Cardoso, Maria Regina Alves; Nascimento-Carvalho, Cristiana Maria Costa; Ferrero, Fernando; Berezin, Eitan Naaman; Ruvinsky, Raul; Sant'Anna, Clemax Couto; Brandileone, Maria Cristina de Cunto; March, Maria de Fátima Bazhuni Pombo; Maggi, Ruben; Feris-Iglesias, Jesus; Benguigui, Yehuda; Camargos, Paulo Augusto Moreira
We compared bacteremic pneumococcal pneumonia (BPP) and pneumococcal empyema (PE), in terms of clinical, radiological, and laboratory findings, in under-fives. A cross-sectional nested cohort study, involving under-fives (102 with PE and 128 with BPP), was conducted at 12 centers in Argentina, Brazil, and the Dominican Republic. Among those with PE, mean age was higher; disease duration was longer; and tachypnea, dyspnea, and high leukocyte counts were more common. Among those with BPP, fever and lethargy were more common. It seems that children with PE can be distinguished from those with BPP on the basis of clinical and laboratory findings. Because both conditions are associated with high rates of morbidity and mortality, prompt diagnosis is crucial. PMID:24626272
Nagaoka, Kentaro; Yanagihara, Katsunori; Morinaga, Yoshitomo; Nakamura, Shigeki; Harada, Tatsuhiko; Hasegawa, Hiroo; Izumikawa, Koichi; Ishimatsu, Yuji; Kakeya, Hiroshi; Nishimura, Masaharu; Kohno, Shigeru
Streptococcus pneumoniae is the leading cause of respiratory infection worldwide. Although oral hygiene has been considered a risk factor for developing pneumonia, the relationship between oral bacteria and pneumococcal infection is unknown. In this study, we examined the synergic effects of Prevotella intermedia, a major periodontopathic bacterium, on pneumococcal pneumonia. The synergic effects of the supernatant of P. intermedia (PiSup) on pneumococcal pneumonia were investigated in mice, and the stimulation of pneumococcal adhesion to human alveolar (A549) cells by PiSup was assessed. The effects of PiSup on platelet-activating factor receptor (PAFR) transcript levels in vitro and in vivo were analyzed by quantitative real-time PCR, and the differences between the effects of pneumococcal infection induced by various periodontopathic bacterial species were verified in mice. Mice inoculated with S. pneumoniae plus PiSup exhibited a significantly lower survival rate, higher bacterial loads in the lungs, spleen, and blood, and higher inflammatory cytokine levels in the bronchoalveolar lavage fluid (macrophage inflammatory protein 2 and tumor necrosis factor alpha) than those infected without PiSup. In A549 cells, PiSup increased pneumococcal adhesion and PAFR transcript levels. PiSup also increased lung PAFR transcript levels in mice. Similar effects were not observed in the supernatants of Porphyromonas gingivalis or Fusobacterium nucleatum. Thus, P. intermedia has the potential to induce severe bacteremic pneumococcal pneumonia with enhanced pneumococcal adhesion to lower airway cells.
Beatty, Jessica A.; Majumdar, Sumit R.; Tyrrell, Gregory J.; Marrie, Thomas J.; Eurich, Dean T.
Abstract Bacteremic pneumococcal pneumonia (BPP) causes considerable mortality and morbidity. We aimed to identify prognostic factors associated with mortality and major in-hospital complications in BPP. A prospective, population-based clinical registry of 1636 hospitalized adult patients (≥18 years) with BPP was established between 2000 and 2010 in Northern Alberta, Canada. Prognostic factors for mortality and major in-hospital complications (e.g., cardiac events, mechanical ventilation, aspiration) were evaluated using multivariable logistic regression. Average age was 54 (standard deviation 18) years, 57% males, and 59% had high case-fatality rate (CFR) serotypes. Overall, 14% (226/1636) of patients died and 22% (315/1410) of survivors developed at least 1 complication. Independent prognostic factors for mortality were age (adjusted odds ratio [aOR], 1.5 per decade; 95% confidence interval [CI], 1.3–1.7), nursing home residence (aOR, 3.7; 95% CI 1.8–7.4), community-dwelling dementia (aOR 3.7; 95% CI, 1.6–8.6), alcohol abuse (aOR, 2.2; 95% CI, 1.4–3.4), acid-suppressing drugs (aOR, 1.5; 95% CI, 1.0–2.3), guideline-discordant antibiotics (aOR, 3.4; 95% CI, 2.4–4.8), multilobe pneumonia (aOR, 2.6; 95% CI, 1.8–3.6), and high CFR serotypes (aOR, 1.8; 95% CI, 1.2–2.8). Similar prognostic factors were observed for major in-hospital complications. Pneumococcal vaccination was associated with reduced in-hospital mortality (aOR, 0.2; 95% CI, 0.05–0.9) but not major complications (P = 0.2). Older and frailer patients, and those who abuse alcohol or take acid-suppressing drugs, are at increased risk of BPP-related mortality and complications, as are those with high CFR serotypes. Beyond identifying those at highest risk, our findings demonstrate the importance of guideline-concordant antibiotics and pneumococcal vaccination in those with BPP. PMID:27861340
Campins Martí, Magda
Pneumococcal infections are a significant cause of morbidity and mortality, and are one of the 10 leading causes of death worldwide. Children under 2 years have a higher incidence rate, followed by adults over 64 years. The main risk group are individuals with immunodeficiency, and those with anatomical or functional asplenia, but can also affect immunocompetent persons with certain chronic diseases. Significant progress has been made in the last 10 years in the prevention of these infections. Until a few years ago, only the 23-valent non-conjugate pneumococcal vaccine was available. Its results were controversial in terms of efficacy and effectiveness, and with serious limitations on the type of immune response induced. The current possibility of using the 13-valent conjugate vaccine in adults has led to greater expectations in improving the prevention of pneumococcal disease in these age groups.
The pneumococcal conjugate vaccine (PCV) was developed to overcome the limitations of the pneumococcal polysaccharide vaccine, which produces poor immunogenicity in infants younger than 2 years. As many countries have included PCVs in national immunization programs for children, the incidence of invasive pneumococcal disease caused by vaccine type Streptococcus pneumoniae has declined markedly, not only among the vaccinated pediatric population, but also among unvaccinated adults. In this review, we present a concise overview of the indirect effects of mass pediatric PCV immunization on unvaccinated adults. PMID:28032483
Background Invasive (IPD, defined as detection of pneumococci in sterile body fluids like meningitis or bacteremic pneumonia) and non-invasive Streptococcus pneumoniae infections (i.e. non-bacteremic pneumonia, otitis media) in adults are associated with substantial morbidity, mortality and costs. In Germany, Pneumococcal polysaccharide vaccination (PPV23) is recommended for all persons >60 years and for defined risk groups (age 5–59). The aim of this model was to estimate the potential cost-effectiveness and benefit-cost ratios of the adult vaccination program (18 years and older), considering the launch of the pneumococcal conjugate vaccine for adults (PCV13). Methods A cross-sectional steady state Markov model was developed to estimate the outcomes of PCV13, PPV23 vaccination schemes and ‘no vaccination’. Conservative assumptions were made if no data were available for PCV13 and PPV23 respectively. The effectiveness of individual pneumococcal vaccination in adults was adjusted for expected indirect effects due to the vaccination in infants. Data on incidences, effectiveness and costs were derived from scientific literature and publicly available databases. All resources used are indicated. Benefit-cost ratios and cost-effectiveness were evaluated from the perspective of the German Statutory Health Insurance as well as from social perspective. Results Under the assumption that PCV13 has a comparable effectiveness to PCV7, a vaccination program with PCV13 revealed the potential to avoid a greater number of yearly cases and deaths in IPD and pneumonia in Germany compared to PPV23. For PCV13, the costs were shown to be overcompensated by monetary savings resulting from reduction in the use of health care services. These results would render the switch from PPV23 to PCV13 as a dominant strategy compared to PPV23 and ‘no vaccination’. Given the correctness of the underlying assumptions every Euro spent on the PCV13 vaccination scheme yields savings of 2
Pneumococcal Vaccination Recommendations for Children 1 and Adults by Age and/or Risk Factor Routine Recommendations for Pneumococcal Conjugate ... X X X X X 1 For PCV13 vaccination of healthy children, see “Recommen- dations for Pneumococcal ...
Rodrigo, Chamira; Bewick, Thomas; Sheppard, Carmen; Greenwood, Sonia; McKeever, Tricia M.; Slack, Mary; Lim, Wei Shen
Child contact is a recognised risk factor for adult pneumococcal disease. Peaks in invasive pneumococcal disease incidence observed during winter holidays may be related to changes in social dynamics. This analysis was conducted to examine adult pneumococcal community-acquired pneumonia (CAP) incidence during school holiday periods. Between September 2008 and 2013, consecutive adults admitted to hospitals covering the Greater Nottingham area with a diagnosis of CAP were studied. Pneumococcal pneumonia was detected using culture and antigen detection methods. Of 2221 adults studied, 575 (25.9%) were admitted during school holidays and 643 (29.0%) had pneumococcal CAP. CAP of pneumococcal aetiology was significantly more likely in adults admitted during school holidays compared to term time (35.3% versus 26.7%; adjusted OR 1.38, 95% CI 1.11–1.72, p=0.004). Over the 5-year period, the age-adjusted incidence of hospitalised pneumococcal CAP was higher during school holidays compared to term time (incident rate ratio 1.35, 95% CI 1.14–1.60, p<0.001); there was no difference in rates of all-cause CAP or non-pneumococcal CAP. Reported child contact was higher in individuals with pneumococcal CAP admitted during school holidays compared to term time (42.0% versus 33.7%, OR 1.43, 95% CI 1.00–2.03, p=0.046). Further study of transmission dynamics in relation to these findings and to identify appropriate intervention strategies is warranted. PMID:28326311
Piralam, Barameht; Tomczyk, Sara M.; Rhodes, Julia C.; Thamthitiwat, Somsak; Gregory, Christopher J.; Olsen, Sonja J.; Praphasiri, Prabda; Sawatwong, Pongpun; Naorat, Sathapana; Chantra, Somrak; Areerat, Peera; Hurst, Cameron P.; Moore, Matthew R.; Muangchana, Charung; Baggett, Henry C.
The incidence of pneumococcal pneumonia among adults is a key driver for the cost-effectiveness of pneumococcal conjugate vaccine used among children. We sought to obtain more accurate incidence estimates among adults by including results of pneumococcal urine antigen testing (UAT) from population-based pneumonia surveillance in two Thai provinces. Active surveillance from 2006 to 2011 identified acute lower respiratory infection (ALRI)–related hospital admissions. Adult cases of pneumococcal pneumonia were defined as hospitalized ALRI patients aged ≥ 18 years with isolation of Streptococcus pneumoniae from blood or with positive UAT. Among 39,525 adult ALRI patients, we identified 481 pneumococcal pneumonia cases (105 by blood culture, 376 by UAT only). Estimated incidence of pneumococcal pneumonia hospitalizations was 30.5 cases per 100,000 persons per year (2.2 and 28.3 cases per 100,000 persons per year by blood culture and UAT, respectively). Incidence varied between 22.7 in 2007 and 43.5 in 2010, and increased with age to over 150 per 100,000 persons per year among persons aged ≥ 70 years. Viral coinfections including influenza A/B, respiratory syncytial virus (RSV), and adenovirus occurred in 11% (44/409) of pneumococcal pneumonia cases tested. Use of UAT to identify cases of pneumococcal pneumonia among adults in rural Thailand substantially increases estimates of pneumococcal pneumonia burden, thereby informing cost-effectiveness analyses and vaccine policy decisions. PMID:26503277
Shea, Kimberly M.; Edelsberg, John; Weycker, Derek; Farkouh, Raymond A.; Strutton, David R.; Pelton, Stephen I.
Background. Although it is widely accepted that adults with immunocompromising conditions are at greatly increased risk of pneumococcal infection, the extent of risk among immunocompetent adults with chronic medical conditions is less certain, particularly in the current era of universal vaccination of children with pneumococcal conjugate vaccines. Methods. We conducted a retrospective cohort study using data from 3 healthcare claims repositories (2006–2010) to compare rates of pneumococcal disease in immunocompetent adults with chronic medical conditions (“at-risk”) and immunocompromised adults (“high-risk”), with rates in adults without these conditions (“healthy”). Risk profiles and episodes of pneumococcal disease—all-cause pneumonia, pneumococcal pneumonia, and invasive pneumococcal disease (IPD)—were ascertained from diagnosis, procedure, and drug codes. Results. Rates of all-cause pneumonia among at-risk persons aged 18–49 years, 50–64 years, and ≥65 years were 3.2 (95% confidence interval [CI], 3.1–3.2), 3.1 (95% CI, 3.1–3.1), and 3.0 (95% CI, 3.0–3.0) times the rates in age-matched healthy counterparts, respectively. We identified rheumatoid arthritis, systemic lupus erythematosus, Crohn's disease, and neuromuscular or seizure disorders as additional at-risk conditions for pneumococcal disease. Among persons with at-risk conditions, the rate of all-cause pneumonia substantially increased with the accumulation of concurrent at-risk conditions (risk stacking): among persons 18–49 years, rate ratios increased from 2.5 (95% CI, 2.5–2.5) in those with 1 at-risk condition to 6.2 (95% CI, 6.1–6.3) in those with 2 conditions, and to 15.6 (95% CI, 15.3–16.0) in those with ≥3 conditions. Findings for pneumococcal pneumonia and IPD were similar. Conclusions. Despite widespread use of pneumococcal conjugate vaccines, rates of pneumonia and IPD remain disproportionately high in adults with at-risk conditions
Vila-Córcoles, Angel; Ochoa-Gondar, Olga
There are currently two anti-pneumococcal vaccines available for use in adults: the classical 23-valent polysaccharide pneumococcal vaccine (PPV23) and the new 13-valent pneumococcal conjugate vaccine (PCV13). The main advantage of the PCV13 is the potentially better immunogenicity, with its major disadvantages being the higher cost and the lower serotype-coverage than the PPV23. The currently available scientific evidence supports the following basic recommendations: (i)among adults with greatest risk (basically asplenia and immunocompromised), a dual vaccination (PCV13+PPV23) is recommended; (ii)among adults with increased risk (basically persons >65years-old and patients 15-64years with chronic pulmonary or heart disease, diabetes and/or alcoholism), a single vaccination with PPV23 is recommended (single dose in primo-vaccinated >65years; re-vaccination at 5-10years in those primo-vaccinated <65years-old); and (iii) in the rest of adults (risk normal/low) vaccination is not recommended.
Kang, Cheol-In; Baek, Jin Yang; Jeon, Kyeongman; Kim, So Hyun; Chung, Doo Ryeon; Peck, Kyong Ran; Lee, Nam Yong; Song, Jae-Hoon
The emergence of antimicrobial resistance threatens the successful treatment of pneumococcal infections. Here we report a case of bacteremic pneumonia caused by an extremely drug-resistant strain of Streptococcus pneumoniae, nonsusceptible to at least one agent in all classes but vancomycin and linezolid, posing an important new public health threat in our region.
Viladrich, P F; Gudiol, F; Liñares, J; Pallarés, R; Sabaté, I; Rufí, G; Ariza, J
The emergence of pneumococci resistant to penicillin and other agents prompted us to evaluate intravenous vancomycin for the therapy of pneumococcal meningitis, which has an overall mortality of 30%. Eleven consecutive adult patients with cerebrospinal fluid (CSF)-culture-proven pneumococcal meningitis and positive initial CSF Gram stain were given intravenous vancomycin (usual dosage, 7.5 mg/kg every 6 h for 10 days). The MBCs of vancomycin ranged from 0.25 to 0.5 micrograms/ml. Early adjunctive therapy with intravenous dexamethasone, mannitol, and sodium phenytoin was also instituted. After 48 h of therapy, all 11 patients showed a satisfactory clinical response, although the CSF culture remained positive in one case; median trough CSF and serum vancomycin levels were 2 and 5.1 micrograms/ml, respectively, and trough CSF bactericidal titers ranged from less than 1:2 to 1:16. On day 3, one patient died of acute heart failure. Four patients had clinical failure at on days 4 (two patients), 7 (one), and 8 (one) of therapy; they all immediately responded to a change in antibiotic therapy. The remaining six patients were cured after 10 days of vancomycin therapy. At this point, median peak CSF and serum vancomycin levels were 1.9 and 18.5 micrograms/ml, respectively. A transient alteration of renal function occurred in two patients, and persistent slight hypoacusia occurred in three patients. In summary, 11 adults with pneumococcal meningitis were treated with vancomycin and early adjunctive therapy including dexamethasone. All patients initially improved, and 10 were ultimately cured of the infection. However, four patients experienced a therapeutic failure, which led to a change in vancomycin therapy. PMID:1810180
Lee, Kuan-Yeh; Tsai, Mao-Song; Kuo, Kuang-Che; Tsai, Jen-Chih; Sun, Hsin-Yun; Cheng, Aristine C; Chang, Sui-Yuan; Lee, Chen-Hsiang; Hung, Chien-Ching
HIV-infected patients remain at higher risk for pneumococcal disease than the general population despite immune reconstitution and suppression of HIV replication with combination antiretroviral therapy. Vaccination with 23-valent pneumococcal polysaccharide vaccine (PPV23) composed of T-cell-independent antigens has been recommended to reduce the risk of pneumococcal disease in HIV-infected adults. However, given the heterogeneity of study design, execution and subjects enrolled, studies examining serological responses to PPV23 yielded conflicting results and observational studies of clinical effectiveness only provided moderate evidence to support the routine use of PPV23 in HIV-infected adults. Pneumococcal conjugate vaccine (PCV), with conjugation of the capsular polysaccharide to a protein carrier, is more immunogenic than PPV23 and has been demonstrated to protect against pneumococcal disease in HIV-infected children and recurrent invasive pneumococcal disease in HIV-infected adolescents and adults. Guidelines have recently been revised to recommend that HIV-infected patients aged 19 y or older receive one dose of 13-valent pneumococcal conjugate vaccine (PCV13) followed by a booster vaccination with PPV23. In this paper, we review the studies using different vaccination strategies to improve immunogenicity among HIV-infected adult patients. PMID:25483681
Pelton, Stephen I; Shea, Kimberly M; Weycker, Derek; Farkouh, Raymond A; Strutton, David R; Edelsberg, John
Using data from 3 private healthcare claims repositories, we evaluated the incidence of pneumococcal disease among adults with US Advisory Committee on Immunization Practices (ACIP) defined at-risk conditions or rheumatoid arthritis, lupus, Crohn's disease, and neuromuscular disorder/seizures and those with traditional high-risk conditions. We observed that adults with ≥2 concurrent comorbid conditions had pneumococcal disease incidence rates that were as high as or higher than rates observed in those with traditional high-risk conditions.
Gil-Prieto, Ruth; Pascual-Garcia, Raquel; Walter, Stefan; Álvaro-Meca, Alejandro; Gil-De-Miguel, Ángel
ABSTRACT Pneumococcal disease causes a high burden of disease in adults, leading to high rates of hospitalization, especially in the elderly. All hospital discharges for pneumococcal disease and pneumococcal pneumonia among adults over 18 y of age reported in first diagnostic position in 2011 (January 1, 2011 through December 31, 2011) were obtained. A total of 10,861 hospital discharges due to pneumococcal disease were reported in adults in Spain in 2011 with an annual incidence of hospitalization of 0.285 (CI 95%: 0.280–0.291) per 1,000 population over 18 y old. Case-fatality rate was 8%. Estimated cost of these hospitalisations in 2011 was more than 57 million €. Pneumococcal pneumonia accounted for the 92% of the hospital discharges All the chronic condition studied: asplenia, chronic respiratory disease, chronic heart disease, chronic renal disease, Diabetes Mellitus and immunosuppression, increased the risk of hospitalization in patients with pneumococcal pneumonia, especially in those aged 18–64 y old. Case-fatality rate among adult patients hospitalized with at least one underlying condition was significantly higher than among patients without comorbidities. Our results identified asplenia, chronic respiratory disease, chronic heart disease, chronic renal disease, chronic liver disease, Diabetes Mellitus and immunosuppression as risk groups for hospitalization. Older adults, immunocompromised patients and immunocompetent patients with underlying conditions could benefit from vaccination. PMID:26901683
Newall, A T
The cost-effectiveness of 13-type pneumococcal conjugate vaccine (PCV13) use in older adults, and the relative merits when compared to the 23-type polysaccharide pneumococcal vaccine (PPV23), has been a topic of much debate. Although a number of economics evaluations have been conducted many of these were completed before the availability of critical data on PCV13 efficacy in older adults. Recent studies using this data have found conflicting results. This may in part reflect differences in the level of herd protection from infant pneumococcal vaccination programs in different countries. The costs and benefits of pneumococcal vaccination in adults are likely to rest on several critical parameters: the magnitude pneumococcal disease in older adults and the serotypes responsible for it, the efficacy of each vaccine against invasive and non-invasive pneumonia, the duration of vaccine protection, and differences in vaccine price. The ongoing changes in pneumococcal disease patterns highlight the need for economic evaluations to use recent serotype-specific disease estimates from the setting under consideration. In countries that do recommend PCV13 use in adults, post-implementation economic evaluation (using data from after a program is implemented) may be useful to help inform potential future changes to vaccine recommendations as well as the maximum price that should be paid for the vaccines in future negotiations.
Targonski, Paul V; Poland, Gregory A
The US Centers for Disease Control and Prevention recommends vaccination against Streptococcus pneumoniae for all people age 65 and older and also for younger people at high risk. However, experts continue to debate the efficacy of the vaccine; most observational studies found it beneficial, while clinical trials were inconclusive as a group. Although pneumococcal vaccination may or may not protect against pneumonia or death from any cause, it does significantly decrease the risk of invasive pneumococcal disease and is worthwhile for this reason.
Albrich, Werner C; Madhi, Shabir A; Adrian, Peter V; van Niekerk, Nadia; Telles, Jean-Noel; Ebrahim, N; Messaoudi, Melina; Paranhos-Baccalà, Glaucia; Giersdorf, Sven; Vernet, Guy; Mueller, Beat; Klugman, Keith P
Objective A high genomic load of Pneumococcus from blood or cerebrospinal fluid has been associated with increased mortality. We aimed to analyse whether nasopharyngeal colonisation density in HIV-infected patients with community-acquired pneumonia (CAP) is associated with markers of disease severity or poor outcome. Methods Quantitative lytA real-time PCR was performed on nasopharyngeal swabs in HIV-infected South African adults hospitalised for acute CAP at Chris Hani Baragwanath Hospital, Soweto, South Africa. Pneumonia aetiology was considered pneumococcal if any sputum culture or Gram stain, urinary pneumococcal C-polysaccharide-based antigen, blood culture or whole blood lytA real-time PCR revealed pneumococci. Results There was a moderate correlation between the mean nasopharyngeal colonisation densities and increasing CURB65 scores among all-cause patients with pneumonia (Spearman correlation coefficient r=0.15, p=0.06) or with the Pitt bacteraemia score among patients with pneumococcal bacteraemia (p=0.63). In patients with pneumococcal pneumonia, nasopharyngeal pneumococcal colonisation density was higher among non-survivors than survivors (7.7 vs 6.1 log10 copies/mL, respectively, p=0.02) and among those who had pneumococci identified from blood cultures and/or by whole blood lytA real-time PCR than those with non-bacteraemic pneumococcal pneumonia (6.6 vs 5.6 log10 copies/mL, p=0.03). Nasopharyngeal colonisation density correlated positively with the biomarkers procalcitonin (Spearman correlation coefficient r=0.37, p<0.0001), proadrenomedullin (r=0.39, p=0.008) and copeptin (r=0.30, p=0.01). Conclusions In addition to its previously reported role as a diagnostic tool for pneumococcal pneumonia, quantitative nasopharyngeal colonisation density also correlates with mortality and prognostic biomarkers. It may also be useful as a severity marker for pneumococcal pneumonia in HIV-infected adults. PMID:25113557
Plevneshi, Agron; Svoboda, Tomislav; Armstrong, Irene; Tyrrell, Gregory J.; Miranda, Anna; Green, Karen; Low, Donald; McGeer, Allison
Background Identification of high-risk populations for serious infection due to S. pneumoniae will permit appropriately targeted prevention programs. Methods We conducted prospective, population-based surveillance for invasive pneumococcal disease and laboratory confirmed pneumococcal pneumonia in homeless adults in Toronto, a Canadian city with a total population of 2.5 M, from January 1, 2002 to December 31, 2006. Results We identified 69 cases of invasive pneumococcal disease and 27 cases of laboratory confirmed pneumococcal pneumonia in an estimated population of 5050 homeless adults. The incidence of invasive pneumococcal disease in homeless adults was 273 infections per 100,000 persons per year, compared to 9 per 100,000 persons per year in the general adult population. Homeless persons with invasive pneumococcal disease were younger than other adults (median age 46 years vs 67 years, P<.001), and more likely than other adults to be smokers (95% vs. 31%, P<.001), to abuse alcohol (62% vs 15%, P<.001), and to use intravenous drugs (42% vs 4%, P<.001). Relative to age matched controls, they were more likely to have underlying lung disease (12/69, 17% vs 17/272, 6%, P = .006), but not more likely to be HIV infected (17/69, 25% vs 58/282, 21%, P = .73). The proportion of patients with recurrent disease was five fold higher for homeless than other adults (7/58, 12% vs. 24/943, 2.5%, P<.001). In homeless adults, 28 (32%) of pneumococcal isolates were of serotypes included in the 7-valent conjugate vaccine, 42 (48%) of serotypes included in the 13-valent conjugate vaccine, and 72 (83%) of serotypes included in the 23-valent polysaccharide vaccine. Although no outbreaks of disease were identified in shelters, there was evidence of clustering of serotypes suggestive of transmission of pathogenic strains within the homeless population. Conclusions Homeless persons are at high risk of serious pneumococcal infection. Vaccination, physical structure changes or
Pelton, Stephen I.; Shea, Kimberly M.; Weycker, Derek; Farkouh, Raymond A.; Strutton, David R.; Edelsberg, John
Using data from 3 private healthcare claims repositories, we evaluated the incidence of pneumococcal disease among adults with US Advisory Committee on Immunization Practices (ACIP) defined at-risk conditions or rheumatoid arthritis, lupus, Crohn's disease, and neuromuscular disorder/seizures and those with traditional high-risk conditions. We observed that adults with ≥2 concurrent comorbid conditions had pneumococcal disease incidence rates that were as high as or higher than rates observed in those with traditional high-risk conditions. PMID:26034770
Prato, Rosa; Fortunato, Francesca; Martinelli, Domenico
The indirect protection of adults as a result of pneumococcal conjugate vaccination of infants has been discussed from different epidemiological points of view. In some countries, including Italy, even after pediatric vaccination, vaccine serotypes are still responsible for most pneumonia and invasive diseases in the elderly. Although the Community-Acquired Pneumonia Immunization Trial in Adults (CAPITA) produced encouraging results, it has not showed the efficacy of the 13-valent conjugate vaccine in preventing pneumococcal community-acquired pneumonia regardless of the number of episodes and serotype. Addressing these points by monitoring the direct impact of adult vaccination in real life distinguished from the effects of herd immunity will assist public health decision-making on the most effective adult pneumococcal vaccination strategies.
Muley, Vrishali Avinash; Ghadage, Dnyaneshwari Purushottam; Yadav, Gauri Eknath; Bhore, Arvind Vamanrao
Background: Invasive pneumococcal infections often prove rapidly fatal, even where good medical treatment is readily available. In developed countries, up to 20% of people who contract pneumococcal meningitis die; however, in developing world, mortality is closer to 50%, even among hospitalized patients. The World Health Organization estimated 600,000–800,000 adult deaths each year from pneumococcal pneumonia, meningitis, and sepsis. Aims: This study aims to estimate isolation rate of invasive pneumococcal infection in adults, to determine the antimicrobial susceptibility profile of Streptococcus pneumoniae isolates and to study the associated risk factors. Materials and Methods: A total of 120 patients with suspected invasive infection such as meningitis, septicemia, and pleural effusion, were included in the study. Various clinical specimens such as pus, cerebrospinal fluid, and other sterile body fluids were processed for isolation and identification of S. pneumoniae. Kirby–Bauer disc diffusion method was performed to determine the antimicrobial susceptibility profile. Minimum inhibitory concentration test was performed to determine the penicillin resistance. Results: Of 120 patients, 40 (33.33%) cases were proven by culture to have an invasive pneumococcal infection. The most common clinical condition observed was meningitis followed by pneumonia with pleural effusion and sepsis. Pneumococcal isolates exhibited 40% resistance to cotrimoxazole and 12.73% to chloramphenicol. Two meningeal isolates exhibited penicillin resistance. Comorbidities observed in 21 (52.5%) cases were mainly Diabetes mellitus, smoking, and alcoholism. Conclusions: Invasive pneumococcal infection has poor prognosis and penicillin-resistant strains have become increasingly common. This study emphasizes the importance of judicious use of antibiotics, especially to refrain their use in mild self-limiting upper respiratory infections. PMID:28042214
Aslam, Aamir; Chapel, Helen; Ogg, Graham
Streptococcus pneumoniae is an encapsulated bacterium that causes significant global morbidity and mortality. The nasopharynxes of children are believed to be the natural reservoir of pneumococcus and by adulthood nasopharyngeal carriage is infrequent; such infrequency may be due to demonstrable pneumococcal specific T and B-cell responses. HLA Class 2 tetrameric complexes have been used to characterise antigen specific T-cell responses in a variety of models of infection. We therefore sought to determine the frequency and phenotype of pneumococcal specific T-cells, using a novel HLA-DRB1*1501 tetramer complex incorporating a recently defined T-cell epitope derived from the conserved pneumococcal serine/threonine kinase (StkP). We were able to detect direct ex-vivo StkP446–60-tetramer binding in HLA-DRB1*1501 adults. These StkP446–60-tetramer binding T-cells had increased CD38 expression and were enriched in CCR7- CD45RA+ expression indicating recent and on-going activation and differentiation. Furthermore, these StkP446–60-tetramer binding T-cells demonstrated rapid effector function by secreting interferon-gamma on stimulation with recombinant StkP. This is the first study to directly enumerate and characterise pneumococcal specific T-cells using HLA class 2 tetrameric complexes. We found that ex-vivo pneumococcal-specific T cells were detectable in healthy adults and that they were enriched with cell surface markers associated with recent antigen exposure and later stages of antigen-driven differentiation. It is likely that these activated pneumococcal specific T-cells reflect recent immunostimulatory pneumococcal exposure in the nasopharynx and it is possible that they may be preventing subsequent colonisation and disease. PMID:22039412
Principi, Nicola; Esposito, Susanna
Community-acquired pneumonia (CAP) places a considerable burden on society. A substantial number of pediatric and adult CAP cases are due to Streptococcus pneumoniae, but fortunately there are effective vaccines available that have a significant impact on CAP-related medical, social, and economic problems. The main aim of this paper is to evaluate the published evidence concerning the impact of pneumococcal vaccines on the prevention of CAP in children and adults. Available data indicate that pneumococcal conjugate vaccines (PCVs) are effective in children, reducing all-cause CAP cases and bacteremic and nonbacteremic CAP cases. Moreover, at least for PCV7 and PCV13, vaccination of children is effective in reducing the incidence of CAP among adults. Recently use of PCV13 in adults alone or in combination with the pneumococcal polysaccharide vaccine has been suggested and further studies can better define its effectiveness in this group of subjects. The only relevant problem for PCV13 is the risk of a second replacement phenomenon, which might significantly reduce its real efficacy in clinical practice. Protein-based pneumococcal vaccines might be a possible solution to this problem. PMID:28029140
Peñaranda, Maria; Payeras, Antoni; Cambra, Ana; Mila, Joan; Riera, Melcior
This is a randomized trial to compare the immunoglobulin G response and the antibody avidity after two pneumococcal vaccinations, conjugated pneumococcal vaccine (CPV) and polysaccharide pneumococcal vaccine (PPV) 4 weeks after vs. PPV alone in 202 HIV-infected adults. There were no differences in the two strategies, either in the percentage of immunoglobulin G two-fold increase for the CPV included serotypes or immunoglobulin G two-fold increase, reaching the level of 1 microg/ml except for serotype 23F (26% responded after conjugated pneumococcal vaccine + PPV vs. 14% after PPV). No avidity increases were seen in any strategy.
Durando, P; Faust, S N; Fletcher, M; Krizova, P; Torres, A; Welte, T
Streptococcus pneumoniae-related infections are a major cause of morbidity and mortality in people of all ages worldwide. Pneumococcal vaccine development started in 1911 with a whole cell vaccine and more recently multivalent plain polysaccharide and polysaccharide conjugate vaccines have been developed. The recent vaccines rely on capsular polysaccharide antigens to induce serotype-specific immune responses. We summarize here the presentations on pneumococcal polysaccharide conjugate vaccine (conjugated to CRM197 carrier protein) given during the integrated symposium organized and funded by Pfizer International Operations during the 22nd European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) 31 March to 3 April 2012, London, UK. A dramatic reduction in the incidence of invasive pneumococcal diseases (IPD) due to vaccine serotypes (VST-IPD) has been reported since the introduction of a hepta-valent pneumococcal conjugate vaccine (PCV7). An indirect (herd) effect has been demonstrated to be associated with PCV7 infant vaccination programmes, with many studies reporting reductions in VST-IPD in populations that are not eligible for PCV7 vaccination. Since 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) has been introduced into national immunization programmes and results from early surveillance suggest that this vaccine also has an impact on the serotypes unique to PCV13, as well as continuing to protect against the PCV7 serotypes. Data from a passive surveillance system in Europe in 2009, for instance, showed that the highest incidence of IPD remains in those aged >65 years and in children <5 years. PCV13 has now been licensed for vaccination of adults >50 years based on safety and immunogenicity data; an efficacy trial is being conducted. Regardless of previous pneumococcal vaccination status, if the use of 23-valent polysaccharide is considered appropriate, it is recommended to give PCV13 first. Novel immunization strategies remain
Ciprero, Karen L.; Marchese, Rocio D.; Richard, Patrick; Baudin, Martine; Sterling, Tina M.; Manoff, Susan B.; Radley, David; Stek, Jon E.; Soubeyrand, Benoît; Grabenstein, John D.; Samson, Sandrine I.; Musey, Luwy K.
ABSTRACT PNEUMOVAX™ 23, a 23-valent polysaccharide pneumococcal vaccine (PPV23), covers 65% to 91% of the isolates recovered from adult cases of invasive pneumococcal disease. Several studies have demonstrated that pneumococcal serotypes 31, 11A, 35F, 17F, 3, 16F, 19F, 15B, and 10A are associated with higher case-fatality or meningitis rates than other pneumococcal serotypes. This study (U05-PnPS-403; EudraCT: 2008-003648-12) evaluated the immune response followings administration of PPV23 for 4 of these serotypes (10A, 11A, 15B, and 17F), that are included in PPV23 but not in licensed pneumococcal conjugate vaccines. Serotype-specific IgG geometric mean concentrations (GMCs) and geometric mean fold-rises (GMFRs) for these 4 serotypes were measured by a validated enzyme-linked immunosorbent assay (ELISA) in 104 subjects >50 y of age who were enrolled in a study evaluating the safety and immunogenicity of a single-dose of PPV23. At 1 month post-vaccination, GMCs for serotypes10A, 11A, 15B and 17F were 6.5, 4.3, 14.7, and 5.1 µg/mL, respectively. GMFRs from baseline were 9.0, 4.5, 8.4, and 11.5, respectively. The percentages of subjects achieving >2-fold increases in IgG GMCs between pre-vaccination and 1 month post-vaccination were 90%, 85%, 88% and 89%, respectively. In conclusion, PPV23 induces a robust immune response in adults to pneumococcal serotypes 10A, 11A, 15B, and 17F, which have been associated with elevated case-fatality or meningitis rates. PMID:27002793
Neto, Joao Tonolio; Gagliardi, Anna; Pinho, Amanda; Durand, Laure; Fonseca, Marcelo
Vaccination of adults aged 60 years and older against Streptococcus pneumonia is not recommended in Brazil. The 23-valent polysaccharide pneumococcal vaccine (PPV23) is only available for institutionalized persons or with underlying diseases despite the substantial medical and economic burden related to pneumococcal infections in adults over than 59 years. The study aimed at evaluating the cost effectiveness of implementing a large PPV program in this population. This analysis was performed using a static decision tree model. Demographic and epidemiological data were obtained from Brazilian official sources and international literature. Economic data were obtained from a study performed in 2007 in a public and a private hospital located in Sao Paulo. Vaccination was assumed to protect for 5 years with 60% effectiveness against bacteremic pneumococcal pneumonia (BPP) and 21% effectiveness against non bacteremic pneumococcal pneumonia (NBPP). Deterministic and sensitivity analyses were performed. The pneumococcal polysaccharide vaccination saved 5,218 life year gained (LYG). The vaccination program was found to be cost effective in the social security and public health care perspectives with a mean incremental cost-effectiveness ratio of R$10,887 and R$8,281 per LYG respectively. Results were sensitive to the vaccine effectiveness against NBPP, the incidence and case-fatality rate of NBPP. From a societal perspective, PPV23 program for adults 60 and older was found to be cost-saving. Pneumococcal polysaccharide vaccination is clinically and economically favored over the present vaccination strategy, in which persons aged over 59 years in Sao Paulo have not been vaccinated. PMID:21941088
Sadlier, C; O'Dea, S; Bennett, K; Dunne, J; Conlon, N; Bergin, C
The aim of this study was to compare the immunologic response to a prime-boost immunization strategy combining the 13-valent conjugate pneumococcal vaccine (PCV13) with the 23-valent polysaccharide pneumococcal vaccine (PPSV23) versus the PPSV23 alone in HIV-infected adults. HIV-infected adults were randomized to receive PCV13 at week 0 followed by PPSV23 at week 4 (n = 31, prime-boost group) or PPSV23 alone at week 4 (n = 33, PPSV23-alone group). Serotype specific IgG geometric mean concentration (GMC) and functional oposonophagocytic (OPA) geometric mean titer (GMT) were compared for 12 pneumococcal serotypes shared by both vaccines at week 8 and week 28. The prime-boost vaccine group were more likely to achieve a ≥2-fold increase in IgG GMC and a GMC >1 ug/ml at week 8 (odds ratio (OR) 2.00, 95% confidence interval (CI) 1.46-2.74, p < 0.01) and week 28 (OR 1.95, 95% CI 1.40-2.70, p < 0.01). Similarly, the prime-boost vaccine group were more likely to achieve a ≥4-fold increase in GMT at week 8 (OR 1.71, 95% CI 1.22-2.39, p < 0.01) and week 28 (OR 1.6, 95% CI 1.15-2.3, p < 0.01). This study adds to evidence supporting current pneumococcal vaccination recommendations combining the conjugate and polysaccharide pneumococcal vaccines in the United States and Europe for HIV-infected individuals.
Liguori, Giorgio; Parlato, Antonino; Zamparelli, Alessandro Sanduzzi; Belfiore, Patrizia; Gallé, Francesca; Di Onofrio, Valeria; Riganti, Carla; Zamparelli, Bruno
Pneumococcal pneumonia has a high clinical burden in terms of morbidity, mortality and hospitalization rate, with heavy implications for worldwide health systems. In particular, higher incidence and mortality rates of community-acquired pneumonia (CAP) cases, with related costs, are registered among elderly. This study aimed to an economic evaluation about the immunization with PCV13 in the adult population in Campania region, South Italy. For this purpose we performed, considering a period of 5 y, a budget impact analysis (BIA) and a cost-effectiveness analysis which considered 2 scenarios of immunization compared with lack of immunization for 2 targeted cohorts: first, the high risk subjects aged 50-79 y, and second the high risk individuals aged 50-64 y, together with all those aged 65 y. Regarding the first group, the decrease of pneumonia could give savings equal to €29,005,660, while the immunization of the second cohort could allow savings equal to €10,006,017. The economic evaluation of pneumococcal vaccine for adult groups represents an essential instrument to support health policies. This study showed that both hypothesized immunization strategies could produce savings. Obtained results support the use of pneumococcal conjugate vaccine for adults. This strategy could represent a sustainable and savings-producer health policy.
Hamaluba, Mainga; Kandasamy, Rama; Ndimah, Susan; Morton, Richard; Caccamo, Marisa; Robinson, Hannah; Kelly, Sarah; Field, Aimee; Norman, Lily; Plested, Emma; Thompson, Ben A.V.; Zafar, Azhar; Kerridge, Simon A.; Lazarus, Rajeka; John, Tessa; Holmes, Jane; Fenlon, Shannon N.; Gould, Katherine A.; Waight, Pauline; Hinds, Jason; Crook, Derrick; Snape, Matthew D.; Pollard, Andrew J.
Abstract Using nasopharyngeal carriage as a marker of vaccine impact, pneumococcal colonization and its relation to invasive disease were examined in children, their parents, and older adults in the United Kingdom following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) and prior to 13-valent pneumococcal conjugate vaccine (PCV13). A cross-sectional observational study was conducted, collecting nasopharyngeal swabs from children aged 25 to 55 months who had previously received 3 doses of PCV7, their parents, and adults aged ≥65 years. Pneumococcal serotyping was conducted according to World Health Organization guidelines with nontypeable isolates further analyzed by molecular serotyping. A national invasive disease surveillance program was conducted throughout the corresponding period. Pneumococcus was isolated from 47% of children, 9% of parents, and 2.2% of older adults. For these groups, the percentage of serotypes covered by PCV7 were 1.5%, 0.0%, and 15.4%, with a further 20.1%, 44.4%, and 7.7% coverage added by those in PCV13. In each group, the percentage of disease due to serotypes covered by PCV7 were 1.0%, 7.4% and 5.1% with a further 65.3%, 42.1%, and 61.4% attributed to those in PCV13. The prevalence of carriage is the highest in children, with direct vaccine impact exemplified by low carriage and disease prevalence of PCV7 serotypes in vaccinated children, whereas the indirect effects of herd protection are implied by similar observations in unvaccinated parents and older adults. PMID:25569650
Jiang, Yiling; Gervais, Frédéric; Gauthier, Aline; Baptiste, Charles; Martinon, Prescilla; Bresse, Xavier
In 2002, a pneumococcal conjugate vaccine (PCV) was introduced to French infants and toddlers. A change has been witnessed in the incidence of pneumococcal diseases in adults: the incidence of invasive pneumococcal disease (IPD) of serotypes covered by PCV decreased, and serotypes not covered by PCV increased. This study aimed to quantify the public health and budget impact of pneumococcal vaccination strategies in at-risk adults in France over 5 years. A previously published population-based Markov model was adapted to the French situation. At-risk adults received either PPV23 (pneumococcal polysaccharide vaccine; for the immunocompetent) or PCV13 (for the immunosuppressed). The strategy was compared to PCV13 alone. Uncertainty was addressed using extreme scenario analyses. Between 2014 and 2018, vaccination with PPV23/PCV13 led to a higher reduction in terms of IPD and non-bacteremic pneumococcal pneumonia cases avoided in most scenarios analyzed when compared to PCV13 alone. For budget impact, none of the scenarios was in favor of PCV13. Under conservative coverage assumptions, the total incremental budget impact ranged from € 39.8 million to € 69.3 million if PCV13 were to replace PPV23 in the immunocompetent. With the epidemiological changes of pneumococcal diseases and the broader serotype coverage of PPV23, the current program remains an optimal strategy from public health perspective. Given the additional budget required for the use of PCV13 alone and its uncertain public health benefits, vaccination with PPV23 remains the preferred strategy. PMID:26267239
French, Neil; Gordon, Stephen B; Mwalukomo, Thandie; White, Sarah A; Mwafulirwa, Gershom; Longwe, Herbert; Mwaiponya, Martin; Zijlstra, Eduard E; Molyneux, Malcolm E; Gilks, Charles F
Background: Streptococcus pneumoniae is a leading and serious co-infection of HIV-infected adults, particularly in Africa. Prevention of disease by vaccination with the current 23-valent polysaccharide vaccine is sub-optimal. Protein conjugate vaccines offer a further option for protection but no data exist on their clinical efficacy in any adult population. Methods: We conducted a double-blind randomized placebo-controlled clinical efficacy trial of the seven-valent conjugate pneumococcal vaccine in predominantly HIV-infected Malawian adults who had recovered from documented invasive pneumococcal disease (IPD). Vaccine was given as a two dose schedule four weeks apart. The primary end-point was a further episode of IPD caused by a vaccine-serotype or serotype-6A (VST/6A) pneumococcus. Results: Between February 2003 and October 2007, 496 individuals (44% male, 88% HIV seropositive) were followed for 798 person years of observation. There were 67 IPD events in 52 individuals, all in the HIV infected sub-group. There were 24 VST/6A events (19 VST, five 6A) in 24 participants, 5 in vaccine and 19 in the placebo recipients, a vaccine efficacy of 74% (95% CI 30% - 90%). There were 73 deaths in the vaccine arm and 63 in the placebo arm, Hazard Ratio 1.18 (95% confidence intervals 0.84 -1.66). Compared to placebo, serious adverse events were significantly lower (3 vs 17, p = 0.002) and minor adverse events significantly higher (41 vs 13, p = 0.003 ) in vaccine recipients. Conclusions: The seven-valent pneumococcal conjugate vaccine protects HIV infected adults from recurrent IPD of vaccine serotype or serotype 6A. PMID:20200385
Dexheimer, Judith W; Talbot, Thomas R.; Ye, Fei; Shyr, Yu; Jones, Ian; Gregg, William M; Aronsky, Dominik
Background Pneumococcal vaccination is an effective strategy to prevent invasive pneumococcal disease in the elderly. Emergency Department (ED) visits present an underutilized opportunity to increase vaccination rates; however, designing a sustainable vaccination program in an ED is challenging. We examined whether an information technology supported approach would provide a feasible and sustainable method to increase vaccination rates in an adult ED. Methods During a 1-year period we prospectively evaluated a team-oriented, workflow-embedded reminder system that integrated four different information systems. The computerized triage application screened all patients 65 years and older for pneumococcal vaccine eligibility with information from the electronic patient record. For eligible patients the computerized provider order entry system reminded clinicians to place a vaccination order, which was passed to the order tracking application. Documentation of vaccine administration was then added to the longitudinal electronic patient record. The primary outcome was the vaccine administration rate in the ED. Multivariate logistic regression analysis was used to estimate the odds ratios and their 95% confidence intervals, representing the overall relative risks of ED workload related variables associated with vaccination rate. Results Among 3,371 patients 65 years old and older screened at triage 1,309 (38.8%) were up-to-date with pneumococcal vaccination and 2,062 (61.2%) were eligible for vaccination. Of the eligible patients, 621 (30.1%) consented to receive the vaccination during their ED visit. Physicians received prompts for 428 (68.9%) patients. When prompted, physicians declined to order the vaccine in 192 (30.9%) patients, while 222 (10.8%) of eligible patients actually received the vaccine. The computerized reminder system increased vaccination rate from a baseline of 38.8% to 45.4%. Vaccination during the ED visit was associated younger age (OR: 0.972, CI: 0
Zhou, Z.; Deceuninck, G.; Lefebvre, B.
