serotypes 19A and 11A has declined since 2010/2011, from 14.2% to 4.6% and 4.2% to 2.7%, respectively, whereas carriage of serotypes 6C and 23B has increased (4.2% to 6.7% and 3.9% to 7.3%), making serotypes 6C and 23B the most prevalent carriage serotypes. IPD incidence declined in children (20/100,000 cases in 2004/2006 to 6/100,000 cases in 2015/2016) as well as in older adults (63/100,000 cases to 51/100,000 cases). Serotypes 6C, 23B and 11A have high carriage prevalence in children, but show low invasive disease potential. Serotype 8 is the main causative agent for IPD in older adults (11.3%). In conclusion, 10 years after the introduction of pneumococcal vaccination in children in The Netherlands shifts in carriage and disease serotypes are still ongoing. Surveillance of both carriage and IPD is important to assess PCV impact and to predict necessary future vaccination strategies in both children and older adults. [ABSTRACT FROM AUTHOR]

Background: Streptococcus pneumoniae causes morbidity and mortality among all ages in The Netherlands. To reduce this burden, infants in The Netherlands receive the 10-valent pneumococcal conjugated vaccine (PCV10), but older persons are not targeted. We assessed the impact and cost-effectiveness of vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV23) or 13-valent PCV (PCV13) among all those aged 60, 65 or 70 and/or in combination with replacing PCV10 with PCV13 in the infant vaccination programme. Methods: A static cost-effectiveness model was parameterized including projected trends for invasive pneumococcal disease (IPD) and hospitalised community acquired pneumonia (CAP). The different strategies were evaluated using vaccine list prices and a 10-year time horizon. Incremental cost-effectiveness ratios (ICER) were calculated with the current strategy (infant vaccination program with PCV10) as reference. Results: Compared to the reference, the largest impact on pneumococcal disease burden was projected with a combined use of PCV13 among infants and PPV23 at 60, 65 and 70 years, preventing 1,635 cases of IPD and 914 cases of CAP. The most cost-effective strategy was vaccinating with PPV23 at 70 years only with similar low ICERs at age 60 and 65. The impact of the use of PCV13 among infants depends strongly on the projected herd-immunity effect on serotype 19A. Vaccinating elderly with either PCV13 or PPV23 was dominated by PPV23 in all investigated scenarios, mainly due to the lower price of PPV23. Conclusion: Under the current assumptions, the best value for money is the use of PPV23 for elderly, with a single dose or at five year increment between age 60 to age 70. [ABSTRACT FROM AUTHOR]

Streptococcus pneumoniae is one of the major causes of pneumonia, meningitis and other pneumococcal infections in young children and elders. Determination of circulating S. pneumoniae serotypes is an essential service by public health laboratories for the monitoring of putative serotype replacement following the introduction of pneumococcal conjugate vaccines (PCVs) and of the efficacy of the immunization program. The Quellung method remains the gold standard for typing S. pneumoniae. Although this method is very effective, it is also costly, time consuming and not totally reliable due to its subjective nature. The objectives of this study were to test and evaluate the efficiency of 3 different molecular methods compared to the Quellung method. Sequential multiplex PCR, sequetyping and whole genome sequencing (WGS) were chosen and tested using a set of diverse S. pneumoniae. One-hundred and eighteen isolates covering 83 serotypes were subjected to multiplex PCR and sequetyping while 88 isolates covering 53 serotypes were subjected to WGS. Sequential multiplex PCR allowed the identification of a significant proportion (49%) of serotypes at the serogroup or subset level but only 27% were identified at the serotype level. Using WGS, 55% to 60% of isolates were identified at the serotype level depending on the analysis strategy used. Finally, sequetyping demonstrated the lowest performance, with 17% of misidentified serotypes. The use of Jin cpsB database instead of the GenBank database slightly improved results but did not significantly impact the efficiency of sequetyping. Although none of these molecular methods may currently replace the Quellung method, WGS remains the most promising molecular pneumococcal serotyping method. [ABSTRACT FROM AUTHOR]

Background: The 13-valent pneumococcal conjugate vaccine (PCV13) was licensed based on the results of immunogenicity studies and correlates of protection derived from randomized clinical trials of the 7-valent conjugate pneumococcal vaccine. We assessed the vaccination effectiveness (VE) of the PCV13 in preventing invasive pneumococcal disease (IPD) in children aged 7–59 months in a population with suboptimal vaccination coverage of 55%. Methods: The study was carried out in children with IPD admitted to three hospitals in Barcelona (Spain) and controls matched by hospital, age, sex, date of hospitalization and underlying disease. Information on the vaccination status was obtained from written medical records. Conditional logistic regression was made to estimate the adjusted VE and 95% confidence intervals (CI). Results: 169 cases and 645 controls were included. The overall VE of ≥1 doses of PCV13 in preventing IPD due to vaccine serotypes was 75.8% (95% CI, 54.1–87.2) and 90% (95% CI, 63.9–97.2) when ≥2 doses before 12 months, two doses on or after 12 months or one dose on or after 24 months, were administered. The VE of ≥1 doses was 89% (95% CI, 42.7–97.9) against serotype 1 and 86.0% (95% CI, 51.2–99.7) against serotype 19A. Serotype 3 showed a non-statistically significant effectiveness (25.9%; 95% CI, -65.3 to 66.8). Conclusions: The effectiveness of ≥1 doses of PCV13 in preventing IPD caused by all PCV13 serotypes in children aged 7–59 months was good and, except for serotype 3, the effectiveness of ≥1 doses against the most frequent PCV13 serotypes causing IPD was high when considered individually. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to investigate the association between the time to positivity of blood culture (TTP) with clinical outcome and severity of pneumococcal bacteremic pneumonia. Methods: Prospective observational study carried out in 278 hospitalized adult CAP patients with positive blood culture for Streptococcus pneumonia (2003–2015). Results: A total of 278 cases of bacteremic pneumococcal pneumonia were analyzed, median age 62 (46; 79) years. Fifty-one percent of the cases had PSI IV-V. Twenty-one (8%) died within 30-days after admission. The analysis of the TTP showed that the first quartile of the TTP (9.2h) was the best cut-off for differentiating 2 groups of patients at risk, early (TTP <9.2 h) and late (TTP ≥9.2 h) detection groups (AUC 0.66 [95% CI 0.53 to 0.79]). Early TTP was associated with a statistically significant risk of invasive mechanical ventilation (18% vs. 6%, p = 0.007), longer length of hospital stay (12 days vs. 8 days, p<0.001), higher in-hospital mortality (15% vs. 4%, p = 0.010), and 30-day mortality (15% vs. 5%, p = 0.018). After adjustment for potential confounders, regression analyses revealed early TTP as independently associated with high risk of invasive mechanical ventilation (OR 4.60, 95% CI 1.63 to 13.03), longer length of hospital stay (β 5.20, 95% CI 1.81 to 8.52), higher in-hospital mortality (OR 5.35, 95% CI 1.55 to 18.53), and a trend to higher 30-day mortality (OR 2.47, 95% CI 0.85 to 7.21) to be a contributing factor. Conclusion: Our results demonstrate that TTP is an easy to obtain surrogate marker of the severity of pneumococcal pneumonia and a good predictor of its outcome. [ABSTRACT FROM AUTHOR]

Since implementation of the 13-valent polyvalent conjugate vaccine (PCV13) in Canada during 2010, the proportion of PCV13 serotypes causing invasive pneumococcal disease (IPD) has declined from 55% (n = 1492) in 2010 to 31% (n = 764) in 2014. A concurrent increase of non-PCV13 serotypes has occurred and 22F has become the most prevalent serotype in Canada increasing from 7% (n = 183) to 11% (n = 283). Core single nucleotide variant phylogenetic analysis was performed on 137 Streptococcus pneumoniae serotype 22F isolates collected across Canada from 2005–2015. Six phylogenetic lineages (n = 117) were identified among a serotype 22F/ST433 clonal complex (CC), including a recently expanding erythromycin-resistant clone. Erythromycin-resistance was observed in 25 isolates possessing ermB, mef or a 23S rRNA A2061G point mutation; 2 penicillin-resistant isolates had recombinant pbp1a, pbp2a and/or pbp2x; 3 tetracycline-resistant isolates contained tetM; and 1 isolate was multidrug-resistant. Virulence factor analysis indicated a high level of homogeneity among the 22F/ST433 clonal complex strains. A group of 6 phylogenetic outlier strains had differing MLST, antimicrobial resistance and molecular profiles suggestive of capsule switching events. While capsule switch events among S. pneumoniae serotype 22F has been observed, increasing prevalence of S. pneumoniae serotype 22F can be attributed to an evolving homogenous clone expanding nationally through local transmission events. [ABSTRACT FROM AUTHOR]