Background. In Canada, the current recommendation is to offer PPV23 to adults ≥ 65 years. PCV13 is now licensed for adults. Methods. Invasive pneumococcal disease (IPD) cases in adults 65–74 years of age in the Quebec notifiable diseases registry were classified into five serotype categories. Poisson regression models were fitted to monthly rates observed in 2000–2014 and predictions were made for 2015–2024, using theoretical assumptions regarding indirect effects of childhood vaccination and serotype replacement. Results. IPD rates caused by PCV7 serotypes decreased markedly since PCV7 introduction for children in December 2004. This trend is also underway for additional PCV13 serotypes except serotype 3. Additional PPV23 serotypes and nonvaccine serotypes have been on rise since 2004 and this is expected to continue. A small decrease in overall IPD incidence in the next decade is predicted. The proportion of PCV13 serotypes represented 33% of IPD cases in 2014 and would be 20% (95% CI: 15% to 28%) in 2024. PPV23 coverage was 53% in 2014 and is expected to be 47% (95% CI: 26% to 85%) in 2024. Conclusion. The potential usefulness of a combined PCV13 + PPV23 program for elderly adults would decrease over time but PCV13 would be the only option to prevent serotype 3 IPD. PMID:28246534
13-valent-pneumococcal conjugated vaccine was recently approved in the USA and Europe for adults 50 years of age or more. But this approval was followed by recommendations limiting its use to immunocompromised and asplenic patients. The extension of indications to adults was based on the well-demonstrated clinical effectiveness in infants less than 2 years of age, and on a better immune response either quantitatively or qualitatively with conjugated vaccines compared to the immunogenicity of plain polysaccharide vaccines. Nevertheless, the issue was to know whether results observed with the 7-valent pneumococcal conjugate vaccine in children are reproducible in adults with the 13-valent. The answer was given by comparing the epidemiological and physiopathological data, and the immunological response of the two populations. Very few clinical effectiveness studies in adults are available. We had for aim to assess these various issues in infants and adults. A lot of questions remain, such as the unknown impact of serotype replacement with the 13-valent pneumococcal conjugated vaccine on the clinical epidemiology and emergent Streptococcus pneumoniae pathogenicity, while waiting for the CAPITA study results expected in 2014.
Jiang, Yiling; Gauthier, Aline; Annemans, Lieven; van der Linden, Mark; Nicolas-Spony, Laurence; Bresse, Xavier
To assess the comparative public health and budget impact over 5 years of several pneumococcal vaccination strategies (23-valent pneumococcal polysaccharide vaccine [PPV23] and/or 13-valent pneumococcal conjugate vaccine [PCV13]) in Germany, within the context of changing invasive pneumococcal disease (IPD) incidence over time. A multi-cohort, population-based Markov model was developed. Uncertainty around vaccine effectiveness, costs and IPD incidence change was handled through scenario analyses. Between 2012 and 2016, the introduction of PCV13 in adults, compared with the use of PPV23, would be associated with a net estimated budget increase of €59.7 million (+6.7%) to €151.6 million (+13.7%). Impact on IPD incidence ranged from -113 cases (-0.8%) to +298 cases (+2.8%). Introducing PCV13 in adults is expected to significantly affect healthcare budgets. Adult vaccination with PPV23 remains the optimal vaccination strategy from public health and budget perspectives.
Kruspe, Rachel; Lillis, Rebecca; Daberkow, Dayton W; Blais, Christopher M; Wilbright, Wayne; Gupta, Shaminder; Gould, Cynthia A; Sun, Tony; Martinez, Jorge A; deBoisblanc, Ben; Ladabaum, Uri; Sanders, Charles V; Lopez, Fred A
Streptococcus pneumoniae-associated infections are an important cause of hospitalization and mortality in high-risk and elderly patients. Even in the setting of appropriate therapy, the case fatality rate of invasive pneumococcal disease in the elderly may approach 40%. Since approximately 40,000 people die annually from pneumococcal-associated disease, it represents a substantial target for vaccine-preventable, bacterial fatalities. The 23-valent pneumococcal polysaccharide vaccine has proven consistently effective in preventing invasive pneumococcal disease. Despite its endorsement by numerous specialty societies, the pneumococcal vaccine is underutilized in the inpatient setting. In a recent report of quality indicators for Medicare beneficiaries, the percentage of Medicare beneficiaries in Louisiana admitted with pneumonia who were screened or received the pneumococcal vaccination prior to discharge was only 4%, the lowest percentage in the United States. The Louisiana State University-New Orleans Internal Medicine Department and its house staff embarked upon a retrospective study to determine its baseline pneumococcal vaccination or screening rates for all patients with pneumonia on its inpatient services at the The Medical Center of Louisiana in New Orleans from July 2000 through June 2001. From July 2001 through June 2002 an intensive educational intervention concentrating on the indications and benefits of pneumococcal vaccination was directed toward the Louisiana State University Internal Medicine house staff assigned to the inpatient service. Retrospective analysis for pneumococcal vaccine screening and administration of charts of all patients with pneumonia on the LSU Medicine service from July 2001 through June 2002 was performed in order to determine the effects of the intervention. Data from the pre-educational intervention period revealed a baseline pneumococcal vaccine screening or administration rate of 11% for all patients with pneumonia on the
González-Romo, F; Picazo, J J; García Rojas, A; Labrador Horrillo, M; Barrios, V; Magro, M C; Gil Gregorio, P; de la Cámara, R; Rodríguez, A; Barberán, J; Botía Martínez, F; Linares Rufo, M; Jimeno Sanz, I; Portolés, J M; Sanz Herrero, F; Espinosa Arranz, J; García-Sánchez, V; Galindo Izquierdo, M; Mascarós, E
Invasive pneumococcal disease (IPD) and pneumococcal pneumonia (PP) represent an important health problem among aging adults and those with certain underlying pathologies and some diseases, especially immunosuppressed and some immunocompetent subjects, who are more susceptible to infections and present greater severity and worse evolution. Among the strategies to prevent IPD and PP, vaccination has its place, although vaccination coverage in this group is lower than desirable. Nowadays, there are 2 vaccines available for adults. Polysacharide vaccine (PPV23), used in patients aged 2 and older since decades ago, includes a greater number of serotypes (23), but it does not generate immune memory, antibody levels decrease with time, causes an immune tolerance phenomenon, and have no effect on nasopharyngeal colonization. PCV13 can be used from children 6 weeks of age to elderly and generates an immune response more powerful than PPV23 against most of the 13 serotypes included in it. In the year 2013 the 16 most directly related to groups of risk of presenting IPD publised a series of vaccine recommendations based on scientific evidence regarding anti-pneumococcal vaccination in adults with underlying pathologies and special conditions. A commitment was made about updating it if new scientific evidence became available. We present an exhaustive revised document focusing mainly in recommendation by age in which some more Scientific Societies have been involved.
Azzari, Chiara; Cortimiglia, Martina; Nieddu, Francesco; Moriondo, Maria; Indolfi, Giuseppe; Mattei, Romano; Zuliani, Massimo; Adriani, Beatrice; Degl'Innocenti, Roberto; Consales, Guglielmo; Aquilini, Donatella; Bini, Giancarlo; Di Natale, Massimo Edoardo; Canessa, Clementina; Ricci, Silvia; de Vitis, Elisa; Mangone, Giusi; Bechini, Angela; Bonanni, Paolo; Pasinato, Angela; Resti, Massimo
The 7-valent pneumococcal conjugate vaccine (PCV7) produced a significant herd protection in unvaccinated adult population mostly because of pneumococcus carriage decrease in vaccinated children. It is not known if the 13-valent pneumococcal vaccine can give similar effect on adults. Aims of the work were to evaluate whether the 6 additional serotypes are present in nasopharynx of children and serotype distribution in invasive pneumococcal infections (IPD) in adults. Realtime-PCR was used to evaluate pneumococcal serotypes in adults with confirmed IPD and in nasopharyngeal swabs (NP) from 629 children not vaccinated or vaccinated with PCV7 and resident in the same geographical areas. Two hundred twenty-one patients (116 males, median 67.9 years) with IPD were studied (pneumonia n = 103, meningitis n = 61 sepsis n = 50, other n = 7). Two hundred twelve were serotyped. The most frequent serotypes were 3, (31/212; 14.6%), 19A, (19/212; 9.0%), 12 (17/212; 8.0%), 7F, (14/212; 6.6%). In NP of children, the frequency of those serotypes causing over 50% of IPD in adults was very low, ranging from 0.48% for serotype 7F to 7.9% for serotype 19A. On the other side serotype 5, very frequent in NP (18.7%) caused <1% IPD. In conclusion serotypes causing IPD in adults are very rarely found in children NP. We suggest that herd protection obtainable with the additional 6 serotypes included in PCV13 may be more limited than that demonstrated with PCV7 in the past. In order to reduce the burden of disease in adults, adults should be offered a specific vaccination program with highly immunogenic PCV.
Background Nowadays, there are two vaccination strategies in Colombia to prevent pneumococcal diseases in people over 50 years. Our aim is to estimate cost-effectiveness of pneumococcal conjugate vaccine 13-valent (PCV13) versus pneumococcal polysaccharide vaccine 23-valent (PPSV23) to prevent pneumococcal diseases and their related mortality in people over 50 years old in Colombia. Methods A Markov model was developed with national data, including pneumococcal serotypes distribution in Colombia between 2005 and 2010. Vaccination of a cohort was simulated and a five year time horizon was assumed. Analysis was done from a perspective of a third party payer. Direct costs were provided by a national insurance company; sensitive univariate and probabilistic analysis were done for epidemiological and clinical effectiveness parameters and costs. Results PCV13 avoids 3 560 deaths by pneumococcal infections versus PPSV23 and 4 255 deaths versus no vaccine. PCV13 prevents 79 633 cases by all-cause pneumonia versus PPSV23 and 81 468 cases versus no vaccine. Total costs (healthcare and vaccines costs) with PCV13 would be U.S. $ 97,587,113 cheaper than PPSV23 and it would save U.S. $ 145,196,578 versus no vaccine. Conclusion PCV13 would be a cost-saving strategy in the context of a mass vaccination program in Colombia to people over 50 years old because it would reduce burden of disease and specific mortality by pneumococcal diseases, besides, it saves money versus PPSV23. PMID:24679135
Patel, Preeyam S; Kearney, John F
Currently, ∼20% of the global population suffers from an allergic disorder. Allergies and asthma occur at higher rates in developed and industrialized countries. It is clear that many human atopic diseases are initiated neonatally and herald more severe IgE-mediated disorders, including allergic asthma, which is driven by the priming of Th2 effector T cells. The hygiene hypothesis attempts to link the increased excessively sanitary conditions early in life to a default Th2 response and increasing allergic phenomena. Despite the substantial involvement of IgE Abs in such conditions, little attention has been paid to the effects of early microbial exposure on the B cell repertoire prior to the initiation of these diseases. In this study, we use Ab-binding assays to demonstrate that Streptococcus pneumoniae and house dust mite (HDM) bear similar phosphorylcholine (PC) epitopes. Neonatal C57BL/6 mice immunized with a PC-bearing pneumococcal vaccine expressed increased frequencies of PC-specific B cells in the lungs following sensitizing exposure to HDM as adults. Anti-PC IgM Abs in the lung decreased the interaction of HDM with pulmonary APCs and were affiliated with lowered allergy-associated cell infiltration into the lung, IgE production, development of airway hyperresponsiveness, and Th2 T cell priming. Thus, exposure of neonatal mice to PC-bearing pneumococci significantly reduced the development of HDM-induced allergic disease during adult life. Our findings demonstrate that B cells generated against conserved epitopes expressed by bacteria, encountered early in life, are also protective against the development of allergic disease during adult life.
Tramuto, Fabio; Amodio, Emanuele; Calamusa, Giuseppe; Restivo, Vincenzo; Costantino, Claudio; Vitale, Francesco
The spread of Streptococcus pneumoniae within families has been scarcely investigated so far. This feasibility study aimed to estimate the prevalence of pneumococcal carriage in school-aged children and co-habiting relatives and to explore the potential link between the family environment and the sharing of pneumococcal serotypes covered by the vaccine. Oropharyngeal samples of 146 subjects belonging to 36 different family groups were molecularly tested for pneumococcal detection and serotyping. The overall prevalence of pneumococcal carriage was 65.8% (n = 96/146), whereas it was higher among schoolchildren (77.8%, n = 28/36); subjects of seven years of age had the highest odds of being colonized (odds ratio, OR = 5.176; p = 0.145). Pneumococcal serotypes included in the 13-valent conjugate vaccine formulation were largely detected in the study population and multiple serotypes colonization was considerable. Factors relating to a close proximity among people at the family level were statistically associated with pneumococcal carriage (OR = 2.121; p = 0.049), as well as active smoking habit with a clear dose-response effect (ORs = 1.017–3.326). About half of family clusters evidenced similar patterns of carried pneumococcal serotypes and the odds of sustaining a high level of intrafamilial sharing increased with household size (ORs = 1.083–5.000). This study highlighted the potential role played by the family environment in sustaining both the circulation and horizontal transmission of pneumococcus. PMID:28067813
Marcus, Julia L; Baxter, Roger; Leyden, Wendy A; Muthulingam, Dharushana; Yee, Arnold; Horberg, Michael A; Klein, Daniel B; Towner, William J; Chao, Chun R; Quesenberry, Charles P; Silverberg, Michael J
It is unclear whether HIV-infected individuals remain at higher risk of invasive pneumococcal disease (IPD) compared with HIV-uninfected individuals. We conducted a cohort study of HIV-infected and demographically matched HIV-uninfected adults within Kaiser Permanente Northern California during the period 1996-2011. We used Poisson models to obtain rate ratios (RRs) for incident IPD associated with HIV infection and other risk factors. Among 13,079 HIV-infected and 137,643 HIV-uninfected adults, the IPD rate per 100,000 person-years was 160 (n = 109 events) for HIV-infected and 8 (n = 75 events) for HIV-uninfected subjects, with an adjusted RR of 13.0 [95% confidence interval (CI): 9.1-18.7]. For HIV-infected individuals, IPD incidence per 100,000 person-years decreased by 71% during study follow-up, from 305 in 1996-1999 to 88 in 2010-2011 (p < 0.001), with an adjusted RR of 6.6 (95% CI: 2.7-16.1) compared with HIV-uninfected subjects in 2010-2011. Risk factors for IPD among HIV-infected individuals included black compared with white race/ethnicity, smoking, cancer, and higher HIV RNA levels. The 23-valent pneumococcal polysaccharide vaccination was not associated with a reduced risk of IPD in HIV-infected or HIV-uninfected individuals. Among HIV-infected IPD cases, the most common serotype was 19A (33%), and 59% of serotypes were covered by the 13-valent pneumococcal conjugate vaccine (PCV13). Despite a dramatic decline in IPD incidence for HIV-infected adults since 1996, IPD rates were nearly sevenfold higher compared with HIV-uninfected adults in recent years, even after adjustment for risk factors. Timely antiretroviral therapy initiation, risk reduction strategies, and recent guidelines recommending PCV13 use may further reduce IPD incidence among HIV patients.
Dirmesropian, S; Wood, JG; MacIntyre, CR; Newall, AT
The 13-valent pneumococcal conjugated vaccine (PCV13) is already recommended for some adult groups and is being considered for wider use in many countries. In order to identify the strengths and limitations of the existing economic evaluation studies of PCV13 in adults and the elderly a literature review was conducted. The majority of the studies identified (9 out of 10) found that PCV13 was cost-effective in adults and/or the elderly. However, these results were based on assumptions that could not always be informed by robust evidence. Key uncertainties included the efficacy of PCV13 against non-invasive pneumonia and the herd immunity effect of childhood vaccination programs. Emerging trial evidence on PCV13 in adults from the Netherlands offers the ability to parameterize future economic evaluations with empirical efficacy data. However, it is important that these estimates are used thoughtfully when they are transferred to other settings. PMID:25933180
Weinberger, Daniel M.; Grant, Lindsay R.; Steiner, Claudia A.; Weatherholtz, Robert; Santosham, Mathuram; Viboud, Cécile; O'Brien, Katherine L.
Background. Winter-seasonal epidemics of pneumococcal disease provide an opportunity to understand the drivers of incidence. We sought to determine whether seasonality of invasive pneumococcal disease is caused by increased nasopharyngeal transmission of the bacteria or increased susceptibility to invasive infections driven by cocirculating winter respiratory viruses. Methods. We analyzed pneumococcal carriage and invasive disease data collected from children <7 years old in the Navajo/White Mountain Apache populations between 1996 and 2012. Regression models were used to quantify seasonal variations in carriage prevalence, carriage density, and disease incidence. We also fit a multivariate model to determine the contribution of carriage prevalence and RSV activity to pneumococcal disease incidence while controlling for shared seasonal factors. Results. The seasonal patterns of invasive pneumococcal disease epidemics varied significantly by clinical presentation: bacteremic pneumococcal pneumonia incidence peaked in late winter, whereas invasive nonpneumonia pneumococcal incidence peaked in autumn. Pneumococcal carriage prevalence and density also varied seasonally, with peak prevalence occurring in late autumn. In a multivariate model, RSV activity was associated with significant increases in bacteremic pneumonia cases (attributable percentage, 15.5%; 95% confidence interval [CI], 1.8%–26.1%) but was not associated with invasive nonpneumonia infections (8.0%; 95% CI, −4.8% to 19.3%). In contrast, seasonal variations in carriage prevalence were associated with significant increases in invasive nonpneumonia infections (31.4%; 95% CI, 8.8%–51.4%) but not with bacteremic pneumonia. Conclusions.The seasonality of invasive pneumococcal pneumonia could be due to increased susceptibility to invasive infection triggered by viral pathogens, whereas seasonality of other invasive pneumococcal infections might be primarily driven by increased nasopharyngeal
Desai, Shalini; Policarpio, Michelle E.; Wong, Kenney; Gubbay, Jonathan; Fediurek, Jill; Deeks, Shelley
Background: In Ontario, pneumococcal conjugate vaccines (PCVs) have been sequentially introduced into the publicly funded childhood vaccination program since 2005. A 23-valent polysaccharide pneumococcal vaccine (PPV23) has been routinely recommended for adults aged 65 years and older since 1996. To determine the effect of herd immunity, we examined the epidemiology of invasive pneumococcal disease in adults aged 65 years and older. Methods: Invasive pneumococcal disease is a provincially reportable disease. We were therefore able to conduct a descriptive epidemiologic analysis that included assessing time trends for patients aged 65 years and older using surveillance data from 2007 to 2014. Using serotype information within the surveillance data, cases were grouped into categories according to vaccine type and periods and then compared using Poisson regression. Results: A total of 3825 cases of invasive pneumococcal disease were reported among adults aged 65 years and older, for an overall annualized incidence of 25.4 cases per 100 000 population. There was a decrease in incidence due to serotypes included in 7-valent PCV (3.0 to 0.7 cases per 100 000 population) (p < 0.001). For 13-valent PCV serotypes, there was a decrease in incidence between 2011 and 2014 (9.8 to 5.3 cases per 100 000 population (p < 0.001)). Serotypes unique to PPV23 and those not included in a vaccine increased from 2.3 to 5.8 and from 2.4 to 7.2 cases per 100 000 population, respectively (p < 0.001). Interpretation: In older adults, among serotypes contained in PCVs, we have shown a decrease in incidence of invasive pneumococcal disease. This is likely due to herd immunity from the childhood program. A burden of illness due to unique PPV23 serotypes and those that are not covered by a vaccine exists and has increased over time. PMID:27730119
Regev-Yochay, Gili; Rahav, Galia; Strahilevitz, Jacob; Bishara, Jihad; Katzir, Michal; Chowers, Michal; Finkelstein, Renato; Chazan, Bibiana; Zimhony, Oren; Dagan, Ron
Pneumococcal infections in adults vary in severity and incidence is affected by childhood vaccination policy. Here, we try to define the host determinants and the interaction with specific serotypes that result in invasive pneumococcal disease (IPD) before an expected effect of pneumococcal conjugate vaccines. A nationwide active surveillance was initiated on July 2009, at the time of national implementation of PCV7 in Israel. The surveillance included all 27 laboratories and medical centers performing blood cultures in Israel, providing all blood and CSF pneumococcal isolates from persons ≥18y. Capture-recapture method assured that >95% of all cases were reported. IPD outcome and medical history were recorded and isolates were serotyped. Four hundred and sixty IPD cases were reported (annual incidence [/100,000] of 9.25). Incidence increased with age, from 2.6 among 18-34y to 66.8 among ≥85y. The most common diagnosis was pneumonia (72.4%), followed by bacteremia with no apparent focus (20.2%). Case fatality rate increased with age and number of comorbidities (34.5% for ≥75y or those with ≥3 comorbidities vs. 9.2-11.2% among <65y or those with no comorbidities; p=0.015). Variables independently associated with mortality were: age ≥75, chronic renal failure, malignancy, neurosurgery, alcohol abuse, multi-lobar pneumonia and sepsis with no apparent focus. The predominant serotypes in patients 18-49y were 1, 5, 8, 7F and 9V (constituting 56.3% in this age-group vs. 11.9% in ≥75y; p<0.01). The predominant serotypes among patients ≥75y were 3, 19A, 23F and 14 (40.3% of this age-group vs. 12.9% of 18-49y; p<0.01). Overall, PCV7 and PCV13 covered 25.6% and 63.7% of isolates, respectively, and 30.9% and 67.9% of isolates in mortality cases respectively. This nationwide active surveillance provides the baseline incidence, mortality rates and risk group distributions of IPD in adults before expected PCV effect.
Johannesson, Thomas G; Søgaard, Ole S; Tolstrup, Martin; Petersen, Mikkel S; Bernth-Jensen, Jens M; Østergaard, Lars; Erikstrup, Christian
Untreated HIV infection results in severe perturbations of the B-cell population and hyporesponsiveness to vaccination. We studied associations between circulating B-cell subsets and antibody response to pneumococcal conjugate vaccine in treated and untreated HIV patients.Ninety-five HIV-infected adults were grouped according to antiretroviral therapy (ART) and CD4+ cell count as follows: 20 ART-naïve (no prior ART), 62 ART-responders (received ART, and CD4 count >500 cells/µl), and 13 impaired responders (received ART for more than 3 years, and CD4 count <500 cells/µl). All subjects were immunized twice with double-dose 7-valent pneumococcal conjugate vaccine with or without 1 mg CPG 7909 (toll-like receptor 9 agonist) at baseline and after three months. Pre-vaccination B-cell subpopulations were assessed by flow cytometry. Serum IgG concentrations for vaccine serotypes were quantified by ELISA at baseline and 3, 4, and 9 months post-vaccination. ART responders had more isotype-switched memory B cells and more marginal-zone (MZ)-like B cells compared with impaired responders. Furthermore, ART-naïve patients had higher concentration of transitional B cells and plasmablasts compared with B cells of other patient groups. The concentration of MZ-like, isotype switched memory cells and plasmablasts correlated positively with post-vaccination IgG concentration at 3, 4, and 9 months. Low concentrations of isotype-switched memory B cells was the strongest independent predictor of poor pneumococcal conjugate vaccine responsiveness, emphasizing that B-cell subset disturbances are associated with poor vaccine response among HIV-infected patients.
Offersen, Rasmus; Melchjorsen, Jesper; Paludan, Søren R; Østergaard, Lars; Tolstrup, Martin; Søgaard, Ole S
HIV-patients have excess of pneumococcal infection. We immunized 40 HIV-patients twice with pneumococcal conjugate vaccine (Prevnar, Pfizer) +/- a TLR9 agonist (CPG 7909). Peripheral blood mononuclear cells were stimulated with pneumococcal polysaccharides and cytokine concentrations measured. The CPG 7909 adjuvant group had significantly higher relative cytokine responses than the placebo group for IL-1β, IL-2R, IL-6, IFN-γ and MIP-β, which, did not correlate with IgG antibody responses. These findings suggests that CPG 7909 as adjuvant to pneumococcal conjugate vaccine induces cellular memory to pneumococcal polysaccharides in HIV-patients, independently of the humoral response.
Background Bacteremia by Streptococcus pneumoniae has been traditionally associated with poor outcomes in patients with pneumonia; however, data on its impact on outcomes are limited and are sometimes contradictory. Methods We performed a prospective study in two hospitals in northern Spain in which cases diagnosed with pneumococcal pneumonia were selected from a cohort of hospitalized patients with pneumonia between January 2001 and July 2009. We compared patients with pneumococcal bacteremic pneumonia with those with pneumococcal non-bacteremic pneumonia. Results We compared 492 patients with negative blood culture and 399 with positive culture results. Host related factors were very similar in both groups. Severity of illness on admission measured by CURB-65 score was similar in both groups. Adjusted analysis showed a greater likelihood of septic shock during in-hospital course among patients with pneumococcal bacteremia (OR, 2.1; 95% CI, 1.2–3.5; P = 0.006). Likewise, patients with positive blood culture had greater in-hospital mortality (OR 2.1; 95% CI, 1.1 - -3.9; P = 0.02), 15-day mortality (OR 3.6; 95% CI, 1.7 - 7.4; P = 0.0006), and 30-day mortality (OR, 2.7; 95% CI, 1.5 - 5; P = 0.002). Conclusions Although host related factors and severity on admission were very similar in the two groups, bacteremic patients had worse in-hospital course and outcomes. Bacteraemia in pneumococcal pneumonia is of prognostic significance. PMID:25096919
Santos Paulo, Ana Cristina; Valadares, Idalina; Martins, Sara; Breia, Fátima; Brito-Avô, António; Morais, Ana; de Lencastre, Hermínia; Sá-Leão, Raquel
Pneumococcal disease is frequent at the extremes of age. While several studies have looked at colonization among young children, much less is known among the elderly. We aimed to evaluate pneumococcal carriage among elderly adults living in Portugal. Between April 2010 and December 2012, nasopharyngeal and oropharyngeal swabs of adults over 60 years of age, living in an urban area (n = 1,945) or in a rural area (n = 1,416), were obtained. Pneumococci were isolated by culture-based standard procedures, identified by optochin susceptibility, bile solubility and PCR screening for lytA and cpsA, and characterized by antibiotype, serotype, and MLST. Associations between pneumococcal carriage, socio-demographic and clinical characteristics were evaluated by univariate analysis and multiple logistic regression. The global prevalence of carriage was 2.3% (95% CI: 1.8–2.8). In the multiple logistic regression analysis, smoking, being at a retirement home, and living in a rural area increased the odds of being a pneumococcal carrier by 4.4-fold (95% CI: 1.9–9.2), 2.0-fold (95% CI: 1.1–3.6) and 2.0-fold (95% CI: 1.2–3.5), respectively. Among the 77 pneumococcal isolates, 26 serotypes and 40 STs were identified. The most prevalent serotypes were (in decreasing order) 19A, 6C, 22F, 23A, 35F, 11A, and 23B, which accounted, in total, for 60.0% of the isolates. Most isolates (93.5%) had STs previously described in the MLST database. Resistance to macrolides, non-susceptibility to penicillin and multidrug resistance were found in 19.5%, 11.7%, and 15.6% of the isolates, respectively. We conclude that the prevalence of pneumococcal carriage in the elderly, in Portugal, as determined by culture-based methods, is low. Serotype and genotype diversity is high. Living in a rural area, in a retirement home, and being a smoker increased the risk of pneumococcal carriage. This study contributes to the establishment of a baseline that may be used to monitor how novel
Safety and immunogenicity of 13-valent pneumococcal conjugate vaccine formulations with and without aluminum phosphate and comparison of the formulation of choice with 23-valent pneumococcal polysaccharide vaccine in elderly adults
Juergens, Christine; de Villiers, Pierre JT; Moodley, Keymanthri; Jayawardene, Deepthi; Jansen, Kathrin U; Scott, Daniel A; Emini, Emilio A; Gruber, William C; Schmoele-Thoma, Beate
This randomized open-label trial was designed to provide preliminary immunogenicity and safety data to support development of the pediatric 13-valent pneumococcal conjugate vaccine (PCV13) for adults. The aims were to: identify an age-appropriate PCV13 formulation, i.e., with (n = 309) or without (n = 304) aluminum phosphate (AlPO4); compare the selected PCV13 formulation (n = 309) with 23-valent pneumococcal polysaccharide vaccine (PPSV23; n = 301); and, together with an extension study, assess sequential use of pneumococcal vaccines at 1-year intervals in adults aged ≥65 years (n = 105) not pre-vaccinated with PPSV23. Immune responses were measured by ELISA and opsonophagocytic activity assays 1 month postvaccination. Immunoglobulin G responses elicited by PCV13 with AlPO4 and PCV13 without AlPO4 were similar for the majority, and noninferior for all PCV13 serotypes. PCV13 with AlPO4 was generally more reactogenic, with reactions mainly mild or moderate. Thus, PCV13 with AlPO4 (hereafter PCV13) became the selected formulation. Immune responses to PCV13 were noninferior for all but one serotype and for most PCV13 serotypes superior to PPSV23. Vaccine sequence assessments showed that for PCV13/PPSV23, the initial PCV13 dose generally enhanced responses to a subsequent PPSV23 dose, compared with PPSV23 alone. For PCV13/PCV13, a second dose did not enhance the first dose response when given after 1 year. For PCV13/PPSV23/PCV13, priming with PCV13 (vaccination 1) did not protect against lower responses induced by PPSV23 to subsequent PCV13 (vaccination 3). In conclusion, the pediatric PCV13 formulation with AlPO4 is well tolerated and immunogenic in adults, is generally more immunogenic than PPSV23, and subsequent vaccination with PPSV23 is possible if required. PMID:24576885
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... causes meningitis. Causes Pneumococcal meningitis is caused by Streptococcus pneumoniae bacteria (also called pneumococcus, or S pneumoniae ). This type ... Saunders; 2015:chap 89. Wood JB, Peters TR. Streptococcus pneumoniae (pneumococcus). In: Kliegman RM, Stanton BF, St. Geme ...
Madhi, Shabir A.; Adrian, Peter V.; Telles, Jean-Noel; Paranhos-Baccalà, Glaucia; Klugman, Keith P.
Quantitative lytA real-time PCR (rtPCR) results from nasopharyngeal (NP) swabs distinguish community-acquired pneumococcal pneumonia (CAP) from asymptomatic colonization. The use of an optimized cutoff value improved pneumococcal etiology determination compared to that of traditional diagnostic methods. Here, we compare the utility of lytA rtPCR from induced sputum and from NP swabs. Pneumococcus was considered the cause of CAP in HIV-infected South African adults if blood culture, induced-sputum culture or Gram stain, urine antigen test, or whole-blood lytA rtPCR revealed pneumococcus or if lytA rtPCR from NP swabs gave a result of >8,000 copies/ml. lytA rtPCR was also performed on induced sputum. Pneumococcus was detected by lytA rtPCR from sputum in 149 (67.1%) of 222 patients with available induced sputum, whereas the results of either Gram stain or culture of sputum were positive in 105 of 229 patients (45.9%; P < 0.001). The mean copy numbers from sputum were higher when the sputum cultures were positive than when the sputum cultures were negative (7.9 versus 5.6 log10 copies/ml; P < 0.001). Against the composite diagnostic standard, a cutoff value of 10,000 copies/ml for good-quality sputum lytA rtPCR had a sensitivity of 78.1% and a specificity of 80.0%. This cutoff value performed similarly to the previously identified cutoff value of 8,000 copies/ml for NP swab lytA rtPCR (area under the curve receiver operating characteristic [AUC-ROC], 80.4% for sputum of any quality versus 79.6% for NP swabs). The AUC-ROC for good-quality sputum was 83.2%. Overall, lytA rtPCR performs similarly well on induced sputum as on NP swabs for most patients but performs slightly better if good-quality sputum can be obtained. Due to the ease of specimen collection, NP swabs may be preferable for the diagnosis of pneumococcal pneumonia. PMID:25253798
Moore, Matthew R.; Link-Gelles, Ruth; Schaffner, William; Lynfield, Ruth; Lexau, Catherine; Bennett, Nancy M.; Petit, Susan; Zansky, Shelley M.; Harrison, Lee H.; Reingold, Arthur; Miller, Lisa; Scherzinger, Karen; Thomas, Ann; Farley, Monica M.; Zell, Elizabeth R.; Taylor, Thomas H.; Pondo, Tracy; Rodgers, Loren; McGee, Lesley; Beall, Bernard; Jorgensen, James H.; Whitney, Cynthia G.
SUMMARY Background In 2000, 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in the U.S. and resulted in dramatic reductions in invasive pneumococcal disease (IPD) and modest increases in non-PCV7-type IPD. In 2010, a 13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7 in the U.S. immunization schedule. We evaluated the effect of PCV13 use in children on IPD in children and adults in the U.S. Methods We used laboratory- and population-based data on incidence of IPD from CDC’s Emerging Infections Program / Active Bacterial Core surveillance in a time-series model to estimate the impact of vaccination. Cases of IPD during July 2004–June 2013 were classified as being caused by the PCV13 serotypes against which PCV7 has no effect (PCV13/nonPCV7). Findings Compared with incidence expected among children <5 years old if PCV7 alone had been continued, incidence of IPD overall and IPD caused by PCV13/nonPCV7 serotypes declined by 64% (95% interval estimate [IE] 59–68 %) and 93% (95%IE 91–94), respectively, by July 2012–June 2013. Among adults, incidence of IPD overall and PCV13/nonPCV7-type IPD also declined by 12–32% and 58–72%, respectively, depending on age. In all age groups, reductions were driven principally by changes in incidence of serotypes 19A and 7F. We estimate that over 30,000 cases of IPD and 3,000 deaths were averted in the first 3 years following PCV13 introduction. Interpretation PCV13 has reduced IPD among all ages when used routinely in children in the U.S. Serotypes 19A and 7F, which emerged after PCV7 introduction, have been effectively controlled. PMID:25656600
Juergens, Christine; Ruiz Palacios, Guillermo M.; Vazquez-Narvaez, Jorge; Enkerlin-Pauwells, Hermann Leo; Sundaraiyer, Vani; Pathirana, Sudam; Kalinina, Elena; Gruber, William C.; Scott, Daniel A.; Schmoele-Thoma, Beate
This open-label multicenter clinical trial conducted in Mexico assessed the immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine (PCV13) in adults ≥50 years of age not previously vaccinated with the 23-valent pneumococcal polysaccharide vaccine (PPSV23). The PCV13 elicited a robust immune response in this study population, as reflected by the magnitude of fold rises in functional antibody levels measured by serotype-specific opsonophagocytic activity (OPA) assays before and 1 month after vaccination. Although the prevaccination OPA geometric mean titers (GMTs) for the majority of the serotypes were significantly lower in the 50- to 64-year age group than those in the ≥65-year age group, the postvaccination immune responses were generally similar. The overall immune responses were higher for the majority of the serotypes in the Mexican study population than those in similar adult study populations who received the PCV13 in Europe and the United States. PCV13 was well tolerated, and there were no vaccine-related serious adverse events. In conclusion, PCV13 is safe and immunogenic when administered to adults ≥50 years of age in Mexico and has the potential to protect against vaccine-type pneumococcal disease. (This study has been registered at ClinicalTrials.gov under registration no. NCT01432262.) PMID:25499011
Yildirim, Inci; Shea, Kimberly M.
SYNOPSIS Universal immunization of infants and toddlers with PCVs over the past 15 years has dramatically altered the landscape of pneumococcal disease. Decreases in IPD, all cause pneumonia, empyema, mastoiditis, acute otitis media and complicated otitis media have been reported from multiple countries where universal immunization has been implemented. The introduction of the vaccine has also led to expanded understanding of pneumococcal disease; observations have confirmed that most pneumococci are transmitted from children to adults, not all pneumococcal serotypes are equal in terms of common clinical syndromes, likelihood of antibiotic resistance, or likelihood of progression to disease once colonization occurs. Children with comorbid conditions have higher rates of pneumococcal disease and increased case fatality rates compared to otherwise healthy children, and protection for the most vulnerable pediatric patients will require new strategies to address the underlying host susceptibility and the expanded spectrum of serotypes observed. PMID:26610421
Dee, T H; Schiffman, G; Sottile, M I; Rytel, M W
Many patients die from pneumococcal disease despite the availability of effective antimicrobial agents. Immunologic studies including detection, typing, and quantitation of serum pneumococcal capsular polysaccharide (PCP) antigen by counterimmunoelectrophoresis (CIE), quantitation of PCP antibody by radioimmunoassay (RIA), and quantitation of serum complement components C3, C4, and C3PA and serum immunoglobulins IgG, IgM, and IgA by the radial immunodiffusion technique of Mancini were performed with the sera of 18 patients. Five patients died (group I), and 13 survived (group II) pneumococcal infection. Both groups were comparable in age, underlying disease, and leukopenia on admission. All patients of group I and 10 of 13 (77%) of group II patients were bacteremic. Two patients in each group had an extrapulmonary focus infection. PCP antigen was detected in the sera of all group I and nine of 13 group II patients. PCP antigen levels were larger than or equal to 15 microng/ml in four of five group I and two of 13 group II patients (p = 0.022). Levels of antibody to PCP exceeded 100 ng/ml of antibody nitrogen (AbN) in 10 of 12 group II and one of five group I patients (p = 0.027) during the course of illness. All group I patients and three of 12 group II patients had decreased levels of one or more complement components on admission (p less than 0.01). One or more complement components remained decreased until death in four group I patients but returned to normal or elevated levels in all group II patients. No difference in serum immunoglobulin concentrations were found.
Horácio, Andreia N; Silva-Costa, Catarina; Lopes, Joana P; Ramirez, Mário; Melo-Cristino, José
Since 2010 the 13-valent pneumococcal conjugate vaccine (PCV13) replaced the 7-valent vaccine (PCV7) as the leading pneumococcal vaccine used in children through the private sector. Although, neither of the PCVs were used significantly in adults, changes in adult invasive pneumococcal disease (IPD) were expected due to herd protection. We characterized n = 1163 isolates recovered from IPD in adults in 2012-2014 with the goal of documenting possible changes in serotype prevalence and antimicrobial resistance. Among the 54 different serotypes detected, the most frequent, accounting for half of all IPD, were serotypes: 3 (14%), 8 (11%), 19A (7%), 22F (7%), 14 (6%), and 7F (5%). The proportion of IPD caused by PCV7 serotypes remained stable during the study period (14%), but was smaller than in the previous period (19% in 2009-2011, p = 0.003). The proportion of IPD caused by PCV13 serotypes decreased from 51% in 2012 to 38% in 2014 (p < 0.001), mainly due to decreases in serotypes 7F and 19A. However, PCV13 serotype 3 remained relatively stable and the most frequent cause of adult IPD. Non-PCV13 serotypes continued the increase initiated in the late post-PCV7 period, with serotypes 8 and 22F being the most important emerging serotypes. Serotype 15A increased in 2012-2014 (0.7% to 3.5%, p = 0.011) and was strongly associated with antimicrobial resistance. However, the decreases in resistant isolates among serotypes 14 and 19A led to an overall decrease in penicillin non-susceptibility (from 17 to 13%, p = 0.174) and erythromycin resistance (from 19 to 13%, p = 0.034). Introduction of PCV13 in the NIP for children, as well as its availability for adults may further alter the serotypes causing IPD in adults in Portugal and lead to changes in the proportion of resistant isolates.
Horácio, Andreia N.; Silva-Costa, Catarina; Lopes, Joana P.; Ramirez, Mário; Melo-Cristino, José; Vaz, Teresa
Since 2010 the 13-valent pneumococcal conjugate vaccine (PCV13) replaced the 7-valent vaccine (PCV7) as the leading pneumococcal vaccine used in children through the private sector. Although, neither of the PCVs were used significantly in adults, changes in adult invasive pneumococcal disease (IPD) were expected due to herd protection. We characterized n = 1163 isolates recovered from IPD in adults in 2012–2014 with the goal of documenting possible changes in serotype prevalence and antimicrobial resistance. Among the 54 different serotypes detected, the most frequent, accounting for half of all IPD, were serotypes: 3 (14%), 8 (11%), 19A (7%), 22F (7%), 14 (6%), and 7F (5%). The proportion of IPD caused by PCV7 serotypes remained stable during the study period (14%), but was smaller than in the previous period (19% in 2009–2011, p = 0.003). The proportion of IPD caused by PCV13 serotypes decreased from 51% in 2012 to 38% in 2014 (p < 0.001), mainly due to decreases in serotypes 7F and 19A. However, PCV13 serotype 3 remained relatively stable and the most frequent cause of adult IPD. Non-PCV13 serotypes continued the increase initiated in the late post-PCV7 period, with serotypes 8 and 22F being the most important emerging serotypes. Serotype 15A increased in 2012–2014 (0.7% to 3.5%, p = 0.011) and was strongly associated with antimicrobial resistance. However, the decreases in resistant isolates among serotypes 14 and 19A led to an overall decrease in penicillin non-susceptibility (from 17 to 13%, p = 0.174) and erythromycin resistance (from 19 to 13%, p = 0.034). Introduction of PCV13 in the NIP for children, as well as its availability for adults may further alter the serotypes causing IPD in adults in Portugal and lead to changes in the proportion of resistant isolates. PMID:27790208
Olaya-Abril, Alfonso; Jiménez-Munguía, Irene; Gómez-Gascón, Lidia; Obando, Ignacio; Rodríguez-Ortega, Manuel J
Purified polysaccharide and conjugate vaccines are widely used for preventing infections in adults and in children against the Gram-positive bacterium Streptococcus pneumoniae, a pathogen responsible for high morbidity and mortality rates, especially in developing countries. However, these polysaccharide-based vaccines have some important limitations, such as being serotype-dependent, being subjected to losing efficacy because of serotype replacement and high manufacturing complexity and cost. It is expected that protein-based vaccines will overcome these issues by conferring a broad coverage independent of serotype and lowering production costs. In this study, we have applied the "shaving" proteomic approach, consisting of the LC/MS/MS analysis of peptides generated by protease treatment of live cells, to a collection of 16 pneumococcal clinical isolates from adults, representing the most prevalent strains circulating in Spain during the last years. The set of unique proteins identified in all the isolates, called "pan-surfome", consisted of 254 proteins, which included most of the protective protein antigens reported so far. In search of new candidates with vaccine potential, we identified 32 that were present in at least 50% of the clinical isolates analyzed. We selected four of them (Spr0012, Spr0328, Spr0561 and SP670_2141), whose protection capacity has not yet been tested, for assaying immunogenicity in human sera. All of them induced the production of IgM antibodies in infected patients, thus indicating that they could enter the pipeline for vaccine studies. The pan-surfomic approach shows its utility in the discovery of new proteins that can elicit protection against infectious microorganisms.