Background: Although the 13-valent pneumococcal conjugate vaccine (PCV13) showed good efficacy against pneumococcal disease in the the CAPiTA trial, the 23-valent pneumococcal polysaccharide vaccination (PPSV23) program has been ongoing for older adults aged ≥ 65 years in Korea since May of 2013. This study aimed to evaluate the cost-effectiveness of the current vaccination strategy (a single-dose PPSV23 vaccination) compared to a single-dose PCV13 vaccination and sequential PCV13-PPSV23 vaccinations in the elderly population aged ≥ 65 years. Methods: Using a Markov model, the incremental cost-effectiveness ratios (ICERs) of three vaccination strategies were assessed in a societal context. The transition probabilities, utility weights to estimate quality adjusted life year (QALY), and disease treatment costs were either calculated or cited from published data and the Health Insurance Review and Assessment Service. Simulations were performed in hypothetical cohorts of Korean adults aged ≥ 19 years. The vaccine effectiveness of PPSV23 was cited from a Cochrane Review report, while PCV13 effectiveness data were gathered from the CAPiTA trial. Results: Current PPSV23 vaccination strategies were cost-effective (ICER, $25,786 per QALY). However, the administration of PCV13 as a substitute for PPSV23 was shown to be more cost-effective than PPSV23 vaccination (ICER, $797 per QALY). Sequential PCV13-PPSV23 vaccination was also more cost-effective than PPSV23 for elderly people aged ≥ 65 years. In sensitivity analysis assuming significant PPSV23 effectiveness (50%) against non-bacteremic pneumococcal pneumonia, the PCV13 vaccination strategy was superior to the PPSV23 vaccination strategy in terms of cost-effectiveness. Conclusion: The results suggest that PCV13 vaccination is more cost-effective in elderly subjects aged ≥ 65 years compared to the current PPSV23 vaccination strategy. When complete data is obtained in 2018 on the maximal herd effects of childhood PCV13 immunization, the incidence of pneumococcal pneumonia and the cost-effectiveness of vaccination strategies need to be reassessed. [ABSTRACT FROM AUTHOR]

Dysfunction of T follicular-helper (TFH) cells is a possible cause of impaired germinal centre (GC) and IgG antibody responses in individuals with human immunodeficiency virus-1 (HIV-1) infection and might contribute to decreased magnitude and isotype diversification of IgG antibodies to pneumococcal polysaccharides (PcPs). We examined the production of IgG1 and IgG2 antibodies to PcPs 4, 6B, 9V and 14 by enumerating antibody secreting cells (ASCs) at day (D) 7 and determining fold-increase in serum antibody levels at D28 after vaccination with unconjugated PcPs in HIV seronegative subjects (n = 20) and in HIV patients who were receiving antiretroviral therapy (ART) (n = 28) or who were ART-naive (n = 11) and determined their association with ICOS+ and ICOS- circulating memory TFH (cmTFH) cells (CD4+CD45RA-CD27+CXCR5+PD-1+) and short lived plasmablasts (SPBs) at D7, and with PcP-specific and total IgM+ and IgG+ memory B cells at D0. In HIV seronegative subjects, production of IgG1+ and IgG2+ ASCs was consistently associated with the frequency of ICOS+ cmTFH cells but not ICOS- cmTFH cells or memory B cells. In contrast, post-vaccination ASCs in HIV patients, regardless of ART status, were lower than in HIV seronegative subjects and not associated with ICOS+ cmTFH cells, the expansion of which was absent (ART-naive patients) or much lower than in HIV seronegative subjects (ART-treated patients). Production of SPBs was also lower in ART-naive patients. Fold-increase in IgG2 antibodies at D28 also correlated with ICOS+ cmTFH cells at D7 in HIV seronegative subjects but not in HIV patients. These novel findings provide evidence that ICOS+ cmTFH cells contribute to the regulation of PcP-specific IgG antibody responses, including isotype diversification, and that TFH cell dysfunction may be a cause of impaired PcP-specific IgG antibody responses and increased susceptibility to pneumococcal disease in HIV patients. [ABSTRACT FROM AUTHOR]

Welders are more susceptible to pneumococcal pneumonia. The mechanisms are yet unclear. Pneumococci co-opt the platelet activating factor receptor (PAFR) to infect respiratory epithelial cells. We previously reported that exposure of respiratory cells to welding fumes (WF), upregulates PAFR–dependent pneumococcal infection. The signaling pathway for this response is unknown, however, in intestinal cells, hypoxia-inducible factor-1 α (HIF 1α) is reported to mediate PAFR-dependent infection. We sought to assess whether oxidative stress plays a role in susceptibility to pneumococcal infection via the platelet activating factor receptor. We also sought to evaluate the suitability of nasal epithelial PAFR expression in welders as a biomarker of susceptibility to infection. Finally, we investigated the generalisability of the effect of welding fumes on pneumococcal infection and growth using a variety of different welding fume samples. Nasal epithelial PAFR expression in welders and controls was analysed by flow cytometry. WF were collected using standard methodology. The effect of WF on respiratory cell reactive oxygen species production, HIF-1α expression, and pneumococcal infection was determined using flow cytometry, HIF-1α knockdown and overexpression, and pneumococcal infection assays. We found that nasal PAFR expression is significantly increased in welders compared with controls and that WF significantly increased reactive oxygen species production, HIF-1α and PAFR expression, and pneumococcal infection of respiratory cells. In unstimulated cells, HIF-1α knockdown decreased PAFR expression and HIF-1α overexpression increased PAFR expression. However, in knockdown cells pneumococcal infection was paradoxically increased and in overexpressing cells infection was unaffected. Nasal epithelial PAFR expression may be used as a biomarker of susceptibility to pneumococcal infection in order to target individuals, particularly those at high risk such as welders, for the pneumococcal vaccine. Expression of HIF-1α in unexposed respiratory cells inhibits basal pneumococcal infection via PAFR-independent mechanisms. [ABSTRACT FROM AUTHOR]

In the Community of Madrid, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced the 7-valent (PCV7) in the fully government-funded Regional Immunization Program (RIP) in May, 2010, but was later excluded in May, 2012, and included again in January, 2015. These unique changes allowed us to assess the impact of the different pneumococcal vaccination policies on PCV13 uptake in infants and on the incidence rate (IR) of invasive pneumococcal disease (IPD) in children <15 years old. In this prospective, active, surveillance study, we estimated PCV13 uptakes, IR and incidence rate ratios (IRR) for total IPD and for IPD caused by PCV13- and non-PCV13 serotypes in children <15 years, stratified by age, in four periods with different vaccination policies: fully government-funded PCV7 vaccination, fully government-funded PCV13, mixed public/private funding and only private funding. Vaccine uptakes reached 95% in periods with public-funded pneumococcal vaccination, but fell to 67% in the private funding period. Overall, IR of IPD decreased by 68% (p<0.001) in 2014–15, due to 93% reduction in the IR of PCV13-type IPD (p<0.001) without significant changes in non-PCV13-type IPD. A fully government-funded PCV13 vaccination program lead to high vaccine uptake and dramatic reductions in both overall and PCV13-type IPD IR. When this program was switched to private PCV13 vaccination, there was a fall in vaccine coverage and stagnation in the decline of PCV13-type IPD with data suggesting a weakening of herd immunity. [ABSTRACT FROM AUTHOR]

Pneumococcal pneumonia is a serious cause of morbidity and mortality in the elderly, but investigation of the etiological agent of community-acquired pneumonia (CAP) is not possible in most hospitalized patients. The aim of this study was to estimate the effect of pneumococcal polysaccharide vaccination (PPSV23) in preventing CAP hospitalization and reducing the risk of intensive care unit admission (ICU) and fatal outcomes in hospitalized people aged ≥65 years. We made a multicenter case-control study in 20 Spanish hospitals during 2013–2014 and 2014–2015. We selected patients aged ≥65 years hospitalized with a diagnosis of pneumonia and controls matched by sex, age and date of hospitalization. Multivariate analysis was performed using conditional logistic regression to estimate vaccine effectiveness and unconditional logistic regression to evaluate the reduction in the risk of severe and fatal outcomes. 1895 cases and 1895 controls were included; 13.7% of cases and 14.4% of controls had received PPSV23 in the last five years. The effectiveness of PPSV23 in preventing CAP hospitalization was 15.2% (95% CI -3.1–30.3). The benefit of PPSV23 in avoiding ICU admission or death was 28.1% (95% CI -14.3–56.9) in all patients, 30.9% (95% CI -32.2–67.4) in immunocompetent patients and 26.9% (95% CI -38.6–64.8) in immunocompromised patients. In conclusion, PPSV23 showed a modest trend to avoidance of hospitalizations due to CAP and to the prevention of death or ICU admission in elderly patients hospitalized with a diagnosis of CAP. [ABSTRACT FROM AUTHOR]