Pletz, Mathias W
Pneumococcal infections (pneumonia, otitis media, sinusitis, meningitis) are common and usually involve toddlers, immunocompromised and the elderly. Main reservoir of pneumococci is the nasopharyngeal zone of healthy carriers, especially of toddlers. Currently, two types of pneumococcal vaccines are in clinical use, which induce production of antibodies against capsular polysaccharides. The older vaccine consists of pure capsular polysaccharides. It induces a limited immunity, because polysaccharides are poor antigens that stimulate mainly B-cells. In children under two years of age this vaccine is not used, because it does not induce a sufficient immunologic response, presumably because of the immaturity of their immune system. In 2000, a vaccination program with a novel pneumococcal vaccine was launched in the USA. This vaccine contains capsular polysaccharides, that are conjugated with a highly immunogenic protein. It induces both a T cell and B cell response that results in specific humoral and mucosal immunity. U.S. data demonstrate, that serotypes covered by the conjugated vaccine can be reduced in the whole population by vaccination of children being the main reservoir of pneumococci. This so called ,,herd protection" results in a decrease in invasive pneumococcal diseases in vaccinees and non-vaccinees as well as in a reduction of antibiotic resistance rates by reducing resistant pneumococcal cones.
de Soárez, Patrícia Coelho; Sartori, Ana Marli Christovam; Freitas, Angela Carvalho; Nishikawa, Álvaro Mitsunori; Novaes, Hillegonda Maria Dutilh
Objective To evaluate the cost-effectiveness of introducing universal vaccination of adults aged 60 years with the 23-valent pneumococcal polysaccharide vaccine (PPV23) into the National Immunization Program (NIP) in Brazil. Methods Economic evaluation using a Markov model to compare two strategies: (1) universal vaccination of adults aged 60 years with one dose of PPV23 and 2) current practice (vaccination of institutionalized elderly and elderly with underlying diseases). The perspective was from the health system and society. Temporal horizon was 10 years. Discount rate of 5% was applied to costs and benefits. Clinical syndromes of interest were invasive pneumococcal disease (IPD) including meningitis, sepsis and others and pneumonia. Vaccine efficacy against IPD was obtained from a meta-analysis of randomized control trials and randomized studies, whereas vaccine effectiveness against pneumonia was obtained from cohort studies. Resource utilization and costs were obtained from the Brazilian Health Information Systems. The primary outcome was cost per life year saved (LYS). Univariate and multivariate sensitivity analysis were performed. Results The universal vaccination strategy avoided 7,810 hospitalizations and 514 deaths, saving 3,787 years of life and costing a total of USD$31,507,012 and USD$44,548,180, respectively, from the health system and societal perspective. The universal immunization would result in ICERs of USD$1,297 per LYS, from the perspective of the health system, and USD$904 per LYS, from the societal perspective. Conclusion The results suggest that universal vaccination of adults aged 60 years with the 23-valent pneumococcal polysaccharide vaccine (PPV23) is a very cost-effective intervention for preventing hospitalization and deaths for IPD and pneumonia is this age group in Brazil. PMID:26114297
Ariza-Prota, Miguel Angel; Pando-Sandoval, Ana; García-Clemente, Marta; Fole-Vázquez, David; Casan, Pere
Moraxella (formerly Branhamella) catarrhalis was discovered at the end of the nineteenth century, and for many decades it was considered to be a harmless commensal of the upper respiratory tract. It is a Gram-negative, aerobic diplococcus considered to be the third most common pathogen isolated in childhood sinusitis and otitis media and in adult chronic lower respiratory disease, as well as an etiological agent of pneumonia in immunosuppressed patients or those with chronic obstructive pulmonary disease. Moraxella catarrhalis pneumonia is rarely associated with bacteremia. Here, we present two cases of community-acquired Moraxella catarrhalis bacteremic pneumonia. PMID:26989548
Bhengsri, Saithip; Lertiendumrong, Jongkol; Baggett, Henry C; Thamthitiwat, Somsak; Chierakul, Wirongrong; Tisayaticom, Kanjana; Tanwisaid, Kittisak; Chantra, Somrak; Kaewkungwal, Jaranit
Melioidosis is among the most common causes of septicemia in Thailand, but data on economic burden are limited. We describe the economic impact of bacteremic melioidosis hospitalizations in two Thailand provinces during 2006-2008. Costs are presented in US dollars ($1 = 30.49 Thai Baht). The average annual incidence of bacteremic melioidosis cases per 100,000 persons in Sa Kaeo and Nakhon Phanom was 4.6 and 14.4, respectively. The annual cost of bacteremic melioidosis hospitalizations from the societal perspective, including direct and indirect costs, was $152,159 in Sa Kaeo and $465,303 in Nakhon Phanom. The average cost per fatal case was $14,182 and $14,858 in Sa Kaeo and Nakhon Phanom, respectively. In addition to the high morbidity and mortality, the substantial economic burden of melioidosis further supports the need for investments to identify improved prevention and control strategies for melioidosis.
Pneumococcal vaccine is an immunization against Streptococcus pneumoniae , a bacterium that frequently causes meningitis and pneumonia in the elderly, and people with chronic illnesses. Pneumococcal pneumonia accounts for 10 to ...
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Wyllie, Anne L.; Rümke, Lidewij W.; Arp, Kayleigh; Bosch, Astrid A. T. M.; Bruin, Jacob P.; Rots, Nynke Y.; Wijmenga-Monsuur, Alienke J.; Sanders, Elisabeth A. M.; Trzciński, Krzysztof
Carriage of Streptococcus pneumoniae in adults is rarely detected by the gold standard culture method. With molecular tests of high sensitivity now available, we analysed upper respiratory tract samples collected during autumn/winter 2012/2013 from parents of PCV7-vaccinated infants and from childless adults, directly comparing culture and qPCR-based S. pneumoniae detection. As compared to the gold standard of testing nasopharyngeal swabs, qPCR-based analysis of oral samples significantly improved detection of pneumococcal carriage (5% versus 20%, p < 0.0001) with higher carriage rates in parents compared to childless adults (34% versus 7%; p < 0.001). Molecular methods also increased the number of serotype-carriage events detected with higher carriage frequencies of serotypes 3 and 7A/F and lower of serotypes 6C/D and 15A/B/C in parents compared to their infant children. We provide evidence that culture-based methods severely underestimate adult carriage rates and for the superiority of testing oral samples over nasopharyngeal swabs. The substantial circulation of pneumococci in parents is however, not representative for the entire adult population. While age-associated differences in serotype carriage suggests reservoirs outside infants as potential sources of vaccine-serotypes contributing to weakening of vaccine herd effects, we find no evidence for reservoirs in adults contributing to serotype replacement in carriage. PMID:27713565
de Arístegui Fernández, J; Corretger Rauet, J M; García Martín, F; Hernández-Sampelayo, T; Moraga Llop, F A; Rodrigo Gonzalo De Liria, C; Ruiz Contreras, J
Pneumococcal disease is a major cause of morbidity, hospitalization and mortality. Two age groups show a greater incidence and severity of the disease: children under the age of 5 years (mainly during the first 2 years of life) and adults aged more than 65 years. The heptavalent pneumococcal conjugate vaccine, which was commercialized in Spain in June 2001, is efficacious in children aged less than 2 years and, unlike the non-conjugate 23-valent vaccine, it induces immunological memory. In Spain the heptavalent vaccine covers 80 % of serotypes causing pneumococcal invasive disease and acute otitis media in children aged 2-59 months. The heptavalent vaccine has been shown to be immunogenic, efficacious and safe. It has proven efficacy in the prevention of invasive disease caused by the seven vaccine serotypes. In addition, it significantly decreases pneumonia and also prevent acute otitis media. The vaccine is preferably indicated in children aged less than 2 years; children aged 2-5 years may also benefit from the vaccine but those in risk groups should be prioritized. Greater knowledge of the epidemiology of pneumococcal disease and the efficiency of this vaccine in Spain will determine whether it should be included in the immunization schedule.
Casas Maldonado, F; Alfageme Michavila, I; Barchilón Cohen, V S; Peis Redondo, J I; Vargas Ortega, D A
Community-acquired pneumonia is an acute respiratory infectious disease which has an incidence of 3-8 cases/1,000 inhabitants, and increases with age and comorbidities. The pneumococcus is the organism most frequently involved in community-acquired pneumonia in the adult (30-35%). Around 40% of patients with community-acquired pneumonia require hospital admission, and around 10% need to be admitted to an intensive care unit. The most serious forms of pneumococcal infection include invasive pneumococcal disease (IPD), which covers cases of bacteremia (associated or not to pneumonia), meningitis, pleuritis, arthritis, primary peritonitis and pericarditis. Currently, the biggest problem with the pneumococcus is the emergence of resistance to antimicrobial agents, and its high morbimortality, despite the use of appropriate antibiotics and proper medical treatment. Certain underlying medical conditions increase the risk of IPD and its complications, especially, from the respiratory diseases point of view, smoking and chronic respiratory diseases. Pneumococcal disease, according to the WHO, is the first preventable cause of death worldwide in children and adults. Among the strategies to prevent IPD is vaccination. WHO considers that its universal introduction and implementation against pneumococcus is essential and a priority in all countries. There are currently 2 pneumococcal vaccines for adults: the 23 serotypes polysaccharide and conjugate 13 serotypes. The scientific societies represented here have worked to develop some recommendations, based on the current scientific evidence, regarding the pneumococcal vaccination in the immunocompetent adult with chronic respiratory disease and smokers at risk of suffering from IPD.
Hutchison, B. G.; Oxman, A. D.; Shannon, H. S.; Lloyd, S.; Altmayer, C. A.; Thomas, K.
OBJECTIVE: To determine the clinical effectiveness of pneumococcal vaccine. DATA SOURCES: Computerized searches of MEDLINE, EMBASE, and SCISEARCH databases were performed, reference lists of retrieved articles were reviewed, and first authors of published studies were contacted. STUDY SELECTION: Studies of use of pneumococcal vaccines in adults were included if the study design was a randomized or quasi-randomized controlled trial and at least one of the following clinical outcomes was reported: vaccine-type systemic pneumococcal infection, systemic pneumococcal infection, vaccine-type pneumococcal pneumonia, pneumococcal pneumonia, non-vaccine-type pneumococcal pneumonia. SYNTHESIS: Study quality was assessed and descriptive information concerning the study populations, interventions, and outcome measurements was extracted for 13 trials involving more than 65,000 patients. Estimates of vaccine efficacy, based on a meta-analysis of randomized and quasi-randomized trials, were determined for clinical outcomes. CONCLUSIONS: Vaccination with pneumococcal polysaccharide vaccine can be expected to reduce the risk of systemic infection due to pneumococcal types included in the vaccine by 83% and systemic infection due to all pneumococci by 73%. We found no evidence that the vaccine was less efficacious for the elderly, institutionalized people, or those with chronic disease. PMID:10540698
Haas, Karen M; Blevins, Maria W; High, Kevin P; Pang, Bing; Swords, W Edward; Yammani, Rama D
The efficacy of different vaccines in protecting elderly individuals against Streptococcus pneumoniae infections is not clear. In the current study, aged mice (22-25 months old) exhibited significantly increased susceptibility to respiratory infection with serotype 3 S. pneumoniae relative to younger adult mice, regardless of whether mice were naive or immunized with native pneumococcal polysaccharide (PPS; Pneumovax23) or protein-PPS conjugate (Prevnar-13) vaccines. Nonetheless, Pneumovax-immunized aged mice developed limited bacteremia following respiratory challenge and exhibited significantly increased survival following systemic challenge relative to Prevnar-immune aged mice and young mice that had received either vaccine. This was explained by >10-fold increases in PPS-specific immunoglobulin G (IgG) levels in Pneumovax-immunized aged mice relative to other groups. Remarkably, PPS3-specific B-cell expansion, IgG switching, plasmablast differentiation, and spleen and bone marrow antibody-secreting cell frequencies were 10-fold higher in aged mice following Pneumovax immunization relative to young mice, due to significantly increased B-1b cell participation. In summary, this study highlights (1) the need to devise strategies to enhance respiratory immunity in aged populations, (2) the diverse responses young and aged populations generate to Pneumovax vs Prevnar vaccines, and (3) the potential value of exploiting B-1b cell responses in aged individuals for increased vaccine efficacy.
A case of nonpigmented Chromobacterium violaceum bacteremic cellulitis after fish bite in Taiwan is reported. The patient was successfully treated with ciprofloxacin and doxycycline for an extended period. Chromobacterium violaceum should be listed in the differential diagnosis of patients with nonspecific cellulitis associated with marked leukocytosis and rapid progression to septicemia either with or without a distinct history of exposure to water or soil. A combination of prompt diagnosis, optimal antimicrobial therapy, and adequate therapeutic duration for C violaceum infection is the key for successful therapy.
... to 2-Year-Old Your Child's Immunizations: Pneumococcal Vaccines (PCV, PPSV) KidsHealth > For Parents > Your Child's Immunizations: ... or HIV infection); or cochlear implants. Why the Vaccines Are Recommended Children younger than 2 years old, ...
... Your 1- to 2-Year-Old Your Child's Immunizations: Pneumococcal Vaccines (PCV, PPSV) KidsHealth > For Parents > Your ... but also help stop the infections from spreading. Immunization Schedule PCV13 immunizations are given to all infants ...
... the United States.Treatment of pneumococcal infections with penicillin and other drugs used to be more effective. ... get another dose. Anyone who has a severe allergy to any component of PPSV should not receive ...
Nace, David A; Archbald-Pannone, Laurie R; Ashraf, Muhammad S; Drinka, Paul J; Frentzel, Elizabeth; Gaur, Swati; Mahajan, Dheeraj; Mehr, David R; Mercer, William C; Sloane, Philip D; Jump, Robin L P
Efforts at preventing pneumococcal disease are a national health priority, particularly in older adults and especially in post-acute and long-term care settings The Advisory Committee on Immunization Practices recommends that all adults ≥65 years of age, as well as adults 18-64 years of age with specific risk factors, receive both the recently introduced polysaccharide-protein conjugate vaccine against 13 pneumococcal serotypes as well as the polysaccharide vaccine against 23 pneumococcal serotypes. Nursing facility licensure regulations require facilities to assess the pneumococcal vaccination status of each resident, provide education regarding pneumococcal vaccination, and administer the appropriate pneumococcal vaccine when indicated. Sorting out the indications and timing for 13 pneumococcal serotypes and 23 pneumococcal serotypes administration is complex and presents a significant challenge to healthcare providers. Here, we discuss the importance of pneumococcal vaccination for older adults, detail AMDA-The Society for Post-Acute and Long-Term Care Medicine (The Society)'s recommendations for pneumococcal vaccination practice and procedures, and offer guidance to postacute and long-term care providers supporting the development and effective implementation of pneumococcal vaccine policies.
... of antibiotics may also slow or reverse drug-resistant pneumococcal infections. Related Pages Global Pneumococcal Vaccination World Health Organization National Foundation for Infectious Diseases Sepsis File Formats Help: How do I view ...
Background: Pneumococcal vaccination (PV) is important as Streptococcus pneumoniae accounts for one third of all hospitalizations for community-acquired pneumonia. In 2009, 1.1 million people in the U.S. were hospitalized with pneumonia and more than 50,000 people died from the disease. The Centers for Disease Control and Prevention recommend that…
RESOLUTION TEST CHART NATIONAL BUREAU OF STANDARDS-1963-A -411 .oV. AD___ PROSPECTIVE RANDOMIZED TRIAL OF NALOXONE VERSUS DOPAMINE AS ADJUNCTIVE...NALOXONE VERSUS DOPAMINE AS ADJUNCTIVE THERAPY FOR BACTEREMIC Annual/11-8 2--1l-83:’-SHOCK 6. PERFORMING ORG. REPORT NUMBER 7. AUTHOR(o) 1. CONTRACT... DOPAMINE , BACTEREMIC SHOCK Z(. AMSTRAC? (Caohsttle st muvm F1 if namem ead identify by block number) The purpose of this study was to assess the efficacy
Nilsson, Anna C.; Caubet, Magalie; Pascal, Thierry G.; Van Belle, Pascale; Poolman, Jan T.; Vandepapelière, Pierre G.; Verlant, Vincent; Vink, Peter E.
Six vaccine formulations containing AS02V or alum (aluminum phosphate [AlPO4]) adjuvant with pneumococcal proteins, pneumococcal histidine triad D (PhtD), and/or detoxified pneumolysin (dPly), either as a polysaccharide carrier in an 8-valent pneumococcal conjugate vaccine (8PCV) or as free (unconjugated) proteins, were evaluated in adults -65 to 85 years of age. In this phase I observer-blind study, 167 healthy subjects were randomized to receive two doses (days 0 and 60) of 10 or 30 μg PhtD-dPly plus AS02V or alum, 8PCV plus AS02V or alum, or one dose (day 0) of 23-valent polysaccharide pneumococcal vaccine (23PPV) as a control (placebo on day 60). The safety, reactogenicity, and antibody-specific responses to these vaccines were evaluated. No vaccine-related serious adverse events were reported. The incidences of solicited local and specific general (fatigue and myalgia) symptoms tended to be higher in the AS02V groups than in other groups. Anti-PhtD and anti-Ply antibody responses were observed in all groups except the control group. One month post-dose 2, the anti-PhtD and anti-Ply antibody geometric mean concentrations tended to be higher with AS02V than with alum, higher with a dose of 30 μg than with 10 μg for PhtD-dPly and higher with 30-μg PhtD-dPly formulations than with conjugated PhtD and dPly (8PCV) formulations. Functional antibody responses, measured by an opsonophagocytic activity assay, tended to be higher with 8PCV than with 23PPV. In conclusion, vaccine formulations containing free or conjugated PhtD and dPly had acceptable reactogenicity and safety profiles in elderly adults. Immune responses were enhanced with an AS02V-adjuvanted formulation containing free 30-μg PhtD-dPly compared to those with alum adjuvant and conjugated proteins. (This study has been registered at ClinicalTrials.gov under registration no. NCT00756067.) PMID:24599529
Pauksens, Karlis; Nilsson, Anna C; Caubet, Magalie; Pascal, Thierry G; Van Belle, Pascale; Poolman, Jan T; Vandepapelière, Pierre G; Verlant, Vincent; Vink, Peter E
Six vaccine formulations containing AS02V or alum (aluminum phosphate [AlPO4]) adjuvant with pneumococcal proteins, pneumococcal histidine triad D (PhtD), and/or detoxified pneumolysin (dPly), either as a polysaccharide carrier in an 8-valent pneumococcal conjugate vaccine (8PCV) or as free (unconjugated) proteins, were evaluated in adults -65 to 85 years of age. In this phase I observer-blind study, 167 healthy subjects were randomized to receive two doses (days 0 and 60) of 10 or 30 μg PhtD-dPly plus AS02V or alum, 8PCV plus AS02V or alum, or one dose (day 0) of 23-valent polysaccharide pneumococcal vaccine (23PPV) as a control (placebo on day 60). The safety, reactogenicity, and antibody-specific responses to these vaccines were evaluated. No vaccine-related serious adverse events were reported. The incidences of solicited local and specific general (fatigue and myalgia) symptoms tended to be higher in the AS02V groups than in other groups. Anti-PhtD and anti-Ply antibody responses were observed in all groups except the control group. One month post-dose 2, the anti-PhtD and anti-Ply antibody geometric mean concentrations tended to be higher with AS02V than with alum, higher with a dose of 30 μg than with 10 μg for PhtD-dPly and higher with 30-μg PhtD-dPly formulations than with conjugated PhtD and dPly (8PCV) formulations. Functional antibody responses, measured by an opsonophagocytic activity assay, tended to be higher with 8PCV than with 23PPV. In conclusion, vaccine formulations containing free or conjugated PhtD and dPly had acceptable reactogenicity and safety profiles in elderly adults. Immune responses were enhanced with an AS02V-adjuvanted formulation containing free 30-μg PhtD-dPly compared to those with alum adjuvant and conjugated proteins. (This study has been registered at ClinicalTrials.gov under registration no. NCT00756067.).
Moïsi, Jennifer C.; Makawa, Makawa-Sy; Tall, Haoua; Agbenoko, Kodjo; Njanpop-Lafourcade, Berthe-Marie; Tamekloe, Stanislas; Amidou, Moussa; Mueller, Judith E.; Gessner, Bradford D.
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
Background Community-acquired pneumonia (CAP) has large impact on direct healthcare costs, especially those derived from hospitalization. This study determines impact, clinical characteristics, outcome and economic consequences of CAP in the adult (≥18 years) population attended in 6 primary-care centers and 2 hospitals in Badalona (Spain) over a two-year period. Methods Medical records were identified by codes from the International Classification of Diseases in databases (January 1st 2008-December 31st 2009). Results A total of 581 patients with CAP (55.6% males, mean age 57.5 years) were identified. Prevalence: 0.64% (95% CI: 0.5%-0.7%); annual incidence: 3.0 cases/1,000 inhabitants (95% CI: 0.2-0.5). Up to 241 (41.5%) required hospitalization. Hospital admission was associated (p<0.002) with liver disease (OR=5.9), stroke (OR=3.6), dementia (OR=3.5), COPD (OR=2.9), diabetes mellitus (OR=1.9) and age (OR=1.1 per year). Length of stay (4.4±0.3 days) was associated with PSI score (β=0.195), in turn associated with age (r=0.827) and Charlson index (r=0.497). Microbiological tests were performed in all inpatients but only in 35% outpatients. Among patients with microbiological tests, results were positive in 51.7%, and among them, S pneumoniae was identified in 57.5% cases. Time to recovery was 29.9±17.2 days. Up to 7.5% inpatients presented complications, 0.8% required ICU admission and 19.1% readmission. Inhospital mortality rate was 2.5%. Adjusted mean total cost was €2,332.4/inpatient and €698.6/outpatient (p<0.001). Patients with pneumococcal CAP (n=107) showed higher comorbidity and hospitalization (76.6%), higher PSI score, larger time to recovery and higher overall costs among inpatients. Conclusions Strategies preventing CAP, thus reducing hospital admissions could likely produce substantial costs savings in addition to the reduction of CAP burden. PMID:23114195
Weinberger, Daniel M.; Harboe, Zitta B.; Sanders, Elisabeth A.M.; Ndiritu, Moses; Klugman, Keith P.; Rückinger, Simon; Dagan, Ron; Adegbola, Richard; Cutts, Felicity; Johnson, Hope L.; O’Brien, Katherine L.; Scott, J. Anthony; Lipsitch, Marc
Background The 92 capsular serotypes of Streptococcus pneumoniae differ greatly in nasopharyngeal carriage prevalence, invasiveness and disease incidence. There has been some debate, though, as to whether serotype independently affects the outcome of invasive pneumococcal disease (IPD). Published studies have shown variable results with regards to case-fatality ratios for specific serotypes and the role of host factors in affecting these relationships. We evaluated whether risk of death from IPD is a stable serotype-associated property across studies, and then compared the pooled effect estimates with epidemiologic and biological correlates. Methods We performed a systematic review and meta-analysis of serotype-specific disease outcome for pneumonia and meningitis cases. Study-specific estimates of risk of death (risk ratio, RR) were pooled from 9 studies that provided serotype-specific data on pneumonia and meningitis using a random-effects method with serotype 14 as the reference. Pooled RRs were compared to RRs from adult cases with low co-morbidity scores to evaluate potential confounding by host factors. Results There were significant differences in the RR estimates between serotypes among bacteremic pneumonia cases. Overall, types 1, 7F and 8 were associated with decreased RRs and types 3, 6A, 6B, 9N and 19F were associated with increased RRs. Outcomes among meningitis cases did not differ significantly between types. Serotypes with increased RRs tended to have a high carriage prevalence, low invasiveness, and were more heavily encapsulated in vitro. These results suggest that IPD outcome, like other epidemiologic measures, is a stable serotype-associated property. PMID:20715907
Walker, Melissa M; Novak, Lea; Widener, Rebecca; Grubbs, James Aaron; King, Janice; Hale, Joanetha Y; Ochs, Martina M; Myers, Lisa E; Briles, David E; Deshane, Jessy
We used two different infection models to investigate the kinetics of the PcpA-dependent pneumococcal disease in mice. In a bacteremic pneumonia model, we observed a PcpA-dependent increase in bacterial burden in the lungs, blood, liver, bronchoalveolar lavage, and spleens of mice at 24 h postinfection. This PcpA-dependent effect on bacterial burden appeared earlier (within 12 h) in the focal pneumonia model, which lacks bacteremia or sepsis. Histological changes show that the ability of pneumococci to make PcpA was associated with unresolved inflammation in both models of infection. Using our bacteremic pneumonia model we further investigated the effects of PcpA on recruitment of innate immune regulatory cells. The presence of PcpA was associated with increased IL-6 levels, suppressed production of TRAIL, and reduced infiltration of polymorphonuclear cells. The ability of pneumococci to make PcpA negatively modulated both the infiltration and apoptosis of macrophages and the recruitment of myeloid-derived suppressor-like cells. The latter have been shown to facilitate the clearance and control of bacterial pneumonia. Taken together, the ability to make PcpA was strongly associated with increased bacterial burden, inflammation, and negative regulation of innate immune cell recruitment to the lung tissue during bacteremic pneumonia.
Yildirim, Inci; Shea, Kimberly M; Pelton, Stephen I
Universal immunization of infants and toddlers with pneumococcal conjugate vaccines over the last 15 years has dramatically altered the landscape of pneumococcal disease. Decreases in invasive pneumococcal disease, all-cause pneumonia, empyema, mastoiditis, acute otitis media, and complicated otitis media have been reported from multiple countries in which universal immunization has been implemented. Children with comorbid conditions have higher rates of pneumococcal disease and increased case fatality rates compared with otherwise healthy children, and protection for the most vulnerable pediatric patients will require new strategies to address the underlying host susceptibility and the expanded spectrum of serotypes observed.
Alharbi, N. S.; Al-Barrak, A. M.; Al-Moamary, M. S.; Zeitouni, M. O.; Idrees, M. M.; Al-Ghobain, M. O.; Al-Shimemeri, A. A.; Al-Hajjaj, Mohamed S.
Streptococcus pneumoniae (pneumococcus) is the leading cause of morbidity and mortality worldwide. Saudi Arabia is a host to millions of pilgrims who travel annually from all over the world for Umrah and the Hajj pilgrimages and are at risk of developing pneumococcal pneumonia or invasive pneumococcal disease (IPD). There is also the risk of transmission of S. pneumoniae including antibiotic resistant strains between pilgrims and their potential global spread upon their return. The country also has unique challenges posed by susceptible population to IPD due to people with hemoglobinopathies, younger age groups with chronic conditions, and growing problem of antibiotic resistance. Since the epidemiology of pneumococcal disease is constantly changing, with an increase in nonvaccine pneumococcal serotypes, vaccination policies on the effectiveness and usefulness of vaccines require regular revision. As part of the Saudi Thoracic Society (STS) commitment to promote the best practices in the field of respiratory diseases, we conducted a review of S. pneumoniae infections and the best evidence base available in the literature. The aim of the present study is to develop the STS pneumococcal vaccination guidelines for healthcare workers in Saudi Arabia. We recommend vaccination against pneumococcal infections for all children <5 years old, adults ≥50 years old, and people ≥6 years old with certain risk factors. These recommendations are based on the presence of a large number of comorbidities in Saudi Arabia population <50 years of age, many of whom have risk factors for contracting pneumococcal infections. A section for pneumococcal vaccination before the Umrah and Hajj pilgrimages is included as well. PMID:27168856
Piao, Zheng-Hao; Kim, Mi Sun; Jeong, Mira; Yun, Sohyun; Lee, Suk Hyung; Sun, Hu-Nan; Song, Hae Young; Suh, Hyun-Woo; Jung, Haiyoung; Yoon, Suk Ran; Kim, Tae-Don; Lee, Young-Ho; Choi, Inpyo
Vitamin-D3 upregulated protein-1 (VDUP1) is a stress response protein. Pseudomonas aeruginosa (P. aeruginosa) infection is a leading cause of death. Mice infected with live P. aeruginosa exhibit significantly decreased VDUP1 expression. However, the function of VDUP1 during P. aeruginosa-induced mouse bacteremic shock is unknown. To address the function of VDUP1 in P. aeruginosa-infected mice, we constructed a bacteremic shock model wherein both wild-type and VDUP1-deficient mice were infected intra-peritoneally with live P. aeruginosa. We found that VDUP1-deficient mice were more resistant to P. aeruginosa-induced bacteremic shock than wild-type mice, as shown by the increased survival, accelerated bacterial clearance and suppression of cytokine overproduction of the VDUP1-deficient mice. VDUP1 promoted the recruitment of neutrophils into the peritoneal cavities of infected mice. VDUP1 impeded the phagocytosis of non-opsonized P. aeruginosa via phosphatidylinositide 3-kinase (PI3K) pathway in macrophages. P. aeruginosa infection induced the generation of reactive oxygen species (ROS), and the increased production of ROS by the peritoneal cells of VDUP1-deficient mice was advantageous in clearing the bacteria. Overall, VDUP1 aggravates bacteremic shock; thus, VDUP1 can be considered a target molecule for the inhibition of P. aeruginosa-induced bacteremic shock.
Bliss, Sandra J; O'Brien, Katherine L; Janoff, Edward N; Cotton, Mark F; Musoke, Philippa; Coovadia, Hoosen; Levine, Orin S
Pneumococcal conjugate vaccines (PCVs) are a potentially useful complement to existing treatment strategies in HIV-infected children, for whom pneumococcal infections are common and serious. This Review summarises available data on the burden of pneumococcal disease and the safety and efficacy of PCVs in HIV-infected children. The data demonstrate that children with HIV have significantly increased risk of pneumococcal disease compared with uninfected children; the serotypes included in currently licensed or near-licensure conjugate vaccines include most serotypes that cause invasive pneumococcal disease (IPD) in HIV-infected children and adults; PCVs provide substantial protection against IPD and clinical pneumonia when given to HIV-infected infants; and HIV-infected adults gain an indirect benefit when children in the community are vaccinated. PCV should be considered as an important intervention for improving the lives of HIV-infected children.
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Abghari, Pamella F.; Poowuttikul, Pavadee; Secord, Elizabeth
Purpose: Immunoglobulin replacement is the mainstay treatment in patients with humoral immunodeficiencies, yet a handful of patients continue to develop sinopulmonary infections while on therapy. The objective of our study was to compare immunoglobulin G (IgG) pneumococcal antibody levels in patients with humoral immune deficiencies who have been on intravenous immunoglobulin (IVIG) replacement for at least 1 year to those on subcutaneous immunoglobulin (SCIG) therapy for at least 1 year. Methods: A retrospective chart review was completed on 28 patients. These patients’ ages ranged between 1 and 61 years. Pneumococcal serotype titers obtained at least 1 year after initiating therapy were compared between patients on IVIG (19 patients) and SCIG (9 patients). Results: A comparison between the groups demonstrated that SCIG achieved a higher percentage of serotype titers protective for noninvasive disease (≥1.3) and 100% protection for invasive disease (≥0.2). Our data also demonstrated a similar lack of protection (less than 50% ≥1.3) in 9N, 12F, and 23F on IVIG and 4, 9N, 12F, and 23F on SCIG. Conclusions: Our data demonstrated that serotypes 1, 3, 4, 9N, 12F, and 23F exhibited the lowest random IgG means while on IVIG, which was comparable to other published studies that looked at the mean IgG levels. In addition, our retrospective chart review demonstrated a greater number of therapeutic pneumococcal titers with SCIG in comparison to IVIG. PMID:28321436
Lee, Yi-Chien; Hsiao, Chih-Yen; Hung, Miao-Chiu; Hung, Sheng-Che; Wang, Hung-Ping; Huang, Yun-Jhong; Wang, Jann-Tay
The purpose of this study is to compare the clinical features and treatment outcomes among patients with bacteremic urinary tract infection (UTI) caused by multidrug-resistant (MDR) and non-MDR Enterobacteriaceae and to identify whether MDR pathogens were independently associated with severe sepsis or septic shock at presentation.The clinical data of adult patients visiting and being treated at Chia-Yi Christian Hospital due to bacteremic UTI caused by Enterobacteriaceae from January 2006 to August 2015 were retrospectively analyzed.A total of 585 patients were enrolled. Among them, 220 (37.6%) were caused by the MDR Enterobacteriaceae. A total of 206 patients (35.2%) developed severe sepsis or septic shock at presentation. Patients in the MDR group tend to be male and have a past history of gout, recurrent UTI, prior hospitalization, hydronephrosis, renal stone, ureteral stone, indwelling urinary catheter, newly development of renal dysfunction, severe sepsis or septic shock, intensive care unit (ICU) admission, receipt of ineffective empirical therapy, longer hospital stay, and higher in-hospital mortality (2.7% vs 1.9%, P = 0.569). Using multivariate logistic regression analysis, it is revealed that independent predictors associated with severe sepsis or septic shock at presentation were liver cirrhosis (OR 2.868; 95% CI 1.439-5.716; P = 0.003), indwelling urinary catheter (OR 1.936; 95% CI 1.238-3.027; P = 0.004), and MDR Enterobacteriaceae (OR 1.447; 95% CI 1.002-2.090; P = 0.049).Multidrug resistance was associated with the development of severe sepsis or septic shock upon presentation among patients with bacteremic UTI caused by Enterobacteriaceae. Therefore, empirical antibiotics therapy for patients with UTI presented with severe sepsis and/or septic shock should be more broad-spectrum to effectively cover MDR Enterobacteriaceae.
Kauppi, Anna M.; Edin, Alicia; Ziegler, Ingrid; Mölling, Paula; Sjöstedt, Anders; Gylfe, Åsa; Strålin, Kristoffer; Johansson, Anders
A metabolomics approach for prediction of bacteremic sepsis in patients in the emergency room (ER) was investigated. In a prospective study, whole blood samples from 65 patients with bacteremic sepsis and 49 ER controls were compared. The blood samples were analyzed using gas chromatography coupled to time-of-flight mass spectrometry. Multivariate and logistic regression modeling using metabolites identified by chromatography or using conventional laboratory parameters and clinical scores of infection were employed. A predictive model of bacteremic sepsis with 107 metabolites was developed and validated. The number of metabolites was reduced stepwise until identifying a set of 6 predictive metabolites. A 6-metabolite predictive logistic regression model showed a sensitivity of 0.91(95% CI 0.69–0.99) and a specificity 0.84 (95% CI 0.58–0.94) with an AUC of 0.93 (95% CI 0.89–1.01). Myristic acid was the single most predictive metabolite, with a sensitivity of 1.00 (95% CI 0.85–1.00) and specificity of 0.95 (95% CI 0.74–0.99), and performed better than various combinations of conventional laboratory and clinical parameters. We found that a metabolomics approach for analysis of acute blood samples was useful for identification of patients with bacteremic sepsis. Metabolomics should be further evaluated as a new tool for infection diagnostics. PMID:26800189
Walker, Melissa M.; Novak, Lea; Widener, Rebecca; Grubbs, James Aaron; King, Janice; Hale, Joanetha Y.; Ochs, Martina M.; Myers, Lisa E.; Briles, David E.; Deshane, Jessy
We used two different infection models to investigate the kinetics of the PcpA-dependent pneumococcal disease in mice. In a bacteremic pneumonia model, we observed a PcpA-dependent increase in bacterial burden in the lungs, blood, liver, BAL and spleens of mice at 24-hrs post infection. This PcpA-dependent effect on bacterial burden appeared earlier (within 12-hrs) in the focal-pneumonia model, which lacks bacteremia or sepsis. Histological changes show that the ability of pneumococci to make PcpA was associated with unresolved inflammation in both models of infection. Using our bacteremic pneumonia model we further investigated the effects of PcpA on recruitment of innate immune regulatory cells. The presence of PcpA was associated with increased IL-6 levels, suppressed production of TNF-related apoptosis - inducing ligand (TRAIL) and reduced infiltration of polymorphonuclear cells. The ability of pneumococci to make PcpA negatively modulated both the infiltration and apoptosis of macrophages and the recruitment of myeloid-derived suppressor-like cells (MDSCs). The latter have been shown to facilitate clearance and control of bacterial pneumonia. Taken together, the ability to make PcpA was strongly associated with increased bacterial burden, inflammation and negative regulation of innate immune cell recruitment to the lung tissue during bacteremic pneumonia. PMID:26829988
Klugman, K P
The geographic distribution of pneumococci resistant to one or more of the antibiotics penicillin, erythromycin, trimethoprim-sulfamethoxazole, and tetracycline appears to be expanding, and there exist foci of resistance to chloramphenicol and rifampin. Multiply resistant pneumococci are being encountered more commonly and are more often community acquired. Factors associated with infection caused by resistant pneumococci include young age, duration of hospitalization, infection with a pneumococcus of serogroup 6, 19, or 23 or serotype 14, and exposure to antibiotics to which the strain is resistant. At present, the most useful drugs for the management of resistant pneumococcal infections are cefotaxime, ceftriaxone, vancomycin, and rifampin. If the strains are susceptible, chloramphenicol may be useful as an alternative, less expensive agent. Appropriate interventions for the control of resistant pneumococcal outbreaks include investigation of the prevalence of resistant strains, isolation of patients, possible treatment of carriers, and reduction of usage of antibiotics to which the strain is resistant. The molecular mechanisms of penicillin resistance are related to the structure and function of penicillin-binding proteins, and the mechanisms of resistance to other agents involved in multiple resistance are being elucidated. Recognition is increasing of the standard screening procedure for penicillin resistance, using a 1-microgram oxacillin disk. PMID:2187594
... the United States.Treatment of pneumococcal infections with penicillin and other drugs is not as effective as ... should not get PCV13.Anyone with a severe allergy to any component of PCV13 should not get ...
Feldman, Charles; Abdulkarim, Emad; Alattar, Fatma; Al Lawati, Faryal; Al Khatib, Hisham; Al Maslamani, Muna; Al Obaidani, Idris; Al Salah, Mosaab; Farghaly, Mohamed; Husain, Entesar H; Mokadas, Eiman
Pneumococcal disease has substantial incidence, morbidity and mortality in older adults. Decreased birth rates and longer lifespans indicate that the global population is aging, although rates of aging differ between countries . In 2010, the proportion of the population aged >60 years in the general Arab Region was 7%, and this proportion is expected to rise to 19% by 2050 for the region as a whole ; the United Nations estimates for the individual countries of the Arabian Gulf by 2050 are 25.7%, 24.9%, 20.7%, 26.7% and 10.5% in the Kuwait, Bahrain, Qatar, United Arab Emirates (UAE) and Oman, respectively, which are comparable to the 26.9% predicted for the USA and lower than that predicted in European countries, in which the 2050 estimates are 32.7%, 34.0% and 38.1% for France, the UK and Germany, respectively . Globally and in the Gulf Region, pneumococcal disease is an increasingly important public health burden in the elderly. The burden of pneumococcal disease can be reduced by effective vaccination programs, but the recommendations on pneumococcal vaccination in adults vary widely. The major barriers to vaccine implementation among healthcare professionals are an incomplete awareness of pneumococcal disease and the vaccination options in adults. The Gulf Advocate Group calls for healthcare providers in the countries of the Arabian Gulf (Kuwait, Bahrain, Qatar, United Arab Emirates and Oman) to support awareness and education programs about adult pneumococcal disease, particularly in high-risk groups such as those >65 years of age, those with type 2 diabetes mellitus, hematological malignancy, organ and bone marrow transplantation or chronic kidney or lung diseases and pilgrims undertaking the Hajj to improve pneumococcal disease surveillance and optimize and disseminate recommendations for adult vaccination. The Gulf Advocate Group recommends following the U.S. Centers for Disease Control and Prevention (CDC) guidelines for pneumococcal vaccination [3,4].
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Imai, S; Ito, Y; Ishida, T; Hirai, T; Ito, I; Maekawa, K; Takakura, S; Iinuma, Y; Ichiyama, S; Mishima, M
A total of 141 Streptococcus pneumoniae isolates from patients with community-acquired pneumonia were collected from May 2003 through October 2004. The strains were tested for antimicrobial agent susceptibility, serotype and genotype by multilocus sequence typing (MLST) and the presence of the pilus rlrA islet. MLST analysis identified 49 sequence types (STs), of which 19 were novel. eBURST analysis using the MLST database (3773 STs) grouped the isolates into 27 clonal complexes and three singletons. A total of 92 (65.2%) isolates were related to ten of the 43 international Pneumococcal Molecular Epidemiology Network (PMEN) clones; major clones found were multidrug-resistant Netherlands(3)-31 [clonal complex (CC) 180], Taiwan(19F)-14 (CC271), Taiwan(23F)-15 (CC242), and Colombia(23F)-26 (CC138) (the latter new to Asia). We adopted univariate and multiple logistic regression models to identify factors associated with PMEN CCs. Multivariate analysis showed that multidrug resistance (OR 6.3; 95% CI 2.0-22.9), carriage serogroups (OR 7.2; 95% CI 2.5-23.7), prevalence of rlrA (OR 12.6; 95% CI 3.6-59.7) and central nervous system-related disorders (OR 7.7; 95% CI 1.8-48.4) were independently associated with PMEN CCs. Our data indicate that multidrug-resistant PMEN clones are highly prevalent, contributing to the high frequency of resistance to antimicrobial agents in Japan, and suggest that certain predisposing factors in patients contribute to the high frequency of these clones.
Antimicrobial resistance and serotypes in Streptococcus pneumoniae have been evolving with the widespread use of antibiotics and the introduction of pneumococcal conjugate vaccines (PCV). Particularly, among various types of antimicrobial resistance, macrolide resistance has most remarkably increased in many parts of the world, which has been reported to be >70% among clinical isolates from Asian countries. Penicillin resistance has dramatically decreased among nonmeningeal isolates due to the changes in resistance breakpoints, although resistance to other β-lactams such as cefuroxime has increased. Multidrug resistance became a serious concern in the treatment of invasive pneumococcal diseases, especially in Asian countries. After PCV7 vaccination, serotype 19A has emerged as an important cause of invasive pneumococcal diseases which was also associated with increasing prevalence of multidrug resistance in pneumococci. Widespread use of PCV13, which covers additional serotypes 3, 6A and 19A, may contribute to reduce the clonal spread of drug-resistant 19A pneumococci.