Background: S. pneumoniae is a leading cause of meningitis morbidity and mortality in the African meningitis belt, but little is known of its contribution to the burden of pneumonia in the region. We aimed to estimate the incidence of pneumococcal disease in children and adults in northern Togo, before the introduction of pneumococcal conjugate vaccine (PCV). Methods and findings: From May 1st 2010 to April 30th 2013, we systematically enrolled all hospitalized patients meeting a case definition of suspected meningitis or clinical pneumonia, residing in Tone or Cinkasse districts, northern Togo and providing informed consent. We collected clinical data and tested biological specimens according to standardized procedures, including bacteriology and PCR testing of cerebro-spinal fluid for meningitis patients and blood cultures and whole blood lytA PCR for pneumonia patients. Chest X-rays (CXR) were interpreted using the WHO methodology. We included 404 patients with meningitis (104 <5 years of age) and 1550 with pneumonia (251 <5 years) over the study period. Of these, 78 (19%) had pneumococcal meningitis (13 <5 years), 574 (37%) had radiologically-confirmed pneumonia (83 <5 years) and 73 (5%) had culture-confirmed pneumococcal pneumonia (2 <5 years). PCV13 serotypes caused 79% (54/68) of laboratory-confirmed pneumococcal meningitis and 83% (29/35) of culture-confirmed pneumococcal pneumonia. Serotype 1 predominated in meningitis (n = 33) but not in pneumonia patients (n = 1). The incidence of pneumococcal disease was 7.5 per 100,000 among children <5 years of age and 14.8 in persons 5 years of age and above in the study area. When considering CXR-confirmed and blood PCR-positive pneumonia cases as likely pneumococcal, incidence estimates increased to 43.7 and 66.0 per 100,000 in each of these age groups, respectively. Incidence was at least 3-fold higher when we restricted the analysis to the urban area immediately around the study hospitals. Conclusions: Our findings highlight the important role of S. pneumoniae as a meningitis and pneumonia-causing pathogen in the African meningitis belt. Pneumococcal disease incidence in our population was substantially lower than expected from global models; we hypothesize that poor access to hospital care led us to substantially underestimate the burden of disease. Surveillance is ongoing and will enable an evaluation of PCV impact, providing novel, high quality data from the region. [ABSTRACT FROM AUTHOR]

Background: The pneumococcal conjugate vaccine’s (PCV) impact on childhood pneumonia during programmatic conditions in Africa is poorly understood. Following PCV13 introduction in Malawi in November 2011, we evaluated the case burden and rates of childhood pneumonia. Methods and Findings: Between January 1, 2012-June 30, 2014 we conducted active pneumonia surveillance in children <5 years at seven hospitals, 18 health centres, and with 38 community health workers in two districts, central Malawi. Eligible children had clinical pneumonia per Malawi guidelines, defined as fast breathing only, chest indrawing +/- fast breathing, or, ≥1 clinical danger sign. Since pulse oximetry was not in the Malawi guidelines, oxygenation <90% defined hypoxemic pneumonia, a distinct category from clinical pneumonia. We quantified the pneumonia case burden and rates in two ways. We compared the period immediately following vaccine introduction (early) to the period with >75% three-dose PCV13 coverage (post). We also used multivariable time-series regression, adjusting for autocorrelation and exploring seasonal variation and alternative model specifications in sensitivity analyses. The early versus post analysis showed an increase in cases and rates of total, fast breathing, and indrawing pneumonia and a decrease in danger sign and hypoxemic pneumonia, and pneumonia mortality. At 76% three-dose PCV13 coverage, versus 0%, the time-series model showed a non-significant increase in total cases (+47%, 95% CI: -13%, +149%, p = 0.154); fast breathing cases increased 135% (+39%, +297%, p = 0.001), however, hypoxemia fell 47% (-5%, -70%, p = 0.031) and hospital deaths decreased 36% (-1%, -58%, p = 0.047) in children <5 years. We observed a shift towards disease without danger signs, as the proportion of cases with danger signs decreased by 65% (-46%, -77%, p<0.0001). These results were generally robust to plausible alternative model specifications. Conclusions: Thirty months after PCV13 introduction in Malawi, the health system burden and rates of the severest forms of childhood pneumonia, including hypoxemia and death, have markedly decreased. [ABSTRACT FROM AUTHOR]