The 7-valent pneumococcal conjugate vaccine (4, 6B, 9V, 14, 18C, 19F, 23F) is the standard vaccine for the prevention of invasive pneumococcal infections in infants and children under 5 years of age. A 13-valent pneumococcal conjugate vaccine (with the addition of valences 1, 3, 5, 6A, 7F and 19A) has now been authorised to replace the 7-valent vaccine within the European Union. This new vaccine, adapted to recent epidemiological data on invasive pneumococcal infections, is supposed to cover at least 80% of pneumococcal infections in Europe. The protective potency of the 13-valent vaccine has not yet been tested in clinical trials. Clinical evaluation is based on two immunogenicity studies, in which the immunogenic potency of the 13-valent vaccine was similar to that of the 7-valent vaccine for their shared serotypes, but lower for serotypes 3, 6B and 9V. For these last two serotypes and for the new serotypes, the usual target antibody titre was reached after a booster injection. This was not the case for valence 3. * The vaccine used in immunogenicity studies did not contain polysorbate 80 (an excipient), and a non-inferiority study of the marketed vaccine containing polysorbate 80 was therefore conducted in 500 children. Non-inferiority was established for all 13 valences after the booster injection, but not for valences 6B and 23F after primary vaccination. According to the results of 10 studies, simultaneous administration of the 13-valent pneumococcal conjugate vaccine does not affect the immunogenicity of other vaccines generally administered before the age of 5 years. Other immunogenicity studies support the use of a variety of vaccine schedules for infants and children under 5 years of age who have not yet been vaccinated or who have started vaccination with the 7-valent vaccine. Increasing the number of valences in the vaccine from 7 to 13 led to no marked increase in local adverse effects (hypersensitivity, indurations, erythema) or systemic reactions
Chuang, Tzu-Yi; Lin, Chou-Jui; Chi, Chun-Lin; Liu, An-Yu; Lee, Shih-Wei; Lin, T L; Wang, Jin-Town; Hsueh, Po-Ren
Fatal bacteremic Klebsiella pneumoniae pneumonia is commonly encountered in alcoholic and diabetic patients. This report describes a previously healthy young man with rapidly fatal bacteremic pneumonia caused by K. pneumoniae serotype K1, complicated by septic shock and multiple organ dysfunction.
Expansion of Serotype Coverage in the Universal Pediatric Vaccination Calendar: Short-Term Effects on Age- and Serotype-Dependent Incidence of Invasive Pneumococcal Clinical Presentations in Madrid, Spain
Ruiz-Contreras, Jesus; Casado-Flores, Juan; Negreira, Sagrario; García-de-Miguel, Maria-Jesus; Hernández-Sampelayo, Teresa; Otheo, Enrique; Méndez, Cristina
In Madrid, Spain, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7 in the pediatric universal vaccination calendar in June 2010. A prospective clinical surveillance that included all children hospitalized with culture- and/or PCR-confirmed invasive pneumococcal disease (IPD) was performed in all Madrid hospitals. The incidence rates (IRs) (defined as the number of cases/100,000 inhabitants aged <15 years) in the PCV7 (May 2007 to April 2010) versus PCV13 (May 2011 to April 2012) periods were compared. There were 499 cases in the PCV7 period and 79 cases in the PCV13 period. Globally, the IR significantly decreased from 17.09 (PCV7 period) to 7.70 (PCV13 period), with significant decreases (PCV7 versus PCV13 periods) in all age groups for bacteremic pneumonia (5.51 versus 1.56), parapneumonic pneumococcal empyema (PPE) (5.72 versus 3.12), and meningitis (2.16 versus 0.97). In the PCV13 period, significant reductions (the IR in the PCV7 period versus the IR in the PCV13 period) were found in IPDs caused by PCV13 serotypes (13.49 versus 4.38), and specifically by serotypes 1 (globally [4.79 versus 2.53], for bacteremic pneumonia [2.23 versus 0.97], and for PPE [2.26 versus 1.17]), serotype 5 (globally [1.88 versus 0.00], for bacteremic pneumonia [0.89 versus 0.00], and for PPE [0.55 versus 0.00]), and serotype 19A (globally [3.77 versus 0.49], for bacteremic pneumonia [0.72 versus 0.00], for PPE [0.89 versus 0.00], and for meningitis [0.62 versus 0.00]). IPDs caused by non-PCV13 serotypes did not increase (IR, 3.60 in the PCV7 period versus 3.31 in the PCV13 period), regardless of age or presentation. No IPDs caused by the PCV13 serotypes were found in children who received 3 doses of PCV13. The number of hospitalization days and sanitary costs were significantly lower in the PCV13 period. The switch from PCV7 to PCV13 in the universal pediatric vaccination calendar provided sanitary and economical benefits without a replacement by non-PCV13
Expansion of serotype coverage in the universal pediatric vaccination calendar: short-term effects on age- and serotype-dependent incidence of invasive pneumococcal clinical presentations in Madrid, Spain.
Picazo, Juan; Ruiz-Contreras, Jesus; Casado-Flores, Juan; Negreira, Sagrario; García-de-Miguel, Maria-Jesus; Hernández-Sampelayo, Teresa; Otheo, Enrique; Méndez, Cristina
In Madrid, Spain, the 13-valent pneumococcal conjugate vaccine (PCV13) replaced PCV7 in the pediatric universal vaccination calendar in June 2010. A prospective clinical surveillance that included all children hospitalized with culture- and/or PCR-confirmed invasive pneumococcal disease (IPD) was performed in all Madrid hospitals. The incidence rates (IRs) (defined as the number of cases/100,000 inhabitants aged <15 years) in the PCV7 (May 2007 to April 2010) versus PCV13 (May 2011 to April 2012) periods were compared. There were 499 cases in the PCV7 period and 79 cases in the PCV13 period. Globally, the IR significantly decreased from 17.09 (PCV7 period) to 7.70 (PCV13 period), with significant decreases (PCV7 versus PCV13 periods) in all age groups for bacteremic pneumonia (5.51 versus 1.56), parapneumonic pneumococcal empyema (PPE) (5.72 versus 3.12), and meningitis (2.16 versus 0.97). In the PCV13 period, significant reductions (the IR in the PCV7 period versus the IR in the PCV13 period) were found in IPDs caused by PCV13 serotypes (13.49 versus 4.38), and specifically by serotypes 1 (globally [4.79 versus 2.53], for bacteremic pneumonia [2.23 versus 0.97], and for PPE [2.26 versus 1.17]), serotype 5 (globally [1.88 versus 0.00], for bacteremic pneumonia [0.89 versus 0.00], and for PPE [0.55 versus 0.00]), and serotype 19A (globally [3.77 versus 0.49], for bacteremic pneumonia [0.72 versus 0.00], for PPE [0.89 versus 0.00], and for meningitis [0.62 versus 0.00]). IPDs caused by non-PCV13 serotypes did not increase (IR, 3.60 in the PCV7 period versus 3.31 in the PCV13 period), regardless of age or presentation. No IPDs caused by the PCV13 serotypes were found in children who received 3 doses of PCV13. The number of hospitalization days and sanitary costs were significantly lower in the PCV13 period. The switch from PCV7 to PCV13 in the universal pediatric vaccination calendar provided sanitary and economical benefits without a replacement by non-PCV13
Miles, Brodie; Scisci, Elizabeth; Carrion, Julio; Sabino, Gregory J.; Genco, Caroline A.; Cutler, Christopher W.
Maintenance of blood DC homeostasis is essential to preventing autoimmunity while controlling chronic infection. However, the ability of bacteremic pathogens to directly regulate blood DC homeostasis has not been defined. One such bacteremic pathogen, Porphyromonas gingivalis, is shown by our group to survive within mDCs under aerobic conditions and therein, metastasize from its oral mucosal niche. This is accompanied by expansion of the blood mDC pool in vivo, independently of canonical DC poietins. We presently know little of how this bacteremic pathogen causes blood DC expansion and the pathophysiological significance. This work shows that optimum differentiation of MoDCs from primary human monocytes, with or without GM-CSF/IL-4, is dependent on infection with P. gingivalis strains expressing the DC-SIGN ligand mfa-1. DC differentiation is lost when DC-SIGN is blocked with its ligand HIV gp120 or knocked out by siRNA gene silencing. Thus, we have identified a novel, noncanonical pathway of DC differentiation. We term these PDDCs and show that PDDCs are bona fide DCs, based on phenotype and phagocytic activity when immature and the ability to up-regulate accessory molecules and stimulate allo-CD4+ T cell proliferation when matured. The latter is dependent on the P. gingivalis strain used to initially “educate” PDDCs. Moreover, we show that P. gingivalis-infected, conventional MoDCs become resistant to apoptosis and inflammatory pyroptosis, as determined by levels of Annexin V and caspase-8, -3/7, and -1. Taken together, we provide new insights into how a relatively asymptomatic bacteremia may influence immune homeostasis and promote chronic inflammation. PMID:23729500
Reyes, Luis F.; Restrepo, Marcos I.; Hinojosa, Cecilia A.; Soni, Nilam J.; Shenoy, Anukul T.; Gilley, Ryan P.; Gonzalez-Juarbe, Norberto; Noda, Julio R.; Winter, Vicki T.; de la Garza, Melissa A.; Shade, Robert E.; Coalson, Jacqueline J.; Giavedoni, Luis D.; Anzueto, Antonio; Orihuela, Carlos J.
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. PMID:27855182
Madar, R; Strakova, J; Baska, T; Kavcova, E; Straka, S
The authors carried out a survey in outpatient and hospitalised patients with risk factors for invasive pneumococcal disease in a tertiary-care medical faculty affiliated hospital. Data were collected by individual interviews and verified against the medical records of all addressed patients. The authors also attempted to discover the attitude of general practitioners (GPs) from 2 Slovak districts towards the pneumococcal vaccine by means of an anonymous questionnaire. Out of the total of 154 addressed patients, 128 (83.1%) had at least one risk factor for acquiring invasive pneumococcal disease. However, only 8 (6.3%) of them had ever been administered pneumococcal vaccine. Out of 34 hospitalised patients with at least one risk factor 82.4 % had not received any pneumococcal vaccination in the past. When subdivided according to age and risk factors (chronic respiratory, cardiovascular, uropoetic, metabolic, immunne system disorders, asplenia), vaccination coverage in all groups was very low, ranging between --9.3%. In an anonymous questionnaire 74 (94.9%) out of 77 surveyed GPs referred to a lack of information on the polysaccharide pneumococcal vaccine and 22 (28.2%) expressed their general distrust towards vaccination of any kind. The main role in increasing the disturbingly low pneumococcal vaccination coverage lies in the hands of medical professionals, especially GPs who should inform their patients about the possibility of a free vaccine and who should make an effort to explain to their patients the benefit of pneumococcal vaccination. (Tab. 4, Reft 9.)
Cremers, Amelieke J.; van der Gaast-de Jongh, Christa E.; Ferwerda, Gerben; Meis, Jacques F.; Roeleveld, Nel; Bentley, Stephen D.; Pastura, Alexander S.; van Hijum, Sacha A. F. T.; van der Ven, Andre J.; de Mast, Quirijn; Zomer, Aldert
ABSTRACT To improve our understanding about the severity of invasive pneumococcal disease (IPD), we investigated the association between the genotype of Streptococcus pneumoniae and disease outcomes for 349 bacteremic patients. A pneumococcal genome-wide association study (GWAS) demonstrated a strong correlation between 30-day mortality and the presence of the phage-derived gene pblB, encoding a platelet-binding protein whose effects on platelet activation were previously unknown. Platelets are increasingly recognized as key players of the innate immune system, and in sepsis, excessive platelet activation contributes to microvascular obstruction, tissue hypoperfusion, and finally multiorgan failure, leading to mortality. Our in vitro studies revealed that pblB expression was induced by fluoroquinolones but not by the beta-lactam antibiotic penicillin G. Subsequently, we determined pblB induction and platelet activation by incubating whole blood with the wild type or a pblB knockout mutant in the presence or absence of antibiotics commonly administered to our patient cohort. pblB-dependent enhancement of platelet activation, as measured by increased expression of the α-granule protein P-selectin, the binding of fibrinogen to the activated αIIbβ3 receptor, and the formation of platelet-monocyte complex occurred irrespective of antibiotic exposure. In conclusion, the presence of pblB on the pneumococcal chromosome potentially leads to increased mortality in patients with an invasive S. pneumoniae infection, which may be explained by enhanced platelet activation. This study highlights the clinical utility of a bacterial GWAS, followed by functional characterization, to identify bacterial factors involved in disease severity. PMID:28096486
Chin, Bum Sik; Kim, Myung Soo; Han, Sang Hoon; Shin, So Youn; Choi, Hee Kyung; Chae, Yun Tae; Jin, Sung Joon; Baek, Ji-Hyeon; Choi, Jun Yong; Song, Young Goo; Kim, Chang Oh; Kim, June Myung
Urinary tract infection (UTI) is the most frequent cause of bacteremia/sepsis in elderly people and increasing antimicrobial resistance in uropathogens has been observed. To describe the characteristics of bacteremic UTI in elderly patients and to identify the independent risk factors of all-cause in-hospital mortality, a retrospective cohort study of bacteremic UTI patients of age over 65 was performed at a single 2000-bed tertiary hospital. Bacteremic UTI was defined as the isolation of the same organism from both urine and blood within 48 h. Eighty-six elderly bacteremic UTI patients were enrolled. Community-acquired infection was the case for most patients (79.1%), and Escherichia coli accounted for 88.6% (70/79) among Gram-negative organisms. Non-E. coli Gram-negative organisms were more frequent in hospital-acquired cases and male patients while chronic urinary catheter insertion was related with Gram-positive urosepsis. The antibiotic susceptibility among Gram-negative organisms was not different depending on the source of bacteremic UTI, while non-E. coli Gram-negative organisms were less frequently susceptible for cefotaxime, cefoperazone/sulbactam, and aztreonam. All-cause in-hospital mortality was 11.6%, and functional dependency (adjusted hazard ratio=HR=10.9, 95% confidence interval=95%CI=2.2-54.6) and low serum albumin (adjusted HR=27.0, 95%CI=2.0-361.2) were independently related with increased all-cause in-hospital mortality.
Andrews, Ross M; Skull, Susan A; Byrnes, Graham B; Campbell, Donald A; Turner, Joy L; McIntyre, Peter B; Kelly, Heath A
This study was undertaken to assess the uptake of influenza and pneumococcal vaccination based on provider records of the hospitalised elderly, a group at high risk of influenza and pneumococcal disease. The study used a random sample of 3,204 admissions at two Victorian teaching hospitals for patients, aged 65 years or more who were discharged between 1 April 2000 and 31 March 2002. Information on whether the patient had received an influenza vaccination within the year prior to admission or pneumococcal vaccination within the previous five years was ascertained from the patient's nominated medical practitioner/vaccine provider. Vaccination records were obtained from providers for 82 per cent (2,804/2,934) of eligible subjects. Influenza vaccine coverage was 70.9 per cent (95% CI 68.9-72.9), pneumococcal coverage was 52.6 per cent (95% CI 50.4-54.8) and 46.6 per cent (95% CI 44.4-48.8) had received both vaccines. Coverage for each vaccine increased seven per cent over the two study years. For pneumococcal vaccination, there was a marked increase in 1998 coinciding with the introduction of Victoria's publicly funded program. Influenza and pneumococcal vaccine coverage in eligible hospitalised adults was similar to, but did not exceed, estimates in the general elderly population. Pneumococcal vaccination coverage reflected the availability of vaccine through Victoria's publicly funded program. A nationally funded pneumococcal vaccination program for the elderly, as announced recently, should improve coverage. However, these data highlight the need for greater awareness of pneumococcal vaccine among practitioners and for systematic recording of vaccination status, as many of these subjects will soon become eligible for revaccination.
Usuf, Effua; Bottomley, Christian; Adegbola, Richard A.; Hall, Andrew
Background Pneumococcal epidemiology varies geographically and few data are available from the African continent. We assess pneumococcal carriage from studies conducted in sub-Saharan Africa (sSA) before and after the pneumococcal conjugate vaccine (PCV) era. Methods A search for pneumococcal carriage studies published before 2012 was conducted to describe carriage in sSA. The review also describes pneumococcal serotypes and assesses the impact of vaccination on carriage in this region. Results Fifty-seven studies were included in this review with the majority (40.3%) from South Africa. There was considerable variability in the prevalence of carriage between studies (I-squared statistic = 99%). Carriage was higher in children and decreased with increasing age, 63.2% (95% CI: 55.6–70.8) in children less than 5 years, 42.6% (95% CI: 29.9–55.4) in children 5–15 years and 28.0% (95% CI: 19.0–37.0) in adults older than 15 years. There was no difference in the prevalence of carriage between males and females in 9/11 studies. Serotypes 19F, 6B, 6A, 14 and 23F were the five most common isolates. A meta-analysis of four randomized trials of PCV vaccination in children aged 9–24 months showed that carriage of vaccine type (VT) serotypes decreased with PCV vaccination; however, overall carriage remained the same because of a concomitant increase in non-vaccine type (NVT) serotypes. Conclusion Pneumococcal carriage is generally high in the African continent, particularly in young children. The five most common serotypes in sSA are among the top seven serotypes that cause invasive pneumococcal disease in children globally. These serotypes are covered by the two PCVs recommended for routine childhood immunization by the WHO. The distribution of serotypes found in the nasopharynx is altered by PCV vaccination. PMID:24465464
McNeil, Shelly A; Qizilbash, Nawab; Ye, Jian; Gray, Sharon; Zanotti, Giovanni; Munson, Samantha; Dartois, Nathalie; Laferriere, Craig
Background. Routine vaccination against Streptococcus pneumoniae is recommended in Canada for infants, the elderly, and individuals with chronic comorbidity. National incidence and burden of all-cause and pneumococcal pneumonia in Canada (excluding Quebec) were assessed. Methods. Incidence, length of stay, and case-fatality rates of hospitalized all-cause and pneumococcal pneumonia were determined for 2004-2010 using ICD-10 discharge data from the Canadian Institutes for Health Information Discharge Abstract Database. Population-at-risk data were obtained from the Statistics Canada census. Temporal changes in pneumococcal and all-cause pneumonia rates in adults ≥65 years were analyzed by logistic regression. Results. Hospitalization for all-cause pneumonia was highest in children <5 years and in adults >70 years and declined significantly from 1766/100,000 to 1537/100,000 per year in individuals aged ≥65 years (P < 0.001). Overall hospitalization for pneumococcal pneumonia also declined from 6.40/100,000 to 5.08/100,000 per year. Case-fatality rates were stable (11.6% to 12.3%). Elderly individuals had longer length of stay and higher case-fatality rates than younger groups. Conclusions. All-cause and pneumococcal pneumonia hospitalization rates declined between 2004 and 2010 in Canada (excluding Quebec). Direct and indirect effects from pediatric pneumococcal immunization may partly explain some of this decline. Nevertheless, the burden of disease from pneumonia remains high.
McNeil, Shelly A.; Qizilbash, Nawab; Ye, Jian; Gray, Sharon; Zanotti, Giovanni; Munson, Samantha; Dartois, Nathalie; Laferriere, Craig
Background. Routine vaccination against Streptococcus pneumoniae is recommended in Canada for infants, the elderly, and individuals with chronic comorbidity. National incidence and burden of all-cause and pneumococcal pneumonia in Canada (excluding Quebec) were assessed. Methods. Incidence, length of stay, and case-fatality rates of hospitalized all-cause and pneumococcal pneumonia were determined for 2004–2010 using ICD-10 discharge data from the Canadian Institutes for Health Information Discharge Abstract Database. Population-at-risk data were obtained from the Statistics Canada census. Temporal changes in pneumococcal and all-cause pneumonia rates in adults ≥65 years were analyzed by logistic regression. Results. Hospitalization for all-cause pneumonia was highest in children <5 years and in adults >70 years and declined significantly from 1766/100,000 to 1537/100,000 per year in individuals aged ≥65 years (P < 0.001). Overall hospitalization for pneumococcal pneumonia also declined from 6.40/100,000 to 5.08/100,000 per year. Case-fatality rates were stable (11.6% to 12.3%). Elderly individuals had longer length of stay and higher case-fatality rates than younger groups. Conclusions. All-cause and pneumococcal pneumonia hospitalization rates declined between 2004 and 2010 in Canada (excluding Quebec). Direct and indirect effects from pediatric pneumococcal immunization may partly explain some of this decline. Nevertheless, the burden of disease from pneumonia remains high. PMID:27445530
Patel, Shiven S; Fergeson, Jennifer E; Glaum, Mark C; Lockey, Richard F
Selective immunoglobulin M deficiency (SIgMD) is a rare disorder with varying clinical features. The prevalence of SIgMD is 0.03-3%. Patients may be asymptomatic or else present with recurrent infection, autoimmunity, atopic disease and/or malignancy. About 50% of patients with symptomatic SIgMD also have impaired antibody responses to the pneumococcal polysaccharide vaccine. We report on an adult who presented with symptomatic SIgMD with impaired pneumococcal polysaccharide antibody responses and lymphopenia, who experienced a significant clinical improvement in the frequency of infections after subcutaneous immunoglobulin replacement therapy.
Light, R B
Respiratory failure is one of the most important causes of death in patients with acute pneumococcal pneumonia. There are two forms that may or may not coexist: ventilatory failure and hypoxemic respiratory failure. Ventilatory failure is principally caused by mechanical changes in the lungs resulting from pneumonia. Inflammatory exudate fills alveoli at slightly less than their normal functional residual capacity (FRC), causing a volume loss at FRC roughly proportional to the extent of the pulmonary infiltrate. Because this consolidated air space does not inflate easily at higher transpulmonary pressures, at higher lung volumes the volume loss is proportionally greater. This loss of volume reduces total lung compliance and increases the work of breathing. There is also evidence that the dynamic compliance of the remaining ventilated lung is reduced in pneumococcal pneumonia, possibly by reduction in surfactant activity, further increasing the work of breathing. Arterial hypoxemia early in acute pneumococcal pneumonia is principally caused by persistence of pulmonary artery blood flow to consolidated lung resulting in an intrapulmonary shunt, but also, to a varying degree, it is caused by intrapulmonary oxygen consumption by the lung during the acute phase and by ventilation-perfusion mismatch later. The persistence of pulmonary blood flow to consolidated lung appears to be caused by a relative failure of the hypoxic pulmonary vasoconstriction (HPV) mechanism during acute pneumonia, which is at least caused by endogenous vasodilator prostaglandins associated with the inflammatory process but also by other as yet undefined mechanisms. During convalescence, arterial oxygenation improves as blood flow to consolidated lung falls. The magnitude of the intrapulmonary shunt may be influenced by a number of factors that modify the distribution of pulmonary blood flow. Factors that tend to increase flow to consolidated lung and worsen shunt include endogenous vasodilator
Rai, Aswathy N.; Thornton, Justin A.; Stokes, John; Sunesara, Imran; Swiatlo, Edwin; Nanduri, Bindu
Streptococcus pneumoniae is the most common bacterial etiology of pneumococcal pneumonia in adults worldwide. Genomic plasticity, antibiotic resistance and extreme capsular antigenic variation complicates the design of effective therapeutic strategies. Polyamines are ubiquitous small cationic molecules necessary for full expression of pneumococcal virulence. Polyamine transport system is an attractive therapeutic target as it is highly conserved across pneumococcal serotypes. In this study, we compared an isogenic deletion strain of S. pneumoniae TIGR4 in polyamine transport operon (ΔpotABCD) with the wild type in a mouse model of pneumococcal pneumonia. Our results show that the wild type persists in mouse lung 24 h post infection while the mutant strain is cleared by host defense mechanisms. We show that intact potABCD is required for survival in the host by providing resistance to neutrophil killing. Comparative proteomics analysis of murine lungs infected with wild type and ΔpotABCD pneumococci identified expression of proteins that could confer protection to wild type strain and help establish infection. We identified ERM complex, PGLYRP1, PTPRC/CD45 and POSTN as new players in the pathogenesis of pneumococcal pneumonia. Additionally, we found that deficiency of polyamine transport leads to up regulation of the polyamine synthesis genes speE and cad in vitro. PMID:27247105
Lee, Lucia H.; Gu, Xin-Xing; Nahm, Moon H.
Seven-valent pneumococcal conjugate vaccine (PCV7) introduction and routine pediatric use has substantially reduced the burden of Streptococcus pneumoniae disease worldwide. However, a significant amount of disease burden, due to serotypes not contained in PCV7, still exists globally. A newly recognized serotype, 6C, was until recently, identified and reported as serotype 6A. This review summarizes the serotype epidemiology of pneumococcal disease pre- and post-introduction of PCV7, available post-marketing surveillance data following the introduction of higher valency pneumococcal vaccines (PCV10, PCV13) and future prospects for the development of new pneumococcal vaccines. PMID:26344470
Vorob'ev, D S; Semenova, I B
The problem of pneumococcal infections is pressing for the whole world. Existing vaccines based only on pneumococci polysaccharide antigens or polysaccharide antigens and diphtherial anatoxin are not capable of protecting from all serotypes of the microorganism. Reasonability of creation of pneumococcal vaccine based on surface proteins of Streptococcus pneumoniae is discussed in the literature. One of such key pneumococcal proteins is pneumococcal surface protein A (PSPA), because it is detected in all the S. pneumoniae strains, has cross activity and switches B-cell immune response to T-cell. Currently the development of conjugated vaccine based on surface proteins and capsule polysaccharides of pneumococcus seems promising.
Remschmidt, Cornelius; Harder, Thomas; Hummers-Pradier, Eva; Wichmann, Ole; Bogdan, Christian
Background Routine vaccination of elderly people against pneumococcal diseases is recommended in many countries. National guidelines differ, recommending either the 23-valent polysaccharide vaccine (PPV23), the 13-valent conjugate vaccine (PCV13) or both. Considering the ongoing debate on the effectiveness of PPV23, we performed a systematic literature review and meta-analysis of the vaccine efficacy/effectiveness (VE) of PPV23 against invasive pneumococcal disease (IPD) and pneumococcal pneumonia in adults aged ≥60 years living in industrialized countries. Methods We searched for pertinent clinical trials and observational studies in databases MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews. We assessed the risk of bias of individual studies using the Cochrane Risk of Bias tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies. We rated the overall quality of the evidence by GRADE criteria. We performed meta-analyses of studies grouped by outcome and study design using random-effects models. We applied a sensitivity analysis excluding studies with high risk of bias. Results We identified 17 eligible studies. Pooled VE against IPD (by any serotype) was 73% (95%CI: 10–92%) in four clinical trials, 45% (95%CI: 15–65%) in three cohort studies, and 59% (95%CI: 35–74%) in three case-control studies. After excluding studies with high risk of bias, pooled VE against pneumococcal pneumonia (by any serotype) was 64% (95%CI: 35–80%) in two clinical trials and 48% (95%CI: 25–63%) in two cohort studies. Higher VE estimates in trials (follow-up ~2.5 years) than in observational studies (follow-up ~5 years) may indicate waning protection. Unlike previous meta-analyses, we excluded two trials with high risk of bias regarding the outcome pneumococcal pneumonia, because diagnosis was based on serologic methods with insufficient specificity. Conclusions Our meta
Li, Yi; Hill, Andrew; Beitelshees, Marie; Shao, Shuai; Knight, Paul R.; Hakansson, Anders P.; Pfeifer, Blaine A.; Jones, Charles H.
Immunization strategies against commensal bacterial pathogens have long focused on eradicating asymptomatic carriage as well as disease, resulting in changes in the colonizing microflora with unknown future consequences. Additionally, current vaccines are not easily adaptable to sequence diversity and immune evasion. Here, we present a “smart” vaccine that leverages our current understanding of disease transition from bacterial carriage to infection with the pneumococcus serving as a model organism. Using conserved surface proteins highly expressed during virulent transition, the vaccine mounts an immune response specifically against disease-causing bacterial populations without affecting carriage. Aided by a delivery technology capable of multivalent surface display, which can be adapted easily to a changing clinical picture, results include complete protection against the development of pneumonia and sepsis during animal challenge experiments with multiple, highly variable, and clinically relevant pneumococcal isolates. The approach thus offers a unique and dynamic treatment option readily adaptable to other commensal pathogens. PMID:27274071
Siegel, Steven J.; Tamashiro, Edwin; Weiser, Jeffrey N.
Infections are a common cause of infant mortality worldwide, especially due to Streptococcus pneumoniae. Colonization is the prerequisite to invasive pneumococcal disease, and is particularly frequent and prolonged in children, though the mechanisms underlying this susceptibility are unknown. We find that infant mice exhibit prolonged pneumococcal carriage, and are delayed in recruiting macrophages, the effector cells of clearance, into the nasopharyngeal lumen. This lack of macrophage recruitment is paralleled by a failure to upregulate chemokine (C-C) motif ligand 2 (Ccl2 or Mcp-1), a macrophage chemoattractant that is required in adult mice to promote clearance. Baseline expression of Ccl2 and the related chemokine Ccl7 is higher in the infant compared to the adult upper respiratory tract, and this effect requires the infant microbiota. These results demonstrate that signals governing macrophage recruitment are altered at baseline in infant mice, which prevents the development of appropriate innate cell infiltration in response to pneumococcal colonization, delaying clearance of pneumococcal carriage. PMID:26107875
Haber, Michael; Barskey, Albert; Baughman, Wendy; Barker, Lawrence; Whitney, Cynthia G; Shaw, Kate M; Orenstein, Walter; Stephens, David S
Invasive pneumococcal disease in older children and adults declined markedly after introduction in 2000 of the pneumococcal conjugate vaccine for young children. An empirical quantitative model was developed to estimate the herd (indirect) effects on the incidence of invasive disease among persons >or=5 years of age induced by vaccination of young children with 1, 2, or >or=3 doses of the pneumococcal conjugate vaccine, Prevnar (PCV7), containing serotypes 4, 6B, 9V, 14, 18C, 19F and 23F. From 1994 to 2003, cases of invasive pneumococcal disease were prospectively identified in Georgia Health District-3 (eight metropolitan Atlanta counties) by Active Bacterial Core surveillance (ABCs). From 2000 to 2003, vaccine coverage levels of PCV7 for children aged 19-35 months in Fulton and DeKalb counties (of Atlanta) were estimated from the National Immunization Survey (NIS). Based on incidence data and the estimated average number of doses received by 15 months of age, a Poisson regression model was fit, describing the trend in invasive pneumococcal disease in groups not targeted for vaccination (i.e., adults and older children) before and after the introduction of PCV7. Highly significant declines in all the serotypes contained in PCV7 in all unvaccinated populations (5-19, 20-39, 40-64, and >64 years) from 2000 to 2003 were found under the model. No significant change in incidence was seen from 1994 to 1999, indicating rates were stable prior to vaccine introduction. Among unvaccinated persons 5+ years of age, the modeled incidence of disease caused by PCV7 serotypes as a group dropped 38.4%, 62.0%, and 76.6% for 1, 2, and 3 doses, respectively, received on average by the population of children by the time they are 15 months of age. Incidence of serotypes 14 and 23F had consistent significant declines in all unvaccinated age groups. In contrast, the herd immunity effects on vaccine-related serotype 6A incidence were inconsistent. Increasing trends of non
Leporrier, Jérémie; Delbos, Valérie; Unal, Guillemette; Honoré, Patricia; Etienne, Manuel; Bouchaud, Olivier; Caron, François
Background. Despite antiretroviral therapy, it is generally believed that the risk for pneumococcal infections (PnIs) is high among patients infected with human immunodeficiency virus (HIV). However, most studies in this field have been conducted before 2010, and the proportion of virologically suppressed patients has drastically increased in these latter years thanks to larger indications and more effective antiretroviral regimens. This study aimed to re-evaluate the current risk of PnI among adult patients infected with HIV. Methods. The incidence of PnI was evaluated between 1996 and 2014 in 2 French regional hospitals. The 80 most recent cases of PnI (2000–2014) were retrospectively compared with 160 controls (HIV patients without PnI) to analyze the residual risk factors of PnI. Results. Among a mean annual follow-up cohort of 1616 patients, 116 PnIs were observed over 18 years. The risk factors of PnI among patients infected with HIV were an uncontrolled HIV infection or “classic” risk factors of PnI shared by the general population such as addiction, renal or respiratory insufficiency, or hepatitis B or C coinfection. Pneumococcal vaccination coverage was low and poorly targeted, because only 5% of the cases had been previously vaccinated. The incidence of invasive PnIs among HIV patients with a nonvirologically suppressed infection or comorbidities was 12 times higher than that reported in the general population at the country level (107 vs 9/100000 patients), whereas the incidence among virologically suppressed HIV patients without comorbidities was lower (7.6/100000 patients). Conclusions. Human immunodeficiency virus infection no longer per se seems to be a significant risk factor for PnI, suggesting a step-down from a systematic to an “at-risk patient” targeted pneumococcal vaccination strategy. PMID:28018929
... 42 Public Health 2 2012-10-01 2012-10-01 false Pneumococcal vaccine and flu vaccine. 410.57... § 410.57 Pneumococcal vaccine and flu vaccine. (a) Medicare Part B pays for pneumococcal vaccine and its administration when reasonable and necessary for the prevention of disease, if the vaccine is ordered by a...
... 42 Public Health 2 2013-10-01 2013-10-01 false Pneumococcal vaccine and flu vaccine. 410.57... § 410.57 Pneumococcal vaccine and flu vaccine. (a) Medicare Part B pays for pneumococcal vaccine and its administration when reasonable and necessary for the prevention of disease, if the vaccine is ordered by a...
... 42 Public Health 2 2014-10-01 2014-10-01 false Pneumococcal vaccine and flu vaccine. 410.57... § 410.57 Pneumococcal vaccine and flu vaccine. (a) Medicare Part B pays for pneumococcal vaccine and its administration when reasonable and necessary for the prevention of disease, if the vaccine is ordered by a...
... 42 Public Health 2 2011-10-01 2011-10-01 false Pneumococcal vaccine and flu vaccine. 410.57... § 410.57 Pneumococcal vaccine and flu vaccine. (a) Medicare Part B pays for pneumococcal vaccine and its administration when reasonable and necessary for the prevention of disease, if the vaccine is ordered by a...
... 42 Public Health 2 2010-10-01 2010-10-01 false Pneumococcal vaccine and flu vaccine. 410.57... § 410.57 Pneumococcal vaccine and flu vaccine. (a) Medicare Part B pays for pneumococcal vaccine and its administration when reasonable and necessary for the prevention of disease, if the vaccine is ordered by a...
Heinsbroek, Ellen; Tafatatha, Terence; Chisambo, Christina; Phiri, Amos; Mwiba, Oddie; Ngwira, Bagrey; Crampin, Amelia C.; Read, Jonathan M.; French, Neil
The prevalence of Streptococcus pneumoniae (pneumococcus) carriage is higher in adults who are infected with human immunodeficiency virus (HIV) than in adults who are not. We hypothesized that infants exposed to HIV become carriers of nasopharyngeal pneumococcus earlier and more frequently than infants who are not exposed to HIV. We compared infant pneumococcal acquisition by maternal HIV status and household exposure in Karonga District, Malawi, in 2009–2011, before the introduction of pneumococcal conjugate vaccine. Nasopharyngeal swabs were collected every 4–6 weeks in the first year of life from infants with known HIV-exposure status, their mothers, and other household members. We studied infant pneumococcal acquisition by maternal HIV status, serotype-specific household exposure, and other risk factors, including seasonality. We recruited 54 infants who were exposed to HIV and 131 infants who were not. There was no significant difference in pneumococcal acquisition by maternal HIV status (adjusted rate ratio (aRR) = 1.00, 95% confidence interval (CI): 0.87, 1.15). Carriage by the mother was associated with greater acquisition of the same serotype (aRR = 3.09, 95% CI: 1.47, 6.50), but the adjusted population attributable fraction was negligible (1.9%, 95% CI: 0.0, 4.3). Serotype-specific exposure to children under 5 years of age was associated with higher acquisition (aRR = 4.30, 95% CI: 2.80, 6.60; adjusted population attributable fraction = 8.8%, 95% CI: 4.0, 13.4). We found no evidence to suggest that maternal HIV infection would affect the impact of pneumococcal vaccination on colonization in this population. PMID:26628514
Papadatou, Ioanna; Spoulou, Vana
Controversy exists regarding the optimal use of the 23-valent pneumococcal conjugate vaccine for the protection of high-risk individuals, such as children and adults with immunocompromising conditions and the elderly. The effectiveness and immunogenicity of 23-valent pneumococcal polysaccharide vaccine (PPV23) are limited in such high-risk populations compared to the healthy, with meta-analyses failing to provide robust evidence on vaccine efficacy against invasive pneumococcal disease (IPD) or pneumonia. Moreover, several studies have demonstrated a PPV23-induced state of immune tolerance or hyporesponsiveness to subsequent vaccination, where the response to revaccination does not reach the levels achieved with primary vaccination. The clinical significance of hyporesponsiveness is not yet clarified, but attenuated humoral and cellular response could lead to reduced levels of protection and increased susceptibility to pneumococcal disease. As disease epidemiology among high-risk groups shows that we are still in need of maximum serotype coverage, the optimal use of PPV23 in the context of combined conjugate/polysaccharide vaccine schedules is an important priority. In this minireview, we discuss PPV23-induced hyporesponsiveness and its implications in designing highly effective vaccination schedules for the optimal protection for high-risk individuals.
van den Bosch, W J H M
In the Netherlands, in contrast to other countries, pneumococcal vaccination for older people and people at risk is not routine, except for patients under special circumstances, such as after a splenectomy. Although pneumococcal vaccination is an effective way to prevent invasive pneumococcal disease in young healthy persons, there is no conclusive evidence that it is effective in older people and people at risk without a good immune response. Pneumococcal disease can be an important complication of an ordinary flu. Because there is a high level of vaccination against influenza in the Netherlands, the risk of pneumococcal disease is low compared to other countries in the world. Adding a pneumococcal vaccine to the influenza vaccination could decrease the degree of protection against influenza. The experimental introduction of pneumococcal vaccination does not seem to lead to an increase in the number of patients that refuse vaccination against influenza.
Ribeiro, Sofia; Domingues, Vital; Faria, Raquel M; Mendonça, Teresa
Invasive pneumococcal disease (IPD) is a potential life-threatening situation that requires immediate recognition and treatment. Cerebrovascular complications are uncommon and have been reported less frequently in adults than in children. We report a case of 59-year-old man with IPD complicated by cerebral vasculitis, transient central diabetes insipidus and spondylodiscitis. Each of these complications is rare and needs specific approach. Their association is even rarer and to the best of our knowledge this is the first case reported.
Kang, C-I; Song, J-H; Kim, S H; Chung, D R; Peck, K R; So, T M; Hsueh, P-R
This study was performed to evaluate the clinical features of community-onset levofloxacin-nonsusceptible pneumococcal pneumonia and to identify risk factors for levofloxacin resistance. Using the database of a surveillance study of community-acquired pneumococcal infections in Asian countries, we conducted a nested case-control study to identify risk factors for levofloxacin-nonsusceptible S. pneumoniae in community-acquired pneumonia in adults. Of 981 patients with pneumococcal pneumonia, 46 (4.7 %) had levofloxacin-nonsusceptible S. pneumoniae, of whom 39 evaluable cases were included in the analysis. All cases were from Korea, Taiwan, and Hong Kong. Among patients with levofloxacin-susceptible S. pneumoniae, 490 controls were selected based on patient country. Of the 39 cases of levofloxacin-nonsusceptible pneumococcal pneumonia, 23 (59.0 %) were classified as healthcare-associated, while 164 (33.5 %) of the 490 controls of levofloxacin-susceptible S. pneumoniae (P = 0.001) were classified as healthcare-associated. Multivariate analysis showed that previous treatment with fluoroquinolones, cerebrovascular disease, and healthcare-associated infection were significantly associated with levofloxacin-nonsusceptible pneumococcal pneumonia (all P < 0.05). Levofloxacin-nonsusceptible pneumococci pose an important new public health threat in our region, and more information on the emergence and spread of these resistant strains will be necessary to prevent spread throughout the population.
Wallace, Cate; Corben, Paul; Turahui, John; Gilmour, Robin
North Coast Area Health Service (NCAHS) conducted a seven week television advertising campaign to raise community awareness of the availability of free adult pneumococcal vaccination and to increase coverage among North Coast residents in high risk groups. Effectiveness of the campaign was evaluated by examining vaccine ordering patterns of North Coast vaccination providers from 2005/2006 as a proxy for vaccination coverage. In the months during and immediately following (June-September 2006) the advertising campaign, a significantly higher proportion of vaccines were despatched to North Coast immunisation service providers. The advertising campaign was an effective strategy to promote vaccination among NCAHS residents not immunised in the first year of the National Pneumococcal Program for Older Australians. This higher immunisation coverage is expected to contribute to the statewide trend of significant reductions in invasive pneumococcal disease (IPD) notifications.
Fortunato, Francesca; Martinelli, Domenico; Cappelli, Maria Giovanna; Cozza, Vanessa; Prato, Rosa
In Italy, the effectiveness of pneumococcal universal vaccination in preventing vaccine-type invasive pneumococcal disease (IPD) in the PCV7/PCV13 shifting period was estimated to be 84.3% (95% CI: 84.0–84.6%) in children <5 years. This study aims at corroborating the estimation of both the effectiveness (VE) of PCVs and its impact in reducing pneumococcal diseases. A 1 : 3 matched-case-control study was conducted among children <5 years old hospitalized for IPD or pneumococcal pneumonia (PP) between 2006 and 2012 in the Puglia region. Moreover, hospitalizations for pneumococcal outcomes in the pre- and postvaccination period and the hospitalization risk ratios (HRRs) with 95% CIs were computed in Italy and in the first eight regions that introduced PCVs in 2006. The overall effectiveness of PCVs was 75% (95% CI: 61%–84%); it was 69% (95% CI: 30%–88%) against IPD and 77% (95% CI: 61%–87%) against PP. PCVs showed a significant impact on IPD and acute otitis media either at a national level or in those regions with a longer vaccination history, with a nearly 40% reduction of hospitalizations for both outcomes. Our findings provide further evidence of the effectiveness of PCVs against pneumococcal diseases and its impact on nasopharyngeal carriage in children <5 years, indicating the importance of maintaining high immunization coverage. PMID:26351644
Bock, Allison; Chintamaneni, Kathan; Rein, Lisa; Frazer, Tifany; Kayastha, Gyan; MacKinney, Theodore
Streptococcus pneumoniae infection is associated with high morbidity and mortality in low income countries. In Nepal, there is a high lung disease burden and incidence of pneumonia due to multiple factors including indoor air pollution, dust exposure, recurrent infections, and cigarette smoking. Despite the ready availability of effective pneumococcal vaccines (PNV), vaccine coverage rates remain suboptimal globally. Quality Improvement (QI) principles could be applied to improve compliance, but it is a virtually new technology in Nepal. This QI study for Patan Hospital sought to introduce the concept of QI there, to measure the baseline pneumococcal vaccination rate of qualifying adult patients discharged from the medical wards and to assess reasons for non-vaccination. QI interventions were instituted to improve this rate, measuring the effectiveness of QI methods to produce the desired outcomes using the Model for Improvement, Plan-Do-Study-Change (PDSA) methodology. In the three week baseline assessment, 2 out of 81 (2%) eligible patients recalled ever receiving a prior pneumococcal vaccine; 68 (84%) unvaccinated patients responded that they were not asked or were unaware of the PNV. After the QI interventions, the pneumococcal vaccination rate significantly increased to 42% (23/56, p<0.001). Post-intervention, the leading reason for non-vaccination was cost (20%, 11/56). Only 5 (9%) unvaccinated patients were not asked or were unaware of the PNV, a significant change in that process outcome from baseline (p<0.001). Quality improvement measures were effective in increasing pneumococcal vaccination rates, despite the limited familiarity with QI methods at this major teaching hospital. QI techniques may be useful in this and other efforts to improve quality in resource-limited settings, without great cost. PMID:27933153
... With conditions that weaken the immune system (HIV/AIDS, cancer, or damaged/absent spleen) With cochlear implants or cerebrospinal fluid (CSF) leaks (escape of the fluid that surrounds the brain and spinal cord) Who smoke cigarettes Transmission Pneumococcal bacteria spread from person-to-person by ...
Ponvert, C; Scheinmann, P; de Blic, J
Anaphylaxis to pneumococcal vaccines is rare. In the only one child with anaphylaxis to a first injection of the 23-valent pneumococcal vaccine that has been explored, skin tests and specific IgE determination diagnosed immediate-type hypersensitivity to pneumococcal antigens. We report the case of a child who tolerated three injections of the 7-valent pneumococcal vaccine, but experienced anaphylaxis to a fourth injection of the 23-valent vaccine. Immediate responses in skin tests diagnosed immediate-type hypersensitivity to the two vaccines. Immunizations with the 7-valent pneumococcal vaccine may induce IgE-dependent sensitization to pneumococcal antigens, responsible for anaphylaxis to subsequent injections of pneumococcal vaccines.