Rationale: Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and infectious death in adults worldwide. A non-human primate model is needed to study the molecular mechanisms that underlie the development of severe pneumonia, identify diagnostic tools, explore potential therapeutic targets, and test clinical interventions during pneumococcal pneumonia. Objective: To develop a non-human primate model of pneumococcal pneumonia. Methods: Seven adult baboons (Papio cynocephalus) were surgically tethered to a continuous monitoring system that recorded heart rate, temperature, and electrocardiography. Animals were inoculated with 109 colony-forming units of S. pneumoniae using bronchoscopy. Three baboons were rescued with intravenous ampicillin therapy. Pneumonia was diagnosed using lung ultrasonography and ex vivo confirmation by histopathology and immunodetection of pneumococcal capsule. Organ failure, using serum biomarkers and quantification of bacteremia, was assessed daily. Results: Challenged animals developed signs and symptoms of pneumonia 4 days after infection. Infection was characterized by the presence of cough, tachypnea, dyspnea, tachycardia and fever. All animals developed leukocytosis and bacteremia 24 hours after infection. A severe inflammatory reaction was detected by elevation of serum cytokines, including Interleukin (IL)1Ra, IL-6, and IL-8, after infection. Lung ultrasonography precisely detected the lobes with pneumonia that were later confirmed by pathological analysis. Lung pathology positively correlated with disease severity. Antimicrobial therapy rapidly reversed symptomology and reduced serum cytokines. Conclusions: We have developed a novel animal model for severe pneumococcal pneumonia that mimics the clinical presentation, inflammatory response, and infection kinetics seen in humans. This is a novel model to test vaccines and treatments, measure biomarkers to diagnose pneumonia, and predict outcomes. [ABSTRACT FROM AUTHOR]

Prevalence of pneumococcal serotypes in carriage and disease has been described but absolute serotype colonisation densities have not been reported. 515 paediatric nasal swab DNA extracts were subjected to lytA qPCR and molecular serotyping by microarray. Absolute serotype densities were derived from total pneumococcal density (qPCR cycle threshold and standard curve) and relative abundance (microarray) and varied widely. Compared to all serotype densities observed, the strongest evidence of differences was seen for serotypes 21 and 35B (higher) and 3, 38 and non-typeables (lower) (p<0.05) with a similar hierarchy when only a single serotype carriage was assessed. There was no evidence of any overall density differences between children with single or multiple serotypes detected but serotypes with mid-range densities were more prevalent. The hierarchy of distinct pneumococcal serotype carriage densities described here for the first time, may help explain the dynamics of transmission between children. [ABSTRACT FROM AUTHOR]

Pneumococcal lung infections represent a major cause of death worldwide. Single nucleotide polymorphisms (SNPs) in the NFKBIZ gene, encoding the transcription factor IκBζ, are associated with increased susceptibility to invasive pneumococcal disease. We hence analyzed how IκBζ might regulate inflammatory responses to pneumococcal infection. We first demonstrate that IκBζ is expressed in human blood monocytes but not in bronchial epithelial cells, in response to wild type pneumococcal strain D39. D39 transiently induced IκBζ in a dose dependent manner, with subsequent induction of downstream molecules involved in host defense. Of these molecules, IκBζ knockdown reduced the expression of IL-6 and GMCSF. Furthermore, IκBζ overexpression increased the activity of IL-6 and GMCSF promoters, supporting the knockdown findings. Pneumococci lacking either pneumolysin or capsule still induced IκBζ. While inhibition of TLR1/TLR2 blocked D39 induced IκBζ expression, TLR4 inhibition did not. Blockade of p38 MAP kinase and NFκB suppressed D39 induced IκBζ. Overall, our data demonstrates that IκBζ regulates monocyte inflammatory responses to Streptococcus pneumoniae by promoting the production of IL-6 and GMCSF. [ABSTRACT FROM AUTHOR]

Purpose: Pneumococcal disease leads to renal complications ranging from persistent proteinuria to end-stage renal disease. Studies on the association between pneumococcal pneumonia (PP) and acute kidney injury (AKI) are scant. This study assessed the relationship between PP and risk of AKI. Methods: This nationwide population-based cohort study examined data from the Taiwan National Health Insurance Research Database for the period 2000–2011. We identified inpatients with newly diagnosed PP according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. In addition, we selected a comparison cohort from inpatient claims without the diagnosis of PP that was randomly frequency-matched with the PP cohort according to age, sex, index year and comorbidities. We analyzed the risks of AKI by using Cox proportional hazards regression models, adjusted for sex, age, and comorbidities. Results: A total of 10,069 patients with PP and 10,069 controls were enrolled in this study. After adjustments for age, sex, and comorbidities, patients with PP had a 1.11-fold risk of developing AKI compared with the comparison cohort. Conclusion: This study indicates that AKI risks are higher in patients with PP compared with the comparison cohort. Careful follow-up observation and aggressive treatment are necessary for patients with PP to reduce the risk of AKI. [ABSTRACT FROM AUTHOR]