Wang, Zheng; Lam, Wai Yip; Zhou, Haokui; Tsui, Stephen
We report the draft genome sequence of a methicillin-resistant Staphylococcus aureus strain designated CUHK_188, isolated from a bacteremic patient undergoing treatment at a university teaching hospital in Hong Kong. This strain belongs to sequence type 188 (ST188), with spa type t189 and staphylococcal cassette chromosome mec type V. PMID:24744328
Dinleyici, Ener Cagri; Yargic, Zeynel Abidin
At the beginning of a new century, we have gained significant achievements against pneumococcal infections by using conjugated pneumococcal vaccines. In January 2009, the EMEA issued a positive opinion about, and recommended the approval of, GlaxoSmithKline's pediatric pneumococcal candidate vaccine, which is indicated for active immunization against invasive pneumococcal disease (IPD) and acute otitis media caused by Streptococcus pneumoniae in infants and children from 6 weeks up to 2 years of age. The approved 10-valent pneumococcal vaccine (PHiD-CV) contains all serotypes in 7-valent pneumococcal conjugate vaccine (PCV-7) plus serotypes 1, 5 and 7F. Protein D from nontypeable Haemophilus influenzae is the carrier protein for eight serotypes, while tetanus and diphtheria toxins are in the carrier proteins for the remaining two serotypes. It has also been proved that PHiD-CV is immunogenic, safe and well-tolerated in children. This vaccine can be coadministered with routinely used pediatric vaccines. Noninferiority criteria of PHiD-CV compared with PCV-7 were established in shared serotypes, except for serotypes 6B and 23F, and PHiD-CV is immunogenic for additional serotypes as assessed by the percentage of subjects with antibody concentrations. PHiD-CV is also immunogenic for ten serotypes as assessed by post-primary and post-booster dose opsonophagocytic activity responses. Vaccine efficacy against IPD and other conditions should be monitored for shared serotypes and also additional serotypes during the postmarketing period. Optimal scheduling, safety and immunogenicity data in children with different risk factors for IPD, or whether it will provide herd immunity, are the questions waiting for answers in the postmarketing period. Further studies are needed to assess the potential advantages of protein D as a carrier and the potential efficacy of this new vaccine against H. influenzae. The potential public health efficacy of PHiD-CV in low-income countries
Summary: Invasive infections caused by Streptococcus pneumoniae continue to be a major cause of morbidity and mortality worldwide, especially in children under 5 years of age. In the United States, 90% of invasive pneumococcal infections in children are caused by 13 serotypes of S. pneumoniae. The licensure (in 2000) and subsequent widespread use of a heptavalent pneumococcal conjugate vaccine (PCV7) have had a significant impact on decreasing the incidence of serious invasive pneumococcal disease (IPD) in all age groups, especially in children under 2 years of age. However, the emergence of replacement non-PCV7 serotypes, especially serotype 19A, has resulted in an increase in the incidence of serious and invasive infections. In 2010, a 13-valent PCV was licensed in the United States. However, the impact that this vaccine will have on IPD remains to be seen. The objectives of this review are to discuss the epidemiology of serious and invasive pneumococcal infections in the United States in the PCV era and to review some of the pneumococcal vaccines that are in development. PMID:22763632
Watson, Michael; Roche, Paul; Bayley, Kathy; Bell, Jan M; Collignon, Peter; Gilbert, Gwendolyn L; Hogg, Geoff; Keil, Anthony D; Krause, Vicki; Murphy, Denise; Smith, Helen V; Brown, Mitchell; Stylianopoulos, Joanne; Turnidge, John
A comprehensive invasive pneumococcal disease (IPD) laboratory surveillance program was carried out in Australia in 2003. This program provided data on the prevalence of pneumococcal serotypes and antimicrobial resistance. There were 1,995 isolates tested with 34 per cent (683) from children aged less than five years and 27 per cent (535) from the elderly aged more than 65 years. One thousand eight hundred and sixty were isolates from blood, 79 from CSF and 56 from other sterile sites. In young children, 84 per cent of isolates were a serotype and 92 per cent a serogroup in the 7-valent pneumococcal conjugate vaccine (7vPCV). Of penicillin resistant isolates in children less than five years of age 85 per cent and 98 per cent were a serotype and serogroup in the 7vPCV respectively. When the universal 7vPCV vaccine program in young children is introduced in 2005, a proportion of cases of IPD should also be prevented in young adults (estimated reduction of 54 cases annually) and elderly Australians (an estimated reduction of 110 cases annually) as a result of improved herd immunity. Pneumococcal serotypes with higher rates of penicillin resistance (19F, 14 and 6B) were more prevalent in the elderly than in young children. In contrast, erythromycin resistance was more common in children less than five years of age (24%) compared to the elderly (15%). The predominant serotype with erythromycin resistance in Australia was serotype 14 and thus there is likely to be a major reduction in erythromycin resistance as a result of 7vPCV vaccination. Continued surveillance of pneumococcal serotype distribution and antibiotic susceptibility will be essential in order to identify serotype replacement by non-vaccine serotypes and to monitor the overall impact of current and future vaccine programs on invasive pneumococcal disease in Australia, not only in young children but also in other age groups.
Öbrink-Hansen, Kristina; Søgaard, Ole S; Harboe, Zitta B; Schønheyder, Henrik C
HIV-infected individuals have excess rates of invasive pneumococcal disease. We investigated risk factors for nasopharyngeal pneumococcal colonization at baseline and after 9 months in 96 HIV patients immunized twice with 7- valent pneumococcal conjugate vaccine ±1mg CPG 7909. In total, 22 patients (23%) were colonized, 11 at baseline only, four at both baseline and 9 months, and seven at 9 months only. Compared to non-colonized patients, more colonized patients were smokers, had lower CD4+ nadir and had an AIDS-diagnosis. Immunization, antiretroviral treatment and the CPG adjuvant had no impact on colonization. These results suggest preventive strategies in addition to pneumococcal immunization.
Johnstone, Catherine M. K.; Gritzfeld, Jenna F.; Banyard, Antonia; Hancock, Carole A.; Wright, Angela D.; Macfarlane, Laura; Ferreira, Daniela M.
Current diagnostic tests are ineffective for identifying the etiological pathogen in hospitalized adults with lower respiratory tract infections (LRTIs). The association of pneumococcal colonization with disease has been suggested as a means to increase the diagnostic precision. We compared the pneumococcal colonization rates and the densities of nasal pneumococcal colonization by (i) classical culture and (ii) quantitative real-time PCR (qPCR) targeting lytA in patients with LRTIs admitted to a hospital in the United Kingdom and control patients. A total of 826 patients were screened for inclusion in this prospective case-control study. Of these, 38 patients were recruited, 19 with confirmed LRTIs and 19 controls with other diagnoses. Nasal wash (NW) samples were collected at the time of recruitment. Pneumococcal colonization was detected in 1 patient with LRTI and 3 controls (P = 0.6) by classical culture. By qPCR, pneumococcal colonization was detected in 10 LRTI patients and 8 controls (P = 0.5). Antibiotic usage prior to sampling was significantly higher in the LRTI group than in the control group (19 versus 3; P < 0.001). With a clinically relevant cutoff of >8,000 copies/ml on qPCR, pneumococcal colonization was found in 3 LRTI patients and 4 controls (P > 0.05). We conclude that neither the prevalence nor the density of nasal pneumococcal colonization (by culture and qPCR) can be used as a method of microbiological diagnosis in hospitalized adults with LRTI in the United Kingdom. A community-based study recruiting patients prior to antibiotic therapy may be a useful future step. PMID:26791364
Levy, Corinne; Varon, Emmanuelle; Bingen, Edouard; Lécuyer, Aurélie; Boucherat, Michel; Cohen, Robert
In France, despite a high rate of pneumococcal conjugate vaccine coverage, the number of cases of pneumococcal meningitis in children did not decline signiﬁcantly between 2001–2002 (n = 264) and 2007–2008 (n = 244). A decline was observed among children < 2 years old (185 [70.1%] to 134 [54.9%] cases; P = 0.0004), but was counterbalanced by an increase among children ≥ 2 years old (79 [29.9%] to 110 [45.1%] cases). Mean age increased signiﬁcantly, from 2.3 (median 0.8) to 3.8 (median 1.5) years. After pneumococcal conjugate vaccine 7 implementation, a wide diversity of serotypes implicated in pneumococcalmeningitis was observed; serotypes 19A and 7F were the most frequent.
Diamantino-Miranda, Jorge; Aguiar, Sandra Isabel; Carriço, João André; Melo-Cristino, José
Although serogroup 6 was among the first to be recognized among Streptococcus pneumoniae, several new serotypes were identified since the introduction of pneumococcal conjugate vaccines (PCVs). A decrease of the 6B-2 variant among invasive pneumococcal disease (IPD), but not 6B-1, was noted post conjugate vaccine introduction, underpinned by a decrease of CC273 isolates. Serotype 6C was associated with adult IPD and increased in this age group representing two lineages (CC315 and CC395), while the same lineages expressed other serogroup 6 serotypes in children. Taken together, these findings suggest a potential cross-protection of PCVs against serotype 6C IPD among vaccinated children but not among adults. Serotype 6A became the most important serogroup 6 serotype in children but it decreased in adult IPD. No other serogroup 6 serotypes were detected, so available phenotypic or simple genotypic assays remain adequate for distinguishing serotypes within serogroup 6 isolates. PMID:28152029
Roche, Paul W; Krause, Vicki; Cook, Heather; Barralet, Jenny; Coleman, David; Sweeny, Amy; Fielding, James; Giele, Carolien; Gilmour, Robin; Holland, Ros; Kampen, Riemke; Brown, Mitchell; Gilbert, Lyn; Hogg, Geoff; Murphy, Denise
Enhanced surveillance for invasive pneumococcal disease (IPD) was carried out in all Australian states and territories in 2006 with comprehensive comparative data available since 2002. There were 1,445 cases of IPD notified to the National Notifiable Diseases Surveillance System in Australia in 2006; a notification rate of 7 cases per 100,000 population. The rates varied between states and territories and by geographical region with the highest rates in the Northern Territory, the jurisdiction with the largest proportion of Indigenous people. Invasive pneumococcal disease was reported most frequently in those aged 85 years or over (30.8 cases per 100,000 population) and in children aged one year (26.5 cases per 100,000 population). There were 130 deaths attributed to IPD resulting in an overall case fatality rate of 9%. The overall rate of IPD in Indigenous Australians was 4.3 times the rate in non-indigenous Australians. The rate of IPD in the under two years population continued to fall in 2006, but the rate in Indigenous children (73 cases per 100,000 population) was significantly greater than in non-Indigenous children (21 cases per 100,000 population). The rates of disease caused by serotypes in the 7-valent pneumococcal conjugate vaccine (7vPCV) decreased between 2002 and 2006 by 78% in children aged under two years as a result of the introduction of a universal childhood 7vPCV immunisation program. Significant decreases in IPD caused by 7vPCV serotypes also occurred in the 2-14 years and 65 years or over age groups. Rates of disease caused by non-7vPCV in the same periods were little changed. Serotypes were identified in 94% of all notified cases, with 43% of disease caused by serotypes in the 7vPCV and 85% caused by serotypes in the 23-valent polysaccharide pneumococcal vaccine (23vPPV). The number of invasive pneumococcal isolates with reduced penicillin susceptibility remains low and reduced susceptibility to third generation cephalosporins is rare.
Brueggemann, Angela B.; Harrold, Caroline L.; Rezaei Javan, Reza; van Tonder, Andries J.; McDonnell, Angus J.; Edwards, Ben A.
Bacteriophages (phages) infect many bacterial species, but little is known about the diversity of phages among the pneumococcus, a leading global pathogen. The objectives of this study were to determine the prevalence, diversity and molecular epidemiology of prophages (phage DNA integrated within the bacterial genome) among pneumococci isolated over the past 90 years. Nearly 500 pneumococcal genomes were investigated and RNA sequencing was used to explore prophage gene expression. We revealed that every pneumococcal genome contained prophage DNA. 286 full-length/putatively full-length pneumococcal prophages were identified, of which 163 have not previously been reported. Full-length prophages clustered into four major groups and every group dated from the 1930–40 s onward. There was limited evidence for genes shared between prophage clusters. Prophages typically integrated in one of five different sites within the pneumococcal genome. 72% of prophages possessed the virulence genes pblA and/or pblB. Individual prophages and the host pneumococcal genetic lineage were strongly associated and some prophages persisted for many decades. RNA sequencing provided clear evidence of prophage gene expression. Overall, pneumococcal prophages were highly prevalent, demonstrated a structured population, possessed genes associated with virulence, and were expressed under experimental conditions. Pneumococcal prophages are likely to play a more important role in pneumococcal biology and evolution than previously recognised. PMID:28218261
Houseman, Catherine; Hughes, Gareth J.; Chapman, Kaye E.; Wilson, Deborah
Since April 2014, invasive pneumococcal disease incidence has increased substantially across North East England, United Kingdom, reversing the decline that followed the 2006 introduction of pneumococcal conjugate vaccines. Significant increases occurred in 23-valent polysaccharide vaccine serotypes and nonvaccine serotypes. Trends in other regions and long-term effects of multivalent vaccines require further investigation. PMID:27983490
Brueggemann, Angela B; Harrold, Caroline L; Rezaei Javan, Reza; van Tonder, Andries J; McDonnell, Angus J; Edwards, Ben A
Bacteriophages (phages) infect many bacterial species, but little is known about the diversity of phages among the pneumococcus, a leading global pathogen. The objectives of this study were to determine the prevalence, diversity and molecular epidemiology of prophages (phage DNA integrated within the bacterial genome) among pneumococci isolated over the past 90 years. Nearly 500 pneumococcal genomes were investigated and RNA sequencing was used to explore prophage gene expression. We revealed that every pneumococcal genome contained prophage DNA. 286 full-length/putatively full-length pneumococcal prophages were identified, of which 163 have not previously been reported. Full-length prophages clustered into four major groups and every group dated from the 1930-40 s onward. There was limited evidence for genes shared between prophage clusters. Prophages typically integrated in one of five different sites within the pneumococcal genome. 72% of prophages possessed the virulence genes pblA and/or pblB. Individual prophages and the host pneumococcal genetic lineage were strongly associated and some prophages persisted for many decades. RNA sequencing provided clear evidence of prophage gene expression. Overall, pneumococcal prophages were highly prevalent, demonstrated a structured population, possessed genes associated with virulence, and were expressed under experimental conditions. Pneumococcal prophages are likely to play a more important role in pneumococcal biology and evolution than previously recognised.
Johnson, Tamara M; Chitturi, Chandrika; Lange, Michael; Suh, Jin S; Slim, Jihad
Streptococcus pneumoniae vertebral infections have rarely been reported. Herein, we report a case of pneumococcal vertebral osteomyelitis with paraspinal and epidural abscesses as well as concomitant bacteremia following epidural injection. This will be the second case in the literature reporting pneumococcal vertebral osteomyelitis related to epidural manipulation. PMID:27621563
Olaya-Abril, Alfonso; Jiménez-Munguía, Irene; Gómez-Gascón, Lidia; Obando, Ignacio; Rodríguez-Ortega, Manuel J.
Pneumonia is one of the most common and severe diseases associated with Streptococcus pneumoniae infections in children and adults. Etiological diagnosis of pneumococcal pneumonia in children is generally challenging because of limitations of diagnostic tests and interference with nasopharyngeal colonizing strains. Serological assays have recently gained interest to overcome some problems found with current diagnostic tests in pediatric pneumococcal pneumonia. To provide insight into this field, we have developed a protein array to screen the antibody response to many antigens simultaneously. Proteins were selected by experimental identification from a collection of 24 highly prevalent pediatric clinical isolates in Spain, using a proteomics approach consisting of “shaving” the cell surface with proteases and further LC/MS/MS analysis. Ninety-five proteins were recombinantly produced and printed on an array. We probed it with a collection of sera from children with pneumococcal pneumonia. From the set of the most seroprevalent antigens, we obtained a clear discriminant response for a group of three proteins (PblB, PulA, and PrtA) in children under 4 years old. We validated the results by ELISA and an immunostrip assay showed the translation to easy-to-use, affordable tests. Thus, the protein array here developed presents a tool for broad use in serodiagnostics. PMID:26183717
Aspa, Javier; Rajas, Olga; de Castro, Felipe Rodríguez
Streptococcus pneumoniae has been consistently shown to represent the most frequent causative agent of community-acquired pneumonia (CAP) and pneumococcal antibiotic resistance towards different families of antibiotics continues to be a much-debated issue. Microbial resistance causes a great deal of confusion in choosing an empirical treatment for pneumonia and this makes it necessary to know which factors actually determine the real impact of antimicrobial resistance on the outcome of pneumococcal infections. Several different aspects have to be taken into account when analyzing this matter, such as the study design, the condition of the patient at the time of diagnosis, the choice of the initial antimicrobial regimen (combination or monotherapy) and the pharmacokinetic/pharmacodynamic variables of the chosen antibiotic. It is generally accepted that in the treatment of beta-lactam-resistant pneumococcal infections, the use of standard antipneumococcal beta-lactam agents is unlikely to impact negatively on the outcome of CAP when appropriate agents are given in sufficient doses. As a general rule, for infections with penicillin-sensitive strains, penicillin or an aminopenicillin in a standard dosage will be effective; in the cases of strains with intermediate resistance, beta-lactam agents are still considered appropriate treatment although higher dosages are recommended; finally, infections with isolates of high-level penicillin resistance should be treated with alternative agents such as the third-generation cephalosporins or the new antipneumococcal fluoroquinolones. In areas of high prevalence of high-level macrolide resistance, empirical monotherapy with a macrolide is not optimal for the treatment of hospitalised patients with moderate or moderately-severe CAP. Fluoroquinolones are considered to be excellent antibiotics in the treatment of pneumococcal CAP in adults, but their general recommendation has been withheld due to fears of a widespread development
Barichello, Tatiana; Ceretta, Renan A; Generoso, Jaqueline S; Moreira, Ana Paula; Simões, Lutiana R; Comim, Clarissa M; Quevedo, João; Vilela, Márcia Carvalho; Zuardi, Antonio Waldo; Crippa, José A; Teixeira, Antônio Lucio
Pneumococcal meningitis is a life-threatening disease characterized by an acute infection affecting the pia matter, arachnoid and subarachnoid space. The intense inflammatory response is associated with a significant mortality rate and neurologic sequelae, such as, seizures, sensory-motor deficits and impairment of learning and memory. The aim of this study was to evaluate the effects of acute and extended administration of cannabidiol on pro-inflammatory cytokines and behavioral parameters in adult Wistar rats submitted to pneumococcal meningitis. Male Wistar rats underwent a cisterna magna tap and received either 10μl of sterile saline as a placebo or an equivalent volume of S. pneumoniae suspension. Rats subjected to meningitis were treated by intraperitoneal injection with cannabidiol (2.5, 5, or 10mg/kg once or daily for 9 days after meningitis induction) or a placebo. Six hours after meningitis induction, the rats that received one dose were killed and the hippocampus and frontal cortex were obtained to assess cytokines/chemokine and brain-derived neurotrophic factor levels. On the 10th day, the rats were submitted to the inhibitory avoidance task. After the task, the animals were killed and samples from the hippocampus and frontal cortex were obtained. The extended administration of cannabidiol at different doses reduced the TNF-α level in frontal cortex. Prolonged treatment with canabidiol, 10mg/kg, prevented memory impairment in rats with pneumococcal meningitis. Although descriptive, our results demonstrate that cannabidiol has anti-inflammatory effects in pneumococcal meningitis and prevents cognitive sequel.
Angoulvant, François; Lachenaud, Julie; Mariani-Kurkdjian, Patricia; Aubertin, Guillaume; Houdouin, Véronique; Lorrot, Mathie; de Los Angeles, Laure; Bingen, Edouard; Bourrillon, Antoine; Faye, Albert
We describe two cases of aseptic meningitis occurring some time after pneumococcal meningitis. Both cases may have resulted from an inflammatory response to persistent pneumococcal cell membrane components, as the cerebrospinal fluid samples were positive by the Binax NOW Streptococcus pneumoniae antigen test. Potential mechanisms and diagnostic impact are discussed. PMID:17005744
Buchanan, G R; Smith, S J
Although polyvalent pneumococcal vaccine and prophylactic penicillin are used to prevent overwhelming Streptococcus pneumoniae septicemia in infants and young children with sickle cell anemia, infection rates remain high. We have reviewed our seven-year experience with a regimen of twice daily oral penicillin V potassium prophylaxis in 88 affected children. The median age at the start of prophylaxis was 10 months, and the median duration of prophylaxis was 29 months (range, three months to seven years). The total period of observation of patients who were prescribed penicillin was 248 person-years. Most patients also received one or two doses of polyvalent pneumococcal vaccine. Despite penicillin prophylaxis and pneumococcal vaccine, eight episodes of S pneumoniae septicemia have occurred and three have been fatal. Four episodes were in children older than 3 years. Suboptimal compliance with the prescribed oral penicillin regimen was usually apparent. With one possible exception, the infections occurred when penicillin had not been taken during the previous 24 hours. The S pneumoniae septicemia rate in this patient population, 3.2 per 100 person-years, is somewhat less than that described in previous reports of children not receiving penicillin but is still unacceptably high. Vigorous advocacy of a penicillin prophylaxis regimen does not eliminate the risk of pneumococcal septicema in this patient population.
Gaspar, Paula; Al-Bayati, Firas A Y; Andrew, Peter W; Neves, Ana Rute; Yesilkaya, Hasan
Streptococcus pneumoniae is a fermentative microorganism and causes serious diseases in humans, including otitis media, bacteremia, meningitis, and pneumonia. However, the mechanisms enabling pneumococcal survival in the host and causing disease in different tissues are incompletely understood. The available evidence indicates a strong link between the central metabolism and pneumococcal virulence. To further our knowledge on pneumococcal virulence, we investigated the role of lactate dehydrogenase (LDH), which converts pyruvate to lactate and is an essential enzyme for redox balance, in the pneumococcal central metabolism and virulence using an isogenic ldh mutant. Loss of LDH led to a dramatic reduction of the growth rate, pinpointing the key role of this enzyme in fermentative metabolism. The pattern of end products was altered, and lactate production was totally blocked. The fermentation profile was confirmed by in vivo nuclear magnetic resonance (NMR) measurements of glucose metabolism in nongrowing cell suspensions of the ldh mutant. In this strain, a bottleneck in the fermentative steps is evident from the accumulation of pyruvate, revealing LDH as the most efficient enzyme in pyruvate conversion. An increase in ethanol production was also observed, indicating that in the absence of LDH the redox balance is maintained through alcohol dehydrogenase activity. We also found that the absence of LDH renders the pneumococci avirulent after intravenous infection and leads to a significant reduction in virulence in a model of pneumonia that develops after intranasal infection, likely due to a decrease in energy generation and virulence gene expression.
Kalyango, Joan; Alfvén, Tobias; Darenberg, Jessica; Kadobera, Daniel; Bwanga, Freddie; Peterson, Stefan; Henriques-Normark, Birgitta; Källander, Karin
Background Pneumonia is the major cause of death in children globally, with more than 900,000 deaths annually in children under five years of age. Streptococcus pneumoniae causes most deaths, most often in the form of community acquired pneumonia. Pneumococcal conjugate vaccines (PCVs) are currently being implemented in many low-income countries. PCVs decrease vaccine-type pneumococcal carriage, a prerequisite for invasive pneumococcal disease, and thereby affects pneumococcal disease and transmission. In Uganda, PCV was launched in 2014, but baseline data is lacking for pneumococcal serotypes in carriage. Objectives To study pneumococcal nasopharyngeal carriage and serotype distribution in children under 5 years of age prior to PCV introduction in Uganda Methods Three cross-sectional pneumococcal carriage surveys were conducted in 2008, 2009 and 2011, comprising respectively 150, 587 and 1024 randomly selected children aged less than five years from the Iganga/Mayuge Health and Demographic Surveillance Site. The caretakers were interviewed about illness history of the child and 1723 nasopharyngeal specimens were collected. From these, 927 isolates of S. pneumoniae were serotyped. Results Overall, the carriage rate of S. pneumoniae was 56% (957/1723). Pneumococcal carriage was associated with illness on the day of the interview (OR = 1.50, p = 0.04). The most common pneumococcal serotypes were in descending order 19F (16%), 23F (9%), 6A (8%), 29 (7%) and 6B (7%). One percent of the strains were non-typeable. The potential serotype coverage rate for PCV10 was 42% and 54% for PCV13. Conclusion About half of circulating pneumococcal serotypes in carriage in the Ugandan under-five population studied was covered by available PCVs. PMID:27829063
Gentile, Angela; Bazán, Virginia
The Millennium Development Goals (MDGs), adopted by world leaders in the year 2000 with an aim to accomplish them by 2015, provide concrete benchmarks for tackling extreme poverty in its many dimensions. One aim is to reduce by two thirds the mortality rate among children <5 years of age. The deaths of nearly 3 million children under 5 each year worldwide can be attributed to diarrhea and pneumonia. Pneumonia, one form of pneumococcal disease, causes almost 1 in 5 deaths of children under 5 worldwide-more than 1.6 million children each year. Pneumococcal disease is preventable by vaccination; because antibiotic resistance is a growing problem worldwide, there is a great need to promote effective pneumococcal vaccines. Vaccines differ from other types of drugs, because they are administered to healthy individuals. Therefore, a good safety profile is required, there is a large governmental regulatory role, and low efficacy is unacceptable. Other important considerations are as follows: vaccines are often used in infants, are typically given in multiple doses, the manufacturing is a larger part of cost, requires high regulatory and quality control burden and minimization of costs. From a biological standpoint, the induction of vaccine-mediated protection is a complex procedure. Long-term protection typically requires the persistence of anti-microbial antibodies and/or the generation of immune memory cells capable of rapid and effective reactivation after microbial re-exposure. Appreciation of the predominant role of B cells in the efficacy of current vaccines should not minimize the importance of generating a T cell response, as this is essential for the induction of high affinity antibodies and immune memory. Pneumococcal capsular polysaccharides typically elicit B cell responses in a T-independent manner. Because of this, capsular polysaccharides are poorly immunogenic in children below 2 years of age and will generate an IgM isotype-based primary response with only
Roche, Paul; Krause, Vicki; Cook, Heather; Bartlett, Mark; Coleman, David; Davis, Craig; Fielding, James; Giele, Carolien; Gilmour, Robin; Holland, Ros; Kampen, Riemke
Enhanced surveillance for invasive pneumococcal disease (IPD) was carried out in all Australian states and territories in 2005 with comparative data available since 2001. There were 1,680 cases of IPD notified to the National Notifiable Diseases Surveillance System in Australia in 2005; a notification rate of 8.3 cases per 100,000 population. The rates varied between states and territories and by geographical region with the highest rates in the Northern Territory, the jurisdiction with the largest proportion of Indigenous people. Invasive pneumococcal disease was reported most frequently in those aged 85 years or over (41 cases per 100,000 population) and in 1-year-old children (36.5 cases per 100,000 population). Enhanced data provided additional information on 1,015 (60%) of all notified cases. The overall rate of IPD in Indigenous Australians was 8.6 times the rate in non-Indigenous Australians. There were 126 deaths attributed to IPD resulting in an overall case fatality rate of 7.5%. While the rate of IPD in the Indigenous under 2-year-old population decreased from 219 cases per 100,000 population since targeted introduction of the 7-valent conjugate pneumococcal vaccine (7vPCV) in 2001, the rate in 2005 (94 cases per 100,000 population) was significantly greater than in non-Indigenous children (20.4 cases per 100,000 population). Rates of disease in all children aged less than 2 years, caused by serotypes in the 7vPCV decreased by 75% between 2004 and 2005 as a result of the introduction of a universal childhood 7vPCV immunisation program. Significant decreases in IPD caused by 7vPCV serotypes also occurred in the 2-14 years and 65 years or over age groups. There is no evidence of replacement disease with non-vaccine serotypes. Serotypes were identified in 90% of all notified cases, with 61% of disease caused by serotypes in the 7vPCV and 88% caused by serotypes in the 23-valent polysaccharide pneumococcal vaccine (23vPPV). Reduced penicillin susceptibility
In 1978, 89 patients were treated for (S. pneumoniae) pneumonia at New York Hospital-Cornell Medical Center. Only 40 cases met rather strict diagnostic criteria. Of these, 12 demonstrated the classical consolidative (air space) pattern usually ascribed to this disease. A bronchopneumonic (patch) pattern was demonstrated in an equal number of patients; interstitial (irregular linear) infiltrates were manifest in nine cases and a mixed interstitial and patchy presentation shown in seven cases. Absence of the consolidative pattern does not exclude pneumococcal pneumonia. Bacteriologic investigation is required to determine the proper diagnosis and course of therapy.
Imöhl, Matthias; Reinert, Ralf René; van der Linden, Mark
Continuous nationwide surveillance of invasive pneumococcal disease (IPD) was conducted in Germany. A total of 22,208 isolates from invasive pneumococcal disease were collected between July 1, 1992 and June 30, 2013. The present study was conducted to analyze changes in antimicrobial susceptibility and pneumococcal vaccine coverage after the introduction of pneumococcal conjugate vaccination in Germany. Most of the isolates originated from adults ≥16 years (82.5%), while 17.5% were obtained from children <16 years. Penicillin resistance was observed in 7.2% of meningitis cases both among children and adults during the entire study period. In the post-PCV13 period, the resistance rate was 11.3% in children and 10.0% in adults, which is higher than in the pre-PCV7 and post-PCV7 periods. In the non-meningitis group, an overall penicillin nonsusceptibility rate (intermediate resistance and resistance) of 0.5% was detected both among children and adults. Nonsusceptibility rates among children were 6.3% (pre-PCV7), 7.6% (post-PCV7) and 9.0% (post-PCV13). The corresponding nonsusceptibility rates among adults were 4.4%, 6.0% and 7.9%, respectively. Concerning cefotaxime, in meningitis cases 0.8% of all isolates were intermediate and 0.5% resistant among children, while among adults, 0.9% were intermediate and 0.2% resistant. In non meningitis cases, cefotaxime nonsusceptibility rates were 0.5% in children and 0.3% in adults. Macrolide nonsusceptibility rates were lower in the post-PCV13 period (children 8.2%; adults 8.8%) than in the post-PCV7 period (children 17.3%; adults 13.0%) and the pre-PCV7 period (children 24.8%; adults 13.3%). In the pre-PCV7 period, macrolide resistance was mainly caused by M-phenotype clones carrying the mefA gene. In the post-PCV7/13 period, ermB (MLSb-phenotype) was the dominant resistance marker. Overall nonsusceptibility rates were 5.5% for clindamycin (intermediate 0.3%, resistant 5.2%), 0.7% for levofloxacin (intermediate 0
Dubos, F; Marechal, I; Husson, M O; Courouble, C; Aurel, M; Martinot, A
Background The impact of the heptavalent‐pneumococcal conjugate vaccine on the incidence of pneumococcal meningitis in Europe has not yet been assessed. Objective To determine whether heptavalent‐pneumococcal conjugate vaccine implementation in northern France has resulted in a decrease in the incidence of pneumococcal meningitis in children. Design Multicentre retrospective cohort study from 2000 through 2005. Settings All paediatric departments of the 18 hospitals in northern France. Patients Patients <18 years of age, admitted for laboratory‐confirmed pneumococcal meningitis during the study period, were included. Interventions Data were collected from medical files and the microbiological laboratories of each hospital and compared with the regional hospital discharge codes, using a capture–recapture method. Main outcome measures The study assessed and compared global and age‐related incidence rates of pneumococcal meningitis in 2001 (pre‐vaccine era) and 2005. Results 77 cases were found through the capture–recapture method. The incidence rate of pneumococcal meningitis varied from 1.65/100 000 children <18 years in 2001 to 0.80/100 000 children in 2005 (53% reduction, 95% CI 31 to 74; p = 0.08). This has so far been significant only for children <2 years of age (8.9/100 000 in 2001 to 1.8/100 000 in 2005; 82% reduction, 95% CI 52 to 95; p = 0.03). Conclusion A decline in pneumococcal meningitis has been observed in infants since heptavalent‐pneumococcal conjugate vaccination began in our area. PMID:17626145
... the Unites States. Treatment of pneumococcal infections with penicillin and other drugs used to be more effective. ... get another dose. Anyone who has a severe allergy to any component of PPSV should not receive ...
... Unite d States. Treatment of pneumococcal infections with penicillin and other drugs used to be more effective. ... get another dose. • Anyone who has a severe allergy to any component of PPSV should not receive ...
... the United States. Treatment of pneumococcal infections with penicillin and other drugs is not as effective as ... should not get PCV13. Anyone with a severe allergy to any component of PCV13 should not get ...
Harkonen, S; Scannon, P; Mischak, R P; Spitler, L E; Foxall, C; Kennedy, D; Greenberg, R
Nine patients with suspected gram-negative bacterial sepsis were studied to determine the safety, pharmacokinetics, and immunogenicity of XMMEN-0E5, a murine immunoglobulin M monoclonal antibody directed against the core lipid A region of bacterial endotoxin. Antibody was administered by single intravenous infusion of 1 to 4 h duration at doses ranging from 0.1 to 15 mg/kg. Five patients had positive blood cultures for gram-negative bacteria, one patient had Torulopsis septicemia, one patient had gram-negative bacterial meningitis, and two patients were culture negative. No evidence of antibody-mediated toxicity was observed at any dose level. The serum half-life of the antibody was approximately 10 h at doses of 0.1 to 7.5 mg/kg and approximately 18 h at a dose of 15 mg/kg. No apparent difference in clearance of antibody was observed between bacteremic and nonbacteremic patients. Human anti-mouse antibodies were detected in the sera of three evaluable patients that received doses equal to or greater than 2.0 mg/kg but not in patients that received lower doses of antibody. This study demonstrates that XMMEN-0E5 is well tolerated at doses from 0.1 to 15 mg/kg and may be immunogenic at doses of 2.0 mg/kg and above. Controlled trials to establish the efficacy of this antibody in the treatment of gram-negative bacteremia are indicated. PMID:3395101
de Léséleuc, Louis; Harris, Greg; KuoLee, Rhonda; Xu, H Howard; Chen, Wangxue
Bacteremia caused by Acinetobacter baumannii is a highly lethal complication of hospital-acquired pneumonia. In the present study, we investigated the serum resistance, gallium nitrate tolerance and heme consumption of A. baumannii strain LAC-4 which was recently reported to display high virulence in a mouse pneumonia model with extrapulmonary dissemination leading to fatal bacteremia. This strain showed enhanced growth in mouse and fetal bovine serum that was independent of complement and was not observed with regular growth media. The LAC-4 strain was found to possess a high tolerance to gallium nitrate (GaN), whereas serum synergized with GaN in inhibiting A. baumannii strain ATCC 17978. We found that LAC-4 contains a heme oxygenase gene and expresses a highly efficient heme consumption system. This system can be fully blocked in vitro and in vivo by gallium protoporphyrin IX (GaPPIX). Inhibition of heme consumption by GaPPIX completely abrogated the growth advantage of LAC-4 in serum as well as its tolerance to GaN. More importantly, GaPPIX treatment of mice intranasally infected with LAC-4 prevented extrapulmonary dissemination and death. Thus, we propose that heme provides an additional source of iron for LAC-4 to bypass iron restriction caused by serum transferrin, lactoferrin or free gallium salts. Heme consumption systems in A. baumannii may constitute major virulence factors for lethal bacteremic isolates.
Joye, Sebastien; Gao, Anja; Kayemba-Kay’s, Simon; Cotting, Jacques; Perez, Marie-Hélène
Despite good cover with 7-valent vaccination, invasive pneumococcal infections may still be misdiagnosed and may lead to lifethreatening situations or death in young children. New serotypes are emerging and, therefore, clinicians must keep a high level of suspicion in young children regardless of their vaccination status. We report three cases of invasive pneumococcal infection due to new serotypes not covered by the 7-valent conjugated vaccine, two of which led children to death. PMID:24765491
Joye, Sebastien; Gao, Anja; Kayemba-Kay's, Simon; Cotting, Jacques; Perez, Marie-Hélène
Despite good cover with 7-valent vaccination, invasive pneumococcal infections may still be misdiagnosed and may lead to lifethreatening situations or death in young children. New serotypes are emerging and, therefore, clinicians must keep a high level of suspicion in young children regardless of their vaccination status. We report three cases of invasive pneumococcal infection due to new serotypes not covered by the 7-valent conjugated vaccine, two of which led children to death.
Iroh Tam, Pui-Ying; Madoff, Lawrence C; O'Connell, Michael; Pelton, Stephen I
We evaluated prospectively laboratory surveillance data from Massachusetts to investigate whether seasonal variation in invasive pneumococcal disease is associated with the proportion of penicillin-susceptible isolates. The proportion of penicillin-susceptible isolates associated with invasive pneumococcal disease varied by season, with proportions highest in the winter and lowest in the summer, and rates of invasive disease were highest in the autumn and winter seasons and lowest in the summer.
Tam, Pui-Ying Iroh; Madoff, Lawrence C.; O'Connell, Michael; Pelton, Stephen I.
We evaluated prospectively laboratory surveillance data from Massachusetts to investigate whether seasonal variation in invasive pneumococcal disease is associated with the proportion of penicillin susceptible isolates. The proportion of penicillin susceptible isolates associated with invasive pneumococcal disease varied by season, with proportions highest in the winter and lowest in the summer, and rates of invasive disease were highest in the autumn and winter seasons and lowest in the summer. PMID:25379834
Feikin, Daniel R.; Kagucia, Eunice W.; Loo, Jennifer D.; Link-Gelles, Ruth; Puhan, Milo A.; Cherian, Thomas; Levine, Orin S.; Whitney, Cynthia G.; O’Brien, Katherine L.; Moore, Matthew R.
Background Vaccine-serotype (VT) invasive pneumococcal disease (IPD) rates declined substantially following introduction of 7-valent pneumococcal conjugate vaccine (PCV7) into national immunization programs. Increases in non-vaccine-serotype (NVT) IPD rates occurred in some sites, presumably representing serotype replacement. We used a standardized approach to describe serotype-specific IPD changes among multiple sites after PCV7 introduction. Methods and Findings Of 32 IPD surveillance datasets received, we identified 21 eligible databases with rate data ≥2 years before and ≥1 year after PCV7 introduction. Expected annual rates of IPD absent PCV7 introduction were estimated by extrapolation using either Poisson regression modeling of pre-PCV7 rates or averaging pre-PCV7 rates. To estimate whether changes in rates had occurred following PCV7 introduction, we calculated site specific rate ratios by dividing observed by expected IPD rates for each post-PCV7 year. We calculated summary rate ratios (RRs) using random effects meta-analysis. For children <5 years old, overall IPD decreased by year 1 post-PCV7 (RR 0·55, 95% CI 0·46–0·65) and remained relatively stable through year 7 (RR 0·49, 95% CI 0·35–0·68). Point estimates for VT IPD decreased annually through year 7 (RR 0·03, 95% CI 0·01–0·10), while NVT IPD increased (year 7 RR 2·81, 95% CI 2·12–3·71). Among adults, decreases in overall IPD also occurred but were smaller and more variable by site than among children. At year 7 after introduction, significant reductions were observed (18–49 year-olds [RR 0·52, 95% CI 0·29–0·91], 50–64 year-olds [RR 0·84, 95% CI 0·77–0·93], and ≥65 year-olds [RR 0·74, 95% CI 0·58–0·95]). Conclusions Consistent and significant decreases in both overall and VT IPD in children occurred quickly and were sustained for 7 years after PCV7 introduction, supporting use of PCVs. Increases in NVT IPD occurred in most sites, with variable magnitude
Numminen, Elina; Chewapreecha, Claire; Turner, Claudia; Goldblatt, David; Nosten, Francois; Bentley, Stephen D; Turner, Paul; Corander, Jukka
Streptococcus pneumoniae is a significant human pathogen and a leading cause of infant mortality in developing countries. Considerable global variation in the pneumococcal carriage prevalence has been observed and the ecological factors contributing to it are not yet fully understood. We use data from a cohort of infants in Asia to study the effects of climatic conditions on both acquisition and clearance rates of the bacterium, finding significantly higher transmissibility during the cooler and drier months. Conversely, the length of a colonization period is unaffected by the season. Independent carriage data from studies conducted on the African and North American continents suggest similar effects of the climate on the prevalence of this bacterium, which further validates the obtained results. Further studies could be important to replicate the findings and explain the mechanistic role of cooler and dry air in the physiological response to nasopharyngeal acquisition of the pneumococcus.
Domínguez, Angela; Castilla, Jesús; Godoy, Pere; Delgado-Rodríguez, Miguel; Saez, Marc; Soldevila, Núria; Astray, Jenaro; Mayoral, José María; Martín, Vicente; Quintana, José María; González-Candelas, Fernando; Galán, Juan Carlos; Tamames, Sonia; Castro, Ady; Baricot, Maretva; Garín, Olatz; Pumarola, Tomas; Working Group (Spain), CIBERESP Cases and Controls in Pandemic Influenza
Background: Since influenza predisposes to bacterial pneumonia caused by Streptococcus pneumoniae, studies have suggested that pneumococcal vaccination might reduce its occurrence during pandemics. We assessed the effectiveness of pneumococcal polysaccharide vaccination alone and in combination with influenza vaccination in preventing influenza hospitalization during the 2009–2010 pandemic wave and 2010–2011 influenza epidemic. Methods: We conducted a multicenter case-control study in 36 Spanish hospitals. We selected patients aged ≥ 18 y hospitalized with confirmed influenza and two hospitalized controls per case, matched according to age, date of hospitalization and province of residence. Multivariate analysis was performed using conditional logistic regression. Subjects were considered vaccinated if they had received the pneumococcal or seasonal influenza vaccine > 14 d (or > 7 d for pandemic influenza vaccine) before the onset of symptoms (cases) or the onset of symptoms in matched cases (controls). Results: 1187 cases and 2328 controls were included. The adjusted estimate of effectiveness of pneumococcal vaccination in preventing influenza hospitalization was 41% (95% CI 8–62) in all patients and 43% (95% CI 2–78) in patients aged ≥ 65 y. The adjusted effectiveness of dual PPV23 and influenza vaccination was 81% (95% CI 65–90) in all patients and 76% (95% CI 46–90) in patients aged ≥ 65 y. The adjusted effectiveness of influenza vaccination alone was 58% (95% CI 38–72). Conclusions: In elderly people and adults with chronic illness, pneumococcal vaccination may reduce hospitalizations during the influenza season. In people vaccinated with both the influenza and pneumococcal vaccines, the benefit in hospitalizations avoided was greater than in those vaccinated only against influenza. PMID:23563516
van Mens, Suzan P; Meijvis, Sabine C A; Endeman, Henrik; van Velzen-Blad, Heleen; Biesma, Douwe H; Grutters, Jan C; Vlaminckx, Bart J M; Rijkers, Ger T
In up to half of all cases of community-acquired pneumonia (CAP), no pathogen can be identified with conventional diagnostic methods. The most common identified causative agent is Streptococcus pneumoniae. In this study, pneumococcal antibody responses during CAP were analyzed to estimate the contribution of the pneumococcus to all cases of CAP for epidemiological purposes. Pneumococcal antibodies against 14 different serotypes were measured in serum of hospitalized CAP patients. Patients participated in one of two consecutive clinical trials in a general 600-bed teaching hospital in the Netherlands (between October 2004 and June 2009). A significant pneumococcal immune response was defined as at least a 2-fold increase in antibody concentrations against a single serotype between an early (day 1) and a late (day 30) serum sample of each patient with an end concentration above 0.35 μg/ml. A total of 349 adult CAP patients participated in two consecutive clinical trials. For 200 patients, sufficient serum samples were available to determine antibody responses: 62 pneumococcal pneumonia patients, 57 nonpneumococcal pneumonia patients, and 81 patients with an unidentified causative agent. A significant immune response was detected in 45% (28/62 patients) of pneumococcal pneumonia patients, in 5% (3/57) of nonpneumococcal pneumonia patients, and in 28% (23/81) of patients with an unidentified causative agent. The estimated contribution of pneumococci in patients with an unidentified causative agent was calculated to be 57% (95% confidence interval, 36 to 86%). A substantial fraction of pneumococcal pneumonia patients do not elicit a serotype-specific immune response.
Puchta, Alicja; Naidoo, Avee; Verschoor, Chris P; Loukov, Dessi; Thevaranjan, Netusha; Mandur, Talveer S; Nguyen, Phuong-Son; Jordana, Manel; Loeb, Mark; Xing, Zhou; Kobzik, Lester; Larché, Maggie J; Bowdish, Dawn M E
Monocyte phenotype and output changes with age, but why this occurs and how it impacts anti-bacterial immunity are not clear. We found that, in both humans and mice, circulating monocyte phenotype and function was altered with age due to increasing levels of TNF in the circulation that occur as part of the aging process. Ly6C+ monocytes from old (18-22 mo) mice and CD14+CD16+ intermediate/inflammatory monocytes from older adults also contributed to this "age-associated inflammation" as they produced more of the inflammatory cytokines IL6 and TNF in the steady state and when stimulated with bacterial products. Using an aged mouse model of pneumococcal colonization we found that chronic exposure to TNF with age altered the maturity of circulating monocytes, as measured by F4/80 expression, and this decrease in monocyte maturation was directly linked to susceptibility to infection. Ly6C+ monocytes from old mice had higher levels of CCR2 expression, which promoted premature egress from the bone marrow when challenged with Streptococcus pneumoniae. Although Ly6C+ monocyte recruitment and TNF levels in the blood and nasopharnyx were higher in old mice during S. pneumoniae colonization, bacterial clearance was impaired. Counterintuitively, elevated TNF and excessive monocyte recruitment in old mice contributed to impaired anti-pneumococcal immunity since bacterial clearance was improved upon pharmacological reduction of TNF or Ly6C+ monocytes, which were the major producers of TNF. Thus, with age TNF impairs inflammatory monocyte development, function and promotes premature egress, which contribute to systemic inflammation and is ultimately detrimental to anti-pneumococcal immunity.
Das, Rituparna; LaRose, Meredith I; Hergott, Christopher B; Leng, Lin; Bucala, Richard; Weiser, Jeffrey N
Human genetic polymorphisms associated with decreased expression of macrophage migration inhibitory factor (MIF) have been linked to the risk of community-acquired pneumonia. Because Streptococcus pneumoniae is the leading cause of community-acquired pneumonia and nasal carriage is a precursor to invasive disease, we explored the role of MIF in the clearance of pneumococcal colonization in a mouse model. MIF-deficient mice (Mif(-/-)) showed prolonged colonization with both avirulent (23F) and virulent (6A) pneumococcal serotypes compared with wild-type animals. Pneumococcal carriage led to both local upregulation of MIF expression and systemic increase of the cytokine. Delayed clearance in the Mif(-/-) mice was correlated with reduced numbers of macrophages in upper respiratory tract lavages as well as impaired upregulation of MCP-1/CCL2. We found that primary human monocyte-derived macrophages as well as THP-1 macrophages produced MIF upon pneumococcal infection in a pneumolysin-dependent manner. Pneumolysin-induced MIF production required its pore-forming activity and phosphorylation of p38-MAPK in macrophages, with sustained p38-MAPK phosphorylation abrogated in the setting of MIF deficiency. Challenge with pneumolysin-deficient bacteria demonstrated reduced MIF upregulation, decreased numbers of macrophages in the nasopharynx, and less effective clearance. Mif(-/-) mice also showed reduced Ab response to pneumococcal colonization and impaired ability to clear secondary carriage. Finally, local administration of MIF was able to restore bacterial clearance and macrophage accumulation in Mif(-/-) mice. Our work suggests that MIF is important for innate and adaptive immunity to pneumococcal colonization and could be a contributing factor in genetic differences in pneumococcal disease susceptibility.
Greenberg, D N; Ascher, D P; Yoder, B A; Hensley, D M; Heiman, H S; Keith, J F
Latex particle agglutination (LPA) testing for antigen to group B streptococcus (GBS) has been useful in the diagnosis of GBS sepsis in newborns. However, recent reports have demonstrated that the sensitivity of LPA assays may be as low as 27 to 54%. The purposes of the present study were to directly compare the abilities of four urine antigen assays to detect GBS antigen with clinical urine samples from neonates with GBS bacteremia and to evaluate the effect of the urine concentration on the sensitivities and specificities of these assays. Urine samples were collected serially from neonates with blood cultures positive for GBS or on admission from healthy full-term infants. One milliliter of urine was removed, and the remainder was concentrated to a volume of 1 ml. Unconcentrated samples were serially diluted with normal saline and were assayed to determine the highest dilution which would produce a positive test result. The Wellcogen, Bactigen, and Directigen LPA tests and ICON immunoassay were directly compared by using concentrated and unconcentrated urine specimens and urine specimens with known titers. A total of 94 urine specimens, including 61 concentrated and 75 unconcentrated specimens, from bacteremic infants were available for sensitivity testing, and 220 urine specimens from uninfected infants were available for specificity testing. There were significant differences in sensitivity among the four assays when they were performed on concentrated urine specimens, as follows: Directigen, 98%; Bactigen, 92%; ICON, 89%; Wellcogen, 68%. When the assays were performed on unconcentrated urine specimens, the Directigen (84%) and Bactigen (76%) assays were each significantly more sensitive than the ICON (59%) or Wellcogen (43%) assay.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7699040
Lee, Y-T; Kuo, S-C; Yang, S-P; Lin, Y-T; Chiang, D-H; Tseng, F-C; Chen, T-L; Fung, C-P
The phenotypically indistinguishable Acinetobacter baumannii and Acinetobacter nosocomialis have become leading pathogens causing nosocomial pneumonia in critically ill patients. A. baumannii and A. nosocomialis nosocomial pneumonias were grouped as a single clinical entity previously. This study aimed to determine whether they are the same or a different clinical entity. A total of 121 patients with A. baumannii and 131 with A. nosocomialis bacteremic nosocomial pneumonia were included during an 8-year period. Despite the similar Charlson co-morbidity scores at admission, patients with A. baumannii pneumonia were more likely to have abnormal haematological findings, lobar pneumonia, significantly higher Acute Physiology and Chronic Health Evaluation II scores and higher frequency of shock at the onset of bacteraemia than those with A. nosocomialis pneumoni. A. baumannii isolates were resistant to more classes of antimicrobials, except colistin, and therefore the patients with A. baumannii pneumonia were more likely to receive inappropriate antimicrobial therapy. The 14-day mortality was significantly higher in patients with A. baumannii pneumonia (34.7% vs. 15.3%, p 0.001). A. baumannii was an independent risk factor for mortality (OR, 2.03; 95% CI, 1.05-3.90; p 0.035) in the overall cohort after adjustment for other risk factors for death, including inappropriate antimicrobial therapy. The results demonstrated the difference in clinical presentation, microbial characteristics and outcomes between A. baumannii and A. nosocomialis nosocomial pneumonia, and supported that they are two distinct clinical entities.
Huttunen, Reetta; Syrjänen, Jaana; Aittoniemi, Janne; Oja, Simo S; Raitala, Annika; Laine, Janne; Pertovaara, Marja; Vuento, Risto; Huhtala, Heini; Hurme, Mikko
Indoleamine 2,3-dioxygenase (IDO), which is the rate-limiting enzyme for tryptophan (trp) catabolism, may play a critical role in various inflammatory disorders. Recent studies on trauma patients have suggested that the degradation of trp is associated with the development of sepsis. The role of IDO activity in bacteremic patients is unclear. We studied IDO activity in 132 patients with bacteremia caused by Staphylococcus aureus, Streptococcus pneumoniae, beta-hemolytic streptococcae, or Eschericia coli. The serum concentrations of trp and its metabolite kynurenine (kyn) were measured by reverse-phase high-performance liquid chromatography 1 to 4 days after the positive blood culture and on recovery. The kyn-to-trp ratio (kyn/trp), reflecting the activity of the IDO enzyme, was calculated. The maximum value in the ratio for every patient during 1 to 4 days after positive blood culture was used in analysis. The maximum kyn/trp ratio was significantly higher in nonsurvivors versus those who survived (193.7 vs. 82.4 micromol/mmol; P = 0.001). The AUC(ROC) of maximal kyn/trp in the prediction of case fatality was 0.75 (95% confidence interval, 0.64-0.87), and the kyn/trp ratio at a cutoff level of 120 micromol/mmol showed 83% sensitivity and 69% specificity for fatal disease. A kyn/trp ratio greater than 120 micromol/mmol was associated with increased risk of death versus low (
Ciprero, Karen; Zykov, Kirill A; Briko, Nikolay I; Shekar, Tulin; Sterling, Tina M; Bitieva, Elizaveta; Stek, Jon E; Musey, Luwy
Pneumococcal infection is a major cause of pneumonia, bacteremia, and meningitis. Incidence of pneumococcal disease (PD) varies worldwide. The 23-valent pneumococcal polysaccharide vaccine (PPV23) displays an acceptable safety profile and has been demonstrated cost-effective in reducing burden of PD.
Fan, Roger R.; Howard, Leigh M.; Griffin, Marie R.; Edwards, Kathryn M.; Zhu, Yuwei; Williams, John V.; Vidal, Jorge E.; Klugman, Keith P.; Gil, Ana I.; Lanata, Claudio F.
We examined nasopharyngeal pneumococcal colonization density patterns surrounding acute respiratory illnesses (ARI) in young children in Peru. Pneumococcal densities were dynamic, gradually increasing leading up to an ARI, peaking during the ARI, and decreasing after the ARI. Rhinovirus co-infection was associated with higher pneumococcal densities. PMID:27767919
Zielen, S.; Bühring, I.; Strnad, N.; Reichenbach, J.; Hofmann, D.
There is still a lack of effective vaccination strategies for patients with a deficient antibody response to bacterial polysaccharide antigens. In an open trial, we evaluated the immunogenicity and tolerance of a new 7-valent pneumococcal conjugate vaccine in 22 infection-prone nonresponders to pneumococcal polysaccharide vaccine and 21 controls. In the patient group, nonresponsiveness was confirmed by repeated vaccination with a 23-valent pneumococcal polysaccharide vaccine. The study protocol provided two doses of the pneumococcal conjugate vaccine, given 4 to 6 weeks apart, for both groups. The antibody response was determined before each vaccination and on follow-up by an enzyme-linked immunosorbent assay and compared to the response in a functional opsonophagocytosis assay. Patients showed a significantly lower postvaccination immune response for all serotypes than did controls. The postvaccination response was serotype dependent. A median titer of >1 μg/ml in patients was recorded only for serotypes 4, 9V, 14, and 19F, which are known to be more immunogenic than serotypes 6B, 18C, and 23F. In the patient group, 70% responded to serotype 19F (Pnc 19F), 65% responded to Pnc 14 and 4, 60% responded to Pnc 9V, 55% responded to Pnc 18C, 50% responded to Pnc 23F, and 25% responded to Pnc 6B. In the control group >95% of individuals showed a titer of >1 μg/ml to every serotype. The vaccine was tolerated well, and no major side effects have been reported. The new pneumococcal conjugate vaccine is clearly more immunogenic in previous nonresponders than is the 23-valent pneumococcal vaccine. Immunization with a pneumococcal conjugate vaccine should be considered as a strategy to protect high-risk patients. PMID:10678957
Geno, K. Aaron; Gilbert, Gwendolyn L.; Song, Joon Young; Skovsted, Ian C.; Klugman, Keith P.; Jones, Christopher; Konradsen, Helle B.
SUMMARY Streptococcus pneumoniae (the pneumococcus) is an important human pathogen. Its virulence is largely due to its polysaccharide capsule, which shields it from the host immune system, and because of this, the capsule has been extensively studied. Studies of the capsule led to the identification of DNA as the genetic material, identification of many different capsular serotypes, and identification of the serotype-specific nature of protection by adaptive immunity. Recent studies have led to the determination of capsular polysaccharide structures for many serotypes using advanced analytical technologies, complete elucidation of genetic basis for the capsular types, and the development of highly effective pneumococcal conjugate vaccines. Conjugate vaccine use has altered the serotype distribution by either serotype replacement or switching, and this has increased the need to serotype pneumococci. Due to great advances in molecular technologies and our understanding of the pneumococcal genome, molecular approaches have become powerful tools to predict pneumococcal serotypes. In addition, more-precise and -efficient serotyping methods that directly detect polysaccharide structures are emerging. These improvements in our capabilities will greatly enhance future investigations of pneumococcal epidemiology and diseases and the biology of colonization and innate immunity to pneumococcal capsules. PMID:26085553
Smith, M. D.; Stuart, J.; Andrews, N. J.; Telfer Brunton, W. A.; Cartwright, K. A.
Variation in the incidence of invasive pneumococcal disease across South and West England, in 1995, was measured through a survey of microbiology laboratories. A 100% response rate was achieved. The incidence by laboratory varied between 5.2 and 20.4 per 100,000 catchment population (P < 0.001). Adjusting for pneumococcal vaccine uptake rate in over 65 year olds, hospital admission rates, blood culture system used and for the age and sex structure of the population, did not account for this variation. When blood culture sampling rates were included in a logistic regression model, the variation between laboratories was much less and of lower statistical significance (P = 0.019). Higher rates of blood culture sampling were associated with a higher incidence of invasive pneumococcal disease. Consistently high sampling should be encouraged because a higher diagnostic rate should result in more selective prescribing of antibiotics, and secondly because improved ascertainment of severe pneumococcal infections is a prerequisite for the evaluation of new pneumococcal conjugate vaccines. PMID:9593479
Ouédraogo-Traoré, Rasmata; Medah, Isaïe; Sangare, Lassana; Yaméogo, Issaka; Sawadogo, Guetawendé; Ouédraogo, Abdoul-Salam; Hema-Ouangraoua, Soumeya; McGee, Lesley; Srinivasan, Velusamy; Aké, Flavien; Congo-Ouédraogo, Malika; Sanou, Soufian; Ba, Absatou Ky; Novak, Ryan T.; Van Beneden, Chris
Background Following introduction of Haemophilus influenzae type b vaccine in 2006 and serogroup A meningococcal conjugate vaccine in 2010, Streptococcus pneumoniae (Sp) became the leading cause of bacterial meningitis in Burkina Faso. We describe bacterial meningitis epidemiology, focusing on pneumococcal meningitis, before 13-valent pneumococcal conjugate vaccine (PCV13) introduction in the pediatric routine immunization program in October 2013. Methods Nationwide population-based meningitis surveillance collects case-level demographic and clinical information and cerebrospinal fluid (CSF) laboratory results. Sp infections are confirmed by culture, real-time polymerase chain reaction (rt-PCR), or latex agglutination, and CSF serotyped using real-time and conventional PCR. We calculated incidence rates in cases per 100,000 persons, adjusting for age and proportion of cases with CSF tested at national reference laboratories, and case fatality ratios (CFR). Results During 2011–2013, 1,528 pneumococcal meningitis cases were reported. Average annual adjusted incidence rates were 26.9 (<1 year), 5.4 (1–4 years), 7.2 (5–14 years), and 3.0 (≥15 years). Overall CFR was 23% and highest among children aged <1 year (32%) and adults ≥30 years (30%). Of 1,528 cases, 1,036 (68%) were serotyped: 71% were PCV13-associated serotypes, 14% were non-PCV13-associated serotypes, and 15% were non-typeable by PCR. Serotypes 1 (45%) and 12F/12A/12B/44/46 (8%) were most common. Among children aged <1 year, serotypes 5 (15%), 6A/6B (13%) and 1 (12%) predominated. Conclusions In Burkina Faso, the highest morbidity and mortality due to pneumococcal meningitis occurred among children aged <1 year. The majority of cases were due to PCV13-associated serotypes; introduction of PCV13 should substantially decrease this burden. PMID:27832151
Goldblatt, D; Tan, C Y; Burbidge, P; McElhiney, S; McLaughlin, L; Tucker, R; Rauh, M; Sidhu, M; Giardina, P C
The pneumococcal enzyme-linked immunosorbent assay (ELISA) reference standard serum, lot 89SF, has been in use since 1990 and was replaced in 2013 with a new reference standard, 007sp, that is projected to be available for the next 25 years. 007sp was generated under an FDA-approved clinical protocol; 278 adult volunteers were immunized with the 23-valent unconjugated polysaccharide vaccine Pneumovax II, and a unit of blood was obtained twice from each immunized subject within 120 days following immunization. Pooled serum was prepared from the plasma of 262 subjects, filled at 6 ml per vial, and lyophilized. Five independent laboratories participated in bridging the serotype-specific IgG assignments for 89SF to the new reference standard, 007sp, to establish equivalent reference values for 13 pneumococcal capsular serotypes (1,3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) by using the WHO reference ELISA. In a second study involving three laboratories, a similar protocol was used to assign weight-based IgG concentrations in micrograms per ml to 007sp of seven serotypes (8, 10A, 11A, 12F, 15B, 22F, and 33F) also present in the 23-valent pneumococcal unconjugated polysaccharide vaccine. In addition, the IgG assignments for a 12-member WHO quality control (QC) serum panel were also extended to cover these seven serotypes. Agreement was excellent, with a concordance correlation coefficient (r(c)) of >0.996 when each laboratory was compared to the assigned values for the 12 WHO QC serum samples. There are four remaining pneumococcal serotypes (2, 9N, 17F, and 20) found in Pneumovax II for which IgG assignments exist for 89SF and remain to be bridged.
Reiné, J; Zangari, T; Owugha, JT; Pennington, SH; Gritzfeld, JF; Wright, AD; Collins, AM; van Selm, S; de Jonge, MI; Gordon, SB; Weiser, JN; Ferreira, DM
The ability of pneumococcal conjugate vaccine (PCV) to decrease transmission by blocking the acquisition of colonization has been attributed to herd immunity. We describe the role of mucosal IgG to capsular polysaccharide (CPS) in mediating protection from carriage, translating our findings from a murine model to humans. We used a flow-cytometric assay to quantify antibody-mediated agglutination demonstrating that hyperimmune sera generated against an unencapsulated mutant was poorly agglutinating. Passive immunization with this antiserum was ineffective to block acquisition of colonization compared to agglutinating antisera raised against the encapsulated parent strain. In the human challenge model samples were collected from PCV and control vaccinated adults. In PCV-vaccinated subjects IgG levels to CPS were increased in serum and nasal wash (NW). IgG to the inoculated strain CPS dropped in NW samples after inoculation suggesting its sequestration by colonizing pneumococci. In post-vaccination NW samples pneumococci were heavily agglutinated compared to pre-vaccination samples in subjects protected against carriage. Our results indicate that pneumococcal agglutination mediated by CPS specific antibodies is a key mechanism of protection against acquisition of carriage. Capsule may be the only vaccine target that can elicit strong agglutinating antibody responses, leading to protection against carriage acquisition and generation of herd immunity. PMID:27579859
Phuphuakrat, Angsana; Ngamjanyaporn, Pintip; Nantiruj, Kanokrat; Luangwedchakarn, Voravich; Malathum, Kumthorn
Septic arthritis caused by Streptococcus pneumoniae is uncommon. Most of the patients who have invasive pneumococcal infection have underlying diseases associated with impaired immune function. We report a case of polyarticular pneumococcal septic arthritis in a previously healthy adult as the first manifestation of selective immunoglobulin (Ig)M deficiency. The patient had no evidence of autoimmune disease or malignancy. Serum IgG, IgA, and complement levels were normal. Numbers of lymphocyte subsets were in normal range except that of CD4+ cells, which was slightly low. Invasive pneumococcal disease in a healthy adult should lead to further investigation for underlying diseases including primary immunodeficiencies.
Katkocin, D M
A new heptavalent pneumococcal conjugate vaccine, designed to protect against disease due to serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F, was formulated with aluminium phosphate adjuvant and analysed before testing in infants. Analyses were complicated by the presence of the adjuvant, and by the low level of each antigen; for example, all serotypes were formulated at 2 microg of saccharide /dose (except 6B which was formulated at 4 microg). Type specific analyses were performed on the formulated vaccine, and included determination of immunogenicity and antigenicity; the former was measured by ELISA following immunization of rabbits, the latter was measured by rate nephelometry. Non serotype specific information was also collected, and included total and adsorbed saccharide (by Anthrone assay), and total and adsorbed protein (by Lowry assay). These preclinical data supported the use of the vaccine in infants in a large randomized double-blinded clinical trial in a multiethnic population. The results of this trial show that the vaccine is safe and efficacious. Collectively, the data will be used to support licensure of the heptavalent vaccine, and documents successful scale-up of the formulation process to manufacturing level.
Conjugated pneumococal vaccines had a notable impact on prevention of invasive pneumococcal disease (IPD) in vacccinated and non vaccinated (herd immunity) populations. In Chile a 10 valent conjugated vaccine (PCV10) was introduced in the Nacional Immunization Program (NIP) in 2011, initially in a 3+1 schedule at 2, 4, 6 and 12 months of age, and since 2012 in a 2+1 schedule (2, 4 and 12 months). In prematures schedule 3+1 was maintained. No catch up or high risk groups vaccination strategies were used. The inclusion of PCV10 has reduced the rates of IPD; 66% in infants less than 12 months old and a 60% in 12-24 months old. After 3 years of the introduction of PCV10, no herd immunity has been seen. Serotype replacement shows an increase of ST 3 but not ST19A. Surveillance shows that another vaccine with 13 serotypes (PCV13) would cover an additional 5 to 10% of cases. The nule herd immunity and more extense coverage of PCV13, suggests that NIP should switch from PCV10 to PCV13.
Harris, Aaron M; Beekmann, Susan E; Polgreen, Philip M; Moore, Matthew R
Streptococcus pneumoniae (pneumococcus) is the most common bacterial etiology of community-acquired pneumonia (CAP) in adults, a leading cause of death. The majority of pneumococcal CAP is diagnosed by blood culture, which likely underestimates the burden of disease. The 2007 CAP guidelines recommend routine use of the rapid pneumococcal urinary antigen (UAg) test. To assess the how pneumococcal UAg testing is being used among hospitalized adult CAP patients and what barriers restrict its use, a Web-based survey was distributed in 2013 to 1287 infectious disease physician members of the Emerging Infectious disease Network of the Infectious Disease Society of America. Of 493 eligible responses, 65% use the pneumococcal UAg test. The primary barrier to UAg use was availability (46%). UAg users reported ordering fewer other diagnostic tests and tailoring antibiotic therapy. Increased access to UAg tests could improve pneumonia management and pneumococcal CAP surveillance.
Werno, Anja M; Murdoch, David R
The laboratory diagnosis of invasive pneumococcal disease (IPD) continues to rely on culture-based methods that have been used for many decades. The most significant recent developments have occurred with antigen detection assays, whereas the role of nucleic acid amplification tests has yet to be fully clarified. Despite developments in laboratory diagnostics, a microbiological diagnosis is still not made in most cases of IPD, particularly for pneumococcal pneumonia. The limitations of existing diagnostic tests impact the ability to obtain accurate IPD burden data and to assess the effectiveness of control measures, such as vaccination, in addition to the ability to diagnose IPD in individual patients. There is an urgent need for improved diagnostic tests for pneumococcal disease--especially tests that are suitable for use in underresourced countries.
A number of significant challenges remain with regard to the diagnosis, treatment, and prevention of infections with Streptococcus pneumoniae (pneumococcus), which remains the most common bacterial cause of community-acquired pneumonia. Although this infection is documented to be extremely common in younger children and in older adults, the burden of pneumonia it causes is considerably underestimated, since the incidence statistics are derived largely from bacteremic infections, because they are easy to document, and yet the greater burden of pneumococcal pneumonias is non-invasive. It has been estimated that for every bacteremic pneumonia that is documented, three non-bacteremic infections occur. Management of these infections is potentially complicated by the increasing resistance of the isolates to the commonly used antibiotics. Furthermore, it is well recognized that despite advances in medical care, the mortality of bacteremic pneumococcal pneumonia has remained largely unchanged over the past 50 years and averages approximately 12%. Much recent research interest in the field of pneumococcal infections has focused on important virulence factors of the organism, on improved diagnostic and prognostication tools, on defining risk factors for death, on optimal treatment strategies involving both antibiotics and adjunctive therapies, and on disease prevention. It is hoped that through these endeavors the outlook of pneumococcal infections will be improved. PMID:25343039
Godot, Cécile; Levy, Corinne; Varon, Emmanuelle; Picard, Capucine; Madhi, Fouad; Cohen, Robert
We collected cases of pneumococcal meningitis vaccine breakthrough (VBT) and vaccine failure (VF) from 2003 to 2013 after the implementation of pneumococcal conjugate vaccines (PCVs) in France. VBT accounted for 3.2% of the cases (PCV7 era: 24 of 943, PCV13 era: 15 of 290) and VF 0.6% (PCV7 era: 6 of 943, PCV13 era: 2 of 290). VBT and VF are rare and occur in most cases in children younger than 2 years. The serotype 19F was the most frequent cause even after the introduction of PCV13.
Chetty, C; Kreger, A
hypothesis that activity is associated with pneumococcal peptidoglycan solubilized by the bacterium's autolysin.
Background Conflicting results have been recently reported evaluating the relationship between pneumococcal vaccination and the risk of thrombotic vascular events. This study assessed the clinical effectiveness of the 23-valent polysaccharide pneumococcal vaccine (PPV23) against acute myocardial infarction and ischaemic stroke in older adults. Methods Population-based prospective cohort study conducted from December 1, 2008 until November 30, 2009, including all individuals ≥ 60 years-old assigned to nine Primary Care Centres in Tarragona, Spain (N = 27,204 individuals). Primary outcomes were hospitalisation for acute myocardial infarction and/or ischaemic stroke. All cases were validated by checking clinical records. The association between pneumococcal vaccination and the risk of each outcome was evaluated by Multivariable Cox proportional-hazard models (adjusted by age, sex, influenza vaccine status, presence of comorbidities and cardiovascular risk factors). Results Cohort members were followed for a total of 26,444 person-years, of which 34% were for vaccinated subjects. Overall incidence rates (per 1000 person-years) were 4.9 for myocardial infarction and 4.6 for ischaemic stroke. In the multivariable analysis, vaccination was associated with a marginally significant 35% lower risk of stroke (hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.42-0.99; p = 0.046). We found no evidence for an association between pneumococcal vaccination and reduced risk of myocardial infarction (HR: 0.83; 95% CI: 0.56-1.22; p = 0.347). Conclusions Our data supports a benefit of PPV23 against ischaemic stroke among the general population over 60 years, suggesting a possible protective role of pneumococcal vaccination against some acute thrombotic events. PMID:22436146
Zhang, Yan-Yang; Tang, Xue-Feng; Du, Chang-Hui; Wang, Bin-Bing; Bi, Zhen-Wang; Dong, Bi-Rong
ABSTRACT The purpose of this study was to perform a meta-analysis comparing the effectiveness of influenza vaccination alone versus influenza plus pneumococcal dual vaccination for the prevention of pneumonia and mortality in adults ≥ 65 years of age. Medline, Cochrane, CENTRAL, EMBASE, and Google Scholar databases were searched. Inclusion criteria were: 1) Randomized controlled trials (RCTs), 2-arm prospective studies, or retrospective cohort studies; 2) Patients were ≥ 65 years of age with or without chronic respiratory disease; 3) Patients received the influenza vaccine alone or dual pneumococcal and influenza vaccination; 4) Results included incidence of recurrent respiratory tract infections, length of hospital stay, and overall mortality rate. The outcomes were pneumonia and all-cause mortality rates. Of 142 studies identified in the database searches, 6 were ultimately included in the systematic review, and 5 were included in meta-analysis. The number of patients that received the influenza vaccination alone ranged from 211 to 29,346 (total = 53,107), and the number that received influenza+pneumococcal vaccination ranged from 246 to 72,107 (total = 102,068). Influenza+pneumococcal vaccination was associated with a significantly lower pneumonia rate than influenza vaccination alone (relative risk [RR] = 0.835, 95% confidence interval [CI]: 0.718–0.971, P = 0.019), and with a significantly lower all-cause mortality rate than influenza vaccination alone (relative risk [RR] = 0.771, 95% confidence interval [CI]: 0.707–0.842, P = 0.001). In conclusion, the results of this study support concomitant pneumococcal and influenza vaccination of the elderly as a dual vaccination strategy is associated with lower pneumonia and all-cause mortality rates. PMID:27629584
Picazo, Juan Jose; Contreras, Jesús Ruiz; Ríos, Esther; Culebras, Esther; Rodríguez-Avial, Iciar; Méndez, Cristina; Betriu, Carmen
The aim of this study was to evaluate the Binax NOW immunochromatographic pneumococcal antigen test for the identification of Streptococcus pneumoniae in pleural and cerebrospinal fluids from children with suspected invasive pneumococcal disease. The results were compared with those obtained by PCR. Binax NOW was applied to these samples as recommended by the manufacturer for urine and cerebrospinal samples. Detection of pneumococcal DNA was performed by real-time PCR assay targeting the autolysin gene (lytA). Of the 199 samples analyzed, 131 were positive by both Binax NOW and lytA PCR, and 36 samples were negative by both techniques. Using the real-time PCR as a comparative method to the Binax for the detection of S. pneumoniae, the sensitivity and specificity of Binax NOW was 88% and 72.5%, respectively. Of the 145 positive samples analyzed by Binax NOW, 119 showed intense coloring of the sample line and 26 showed weak intensity. Conventional culture is the most common method in clinical settings, but Binax NOW is an easier and faster test for identifying S. pneumoniae in pleural and cerebrospinal fluids from children with suspected invasive pneumococcal disease.
Kloek, Anne T.; van Setten, Jessica; van der Ende, Arie; Bots, Michiel L.; Asselbergs, Folkert W.; Serón, Mercedes Valls; Brouwer, Matthijs C.; van de Beek, Diederik; Ferwerda, Bart
Host genetic variability may contribute to susceptibility of bacterial meningitis, but which genes contribute to the susceptibility to this complex disease remains undefined. We performed a genetic association study in 469 community-acquired pneumococcal meningitis cases and 2072 population-based controls from the Utrecht Health Project in order to find genetic variants associated with pneumococcal meningitis susceptibility. A HumanExome BeadChip was used to genotype 102,097 SNPs in the collected DNA samples. Associations were tested with the Fisher exact test. None of the genetic variants tested reached Bonferroni corrected significance (p-value <5 × 10−7). Our strongest signals associated with susceptibility to pneumococcal meningitis were rs139064549 on chromosome 1 in the COL11A1 gene (p = 1.51 × 10−6; G allele OR 3.21 [95% CI 2.05–5.02]) and rs9309464 in the EXOC6B gene on chromosome 2 (p = 6.01 × 10−5; G allele OR 0.66 [95% CI 0.54–0.81]). The sequence kernel association test (SKAT) tests for associations between multiple variants in a gene region and pneumococcal meningitis susceptibility yielded one significant associated gene namely COL11A1 (p = 1.03 × 10−7). Replication studies are needed to validate these results. If replicated, the functionality of these genetic variations should be further studied to identify by which means they influence the pathophysiology of pneumococcal meningitis. PMID:27389768
Janoir, Claire; Cohen, Robert; Levy, Corinne; Bingen, Edouard; Lepoutre, Agnès; Gutmann, Laurent; Varon, Emmanuelle
In France, the use of the 7-valent pneumococcal conjugate vaccine (PCV7) lead to an overall significant decrease in PCV7 invasive pneumococcal disease (IPD) incidence. However, the decrease in vaccine serotype prevalence was partially counterbalanced by the serotype replacement phenomenon. In this study, we analyzed the role of the newly described serotype 6C as one of the replacement serotypes. This work was conducted on a large time scale from the early PCV7 era (2002-2003) to the PCV13 era (2010-2011), both on IPD strains recovered from the whole population and nasopharyngeal colonizing strains isolated in infant less than two years, who are known to be the main reservoir for pneumococci. Serotype 6C took advantage over 6A and 6B serotypes, which both decreased over time. A continuous and significant increase in 6C IPD was observed in adults along the study period; in contrast, in children less than two years, only an increase in 6C nasopharyngeal carriage was found, the prevalence of serotype 6C in IPD remaining very low over time. Among 101 6C invasive and colonizing strains studied by MLST, 24 STs were found to be related to three major clonal complexes, CC395, CC176, and CC315. STs related to CC176 tend to disappear after 2009 and were essentially replaced by ST386 (CC315), which dramatically increased over time. This clonal expansion may be explained by the erythromycin and tetracycline resistances associated with this clone. Finally, the decrease observed in nasopharyngeal 6C carriage since 2010, likely related to the PCV13 introduction in the French immunization schedule, is expected to lead to a decrease in 6C IPD in adults thereafter.
Janoir, Claire; Cohen, Robert; Levy, Corinne; Bingen, Edouard; Lepoutre, Agnès; Gutmann, Laurent; Varon, Emmanuelle
In France, the use of the 7-valent pneumococcal conjugate vaccine (PCV7) lead to an overall significant decrease in PCV7 invasive pneumococcal disease (IPD) incidence. However, the decrease in vaccine serotype prevalence was partially counterbalanced by the serotype replacement phenomenon. In this study, we analyzed the role of the newly described serotype 6C as one of the replacement serotypes. This work was conducted on a large time scale from the early PCV7 era (2002–2003) to the PCV13 era (2010–2011), both on IPD strains recovered from the whole population and nasopharyngeal colonizing strains isolated in infant less than two years, who are known to be the main reservoir for pneumococci. Serotype 6C took advantage over 6A and 6B serotypes, which both decreased over time. A continuous and significant increase in 6C IPD was observed in adults along the study period; in contrast, in children less than two years, only an increase in 6C nasopharyngeal carriage was found, the prevalence of serotype 6C in IPD remaining very low over time. Among 101 6C invasive and colonizing strains studied by MLST, 24 STs were found to be related to three major clonal complexes, CC395, CC176, and CC315. STs related to CC176 tend to disappear after 2009 and were essentially replaced by ST386 (CC315), which dramatically increased over time. This clonal expansion may be explained by the erythromycin and tetracycline resistances associated with this clone. Finally, the decrease observed in nasopharyngeal 6C carriage since 2010, likely related to the PCV13 introduction in the French immunization schedule, is expected to lead to a decrease in 6C IPD in adults thereafter. PMID:24603763
Horácio, Andreia N.; Lopes, Joana P.; Ramirez, Mário; Melo-Cristino, José
There is limited information on the serotypes causing non-invasive pneumococcal pneumonia (NIPP). Our aim was to characterize pneumococci causing NIPP in adults to determine recent changes in serotype prevalence, the potential coverage of pneumococcal vaccines and changes in antimicrobial resistance. Serotypes and antimicrobial susceptibility profiles of a sample of 1300 isolates recovered from adult patients (≥18 yrs) between 1999 and 2011 (13 years) were determined. Serotype 3 was the most frequent cause of NIPP accounting for 18% of the isolates. The other most common serotypes were 11A (7%), 19F (7%), 19A (5%), 14 (4%), 22F (4%), 23F (4%) and 9N (4%). Between 1999 and 2011, there were significant changes in the proportion of isolates expressing vaccine serotypes, with a steady decline of the serotypes included in the 7-valent conjugate vaccine from 31% (1999–2003) to 11% (2011) (P<0.001). Taking together the most recent study years (2009–2011), the potential coverage of the 13-valent conjugate vaccine was 44% and of the 23-valent polysaccharide vaccine was 66%. While erythromycin resistance increased from 8% in 1999–2003 to 18% in 2011 (P<0.001), no significant trend was identified for penicillin non-susceptibility, which had an average value of 18.5%. The serotype distribution found in this study for NIPP was very different from the one previously described for IPD, with only two serotypes in common to the ones responsible for half of each presentation in 2009–2011 – serotypes 3 and 19A. In spite of these differences, the overall prevalence of resistant isolates was similar in NIPP and in IPD. PMID:25075961
Whitelegg, Alison M E; Birtwistle, Jane; Richter, Alex; Campbell, John P; Turner, James E; Ahmed, Tarana M; Giles, Lynda J; Fellows, Mark; Plant, Tim; Ferraro, Alastair J; Cobbold, Mark; Drayson, Mark T; MacLennan, Calman A
The measurement of antibody responses to vaccination is useful in the assessment of immune status in suspected immune deficiency. Previous reliance on enzyme-linked immunoabsorbent assays (ELISA) has been cumbersome, time-consuming and expensive. The availability of flow cytometry systems has led to the development of multiplexed assays enabling simultaneous measurement of antibodies to several antigens. We optimized a flow cytometric bead-based assay to measure IgG and IgM concentrations in serum to 19 antigens contained in groups of bacterial subunit vaccines: pneumococcal vaccines, meningococcal vaccines, Haemophilus influenzae b (Hib), and tetanus and diphtheria toxoid vaccines. 89-SF was employed as the standard serum. The assay was used to determine specific antibody levels in serum from 193 healthy adult donors. IgG and pneumococcal IgM antibody concentrations were measurable across 3 log10 ranges encompassing the threshold protective IgG antibody levels for each antigen. There was little interference between antibody measurements by the 19-plexed assay compared with monoplexed assays, and a lack of cross-reactive IgG antibody, but evidence for cross-reacting IgM antibody for 3/19 pneumococcal antigens. 90th centile values for 15/19 IgG concentrations and 12/12 IgM concentrations of the 193 adult sera were within these ranges and percentages of sera containing protective IgG antibody levels varied from 4% to 95% depending on antigen. This multiplexed assay can simultaneously measure antibody levels to 19 bacterial vaccine antigens. It is suitable for use in standard clinical practice to assess the in vivo immune response to test vaccinations and measure absolute antibody levels to these antigens.
Lloyd, Adam; Patel, Nishma; Scott, David A; Runge, Claus; Claes, Christa; Rose, Markus
In Germany, the seven-valent conjugate vaccine Prevenar is recommended for use in children at high risk of pneumococcal disease. Recent data suggest that giving conjugate vaccine to all children may lead to a decline in pneumococcal disease in unvaccinated adults, a phenomenon known as herd immunity. This analysis evaluated the cost and economic consequences in Germany of vaccinating (1) children at high risk, (2) all children when considering only benefits for vaccinated individuals and (3) all children when also considering herd immunity benefits. Costs in the model included vaccination, management of meningitis, bacteraemia, pneumonia and acute otitis media, insurance payments to parents and the costs of care for long-term disabilities. The model estimated that the cost-effectiveness of vaccination would be 38,222 euros per life year gained in children at high risk and 100,636 euros per life year gained in all children when not considering herd immunity. When considering herd immunity effects, the model estimated that offering vaccination for all children would reduce adult deaths by 3,027 per year, and vaccination would be broadly cost neutral. The findings are sensitive to the effect of conjugate vaccine on the rates of pneumonia and invasive disease in the elderly. If the herd immunity effect of conjugate vaccination in Germany is similar to that observed elsewhere, offering vaccine to all children will be more attractive than the current policy of restricting vaccination to children at high risk of pneumococcal disease.
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Madhi, Shabir A; Nunes, Marta C
The introduction of pneumococcal conjugate vaccine (PCV) into the South African public immunization program since 2009 adopted a novel vaccination schedule of 3 doses at 6, 14 and 40 weeks of age. Over the past 5 y it has been shown that infant PCV immunization in South Africa is effective in reducing the burden of invasive pneumococcal disease (IPD) among HIV-infected and HIV-uninfected children. Furthermore, indirect protection of unvaccinated age-groups (including high risk groups such as HIV-infected adults) against IPD was demonstrated despite the absence of any substantial catch-up campaign of older children. This indirect effect against IPD is corroborated by the temporal reduction in vaccine-serotype colonization among age-groups targeted for PCV immunization as well as unvaccinated HIV-infected and HIV-uninfected adults, which was evident within 2 y of PCV introduction into the immunization program. Vaccine effectiveness has also been demonstrated in children against presumed bacterial pneumonia. The evaluation of the impact of PCV in South Africa, however, remains incomplete. The knowledge gaps remaining include the evaluation of PCV on the incidence of all-cause pneumonia hospitalization among vaccinated and unvaccinated age-groups. Furthermore, ongoing surveillance is required to determine whether there is ongoing replacement disease by non-vaccine serotypes, which could offset the early gains associated with the immunization program in the country.
Snyder, Christopher M; Begor, Wills; Berndt, Ernst R
Pharmaceutical companies have long been reluctant to invest in producing new vaccines for the developing world because they have little prospect of earning an attractive return. One way to stimulate such investment is the use of an advance market commitment, an innovative financing program that guarantees manufacturers a long-term market. Under this arrangement, international donors pay a premium for initial doses sold to developing countries. In exchange, companies agree to continue supplying the vaccine over the longer term at more sustainable prices. This article provides a preliminary economic analysis of a pilot advance market commitment program for pneumococcal vaccines, explaining the principles behind the program's design and assessing its early performance. Spurred by the advance market commitment--and other contemporaneous initiatives that also increased resources to vaccine suppliers--new, second-generation pneumococcal vaccines have experienced a much more rapid rollout in developing countries than older first-generation vaccines.
Periodic Lateralized Epileptiform Discharges (PLEDs) are usually seen in the context of destructive structural lesions of the cortex, more frequently in acute ischemic stroke and less common in tumours and meningoencephalitis, specially herpes simplex virus. Its origin and prognosis are uncertain but it is known that PLEDs are linked to epilectic seizures, including status epilepticus. We report on a 75-year old woman with pneumococcal meningoencephalitis who presented altered level of consciousness, acute focal deficits, convulsive seizures and PLEDs in left hemisphere. The finding of PLEDs on the electroencephalogram is related to focal lesions of heterogeneous origin, which up to date, have not been documented in pneumococcal infections of the central nervous system. Our case highlights the importance of identifying and addressing any modifiable etiologic factors of PLEDs. PMID:21703002
Bally, Lia; Grandgirard, Denis
Pneumococcal meningitis (PM) causes neurological sequelae in up to half of surviving patients. Neuronal damage associated with poor outcome is largely mediated by the inflammatory host response. Dexamethasone (DXM) is used as an adjuvant therapy in adult PM, but its efficacy in the treatment of pneumococcal meningitis in children is controversially discussed. While DXM has previously been shown to enhance hippocampal apoptosis in experimental PM, its impact on hippocampal cell proliferation is not known. This study investigated the impact of DXM on hippocampal proliferation in infant rat PM. Eleven-day-old nursing Wistar rats (n = 90) were intracisternally infected with Streptococcus pneumoniae to induce experimental meningitis. Treatment with DXM or vehicle was started 18 h after infection, concomitantly with antibiotics (ceftriaxone 100 mg/kg of body weight twice a day [b.i.d.]). Clinical parameters were monitored, and the amount of cells with proliferating activity was assessed using in vivo incorporation of bromodeoxyuridine (BrdU) and an in vitro neurosphere culture system at 3 and 4 d postinfection. DXM significantly worsened weight loss and survival. Density of BrdU-positive cells, as an index of cells with proliferating activity, was significantly lower in DXM-treated animals compared to vehicle controls (P < 0.0001). In parallel, DXM reduced neurosphere formation as an index for stem/progenitor cell density compared to vehicle treatment (P = 0.01). Our findings provide clear evidence that DXM exerts an antiproliferative effect on the hippocampus in infant rat PM. We conclude that an impairment of regenerative hippocampal capacity should be taken into account when considering adjuvant DXM in the therapeutic regimen for PM in children. PMID:26824948
Piantadosi, Claude A.; Benjamin, Ashlee M.; Lucas, Joseph E.; Zaas, Aimee K.; Betancourt-Quiroz, Marisol; Woods, Christopher W.; Chang, Alan L.; Roggli, Victor L.; Marshall, Craig D.; Ginsburg, Geoffrey S.; Welty-Wolf, Karen
Pneumococcal pneumonia is a leading cause of bacterial infection and death worldwide. Current diagnostic tests for detecting Streptococcus pneumoniae can be unreliable and can mislead clinical decision-making and treatment. To address this concern, we developed a preclinical model of pneumococcal pneumonia in nonhuman primates useful for identifying novel biomarkers, diagnostic tests, and therapies for human S. pneumoniae infection. Adult colony-bred baboons (n = 15) were infected with escalating doses of S. pneumoniae (Serotype 19A-7). We characterized the pathophysiological and serological profiles of healthy and infected animals over 7 days. Pneumonia was prospectively defined by the presence of three criteria: (1) change in white blood cell count, (2) isolation of S. pneumoniae from bronchoalveolar lavage fluid (BALF) or blood, and (3) concurrent signs/symptoms of infection. Animals given 109 CFU consistently met our definition and developed a phenotype of tachypnea, tachycardia, fever, hypoxemia, and radiographic lobar infiltrates at 48 hours. BALF and plasma cytokines, including granulocyte colony-stimulating factor, IL-6, IL-10, and IL-1ra, peaked at 24 to 48 hours. At necropsy, there was lobar consolidation with frequent pleural involvement. Lung histopathology showed alveolar edema and macrophage influx in areas of organizing pneumonia. Hierarchical clustering of peripheral blood RNA data at 48 hours correctly identified animals with and without pneumonia. Dose-dependent inoculation of baboons with S. pneumoniae produces a host response ranging from spontaneous clearance (106 CFU) to severe pneumonia (109 CFU). Selected BALF and plasma cytokine levels and RNA profiles were associated with severe pneumonia and may provide clinically useful parameters after validation. PMID:24328793
Miyahara, Hiroyuki; Maruyama, Hidehiko; Kanazawa, Akane; Iwasaki, Yuka; Shigemitsu, Yusuke; Watanabe, Hirokazu; Tokorodani, Chiho; Miyazawa, Mari; Nakata, Yusei; Nishiuchi, Ritsuo; Kikkawa, Kiyoshi
Since the introduction of the seven-valent pneumococcal conjugate vaccine (PCV7) in 2007, invasive pneumococcal disease has declined, but the incidence of Streptococcus pneumoniae serotype 19A has risen worldwide. The present study examined changes in the features of invasive pneumococcal disease since the introduction of the PCV7 in Kochi, Japan. Pediatric cases of invasive pneumococcal disease were investigated before and after vaccine introduction (January 2008 to December 2013). Cases of invasive pneumococcal disease tended to decrease after PCV7 introduction. In addition, before introduction of the vaccine, most serotypes causing invasive pneumococcal disease were those included in the vaccine. However, after the introduction, we found cases infected by serotypes not covered by vaccine. Penicillin-resistant S. pneumoniae was the predominant serotype causing invasive pneumococcal disease before introduction of the PCV7, and the susceptibility of this serotype to antibiotics improved after vaccine introduction. Serotype isolates identified after vaccine introduction were also relatively susceptible to antibiotic therapy, but decreased susceptibility is expected.