Pneumonia is considered to be one of the leading causes of death worldwide. The outcome depends on both, proper antibiotic treatment and the effectivity of the immune response of the host. However, due to the complexity of the immunologic cascade initiated during infection, the latter cannot be predicted easily. We construct a biomathematical model of the murine immune response during infection with pneumococcus aiming at predicting the outcome of antibiotic treatment. The model consists of a number of non-linear ordinary differential equations describing dynamics of pneumococcal population, the inflammatory cytokine IL-6, neutrophils and macrophages fighting the infection and destruction of alveolar tissue due to pneumococcus. Equations were derived by translating known biological mechanisms and assuming certain response kinetics. Antibiotic therapy is modelled by a transient depletion of bacteria. Unknown model parameters were determined by fitting the predictions of the model to data sets derived from mice experiments of pneumococcal lung infection with and without antibiotic treatment. Time series of pneumococcal population, debris, neutrophils, activated epithelial cells, macrophages, monocytes and IL-6 serum concentrations were available for this purpose. The antibiotics Ampicillin and Moxifloxacin were considered. Parameter fittings resulted in a good agreement of model and data for all experimental scenarios. Identifiability of parameters is also estimated. The model can be used to predict the performance of alternative schedules of antibiotic treatment. We conclude that we established a biomathematical model of pneumococcal lung infection in mice allowing predictions regarding the outcome of different schedules of antibiotic treatment. We aim at translating the model to the human situation in the near future. [ABSTRACT FROM AUTHOR]

Immunoproteasomes, harboring the active site subunits β5i/LMP7, β1i/LMP2, and β2i/MECL1 exert protective, regulatory or modulating functions during infection-induced immune responses. Immunoproteasomes are constitutively expressed in hematopoietic derived cells, constituting the first line of defense against invading pathogens. To clarify the impact of immunoproteasomes on the innate immune response against Streptococcus pneumoniae, we characterized the progression of disease and analyzed the systemic immune response in β5i/LMP7-/- mice. Our data show that β5i/LMP7 deficiency, which affected the subunit composition of proteasomes in murine macrophages and liver, was accompanied by reduced transcription of genes encoding immune modulating molecules such as pentraxins, ficolins, and collectins. The diminished opsonin expression suggested an impaired humoral immune response against invading pneumococci resulting in an aggravated systemic dissemination of S. pneumoniae in β5i/LMP7-/- mice. The impaired bacterial elimination in β5i/LMP7-/- mice was accompanied by an aggravated course of pneumonia with early mortality as a consequence of critical illness during the late phase of disease. In summary our results highlight an unsuspected role for immuno-subunits in modulating the innate immune response to extracellular bacterial infections. [ABSTRACT FROM AUTHOR]

Background: Pneumococcal community-acquired pneumonia (pCAP) is the most frequent form of pneumonia. The elderly and adults with underlying diseases are at an increased risk of developing pCAP. The 23-valent pneumococcal polysaccharide vaccine (PPV23) was licensed over 30 years ago and is recommended as the standard intervention in many countries across the globe, although its efficacy continues to be debated. We performed a meta-analysis of randomized controlled trials (RCTs) to investigate the effect of PPV23 for preventing pCAP in adults ≥60 years of age. Methods: An existing Cochrane Review was updated to Oct 2014 using a systematic literature search to select appropriate RCTs. DerSimonian and Laird random-effects meta-analyses were performed and odd ratios (OR) with 95%-confidence intervals (CI) and p-values were calculated for the descriptive analyses. Reasons for heterogeneity were explored by subgroup analyses. Results: Meta-analysis of PPV23 efficacy included four studies. Three of them did not demonstrate efficacy for PPV23. The body of evidence indicated statistically significant heterogeneity (I2 = 78%, p = 0.004) that could be explained by subgroup analysis by “study setting”. Further effect modifiers for pCAP were “continent of trial” (p<0.01), and “method of pneumococcal diagnostics” (p = 0.001). Subgroup analyses revealed that the only study showing efficacy for PPV23 was an outlier. Overall, the validity of the meta-analytic PPV23 efficacy assessment was confirmed by the meta-analysis of all-cause CAP including six studies. Discussion: Inconsistencies in PPV23 treatment effects to prevent pCAP could solely be explained by one outlier study that was performed in nursing homes in Japan. The effect modifier “method of pneumococcal diagnostics” should be interpreted carefully, since methodological weaknesses are not restricted to one special method only, which would justify the exclusion of certain studies. Overall, we conclude from our meta-analysis that to date there is no proof that PPV23 can prevent pCAP in a general, community-dwelling elderly population. [ABSTRACT FROM AUTHOR]