Sparding, Nadja; Dayie, Nicholas T K D; Mills, Richael O; Newman, Mercy J; Dalsgaard, Anders; Frimodt-Møller, Niels; Slotved, Hans-Christian
Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide. Pneumococcal strains are classified according to their capsular polysaccharide and more than 90 different serotypes are currently known. In this project, three distinct groups of pneumococcal carriage isolates from Ghana were investigated; isolates from healthy children in Tamale and isolates from both healthy and children attending the outpatient department at a hospital in Accra. The isolates were previously identified and characterized by Gram staining, serotyping and susceptibility to penicillin. In this study, isolates of the common serotype 19F were further investigated by Multi-Locus Sequence Typing (MLST). Overall, 14 different Sequence Types (STs) were identified by MLST, of which nine were novel based on the international MLST database. Two clones within serotype 19F seem to circulate in Ghana, a known ST (ST 4194) and a novel ST (ST 9090). ST 9090 was only found in healthy children in Accra, whereas ST 4194 was found equally in all children studied. In the MLST database, other isolates of ST 4194 were also associated with serotype 19F, and these isolates came from other West African countries. The majority of isolates were penicillin intermediate resistant. In conclusion, two clones within serotype 19F were found to be dominating in pneumococcal carriage in Accra and Tamale in Ghana. Furthermore, it seems as though the clonal distribution of serotype 19F may be different from what is currently known in Ghana in that many new clones were identified. This supports the importance of continued monitoring of pneumococcal carriage in Ghana and elsewhere when vaccines, e.g., PCV-13, have been introduced to monitor the possible future spread of antimicrobial resistant clones.
Martinelli, Domenico; Pedalino, Biagio; Cappelli, Maria Giovanna; Caputi, Giovanni; Sallustio, Anna; Fortunato, Francesca; Tafuri, Silvio; Cozza, Vanessa; Germinario, Cinzia; Chironna, Maria; Prato, Rosa; surveillance of pediatric IPD, Apulian Group for the
Pneumococcal disease epidemiology has changed after introduction of pneumococcal conjugate vaccines. Seven-valent vaccine (PCV7) has been effective in reducing invasive pneumococcal disease (IPD). In Europe, PCV13 effectiveness was estimated at 78% (95% CI: −18–96%) for 2-priming doses. In Italy, PCV7 was introduced in 2006 in the childhood immunization schedule and replaced with PCV13 in 2010. In Apulia, vaccination coverage has reached 95.1% (birth-cohort 2010). We estimated PCV program effectiveness and its impact on S. pneumoniae diseases. PCV Effectiveness: We used the screening method. We calculated the Proportion of Population Vaccinated from immunization registries and detected cases through a laboratory-confirmed surveillance among hospitalized children ≤60 months. A confirmed IPD case was a child with PCR positive for S. pneumoniae. Differences among children were assessed with the Chi-square or the Fisher exact test (P value < 0.05). PCV Impact: We constructed time series using outcome-specific Poisson regression models: hospitalization rate in pre-PCV era and hospitalization risk ratios (RRs) with 95% CIs for both PCV7 and PCV7/PCV13 shifting era. We calculated hospitalization RR with 95% CIs comparing pre-PCV years with vaccination period. The PCV effectiveness was 84.3% (95% CI: 84.0–84.6%). In May 2010-January 2013, we enrolled 159 suspected IPD of whom 4 were confirmed. Two (fully vaccinated) were caused by serotype 9V, 1 (not vaccinated) by serotype 3, 1 (vaccinated with 2 PCV13 doses) by 15B/C. The most important reduction was for pneumococcal pneumonia (RR: 0.43, 95% CI: 0.21–0.90). The PCV program show promising results in terms of both PCV13 effectiveness and its impact in reducing IPD in children <5 years. PMID:24096297
Giglio, Norberto; Micone, Paula; Gentile, Angela
Streptococcus pneumoniae continues to be the most important causative agent of invasive bacterial infections in children and is the most common cause of vaccine-preventable deaths in children less than 5 years of age. Due to some conditions in the Latin America region, economic assessments of pneumococcal conjugate vaccines (PCVs) have unique characteristics. First, distribution of S. pneumoniae serotypes, and thus coverage by vaccines that incorporate certain serotypes, varies within the region and compared with other parts of the world. Second, the mortality rate of pneumococcal infections in developing countries is significantly higher than in the US and Europe. Third, the economies of the Latin American region are very different from those of developed countries. For these reasons, the Pan American Health Organization (PAHO) is promoting the need for economic valuation studies of the impact of pneumococcal vaccines Latin America. Given the importance of pneumonia in the burden of pneumococcal disease in Latin America, the number of pneumonia cases prevented by the vaccine has a large impact on the economic valuation of PCVs, due to a strong correlation with numbers of deaths averted, quality-adjusted life-years (QALYs) gained or disability-adjusted life-years (DALYs) avoided. In terms of cost, analysis of impact on acute otitis media (short-term) and sequelae (long-term) show a significant and important expenditure avoided by vaccination. Cost-effectiveness is significantly modified by vaccine cost, mortality due to pneumonia, vaccine efficacy/effectiveness and herd immunity. Finally the validity of certain assumptions based on the uncertainty of the data should be considered in economic assessments of new PCVs. These include assumptions related to the impact on otitis media, estimates of efficacy/effectiveness based on measured antibody levels and the extrapolation to PCV10 and PCV13 of previous experience with PCV7.
Less than 1 year after recommendations for the routine vaccination of infants with the newly licensed 7-valent polysaccharide-protein conjugate pneumococcal vaccine were issued in February 2000, shortages of the 7-valent polysaccharide-protein conjugate pneumococcal vaccine supply began to occur. A national shortage developed in 2001, involving both the public and private sectors, and it resulted in temporary recommendations to conserve vaccine supply for infants and young children at the highest risk for invasive disease. Multiple factors contributed to this vaccine shortage, including demand that exceeded the expectations of the manufacturer and the need for compliance with the Good Manufacturing Practice of the US Food and Drug Administration. Of the possible strategies that might have averted this shortage, establishment of a vaccine stockpile is the most likely solution. However, establishing a stockpile for a newly licensed vaccine, such as 7-valent polysaccharide-protein conjugate pneumococcal vaccine, presents unique challenges. Improved communication with physicians and parents regarding changes in vaccine schedules also will promote better adherence to recommended changes and conservation of limited vaccine supplies during a shortage.
Chewapreecha, Claire; Harris, Simon R; Croucher, Nicholas J; Turner, Claudia; Marttinen, Pekka; Cheng, Lu; Pessia, Alberto; Aanensen, David M; Mather, Alison E; Page, Andrew J; Salter, Susannah J.; Harris, David; Nosten, Francois; Goldblatt, David; Corander, Jukka; Parkhill, Julian
Evasion of clinical interventions by Streptococcus pneumoniae occurs through selection of non-susceptible genomic variants. Here we use genome sequencing of 3,085 pneumococcal carriage isolates from a 2.4 km2 refugee camp to enable unprecedented resolution of the process of recombination, and highlight its impact on population evolution. Genomic recombination hotspots show remarkable consistency between lineages, indicating common selective pressures acting at certain loci, particularly those associated with antibiotic resistance. Temporal changes in antibiotic consumption are reflected in changes in recombination trends demonstrating rapid spread of resistance when selective pressure is high. The highest frequencies of receipt and donation of recombined DNA fragments were observed in non-encapsulated lineages, implying that this largely overlooked pneumococcal group, which is beyond the reach of current vaccines, may play a major role in genetic exchange and adaptation of the species as a whole. These findings advance our understanding of pneumococcal population dynamics and provide important information for the design of future intervention strategies. PMID:24509479
Hernandez-Bou, Susanna; Garcia-Garcia, Juan Jose; Gene, Amadeu; Esteva, Cristina; del Amo, Eva; Muñoz-Almagro, Carmen
Between April 2004 and March 2006 an oropharyngeal swab was obtained from 502 asymptomatic children, aged 6 months to 6 years, at a tertiary children's hospital outpatient department to assess the pneumococcal colonisation rate, risk factors, serotype distribution and antimicrobial susceptibility. Only 126 (25.3%) children had received ≥ 1 dose of PCV7. The pneumococcal carriage rate was 23.5%. Carrier rates were significantly higher in children aged ≥ 24 months and children attending daycare center. Thirty six (31.0%) of the isolates were contained in PCV7, 39 (33.6%) in PCV10 and 62 (53.4%) in PCV13. Forty-four strains (37.9%) were resistant to penicillin. Vaccine serotype (VT) strains were more likely to be penicillin-nonsusceptible S. pneumoniae than non-PCV7 serotype (NVT) strains (66.7% vs. 21.6%; P < 0.001). In our pediatric population, NVT were predominant among pneumococcal carriers whereas antibiotic resistance was significantly associated with VT. PCV13 can substantially increase the serotype coverage of S.pneumoniae in healthy carriers.
Pickren, Elizabeth; Crane, Brad
Background: Centers for Disease Control and Prevention (CDC) guidelines for pneumococcal vaccinations were updated in 2014. Given the complexity of the guidelines and the fact that hospitals are no longer required to keep records for pneumococcal vaccinations, many hospitals are determining whether to continue this service. Objective: The primary objective of this study was to determine the impact on compliance with the revised pneumococcal vaccination guidelines from the CDC after involving pharmacy in the screening and selection processes. Secondary objectives were to determine the impact of the new process on inappropriate vaccination duplications, the time spent by pharmacy on assessments, and financial outcomes. Methods: This institutional review board (IRB)-approved, retrospective, cohort study examined all patients who received a pneumococcal vaccination from January to February 2016 after implementing a new process whereby pharmacy performed pneumococcal vaccination screening and selection (intervention group). These patients were compared to patients who received a pneumococcal vaccination from January to February 2015 (control group). Results: Of 274 patients who received a pneumococcal vaccine, 273 were included in the study. Compliance to CDC guidelines increased from 42% to 97%. Noncompliant duplications decreased from 16% to 2%. In the intervention group, labor cost for assessments and expenditure for vaccines increased. For Medicare patients, the increased reimbursement balanced the increased expenditure in the intervention group. Conclusions: Involving pharmacy in the pneumococcal vaccine screening and selection process improves compliance to CDC guidelines, but further clinical and financial analysis is needed to determine financial sustainability of the new process.
Deng, Xianding; Memari, Nader; Teatero, Sarah; Athey, Taryn; Isabel, Marc; Mazzulli, Tony; Fittipaldi, Nahuel; Gubbay, Jonathan B.
Background: Molecular typing is essential for inferring genetic relatedness between bacterial pathogens. In this study, we applied whole genome sequencing (WGS) for rapid prediction of sequence type and antibiotic resistance for invasive pneumococcal isolates. Methods: 240 isolates from adults (≥50 years old) in Ontario, Canada during 2009 to 2013 were subjected to WGS. Sequence type, antibiotic susceptibility and resistance were predicted directly from short reads. Emerging non-vaccine serotype 22F was further characterized by WGS. Results: Sequence type was successfully determined for 98.3% of isolates. The overall sensitivity and specificity for antibiotic resistance prediction were 95 and 100% respectively, compared to standard susceptibility testing methods. WGS-based phylogeny divided emerging 22F (ST433) strains into two distinct clades: clade A harboring a 23 kb-prophage and anti-phage PhD/Doc system and clade B with virulence-related proteases. Five isolates in clade A developed macrolide resistance via 5.1 kb mega element recombination (encoding mefE and msrD), while one isolate in clade B displayed quinolone resistance via a gyrA mutation. Conclusions: WGS is valuable for routine surveillance of pneumococcal clinical isolates and facilitates prediction of genotype and antibiotic resistance. The emergence of 22F in Ontario in the post-vaccine era and evidence of evolution and divergence of the 22F population warrants heightened pneumococcal molecular surveillance. PMID:28082965
Setchanova, Lena Petrova; Alexandrova, Alexandra; Dacheva, Daniela; Mitov, Ivan; Kaneva, Radka; Mitev, Vanio
A pneumococcal conjugate vaccine (PCV10) was introduced in Bulgarian national immunization program since April 2010. Clonal composition based on pulsed-field gel electrophoresis and multilocus sequence typing genotyping of 52 serotype 19A Streptococcus pneumoniae isolates was analyzed. These were invasive and respiratory isolates collected between 1992 and 2013 from both children (78.8% <5 years) and adults with pneumococcal infections. Multidrug resistance was found in 82.7% of all 19A isolates. The most prevalent genotype (63.5%) among serotype 19A pneumococcal strains was the multidrug-resistant clonal complex CC230, which is a capsular switched variant of the Denmark(14)-32 (ST230) global clone. The most frequent sequence type (ST) was ST230 (48.1%) and together with four other closely related STs (15.4%), belonging to ST1611, ST276, ST7466, and ST2013, which were single- and double-locus variants; they were included in the main CC230. The disappearance of highly drug-resistant ST663 clone and emergence of new clones as CC320 and CC199 was also observed among the rest 19A isolates. A comparison of clonal composition between invasive and noninvasive isolates did not show a great genetic diversity among both kinds of isolates. Continuous surveillance of serotype 19A population following the introduction of PCV10 is essential to evaluate the impact of the vaccine on the epidemiology of this serotype.
Deng, Xianding; Memari, Nader; Teatero, Sarah; Athey, Taryn; Isabel, Marc; Mazzulli, Tony; Fittipaldi, Nahuel; Gubbay, Jonathan B
Background: Molecular typing is essential for inferring genetic relatedness between bacterial pathogens. In this study, we applied whole genome sequencing (WGS) for rapid prediction of sequence type and antibiotic resistance for invasive pneumococcal isolates. Methods: 240 isolates from adults (≥50 years old) in Ontario, Canada during 2009 to 2013 were subjected to WGS. Sequence type, antibiotic susceptibility and resistance were predicted directly from short reads. Emerging non-vaccine serotype 22F was further characterized by WGS. Results: Sequence type was successfully determined for 98.3% of isolates. The overall sensitivity and specificity for antibiotic resistance prediction were 95 and 100% respectively, compared to standard susceptibility testing methods. WGS-based phylogeny divided emerging 22F (ST433) strains into two distinct clades: clade A harboring a 23 kb-prophage and anti-phage PhD/Doc system and clade B with virulence-related proteases. Five isolates in clade A developed macrolide resistance via 5.1 kb mega element recombination (encoding mefE and msrD), while one isolate in clade B displayed quinolone resistance via a gyrA mutation. Conclusions: WGS is valuable for routine surveillance of pneumococcal clinical isolates and facilitates prediction of genotype and antibiotic resistance. The emergence of 22F in Ontario in the post-vaccine era and evidence of evolution and divergence of the 22F population warrants heightened pneumococcal molecular surveillance.
Guevara, Marcela; Ezpeleta, Carmen; Gil-Setas, Alberto; Torroba, Luis; Beristain, Xabier; Aguinaga, Aitziber; García-Irure, José Javier; Navascués, Ana; García-Cenoz, Manuel; Castilla, Jesús
Pneumococcal conjugate vaccines (PCVs) were licensed for use in children and became available for private purchase in Spain in 2001 (PCV7), 2009 (PCV10) and 2010 (PCV13). This study evaluates changes in the incidence of invasive pneumococcal disease (IPD) and the pattern of serotypes isolated in Navarre, Spain, between the period of use of PCV7 (2004-2009) and that of PCV13 (2010-2013). The percentage of children <2 years who received at least one dose of PCV in these periods ranged from 25 to 61% and 61 to 78%, respectively. Between the periods 2004-2009 and 2010-2013 IPD incidence declined by 37%, from 14.9 to 9.4 cases/100,000 inhabitants (p<0.001). In children <5 years it fell by 69% (p<0.001), in persons aged 5-64 years, by 34% (p<0.001), and in those ≥ 65, by 23% (p=0.024). The incidence of cases due to PCV13 serotypes declined by 81% (p<0.001) in children <5 years and by 52% (p<0.001) in the whole population. No significant changes were seen in the distribution of clinical presentations or in disease severity. The incidence of IPD has declined and the pattern of serotypes causing IPD has changed notably in children and moderately in adults following the replacement of PCV7 by PCV13.
Long, Joanna E; Ring, Christopher; Drayson, Mark; Bosch, Jos; Campbell, John P; Bhabra, Jagraj; Browne, David; Dawson, Joel; Harding, Sarah; Lau, Jamie; Burns, Victoria E
High intensity acute exercise at the time of vaccination has been shown to enhance the subsequent antibody response. This study examines whether an acute moderate intensity aerobic intervention prior to vaccination can enhance antibody response to pneumonia and half dose influenza vaccination. Sixty young (age (SD)=22.0 (6.1) years) and 60 older (age (SD)=57.5 (6.5) years) adults attended the laboratory on two separate occasions. At the first session, baseline antibody titres were determined, before participants completed either a brisk walk around campus at >55% of their age-predicted heart rate maximum, or a resting control condition, for 45 min. After the intervention, all participants received a full-dose pneumococcal vaccination and a half-dose influenza vaccination. Four weeks later, participants returned for a follow up blood sample. Multivariate ANOVA revealed an increase in total antibody titres against the influenza vaccine (F((12,106))=25.76, p<.001, η(2)=.75) and both the IgM (F((12,106))=17.10, p<.001, η(2)=.66) and IgG (F((12,106))=25.76, p<.001, η(2)=.75) antibody titres against the pneumococcal vaccine. However, there were no significant Time×Group interactions (p's all >.15), indicating that a 45 min brisk walk prior to vaccination did not affect antibody response to either the influenza or pneumonia vaccine. The results suggest that higher intensity exercise is necessary to augment antibody response to vaccination.
Schejbel, Lone; Lundstedt, A.C.; Jensen, Lise; Laursen, Inga A.; Ryder, Lars P.; Heegaard, Niels H.H.; Konradsen, Helle; Christensen, Jens Jørgen; Heilmann, Carsten; Marquart, Hanne V.
Background: Recurrent invasive pneumococcal disease (rIPD) occurs mostly in children with an underlying disease, but some cases remain unexplained. Immunodeficiency has been described in children with rIPD, but the prevalence is unknown. We used a nationwide registry of all laboratory-confirmed cases of rIPD to identify cases of unexplained rIPD and examine them for immunodeficiency. Methods: Cases of rIPD in children 0–15 years of age from 1980 to 2008 were identified. Children without an obvious underlying disease were screened for complement function, T-cell, B-cell, natural killer--cell counts and concentration of immunoglobulins. B-cell function was evaluated by measuring antibody response to polysaccharide-based pneumococcal vaccination and the extent of fraction of somatic hypermutation. Toll-Like receptor (TLR) signaling function and mutations in key TLR-signaling molecules were examined. Results: In total, rIPD were observed in 54 children (68 cases of rIPD of 2192 IPD cases). Children with classical risk factors for IPD were excluded, and among the remaining 22 children, 15 were eligible for analysis. Of these 6 (40%) were complement C2-deficient. Impaired vaccination response was found in 6 children of whom 3 were C2 deficient. One patient had a severe TLR signaling dysfunction. No mutations in IRAK4, IKBKG or MYD88 were found. Conclusion: Of an unselected cohort of children with rIPD at least 11% were C2 deficient. Data suggest that screening for complement deficiencies and deficient antibody response to pneumococcal vaccines in patients with more than 1 episode of IPD is warranted. PMID:25831419
Coimbra, Roney S; Voisin, Veronique; de Saizieu, Antoine B; Lindberg, Raija LP; Wittwer, Matthias; Leppert, David; Leib, Stephen L
Background Pneumococcal meningitis is associated with high mortality (~30%) and morbidity. Up to 50% of survivors are affected by neurological sequelae due to a wide spectrum of brain injury mainly affecting the cortex and hippocampus. Despite this significant disease burden, the genetic program that regulates the host response leading to brain damage as a consequence of bacterial meningitis is largely unknown. We used an infant rat model of pneumococcal meningitis to assess gene expression profiles in cortex and hippocampus at 22 and 44 hours after infection and in controls at 22 h after mock-infection with saline. To analyze the biological significance of the data generated by Affymetrix DNA microarrays, a bioinformatics pipeline was used combining (i) a literature-profiling algorithm to cluster genes based on the vocabulary of abstracts indexed in MEDLINE (NCBI) and (ii) the self-organizing map (SOM), a clustering technique based on covariance in gene expression kinetics. Results Among 598 genes differentially regulated (change factor ≥ 1.5; p ≤ 0.05), 77% were automatically assigned to one of 11 functional groups with 94% accuracy. SOM disclosed six patterns of expression kinetics. Genes associated with growth control/neuroplasticity, signal transduction, cell death/survival, cytoskeleton, and immunity were generally upregulated. In contrast, genes related to neurotransmission and lipid metabolism were transiently downregulated on the whole. The majority of the genes associated with ionic homeostasis, neurotransmission, signal transduction and lipid metabolism were differentially regulated specifically in the hippocampus. Of the cell death/survival genes found to be continuously upregulated only in hippocampus, the majority are pro-apoptotic, while those continuously upregulated only in cortex are anti-apoptotic. Conclusion Temporal and spatial analysis of gene expression in experimental pneumococcal meningitis identified potential targets for therapy. PMID
Incidence of pediatric invasive pneumococcal disease in the Island of Majorca (2008-2010), an area with non-universal vaccination, and estimations of serotype & children population coverage by available conjugate vaccines
Background The World Health Organization reported in 2007 that inclusion of PCV7 in national immunization programs should be seen as a priority, also encouraging countries to conduct appropriate surveillances for monitoring the impact of vaccination. These analyses should be conducted in specific geographical areas and should be aimed to evolution of invasive pneumococcal disease (IPD), by age groups, clinical presentation, and vaccine serotypes (and non-vaccine serotypes to detect possible replacement). This study aimed to monitor the evolution of IPD incidence in children <15 years requiring hospitalization in the Island of Majorca. Methods A prospective clinical surveillance of all culture and/or PCR-confirmed IPD in children <15 years was performed in all hospitals in the Island of Majorca (approximately 900,000 inhabitants) from January 2008 to December 2010. Incidence rate (IR) was calculated as cases/100000 inhabitants using children population data. Results 66 IPDs were identified: 39 (59.1%) parapneumonic pneumococcal empyema (PPE), 16 (24.2%) bacteremic pneumonia (BP), 7 (10.6%) primary bacteremia, 3 (4.5%) meningitis, and 1 (1.5%) osteomyelitis. IRs in the three-year study period were: 64.22 for children 12- < 24 months, 37.21 for those 24-59 months, 22.62 for those <12 months, and 3.98 for children >59 months. By study year, IRs were 21.25 in 2008, 19.89 in 2009 and 9.80 in 2010. The reduction found in 2010 was significant and due to significant reductions in IRs of IPDs caused by serotypes included in PCV10 and PCV13. Overall, estimated serotype coverage by conjugate vaccines was 12.1% for PCV7, 37.9% for PCV10 and 65.2% for PCV13. Of the 66 hospitalized children with IPD, 20 had received at least one dose of PCV7 (13 cases with identified serotype). None of these 13 cases was caused by PCV7 serotypes, all were caused by PCV13 serotypes and only 53.8% by PCV10 serotypes. Conclusions The results of the present study evidence the importance of
American Academy of Pediatrics. Committee on Infectious Diseases. Technical report: prevention of pneumococcal infections, including the use of pneumococcal conjugate and polysaccharide vaccines and antibiotic prophylaxis.
Overturf, G D
Pneumococcal infections are the most common invasive bacterial infections in children in the United States. The incidence of invasive pneumococcal infections peaks in children younger than 2 years, reaching rates of 228/100,000 in children 6 to 12 months old. Children with functional or anatomic asplenia (including sickle cell disease [SCD]) and children with human immunodeficiency virus infection have pneumococcal infection rates 20- to 100-fold higher than those of healthy children during the first 5 years of life. Others at high risk of pneumococcal infections include children with congenital immunodeficiency; chronic cardiopulmonary disease; children receiving immunosuppressive chemotherapy; children with immunosuppressive neoplastic diseases; children with chronic renal insufficiency, including nephrotic syndrome; children with diabetes; and children with cerebrospinal fluid leaks. Children of Native American (American Indian and Alaska Native) or African American descent also have higher rates of invasive pneumococcal disease. Outbreaks of pneumococcal infection have occurred with increased frequency in children attending out-of-home care. Among these children, nasopharyngeal colonization rates of 60% have been observed, along with pneumococci resistant to multiple antibiotics. The administration of antibiotics to children involved in outbreaks of pneumococcal disease has had an inconsistent effect on nasopharyngeal carriage. In contrast, continuous penicillin prophylaxis in children younger than 5 years with SCD has been successful in reducing rates of pneumococcal disease by 84%. Pneumococcal polysaccharide vaccines have been recommended since 1985 for children older than 2 years who are at high risk of invasive disease, but these vaccines were not recommended for younger children and infants because of poor antibody response before 2 years of age. In contrast, pneumococcal conjugate vaccines (Prevnar) induce proposed protective antibody responses (>.15
Daudin, M; Tattevin, P; Lelong, B; Flecher, E; Lavoué, S; Piau, C; Ingels, A; Chapron, A; Daubert, J-C; Revest, M
Case series have suggested that pneumococcal endocarditis is a rare disease, mostly reported in patients with co-morbidities but no underlying valve disease, with a rapid progression to heart failure, and high mortality. We performed a case-control study of 28 patients with pneumococcal endocarditis (cases), and 56 patients with non-pneumococcal endocarditis (controls), not matched for sex and age, during the years 1991-2013, in one referral centre. Alcoholism (39.3% versus 10.7%; p <0.01), smoking (60.7% versus 21.4%; p <0.01), the absence of previously known valve disease (82.1% versus 60.7%; p 0.047), heart failure (64.3% versus 23.2%; p <0.01) and shock (53.6% versus 23.2%; p <0.01) were more common in pneumococcal than in non-pneumococcal endocarditis. Cardiac surgery was required in 64.3% of patients with pneumococcal endocarditis, much earlier than in patients with non-pneumococcal endocarditis (mean time from symptom onset, 14.1 ± 18.2 versus 69.0 ± 61.1 days). In-hospital mortality rates were similar (7.1% versus 12.5%). Streptococcus pneumoniae causes rapidly progressive endocarditis requiring life-saving early cardiac surgery in most cases.
Johnson, Hope L.; Deloria-Knoll, Maria; Levine, Orin S.; Stoszek, Sonia K.; Freimanis Hance, Laura; Reithinger, Richard; Muenz, Larry R.; O'Brien, Katherine L.
Background Approximately 800,000 children die each year due to pneumococcal disease and >90% of these deaths occur in developing countries where few children have access to life-saving serotype-based vaccines. Understanding the serotype epidemiology of invasive pneumococcal disease (IPD) among children is necessary for vaccine development and introduction policies. The aim of this study was to systematically estimate the global and regional distributions of serotypes causing IPD in children <5 years of age. Methods and Findings We systematically reviewed studies with IPD serotype data among children <5 years of age from the published literature and unpublished data provided by researchers. Studies conducted prior to pneumococcal conjugate vaccine (PCV) introduction, from 1980 to 2007, with ≥12 months of surveillance, and reporting ≥20 serotyped isolates were included. Serotype-specific proportions were pooled in a random effects meta-analysis and combined with PD incidence and mortality estimates to infer global and regional serotype-specific PD burden. Of 1,292, studies reviewed, 169 were included comprising 60,090 isolates from 70 countries. Globally and regionally, six to 11 serotypes accounted for ≥70% of IPD. Seven serotypes (1, 5, 6A, 6B, 14, 19F, 23F) were the most common globally; and based on year 2000 incidence and mortality estimates these seven serotypes accounted for >300,000 deaths in Africa and 200,000 deaths in Asia. Serotypes included in both the 10- and 13-valent PCVs accounted for 10 million cases and 600,000 deaths worldwide. Conclusions A limited number of serotypes cause most IPD worldwide. The serotypes included in existing PCV formulations account for 49%–88% of deaths in Africa and Asia where PD morbidity and mortality are the highest, but few children have access to these life-saving vaccines. Please see later in the article for the Editors' Summary PMID:20957191
Elberse, Karin E M; van der Heide, Han G J; Witteveen, Sandra; van de Pol, Ingrid; Schot, Corrie S; van der Ende, Arie; Berbers, Guy A M; Schouls, Leo M
The implementation of nationwide pneumococcal vaccination may lead to alterations in the pneumococcal population due to selective pressure induced by the vaccine. To monitor such changes, pneumococcal isolates causing invasive pneumococcal disease (IPD) before (2004-2005, n=1154) and after (2008-2009, n=1190) the implementation of the 7-valent pneumococcal vaccine (PCV7) in 2006 in the national immunization program (NIP) of The Netherlands were characterized by molecular typing using multiple-locus variable number tandem repeat analysis (MLVA) and capsular sequence typing (CST). The IPD incidence after the implementation of PCV7 in children <5 years of age declined, mainly due to an impressive reduction of cases caused by vaccine serotypes. In the age group of patients ≥5 years of age, the overall IPD incidence remained constant, but the IPD incidence due to vaccine serotypes declined in this age cohort as well, indicating herd immunity. IPD incidence of non-vaccine serotypes 1 and 22F isolates increased significantly and a shift in genetic background of the isolates belonging to these serotypes was observed. In general the composition of the pneumococcal population remained similar after the introduction of PCV7. Both before and after introduction of the vaccine several possible capsular switch events were noticed. We found 4 isolates from the pre-vaccination period in which the serotype 19F capsular locus had been horizontally transferred to a different genetic background. Remarkably, none of the 5 post-vaccination isolates in which we observed possible capsule switch belonged to the 19F serotype, possibly due to vaccine induced pressure. In the post-vaccine implementation period we found no evidence for capsular switch of a vaccine serotype to a non-vaccine serotype, indicating that capsular switch is not the main driving force for replacement. This study provides insights into the effects of nationwide vaccination on the pneumococcal population causing IPD.
Song, Jae-Hoon; Dagan, Ron; Klugman, Keith P; Fritzell, Bernard
Streptococcus pneumoniae (SP) causes significant burden of disease, including invasive pneumococcal disease and noninvasive diseases such as pneumonia and acute otitis media. SP has at least 93 different capsular serotypes, with the various serotypes having different propensities for producing disease or developing antibiotic resistance. An increase in the prevalence of antibiotic-resistant SP serotypes has been observed globally. The objective of this paper was to examine the relationship between antibiotic resistance and SP serotypes, with a primary focus on studies published in the past 10 years. Changing trends in antibiotic resistance and serotype distribution during this time, including those before and after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7), were analyzed. Factors that influence the prevalence of antibiotic-resistant serotypes include antibiotic selection pressure, the use of PCV7, and the emergence and spread of antibiotic-resistant clones. The emergence of multidrug resistant serotype 19A is of particular concern. Antibiotic-resistant SP is a global problem that must be addressed through multiple strategies, including national vaccination programs, antibiotic control programs, and ongoing surveillance.
Shen, Pamela; Morissette, Mathieu C.; Vanderstocken, Gilles; Gao, Yang; Hassan, Muhammad; Roos, Abraham; Thayaparan, Danya; Merlano, Maria; Dorrington, Michael G.; Nikota, Jake K.; Bauer, Carla M. T.; Kwiecien, Jacek M.; Labiris, Renee; Bowdish, Dawn M. E.; Stevenson, Christopher S.
Streptococcus pneumoniae is a leading cause of invasive bacterial infections, with nasal colonization an important first step in disease. While cigarette smoking is a strong risk factor for invasive pneumococcal disease, the underlying mechanisms remain unknown. This is partly due to a lack of clinically relevant animal models investigating nasal pneumococcal colonization in the context of cigarette smoke exposure. We present a model of nasal pneumococcal colonization in cigarette smoke-exposed mice and document, for the first time, that cigarette smoke predisposes to invasive pneumococcal infection and mortality in an animal model. Cigarette smoke increased the risk of bacteremia and meningitis without prior lung infection. Mechanistically, deficiency in interleukin 1α (IL-1α) or platelet-activating factor receptor (PAFR), an important host receptor thought to bind and facilitate pneumococcal invasiveness, did not rescue cigarette smoke-exposed mice from invasive pneumococcal disease. Importantly, we observed cigarette smoke to attenuate nasal inflammatory mediator expression, particularly that of neutrophil-recruiting chemokines, normally elicited by pneumococcal colonization. Smoking cessation during nasal pneumococcal colonization rescued nasal neutrophil recruitment and prevented invasive disease in mice. We propose that cigarette smoke predisposes to invasive pneumococcal disease by suppressing inflammatory processes of the upper respiratory tract. Given that smoking prevalence remains high worldwide, these findings are relevant to the continued efforts to reduce the invasive pneumococcal disease burden. PMID:26930709
Jack, Leonard; Sokler, Lynn A; Squiers, Linda; Mitchell, Patricia
The Division of Diabetes Translation, Centers for Disease Control and Prevention, collaborated with its 59 Diabetes Prevention and Control Programs (DPCPs) to implement in 1998-1999 the National Diabetes Influenza and Pneumococcal Campaign. Postcampaign evaluation examined DPCPs' perceptions of the relevancy of the campaign in reaching the target population (adults aged 25-64 years with diabetes), establishing successful partnerships, and engaging the media. Most DPCPs stated the campaign reached their target population. DPCPs most commonly partnered with existing networks such as public health organizations or government agencies and direct health care providers. A majority of DPCPs did not find partnerships with direct health care providers to be effective in this campaign, but public health organizations, peer review organizations, and coalitions were described as successful partners. States in which DPCPs conducted follow-up calls to television stations regarding the airing of public service announcements generally had more announcements aired than states in which such calls were not made. Postcampaign evaluation findings also indicate that DPCPs who attempted to engage nontraditional partners (e.g., media outlets) achieved greater campaign success than those who did not. Future campaign efforts will likely benefit from relationships established with nontraditional partners, such as retailers, media outlets, local pharmacies, and faith-based organizations.
Irfan, Seema; Idrees, Faiza; Mehraj, Vikram; Habib, Faizah; Adil, Salman; Hasan, Rumina
Background This study was conducted to evaluate drug resistance amongst bacteremic isolates of febrile neutropenic patients with particular emphasis on emergence of carbapenem resistant Gram negative bacteria and vancomycin resistant Enterococcus species. Methods A descriptive study was performed by reviewing the blood culture reports from febrile neutropenic patients during the two study periods i.e., 1999–00 and 2001–06. Blood cultures were performed using BACTEC 9240 automated system. Isolates were identified and antibiotic sensitivities were done using standard microbiological procedures. Results Seven twenty six febrile neutropenic patients were admitted during the study period. A total of 5840 blood cultures were received, off these 1048 (18%) were culture positive. Amongst these, 557 (53%) grew Gram positive bacteria, 442 (42%) grew Gram negative bacteria, 43 (4%) fungi and 6 (1%) anaerobes. Sixty (5.7%) out of 1048 positive blood cultures were polymicrobial. In the Gram negative bacteria, Enterobacteriaceae was the predominant group; E. coli was the most frequently isolated organism in both study periods. Amongst non- Enterobacteriaceae group, Pseudomonas aeruginosa was the commonest organism isolated during first study period followed by Acinetobacter spp. However, during the second period Acinetobacter species was the most frequent pathogen. Enterobacteriaceae group showed higher statistically significant resistance in the second study period against ceftriaxone, quinolone and piperacillin/tazobactam, whilst no resistance observed against imipenem/meropenem. The susceptibility pattern of Acinetobacter species shifted from sensitive to highly resistant one with significant p values against ceftriaxone, quinolone, piperacillin/tazobactam and imipenem/meropenem. Amongst Gram positive bacteria, MRSA isolation rate remained static, vancomycin resistant Enterococcus species emerged in second study period while no Staphylococcus species resistant to
Angele, Barbara; Geldhoff, Madelijn; Marquez, Gabriel; Varona, Rosa; Häcker, Georg; Schmetzer, Helga; Häcker, Hans; Hammerschmidt, Sven; van der Ende, Arie; Pfister, Hans-Walter
We previously identified CCL20 as an early chemokine in the cerebrospinal fluid (CSF) of patients with pneumococcal meningitis but its functional relevance was unknown. Here we studied the role of CCL20 and its receptor CCR6 in pneumococcal meningitis. In a prospective nationwide study, CCL20 levels were significantly elevated in the CSF of patients with pneumococcal meningitis and correlated with CSF leukocyte counts. CCR6-deficient mice with pneumococcal meningitis and WT mice with pneumococcal meningitis treated with anti-CCL20 antibodies both had reduced CSF white blood cell counts. The reduction in CSF pleocytosis was also accompanied by an increase in brain bacterial titers. Additional in vitro experiments showed direct chemoattractant activity of CCL20 for granulocytes. In summary, our results identify the CCL20-CCR6 axis as an essential component of the innate immune defense against pneumococcal meningitis, controlling granulocyte recruitment. PMID:24699535
Moore, R Andrew; Wiffen, Philip J; Lipsky, Benjamin A
The objective was to review the evidence of effectiveness of the polyvalent polysaccharide pneumococcal vaccine from prospective properly randomised controlled trials comparing pneumococcal vaccines with placebo in subjects who are immunocompetent and those likely to have an impaired immune system. Databases searched included the Cochrane Library, (issue 2, 2000), MEDLINE (1966-August 2000), PubMed (to August 2000) and EMBASE ( to August 2000). Reference lists of reports and reviews were also searched. To be included in the analysis, a study had to have been a prospective randomised comparison of a polysaccharide pneumococcal vaccine (any valency) and to have a placebo or no treatment comparison group. Papers had to report important clinical outcomes, such as rates of pneumonia, pneumococcal pneumonia, lower respiratory tract infections, pneumonia deaths or bacteraemia. Serological outcomes were not sought. Thirteen randomised comparisons with over 45,000 subjects were identified in an extensive literature review. Eight studies had a quality score of 3 or more on a scale of 1 to 5. In three comparisons with 21,152 immunocompetent subjects (South African gold miners, New Guinea highlanders) pneumococcal vaccination was effective in reducing the incidence of all-cause pneumonia (relative risk 0.56, 95% confidence interval 0.47 to 0.66), pneumococcal pneumonia (0.16; 0.11 to 0.23), pneumonia deaths (0.70; 0.50 to 0.96) and bacteraemia (0.18; 0.09 to 0.34). In ten comparisons in over 24,000 people who were elderly or likely to have impaired immune systems, pneumococcal vaccination was without effect for any outcome. Present guidelines recommend pneumococcal vaccination for "high-risk" groups. There is no evidence from randomised trials that this is of any benefit. PMID:11038265
Belvisi, V; Del Borgo, C; Morelli, F; Marocco, R; Tieghi, T; Fabietti, P; Vetica, A; Lichtner, M; Mastroianni, C M
Invasive disease caused by Streptococcus pneumoniae is a major cause of morbidity and mortality in high-risk individuals with severe comorbidities, including asplenia, chronic alcoholism, and altered immune status. The risk of invasive pneumococcal disease has been significantly higher in transplant patients compared with the general population. Here, we report an unusual case of a disseminated pneumococcal infection with meningitis, endocarditis, spondylodiscitis, and muscle abscess in an asplenic patient on chronic immunosuppressive therapy for liver transplantation performed 17 years before.
Domínguez, Angela; Soldevila, Núria; Toledo, Diana; Godoy, Pere; Torner, Núria; Force, Luis; Castilla, Jesús; Mayoral, José María; Tamames, Sonia; Martín, Vicente; Egurrola, Mikel; Sanz, Francisco; Astray, Jenaro; Project Pi12/02079 Working Group
Vaccination of the elderly is an important factor in limiting the impact of pneumonia in the community. The aim of this study was to investigate the factors associated with pneumococcal polysaccharide vaccination in patients aged ≥ 65 years hospitalized for causes unrelated to pneumonia, acute respiratory disease, or influenza-like illness in Spain. We made a cross-sectional study during 2013-2014. A bivariate analysis was performed comparing vaccinated and unvaccinated patients, taking into account sociodemographic variables and risk medical conditions. A multivariate analysis was performed using multilevel regression models. 921 patients were included; 403 (43.8%) had received the pneumococcal vaccine (394 received the polysaccharide vaccine). Visiting the general practitioner ≥ 3 times during the last year (OR = 1.79; 95% CI 1.25-2.57); having received the influenza vaccination in the 2013-14 season (OR = 2.57; 95% CI 1.72-3.84) or in any of the 3 previous seasons (OR = 11.70; 95% CI 7.42-18.45) were associated with receiving the pneumococcal polysaccharide vaccine. Pneumococcal vaccination coverage of hospitalized elderly people is low. The elderly need to be targeted about pneumococcal vaccination and activities that encourage healthcare workers to proactively propose vaccination might be useful. Educational campaigns aimed at the elderly could also help to increase vaccination coverages and reduce the burden of pneumococcal disease in the community.
Pletz, M W; Maus, U; Hohlfeld, J M; Lode, H; Welte, T
Pneumococcal infections (pneumonia, otitis media, sinusitis, meningitis) are common and usually involve toddlers and the elderly. Currently, two pneumococcal vaccines are in clinical use. The older vaccine consists of pure capsular polysaccharides from 23 pneumococcal serotypes and induces only a limited B-cell response because polysaccharides are poor antigens that stimulate mainly B-cells. In 2000, a vaccination program with a novel 7-valent pneumococcal conjugate vaccine was launched in the U.S. The conjugation of capsular polysaccharides with a highly immunogenic diphtheria toxoid protein induces both a T cell and B cell response that results in specific humoral and mucosal immunity. Since children are the main reservoir of pneumococci, the 7-valent conjugate vaccine seems to eradicate the respective pneumococcal serotypes within the population, as demonstrated by recent US data. Pronounced herd immunity resulted in a decrease in invasive pneumococcal diseases in vaccinees and non-vaccinees as well as in a reduction of antibiotic resistance rates. However, recent data suggest a replacement of vaccine-serotypes by non-vaccine serotypes, which conquer the ecological niche created by the vaccine. In order to encounter this problem a 13-valent conjugated vaccine is currently under development.
Eichmann, Klaus; Krause, Richard M
During the first decade of the twentieth century, the German bacteriologist Fred Neufeld, later Director of the Robert Koch-Institute in Berlin, first described the differentiation of pneumococci into serotypes on the basis of type-specific antisera. This finding was essential for subsequent research at the Rockefeller Institute of Medical Research (RIMR) in New York, and elsewhere, aiming for the conquest of human pneumococcal pneumonia, including antiserum therapy, the discovery that the type-specific antigens were carbohydrates, and the development of effective multivalent pneumococcal polysaccharide vaccines. Moreover, on the basis of pneumococcal serotypes Fred Griffith, in 1928 in London, discovered pneumococcal transformation, and Oswald T. Avery and coworkers, in 1944 at RIMR, identified DNA as the transforming substance. This sequence of events, leading to today's knowledge that genes consist of DNA, was initiated by a farsighted move of Simon Flexner, first Director of the RIMR, who asked Neufeld to send his pneumococcal typing strains, thus setting the stage for pneumococcal research at RIMR. Here, we describe Fred Neufeld's contributions in this development, which have remained largely unknown.