Across bacterial species, metal binding proteins can serve functions in pathogenesis in addition to regulating metal homeostasis. We have compared and contrasted the activities of zinc (Zn2+)-binding lipoproteins AdcA and AdcAII in the Streptococcus pneumoniae TIGR4 background. Exposure to Zn2+-limiting conditions resulted in delayed growth in a strain lacking AdcAII (ΔAdcAII) when compared to wild type bacteria or a mutant lacking AdcA (ΔAdcA). AdcAII failed to interact with the extracellular matrix protein laminin despite homology to laminin-binding proteins of related streptococci. Deletion of AdcA or AdcAII led to significantly increased invasion of A549 human lung epithelial cells and a trend toward increased invasion in vivo. Loss of AdcAII, but not AdcA, was shown to negatively impact early colonization of the nasopharynx. Our findings suggest that expression of AdcAII affects invasiveness of S. pneumoniae in response to available Zn2+ concentrations. [ABSTRACT FROM AUTHOR]

Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia. Nucleotide-binding oligomerization domain-containing (NOD) 2 is a pattern recognition receptor located in the cytosol of myeloid cells that is able to detect peptidoglycan fragments of S. pneumoniae. We here aimed to investigate the role of NOD2 in the host response during pneumococcal pneumonia. Phagocytosis of S. pneumoniae was studied in NOD2 deficient (Nod2-/-) and wild-type (Wt) alveolar macrophages and neutrophils in vitro. In subsequent in vivo experiments Nod2-/- and Wt mice were inoculated with serotype 2 S. pneumoniae (D39), an isogenic capsule locus deletion mutant (D39Δcps) or serotype 3 S. pneumoniae (6303) via the airways, and bacterial growth and dissemination and the lung inflammatory response were evaluated. Nod2-/- alveolar macrophages and blood neutrophils displayed a reduced capacity to internalize pneumococci in vitro. During pneumonia caused by S. pneumoniae D39 Nod2-/- mice were indistinguishable from Wt mice with regard to bacterial loads in lungs and distant organs, lung pathology and neutrophil recruitment. While Nod2-/- and Wt mice also had similar bacterial loads after infection with the more virulent S. pneumoniae 6303 strain, Nod2-/- mice displayed a reduced bacterial clearance of the normally avirulent unencapsulated D39Δcps strain. These results suggest that NOD2 does not contribute to host defense during pneumococcal pneumonia and that the pneumococcal capsule impairs recognition of S. pneumoniae by NOD2. [ABSTRACT FROM AUTHOR]

Background: Streptococcus pneumoniae is a leading cause of pneumonia worldwide. However, the burden of pneumococcal pneumonia among adults in low- and middle-income countries is not well described. Methods: Data from 2008–2012 was analyzed from two surveillance sites in Guatemala to describe the incidence of pneumococcal pneumonia in adults. A case of hospitalized pneumococcal pneumonia was defined as a positive pneumococcal urinary antigen test or blood culture in persons aged ≥ 18 years hospitalized with an acute respiratory infection (ARI). Results: Among 1595 adults admitted with ARI, 1363 (82%) had either urine testing (n = 1286) or blood culture (n = 338) performed. Of these, 188 (14%) had pneumococcal pneumonia, including 173 detected by urine only, 8 by blood culture only, and 7 by both methods. Incidence rates increased with age, with the lowest rate among 18–24 year-olds (2.75/100,000) and the highest among ≥65 year-olds (31.3/100,000). The adjusted incidence of hospitalized pneumococcal pneumonia was 18.6/100,000 overall, with in-hospital mortality of 5%. Conclusions: An important burden of hospitalized pneumococcal pneumonia in adults was described, particularly for the elderly. However, even adjusted rates likely underestimate the true burden of pneumococcal pneumonia in the community. These data provide a baseline against which to measure the indirect effects of the 2013 introduction of the pneumococcal conjugate vaccine in children in Guatemala. [ABSTRACT FROM AUTHOR]