Woehrl, Bianca; Brouwer, Matthijs C; Murr, Carmen; Heckenberg, Sebastiaan G B; Baas, Frank; Pfister, Hans W; Zwinderman, Aeilko H; Morgan, B Paul; Barnum, Scott R; van der Ende, Arie; Koedel, Uwe; van de Beek, Diederik
Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the proinflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Additionally, SNPs in genes encoding complement pathway proteins have been linked to susceptibility to pneumococcal infection, although no associations with disease severity or outcome have been established. Here, we have performed a robust prospective nationwide genetic association study in patients with bacterial meningitis and found that a common nonsynonymous complement component 5 (C5) SNP (rs17611) is associated with unfavorable disease outcome. C5 fragment levels in cerebrospinal fluid (CSF) of patients with bacterial meningitis correlated with several clinical indicators of poor prognosis. Consistent with these human data, C5a receptor-deficient mice with pneumococcal meningitis had lower CSF wbc counts and decreased brain damage compared with WT mice. Adjuvant treatment with C5-specific monoclonal antibodies prevented death in all mice with pneumococcal meningitis. Thus, our results suggest C5-specific monoclonal antibodies could be a promising new antiinflammatory adjuvant therapy for pneumococcal meningitis.
Woehrl, Bianca; Brouwer, Matthijs C.; Murr, Carmen; Heckenberg, Sebastiaan G.B.; Baas, Frank; Pfister, Hans W.; Zwinderman, Aeilko H.; Morgan, B. Paul; Barnum, Scott R.; van der Ende, Arie; Koedel, Uwe; van de Beek, Diederik
Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the proinflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Additionally, SNPs in genes encoding complement pathway proteins have been linked to susceptibility to pneumococcal infection, although no associations with disease severity or outcome have been established. Here, we have performed a robust prospective nationwide genetic association study in patients with bacterial meningitis and found that a common nonsynonymous complement component 5 (C5) SNP (rs17611) is associated with unfavorable disease outcome. C5 fragment levels in cerebrospinal fluid (CSF) of patients with bacterial meningitis correlated with several clinical indicators of poor prognosis. Consistent with these human data, C5a receptor–deficient mice with pneumococcal meningitis had lower CSF wbc counts and decreased brain damage compared with WT mice. Adjuvant treatment with C5-specific monoclonal antibodies prevented death in all mice with pneumococcal meningitis. Thus, our results suggest C5-specific monoclonal antibodies could be a promising new antiinflammatory adjuvant therapy for pneumococcal meningitis. PMID:21926466
Akduman, D; Ehret, J M; Judson, F N
Invasive pneumococcal isolates from three hospitals in Denver, CO, USA were serotyped between 1971 and 2004. Serotype 14 was most common (13.2%), and other prevalent serotypes (3, 4, 6, 9 and 19) together accounted for 44.1% of the isolates. All prevalent serotypes and 91.3% of the total isolates were covered by pneumococcal polysaccharide vaccine, while 79.1% of prevalent serotypes and 56.7% of total isolates were covered by pneumococcal conjugate vaccine. Serotypes 6, 9 and 14 were more common in the final decade than in the first decade studied (37.3% vs. 20.2%), whereas serotypes 3 and 23 were more common in the first decade (18.5% vs. 11.0%).
Rosch, Jason W
The pneumococcus is a remarkably adaptable pathogen whose disease manifestations range from mucosal surface infections such as acute otitis media and pneumonia to invasive infections such as sepsis and meningitis. Currently approved vaccines target the polysaccharide capsule, of which there are over 90 distinct serotypes, leading to rapid serotype replacement in vaccinated populations. Substantial progress has been made in the development of a universal pneumococcal vaccine, with efforts focused on broadly conserved and protective protein antigens. An area attracting considerable attention is the potential application of live attenuated vaccines to confer serotype-independent protection against mucosal and systemic infection. On the basis of recent work to understand the mucosal and systemic responses to nasal administration of pneumococci and to develop novel attenuation strategies, the prospect of a practical and protective live vaccine remains promising.
Gadzinowski, Janusz; Albrecht, Piotr; Hasiec, Barbara; Konior, Ryszard; Dziduch, Jerzy; Witor, Anita; Mellelieu, Tracey; Tansey, Susan P; Jones, Thomas; Sarkozy, Denise; Emini, Emilio A; Gruber, William C; Scott, Daniel A
13-valent pneumococcal conjugate vaccine (PCV13) includes polysaccharide conjugates from six pneumococcal serotypes in addition to those in the licensed 7-valent vaccine, thereby offering expanded protection against pneumococcal disease. The phase 3 trial reported here was conducted per a regulatory requirement to evaluate the immunogenicity, safety, and tolerability of two lots of the final PCV13 formulation that differed with respect to production scale but not the manufacturing process. The anti-pneumococcal polysaccharide immunogenicity and safety/tolerability were found to be similar between the two PCV13 vaccine lots.
Peng, Chun-Chih; Chang, Hung-Yang; Huang, Daniel Tsung-Ning; Chang, Lung; Lei, Wei-Te
Streptococcus pneumoniae remains the leading causative pathogen in pediatric pneumonia and bacteremia throughout the world. The invasive pneumococcal disease (IPD) is known as isolation of S. pneumoniae from a normally sterile site (e.g., blood, cerebrospinal fluid, synovial fluid, pericardial fluid, pleural fluid, or peritoneal fluid). The aim of this study is to survey the clinical manifestations and laboratory results of IPD and identify the prognostic factors of mortality. From January 2001 to December 2006, a retrospective review of chart was performed in a teaching hospital in Taipei. The hospitalized pediatric patients with the diagnosis of pneumonia, arthritis, infectious endocarditis, meningitis or sepsis were recruited. Among them, 50 patients were pneumococcal infections proved by positive culture results or antigen tests. Clinical manifestations, laboratory data and hospitalization courses were analyzed. The median age was 3.5-year-old and there were 30 male patients (60%). Eight patients (16%) had underlying disease such as leukemia or congenital heart disease. Hemolytic uremic syndrome (HUS) was observed in ten patients and extracorporeal membrane oxygenation (ECMO) was performed in three patients. Leukocytosis, elevated C-reactive protein and AST level were noted in most of the patients. The overall mortality rate was 10%. We found that leukopenia, thrombocytopenia and high CRP level were significant predictors for mortality. In conclusion, S. pneumoniae remains an important health threat worldwide and IPD is life-threatening with high mortality rate. We found leukopenia, thrombocytopenia, and high CRP levels to be associated with mortality in pediatric IPD, and these factors are worthy of special attention at admission. Although we failed to identify a statistically significant prognostic factor in multivariate analysis due to relatively small sample size, we suggest an aggressive antibiotic treatment in patients with these factors at admission
Madoff, Lawrence C.; Coombes, Brandon; Pelton, Stephen I.
OBJECTIVE: To examine whether there is a different clinical profile and severity of invasive pneumococcal disease (IPD) in children caused by nonvaccine types in the era of 13-valent pneumococcal conjugate vaccine (PCV13). METHODS: Observational study of childhood IPD in Massachusetts based on state public health surveillance data comparing pre-PCV13 (2007–2009) and post-PCV13 (2010–2012) eras. RESULTS: There were 168 pre-PCV13 cases of IPD and 85 post-PCV13 cases of IPD in Massachusetts children ≤5 years of age. PCV13 serotypes declined by 18% in the first 2 years after PCV13 use (P = .011). In the post-PCV13 phase, a higher proportion of children were hospitalized (57.6% vs 50.6%), and a higher proportion of children had comorbidity (23.5% vs 19.6%). Neither difference was statistically significant, nor were comparisons of IPD caused by vaccine and nonvaccine types. Children with comorbidities had higher rates of IPD caused by a nonvaccine type (27.6% vs 17.2%; P = .085), were more likely to be hospitalized (80.4% vs 50%; P < .0001), and were more likely to have a longer hospital stay (median of 3 days vs 0.5 days; P = .0001). CONCLUSIONS: Initial data suggest that nonvaccine serotypes are more common in children with underlying conditions, who have greater morbidity from disease. In the post-PCV13 era, a larger proportion of patients are hospitalized, but mortality rates are unchanged. Routine vaccination with PCV13 may not be enough to reduce the risk in patients with comorbidity. PMID:25002663
Romero-Steiner, Sandra; Pilishvili, Tamar; Sampson, Jacquelyn S.; Johnson, Scott E.; Stinson, Annie; Carlone, George M.; Ades, Edwin W.
The role of pneumococcal (Pnc) surface adhesin A (PsaA) in the adherence of Streptococcus pneumoniae (pneumococcus) to host cells is not well defined. We examined the effect of anti-PsaA antibodies in an inhibition of adherence assay using Detroit 562 nasopharyngeal human epithelial cells. Rabbit polyclonal (Pab) anti-recombinant PsaA (rPsaA) sera, a purified mouse monoclonal antibody (MAb) (MAb 6F62G8E12), and 22 healthy adult sera with known anti-PsaA IgG levels (obtained by enzyme-linked immunosorbent assay) were evaluated for their abilities to inhibit Pnc adherence to confluent monolayers (measured as percent reduction in CFU counts compared to those of uninhibited controls). Pnc adherence was dependent on capsular phenotype (no or low adherence for opaque strains). With an inoculum of 104 to 105 bacteria/well, the mean ± standard deviation count in controls was 163 ± 32 CFU/well for transparent strains. Low adherence was observed for a PsaA-minus mutant even at higher inoculum doses. Mean percent inhibitions of adherence with Pab and MAb were 54 and 50%, respectively. Adult sera showed inhibition in a dose-response fashion with a range of 98 to 8%, depending on the serum anti-PsaA antibody concentration. Absorption of Pab with rPsaA restored Pnc adherence to control levels. Absorption of sera with a PsaA-minus mutant did not result in a significant decrease (P >0.05) of inhibition of adherence activity. Additionally, nearly 100% of Pnc adherence was inhibited by lipidated rPsaA at 2.5 μg/ml. Our data support the argument that PsaA is an adhesin that mediates Pnc adherence to human nasopharyngeal cells. This functional assay may be useful in evaluating antibodies elicited in response to PsaA vaccination. PMID:12626450
Mathai, Dilip; Shamsuzzaman, Abul Khair Mohammad; Feroz, Ahrar Ahmed; Virani, Amin R; Hasan, Ashfaq; Ravi Kumar, KL; Ansari, Khalid; Forhad Hossain, Khandaker ATM; Marda, Mahesh; Wahab Zubair, MA; Ali, Mohammed Mukarram; Ashraf, N; Basha, Riyaz; Mirza, Shaeq; Ahmed, Shafeeq; Akhtar, Shamim; Ashraf, Syed Mustafa; Haque, Zahirul
Respiratory tract infections are prevalent among Hajj pilgrims with pneumonia being a leading cause of hospitalization. Streptococcus pneumoniae is a common pathogen isolated from patients with pneumonia and respiratory tract infections during Hajj. There is a significant burden of pneumococcal disease in India, which can be prevented. Guidelines for preventive measures and adult immunization have been published in India, but the implementation of the guidelines is low. Data from Bangladesh are available about significant mortality due to respiratory infections; however, literature regarding guidelines for adult immunization is limited. There is a need for extensive awareness programs across India and Bangladesh. Hence, there was a general consensus about the necessity for a rapid and urgent implementation of measures to prevent respiratory infections in pilgrims traveling to Hajj. About ten countries have developed recommendations for pneumococcal vaccination in Hajj pilgrims: France, the USA, Kuwait, Qatar, Bahrain, the UAE (Dubai Health Authority), Singapore, Malaysia, Egypt, and Indonesia. At any given point whether it is Hajj or Umrah, more than a million people are present in the holy places of Mecca and Madina. Therefore, the preventive measures taken for Hajj apply for Umrah as well. This document puts forward the consensus recommendations by a group of twenty doctors following a closed-door discussion based on the scientific evidence available for India and Bangladesh regarding the prevention of respiratory tract infections in Hajj pilgrims. PMID:27942192
Wagenvoort, Gertjan H J; Sanders, Elisabeth A M; Vlaminckx, Bart J; de Melker, Hester E; van der Ende, Arie; Knol, Mirjam J
Implementation of pneumococcal conjugate vaccines in the Netherlands (PCV7 in 2006 and PCV10 in 2011) for infants caused a shift in serotypes in invasive pneumococcal disease (IPD). We explored sex differences in serotype-specific IPD incidence before and after vaccine introduction. Incidences in the pre-PCV7 (June 2004–May 2006), post-PCV7 (June 2008–May 2011) and post-PCV10 period (June 2013–May 2015), stratified by age, were compared. Incidence was higher in men for all age groups (overall in men: 16.7, 15.5 and 14.4/100,000 and women: 15.4, 13.6 and 13.9/100,000 pre-PCV7, post-PCV7 and post-PCV10, respectively), except for 20–39 year-olds after PCV7 and 40–64 year-olds after PCV10 introduction. After PCV7 and PCV10 introduction, the overall IPD incidence decreased in men aged 20–39 years (from 5.3 pre-PCV7 to 4.7 and 2.6/100,000 post-PCV7 and post-PCV10, respectively), whereas it showed a temporary increase in women (from 3.9/100,000 pre-PCV7 to 5.0/100,000 post-PCV7 and back to 4.0/100,000 post-PCV10) due to replacement disease. PCV10 herd effects were observed throughout, but in women older than 40 years, a significant increase in non-PCV10 serotype offset a decrease in overall IPD incidence. Ongoing surveillance of IPD incidence by sex is important to evaluate the long-term effects of PCV implementation. PMID:28300529
nasopharynx of healthy children and adults. Pneumococcus can be transmitted from person to person during close contact. The bacteria can cause illnesses such as otitis media and sinusitis, and may become more aggressive and affect other areas of the body such as the lungs, brain, joints, and blood stream. More severe infections caused by pneumococcus are pneumonia, bacterial sepsis, meningitis, peritonitis, arthritis, osteomyelitis, and in rare cases, endocarditis and pericarditis. People with impaired immune systems are susceptible to pneumococcal infection. Young children, elderly people, patients with underlying medical conditions including chronic lung or heart disease, human immunodeficiency virus (HIV) infection, sickle cell disease, and people who have undergone a splenectomy are at a higher risk for acquiring pneumococcal pneumonia. Technology Influenza and Pneumococcal Vaccines Trivalent Influenza Vaccines in Canada In Canada, 5 trivalent influenza vaccines are currently authorized for use by injection. Four of these are formulated for intramuscular use and the fifth product (Intanza®) is formulated for intradermal use. The 4 vaccines for intramuscular use are: Fluviral (GlaxoSmithKline), split virus, inactivated vaccine, for use in adults and children ≥ 6 months; Vaxigrip (Sanofi Pasteur), split virus inactivated vaccine, for use in adults and children ≥ 6 months; Agriflu (Novartis), surface antigen inactivated vaccine, for use in adults and children ≥ 6 months; and Influvac (Abbott), surface antigen inactivated vaccine, for use in persons ≥ 18 years of age. FluMist is a live attenuated virus in the form of an intranasal spray for persons aged 2 to 59 years. Immunization with current available influenza vaccines is not recommended for infants less than 6 months of age. Pneumococcal Vaccine Pneumococcal polysaccharide vaccines were developed more than 50 years ago and have progressed from 2-valent vaccines to the current 23-valent vaccines to prevent
Grigg, Jonathan; Miyashita, Lisa
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
Grigg, Jonathan; Miyashita, Lisa; Suri, Reetika
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
Kahya, Hasan F.; Andrew, Peter W.
Pneumococcal neuraminidase is a key enzyme for sequential deglycosylation of host glycans, and plays an important role in host survival, colonization, and pathogenesis of infections caused by Streptococcus pneumoniae. One of the factors that can affect the activity of neuraminidase is the amount and position of acetylation present in its substrate sialic acid. We hypothesised that pneumococcal esterases potentiate neuraminidase activity by removing acetylation from sialic acid, and that will have a major effect on pneumococcal survival on mucin, colonization, and virulence. These hypotheses were tested using isogenic mutants and recombinant esterases in microbiological, biochemical and in vivo assays. We found that pneumococcal esterase activity is encoded by at least four genes, SPD_0534 (EstA) was found to be responsible for the main esterase activity, and the pneumococcal esterases are specific for short acyl chains. Assay of esterase activity by using natural substrates showed that both the Axe and EstA esterases could use acetylated xylan and Bovine Sub-maxillary Mucin (BSM), a highly acetylated substrate, but only EstA was active against tributyrin (triglyceride). Incubation of BSM with either Axe or EstA led to the acetate release in a time and concentration dependent manner, and pre-treatment of BSM with either enzyme increased sialic acid release on subsequent exposure to neuraminidase A. qRT-PCR results showed that the expression level of estA and axe increased when exposed to BSM and in respiratory tissues. Mutation of estA alone or in combination with nanA (codes for neuraminidase A), or the replacement of its putative serine active site to alanine, reduced the pneumococcal ability to utilise BSM as a sole carbon source, sialic acid release, colonization, and virulence in a mouse model of pneumococcal pneumonia. PMID:28257499
Trevejo-Nunez, Giraldina; Elsegeiny, Waleed; Conboy, Parker; Chen, Kong; Kolls, Jay K
IL-22-IL-22R signaling plays a crucial role in regulating host defenses against extracellular pathogens, particularly in the intestine, through the induction of antimicrobial peptides and chemotactic genes. However, the role of IL-22-IL-22R is understudied in Streptococcus pneumoniae lung infection, a prevalent pathogen of pneumonia. This paper presents the findings of IL-22 signaling during a murine model of pneumococcal pneumonia and improvement of bacterial burden upon IL-22 administration. IL-22 was rapidly induced in the lung during pneumococcal infection in wild-type mice, and Il22(-/-) mice had higher pneumococcal burdens compared with controls. Additionally, mice with hepatic-specific deletion of Il22ra1 also had higher bacterial burdens in lungs compared with littermate controls after intrapulmonary pneumococcal infection, suggesting that IL-22 signaling in the liver is important to control pneumococcal pneumonia. Thus, we hypothesized that enhancement of IL-22 signaling would control pneumococcal burden in lung tissues in an experimental pneumonia model. Administration of rIL-22 systemically to infected wild-type mice decreased bacterial burden in lung and liver at 24 h postinfection. Our in vitro studies also showed that mice treated with IL-22 had increased C3 expression in the liver compared with the isotype control group. Furthermore, serum from mice treated with IL-22 had improved opsonic capacity by increasing C3 binding on S. pneumoniae Taken together, endogenous IL-22 and hepatic IL-22R signaling play critical roles in controlling pneumococcal lung burden, and systemic IL-22 decreases bacterial burden in the lungs and peripheral organs by potentiating C3 opsonization on bacterial surfaces, through the increase of hepatic C3 expression.
Huttunen, Reetta; Hurme, Mikko; Aittoniemi, Janne; Huhtala, Heini; Vuento, Risto; Laine, Janne; Jylhävä, Juulia; Syrjänen, Jaana
Introduction Long pentraxin 3 (PTX3) is an acute-phase protein secreted by various cells, including leukocytes and endothelial cells. Like C-reactive protein (CRP), it belongs to the pentraxin superfamily. Recent studies indicate that high levels of PTX3 may be associated with mortality in sepsis. The prognostic value of plasma PTX3 in bacteremic patients is unknown. Methods Plasma PTX3 levels were measured in 132 patients with bacteremia caused by Staphylococcus aureus, Streptococcus pneumoniae, β-hemolytic streptococcae and Escherichia coli, using a commercial solid-phase enzyme-linked immunosorbent assay (ELISA). Values were measured on days 1–4 after positive blood culture, on day 13–18 and on recovery. Results The maximum PTX3 values on days 1–4 were markedly higher in nonsurvivors compared to survivors (44.8 vs 6.4 ng/ml, p<0.001) and the AUCROC in the prediction of case fatality was 0.82 (95% CI 0.73–0.91). PTX3 at a cut-off level of 15 ng/ml showed 72% sensitivity and 81% specificity for fatal disease. High PTX3 (>15 ng/ml) was associated with hypotension (MAP <70 mmHg)(OR 7.9;95% CI 3.3–19.0) and high SOFA score (≥4)(OR 13.2; 95% CI 4.9–35.4). The CRP level (maximum value on days 1 to 4) did not predict case fatality at any cut-off level in the ROC curve (p = 0.132). High PTX3 (>15 ng/ml) remained an independent risk factor for case fatality in a logistic regression model adjusted for potential confounders. Conclusions PTX3 proved to be a specific independent prognostic biomarker in bacteremia. PTX3 during the first days after diagnosis showed better prognostic value as compared to CRP, a widely used biomarker in clinical settings. PTX3 measurement offers a novel opportunity for the prognostic stratification of bacteremia patients. PMID:21423699
Hanke, Christiane R.; Grijalva, Carlos G.; Chochua, Sopio; Pletz, Mathias W.; Hornberg, Claudia; Edwards, Kathryn M.; Griffin, Marie R.; Verastegui, Hector; Gil, Ana I.; Lanata, Claudio F.; Klugman, Keith P.; Vidal, Jorge E.
Background Pneumococcal conjugate vaccines (PCV) have decreased nasopharyngeal carriage of vaccine-types but little data exists from rural areas. We investigated bacterial density, serotype distribution and antibiotic resistance of pneumococcal strains within the nasopharynx of young children in the Peruvian Andes, two years after PCV7 was introduced. Methods Pneumococcal strains were isolated from a subset of 125 children from our Peruvian cohort, who entered the study in 2009 and had pneumococcus detected in the nasopharynx in both 2009 and during follow-up in 2011. Strains were quellung-serotyped and tested for susceptibility to antibiotics. Bacterial density was determined by qPCR. Results The prevalence of PCV7 strains decreased from 48% in 2009 to 28.8% in 2011, whereas non-PCV7 types increased from 52% to 71.2% (p=0.002). There was a 3.5-fold increase in carriage of serotype 6C in 2011 (p=0.026). Vaccination with PCV7 did not affect pneumococcal density in children colonized by a PCV7 type but did increased density in those colonized with a non-PCV7 type. Antibiotic resistance did not change after vaccine introduction; strains were non-susceptible to tetracycline (97.2%), trimethoprim-sulfamethoxazole (56.4%), penicillin (34%), erythromycin (22.4%), chloramphenicol (18.8%) and clindamycin (12.4%). Conclusions Serotype replacement was observed post-PCV7 vaccination with a concomitant, not previously recognized, increased nasopharyngeal density. PMID:26974749
Chang, Xin; Yu, Weili; Ji, Shaoyang; Shen, Lijuan; Tan, Aijuan; Hu, Tao
Streptococcus pneumoniae is a serious Gram-positive pathogen that can lead to an invasive pneumococcal disease with high mortality rate. Pneumococcal capsular polysaccharide (PS) is a key virulence determinant and its immunogenicity can be increased by conjugation with a carrier protein. However, the PS-specific cellular and humoral immunity of pneumococcal conjugate vaccine needs further improvement. Hexadecane (HD) is an element of lipid that decorates the surface of nearly all microbial classes. Polyethylene glycol (PEG)-HD conjugate (PEG-HD) is soluble and can act as an adjuvant. In the present study, a novel pneumococcal polysaccharide conjugate vaccine was prepared by conjugation of tetanus toxoid (TT) portion of PS-TT conjugate (PS-TT) with PEG-HD. As compared with PS-TT, conjugation with PEG-HD led to an 8.0-fold increase in the PS-specific IgG titers. Conjugation with PEG-HD also gave rise to 34.9-, 3.6- and 7.7-fold increase in the IFN-γ, TNF-α and IL-5 levels, respectively. Thus, the conjugated PEG-HD has a stimulatory adjuvant activity to potentiate a robust humoral and cellular immunity. Our proposed conjugate was expected to act as an effective pneumococcal conjugate vaccine for prevention of S. pneumoniae infections.
Kumar, Rakesh; Arora, Narendra; Santosham, Mathuram
Despite the licensure of the pneumococcal conjugate vaccine (PCV) in the US and other Western countries for over 14 years, as of September 2014 only 4 South Asian countries were using PCV in their universal immunization program. To generate momentum toward addressing this issue a “South Asia symposium on pneumococcal disease and the promise of vaccines” was organized just prior to the 9th international symposium on pneumococci and pneumococcal diseases held in India recently. Leading scientists, program managers, and decision makers including ministry officials from the region participated in the meeting. The participants discussed available data on pneumococcal disease burden in South Asia, surveillance methods, efficacy and safety of pneumococcal conjugate vaccines (PCV), the status of PCV introduction, programmatic challenges in introducing PCV and available data on the impact of PCV in South Asia and globally. There was a strong consensus that available data on disease burden and the global experience with PCV justified the introduction PCV in all Asian countries in order to accelerate the gains in child survival in the region. PMID:27026150
Virolainen, A; Jero, J; Käyhty, H; Karma, P; Eskola, J; Leinonen, M
Pneumolysin, an intracellular protein toxin of all clinically relevant pneumococcal serotypes, is released in vivo during the autolysis of pneumococci and is believed to pave the way for intact pneumococci to invade and cause disease. Therefore, antibodies to pneumolysin should prevent its destructive function. We measured antibodies to pneumococcal pneumolysin in acute- and convalescent-phase nasopharyngeal aspirate samples of 120 children (median age, 2.5 years) with acute otitis media by enzyme immunoassay. Nasopharyngeal immunoglobulin M (IgM) and IgG class antibodies to pneumolysin were rarely detectable, whereas IgA class antibody was detected often, occurred independently of serum IgA antibody in serum, and correlated with the presence of the secretory component in pneumococcal antibody, indicating local production of IgA antibodies. Nasopharyngeal IgA antibody to pneumolysin was detected in 93% of the children already in the acute phase of otitis. Twenty percent of the children developed at least a threefold rise in the pneumolysin-specific IgA antibody concentration by the convalescent phase of otitis, with the youngest at 6 months of age, regardless of the pneumococcal findings in the nasopharynx or middle ear fluid. We suggest that nasopharyngeal IgA antibody to pneumolysin can be produced early in life by pneumococcal colonization. PMID:8574834
Khan, M Nadeem; Pichichero, Michael E
The human nasopharynx (NP) microbiota is complex and diverse and Streptococcus pneumoniae (pneumococcus) is a frequent member. In the first few years of life, children experience maturation of their immune system thereby conferring homeostatic balance in which pneumococci are typically rendered as harmless colonizers in the upper respiratory environment. Pneumococcal carriage declines in many children before they acquire capsular-specific antibodies, suggesting a capsule antibody-independent mechanism of natural protection against pneumococcal carriage in early childhood. A child's immune system in the first few years of life is Th2-skewed so as to avoid inflammation-induced immunopathology. Understanding Th1/Th2 and Th17 ontogeny in early life and how adjuvant vaccine formulations shift the balance of T helper-cell differentiation, may facilitate the development of new protein-based pneumococcal vaccines. This article will discuss the immune dynamics of pneumococcal colonization in infants. The discussion aims to benefit the design and improvement of protein subunit-based next-generation pneumococcal vaccines. PMID:25668673
Neill, Daniel R.; Fernandes, Vitor E.; Wisby, Laura; Haynes, Andrew R.; Ferreira, Daniela M.; Laher, Ameera; Strickland, Natalie; Gordon, Stephen B.; Denny, Paul; Kadioglu, Aras; Andrew, Peter W.
Streptococcus pneumoniae is an important human pathogen responsible for a spectrum of diseases including pneumonia. Immunological and pro-inflammatory processes induced in the lung during pneumococcal infection are well documented, but little is known about the role played by immunoregulatory cells and cytokines in the control of such responses. We demonstrate considerable differences in the immunomodulatory cytokine transforming growth factor (TGF)-β between the pneumococcal pneumonia resistant BALB/c and susceptible CBA/Ca mouse strains. Immunohistochemistry and flow cytometry reveal higher levels of TGF-β protein in BALB/c lungs during pneumococcal pneumonia that correlates with a rapid rise in lung Foxp3+Helios+ T regulatory cells. These cells have protective functions during pneumococcal pneumonia, because blocking their induction with an inhibitor of TGF-β impairs BALB/c resistance to infection and aids bacterial dissemination from lungs. Conversely, adoptive transfer of T regulatory cells to CBA/Ca mice, prior to infection, prolongs survival and decreases bacterial dissemination from lungs to blood. Importantly, strong T regulatory cell responses also correlate with disease-resistance in outbred MF1 mice, confirming the importance of immunoregulatory cells in controlling protective responses to the pneumococcus. This study provides exciting new evidence for the importance of immunomodulation during pulmonary pneumococcal infection and suggests that TGF-β signalling is a potential target for immunotherapy or drug design. PMID:22563306
van der Linden, Mark; Al-Lahham, Adnan; Nicklas, Werner; Reinert, Ralf René
Background Between 1986 and 2008 Streptococcus pneumoniae was isolated from 41 pets/zoo animals (guinea pigs (n = 17), cats (n = 12), horses (n = 4), dogs (n = 3), dolphins (n = 2), rat (n = 2), gorilla (n = 1)) treated in medical veterinary laboratories and zoos, and 44 laboratory animals (mastomys (multimammate mice; n = 32), mice (n = 6), rats (n = 4), guinea pigs (n = 2)) during routine health monitoring in an animal facility. S. pneumoniae was isolated from nose, lung and respiratory tract, eye, ear and other sites. Methodology/Principal Findings Carriage of the same isolate of S. pneumoniae over a period of up to 22 weeks was shown for four mastomys. Forty-one animals showed disease symptoms. Pneumococcal isolates were characterized by optochin sensitivity, bile solubility, DNA hybridization, pneumolysin PCR, serotyping and multilocus sequence typing. Eighteen of the 32 mastomys isolates (56%) were optochin resistant, all other isolates were optochin susceptible. All mastomys isolates were serotype 14, all guinea pig isolates serotype 19F, all horse isolates serotype 3. Rats had serotypes 14 or 19A, mice 33A or 33F. Dolphins had serotype 23F, the gorilla serotype 14. Cats and dogs had many different serotypes. Four isolates were resistant to macrolides, three isolates also to clindamycin and tetracyclin. Mastomys isolates were sequence type (ST) 15 (serotype 14), an ST/serotype combination commonly found in human isolates. Cats, dogs, pet rats, gorilla and dolphins showed various human ST/serotype combinations. Lab rats and lab mice showed single locus variants (SLV) of human STs, in human ST/serotype combinations. All guinea pig isolates showed the same completely new combination of known alleles. The horse isolates showed an unknown allele combination and three new alleles. Conclusions/Significance The isolates found in mastomys, mice, rats, cats, dogs, gorilla and dolphins are most likely identical to human
Kim, Chung Jong; Song, Jin-Su; Choi, Su-Jin; Song, Kyoung Ho; Choe, Pyeong Gyun; Park, Wan Beom; Bang, Ji Hwan; Kim, Eu Suk; Park, Sang Won; Kim, Hong Bin; Kim, Nam-Joong; Kim, Eui-Chong; Oh, Myoung-don
In Republic of Korea, a 7-valent pneumococcal conjugated vaccine (PCV7) was licensed for use in infants in 2003, and 13-valent PCV (PCV13) replaced it since 2010. We investigated trends in serotype distribution and antibiotic susceptibility of pneumococcal isolates from adult patients with invasive pneumococcal diseases (IPD). Invasive pneumococcal isolates from adult patients of ≥ 16 years of age were collected from 1997 to 2012. Serotypes of the isolates were determined by the Quellung reaction. Distribution of serotypes was analyzed according to the vaccine types. Antibiotic susceptibility was tested by using E-test strips. A total of 272 invasive pneumococcal isolates were included. The most common serotypes were serotype 19F (8.5%, 23/272), and serotype 3 (8.1%, 22/272), and 24.6% (67/272) of the isolates were of non-vaccine serotypes. Of the 272 isolates, 2.6% (7/272) were penicillin MICs of ≥ 4 µg/mL. The proportion of the PCV13 serotypes decreased from 63.3% (50/79) in 1997-2003 to 48.6% (17/35) in 2011-2012, whereas that of non-vaccine serotypes was 26.6% (21/79) and 25.7% (9/35), respectively, for the same periods. The proportion of the PCV13 serotypes showed a decreasing trend among adult patients with IPD over the study period.
Floyd, Mark W; Boyce, Brandon M; Castellan, Robert M; McDonough, E Barry
Pseudoseptic arthritis is primarily described in rheumatoid arthritis and other systemic inflammatory conditions. To our knowledge, only 1 case report of pseudoseptic arthritis associated with intra-articular injection of a pneumococcal polyvalent vaccine (PPV) has been published. Here, a second case is presented in which a patient presented with swelling, pain, and erythema of the affected shoulder. A 59-year-old woman presented to the emergency department with a 3-day history of severe pain and decreased mobility of her left shoulder after receiving a PPV vaccination. Her clinical and laboratory workup was suspicious for septic arthritis; however, magnetic resonance imaging of the affected shoulder with and without contrast showed only a partial thickness tear of the rotator cuff, fluid in the subacromial/subdeltoid bursa, and subcutaneous edema without evidence of an abscess. Based on the clinical and laboratory data, she underwent arthroscopic debridement. There was inflammatory tissue throughout the shoulder but no obvious purulent material. She did well postoperatively with a supervised range of motion rehabilitation protocol. Her cultures remained negative. At 12 weeks, she was discharged from follow-up. We suspect that the vaccination was inadvertently injected into the glenohumeral joint directly through the rotator cuff given the lack of a full-thickness tear and the patient's thin body habitus, which could explain her aseptic inflammatory arthritis.
Dicuonzo, Giordano; Gherardi, Giovanni; Gertz, Robert E.; D'Ambrosio, Fabio; Goglio, Antonio; Lorino, Giulia; Recchia, Simona; Pantosti, Annalisa; Beall, Bernard
We examined 73 recent invasive pneumococcal isolates within selected areas of Italy for genotypic variability. Thirty-three genomic macrorestriction types were found, three of which represented multiple serotypes. Restriction fragment patterns of pbp2b, pbp2x, and pspA were conserved within the majority of isolates that shared macrorestriction types. Of the nine macrorestriction types found among the 22 penicillin-nonsusceptible Streptococus pneumoniae (PNSP) isolates, seven comprised isolates with allelic profiles showing five to seven allelic matches to profiles in the multilocus sequence typing database (www.mlst.net); however, three of the seven profiles represented serotypes not previously associated with these clonal clusters. Two PNSP macrorestriction types represented new clones with unique allelic profiles. Allelic profiles obtained from isolates of 3 of the 25 macrorestriction types found among the 51 penicillin-susceptible S. pneumoniae (PSSP) isolates were closely related to previously described profiles. One PSSP isolate was a novel type 24F isolate related to the multiresistant clone France9V-3. This work reports new PNSP strains and new serotype-clone associations. PMID:12354862
Zierhut, Marco; Dyckhoff, Susanne; Masouris, Ilias; Klein, Matthias; Hammerschmidt, Sven; Pfister, Hans-Walter; Ayata, Korcan; Idzko, Marco; Koedel, Uwe
Excessive neutrophilic inflammation contributes to brain pathology and adverse outcome in pneumococcal meningitis (PM). Recently, we identified the NLRP3 inflammasome/interleukin (IL)-1β pathway as a key driver of inflammation in PM. A critical membrane receptor for NLRP3 inflammasome activation is the ATP-activated P2 purinoceptor (P2R) P2X7. Thus, we hypothesized involvement of ATP and P2Rs in PM. The functional role of ATP was investigated in a mouse meningitis model using P2R antagonists. Brain expression of P2Rs was assessed by RT-PCR. ATP levels were determined in murine CSF and cell culture experiments. Treatment with the P2R antagonists suramin or brilliant blue G did not have any impact on disease course. This lack of effect might be attributed to meningitis-associated down-regulation of brain P2R expression and/or a drop of cerebrospinal fluid (CSF) ATP, as demonstrated by RT-PCR and ATP analyses. Supplemental cell culture experiments suggest that the reduction in CSF ATP is, at least partly, due to ATP hydrolysis by ectonucleotidases of neutrophils and macrophages. In conclusion, this study suggests that ATP-P2R signaling is only of minor or even no significance in PM. This may be explained by down-regulation of P2R expression and decreased CSF ATP levels. PMID:28300164
Grandgirard, Denis; Valente, Luca G.; Täuber, Martin G.; Leib, Stephen L.
Streptococcus pneumoniae bacteria can be characterized into over 90 serotypes according to the composition of their polysaccharide capsules. Some serotypes are common in nasopharyngeal carriage whereas others are associated with invasive disease, but when carriage serotypes do invade disease is often particularly severe. It is unknown whether disease severity is due directly to the capsule type or to other virulence factors. Here, we used a clinical pneumococcal isolate and its capsule-switch mutants to determine the effect of capsule, in isolation from the genetic background, on severity of meningitis in an infant rat model. We found that possession of a capsule was essential for causing meningitis. Serotype 6B caused significantly more mortality than 7F and this correlated with increased capsule thickness in the cerebrospinal fluid (CSF), a stronger inflammatory cytokine response in the CSF and ultimately more cortical brain damage. We conclude that capsule type has a direct effect on meningitis severity. This is an important consideration in the current era of vaccination targeting a subset of capsule types that causes serotype replacement. PMID:27009189
Yamamoto, Kazuko; Ahyi, Ayele-Nati N; Pepper-Cunningham, Zachary A; Ferrari, Joseph D; Wilson, Andrew A; Jones, Matthew R; Quinton, Lee J; Mizgerd, Joseph P
Epithelial cells line the respiratory tract and interface with the external world. Epithelial cells contribute to pulmonary inflammation, but specific epithelial roles have proven difficult to define. To discover unique epithelial activities that influence immunity during infection, we generated mice with nuclear factor-κB RelA mutated throughout all epithelial cells of the lung and coupled this approach with epithelial cell isolation from infected and uninfected lungs for cell-specific analyses of gene induction. The RelA mutant mice appeared normal basally, but in response to pneumococcus in the lungs they were unable to rapidly recruit neutrophils to the air spaces. Epithelial cells expressed multiple neutrophil-stimulating cytokines during pneumonia, all of which depended on RelA. Cytokine expression by nonepithelial cells was unaltered by the epithelial mutation of RelA. Epithelial cells were the predominant sources of CXCL5 and granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas nonepithelial cells were major sources for other neutrophil-activating cytokines. Epithelial RelA mutation decreased whole lung levels of CXCL5 and GM-CSF during pneumococcal pneumonia, whereas lung levels of other neutrophil-recruiting factors were unaffected. Defective neutrophil recruitment in epithelial mutant mice could be rescued by administration of CXCL5 or GM-CSF. These results reveal a specialized immune function for the pulmonary epithelium, the induction of CXCL5 and GM-CSF, to accelerate neutrophil recruitment in the infected lung.
Zierhut, Marco; Dyckhoff, Susanne; Masouris, Ilias; Klein, Matthias; Hammerschmidt, Sven; Pfister, Hans-Walter; Ayata, Korcan; Idzko, Marco; Koedel, Uwe
Excessive neutrophilic inflammation contributes to brain pathology and adverse outcome in pneumococcal meningitis (PM). Recently, we identified the NLRP3 inflammasome/interleukin (IL)-1β pathway as a key driver of inflammation in PM. A critical membrane receptor for NLRP3 inflammasome activation is the ATP-activated P2 purinoceptor (P2R) P2X7. Thus, we hypothesized involvement of ATP and P2Rs in PM. The functional role of ATP was investigated in a mouse meningitis model using P2R antagonists. Brain expression of P2Rs was assessed by RT-PCR. ATP levels were determined in murine CSF and cell culture experiments. Treatment with the P2R antagonists suramin or brilliant blue G did not have any impact on disease course. This lack of effect might be attributed to meningitis-associated down-regulation of brain P2R expression and/or a drop of cerebrospinal fluid (CSF) ATP, as demonstrated by RT-PCR and ATP analyses. Supplemental cell culture experiments suggest that the reduction in CSF ATP is, at least partly, due to ATP hydrolysis by ectonucleotidases of neutrophils and macrophages. In conclusion, this study suggests that ATP-P2R signaling is only of minor or even no significance in PM. This may be explained by down-regulation of P2R expression and decreased CSF ATP levels.
Hurwitz, Julia L.
ABSTRACT In modern-day vaccine design, a good pneumococcal capsular polysaccharide vaccine is measured by its ability to induce opsonic antibodies. These antibodies label bacteria for phagocytosis by neutrophils and thereby overcome the capsule’s barrier function. Doyle and Pirofski have raised a serious challenge to the current paradigm by describing anti-capsular antibodies that are highly protective but nonopsonic [C.R. Doyle and L. Pirofski, mBio 7(1):e02260-15, 2016, doi:10.1128/mBio.02260-15]. In fact, some functions are not related to neutrophils or phagocytosis at all. An increased awareness of these activities is critical not only for accurate comparisons of vaccine candidates but also for improvements in vaccination outcomes in settings of neutropenia. When vaccine developers select a single gatekeeper assay (e.g., an opsonophagocytic assay for bacteria or a neutralization assay for viruses), promising vaccine candidates may be missed. Doyle and Pirofski stress that multiple functions, not just one, should be investigated to enhance discovery of antibody mechanisms and to best assess vaccine-induced correlates of immune protection. PMID:26908576
Marzouk, Manel; Ferjani, Asma; Bouafia, Nabiha; Harb, Hanen; Ben Salem, Youssef; Boukadida, Jalel
Pneumococcal conjugate vaccines have not yet been introduced into the national program for childhood vaccination in Tunisia. The aim of this 7-year study was to obtain local data about serotype distribution and antimicrobial resistance of Streptococcus pneumoniae. A total of 203 isolates of culture confirmed that S. pneumoniae was evaluated. Invasive (n=108) and noninvasive (n=95) pneumococcal isolates were obtained from patients aged from 1 month to 85 years old. Considering all age groups, vaccine coverage was 40%, 62%, and 68% for PCV7, PCV10, and PCV13 serotypes, respectively. Overall, 31% of these isolates were penicillin G nonsusceptible. The most prevalent serotypes identified were those found in currently available pneumococcal conjugate vaccines, emphasizing the importance of implementing the vaccine in the routine immunization schedule at the national level.
Mathew, Joseph L
Recently Pneumococcal vaccines have generated considerable interest in developing countries as an intervention for protecting children from pneumonia and thereby reducing childhood mortality. Many convincing scientific arguments have been put forward, although they are often based either on extension of information from developed countries, or estimation plus extrapolation of limited local data. In addition, there is also significant commercial pressure to prescribe/recommend Pneumococcal vaccine(s). Against such a background, it is important for developing countries to critically appraise the issues involved in order to make a rational choice. This brief paper explores these issues, showing that the current Pneumococcal vaccines have limited effectiveness in developing countries and the hype surrounding them is more commercial than scientific.
Wiertsema, Selma P.; Corscadden, Karli J.; Mateus, Tulia; Mullaney, Gemma L.; Zhang, Guicheng; Richmond, Peter C.; Thornton, Ruth B.
ABSTRACT The pneumococcus is a major otitis media (OM) pathogen, but data are conflicting regarding whether otitis-prone children have impaired humoral immunity to pneumococcal antigens. We and others have shown that otitis-prone and healthy children have similar antibody titers to pneumococcal proteins and polysaccharides (vaccine and nonvaccine types); however, the quality of antibodies from otitis-prone children has not been investigated. Antibody function, rather than titer, is considered to be a better correlate of protection from pneumococcal disease. Therefore, we compared the capacities of antibodies from otitis-prone (cases) and healthy (controls) children to neutralize pneumolysin, the pneumococcal toxin currently in development as a vaccine antigen, and to opsonize pneumococcal vaccine and nonvaccine serotypes. A pneumolysin neutralization assay was conducted on cholesterol-depleted complement-inactivated sera from 165 cases and 61 controls. A multiplex opsonophagocytosis assay (MOPA) was conducted on sera from 20 cases and 20 controls. Neutralizing and opsonizing titers were calculated with antigen-specific IgG titers to determine antibody potency for pneumolysin, pneumococcal conjugate vaccine (PCV) polysaccharides, and non-PCV polysaccharides. There was no significant difference in antibody potencies between cases and controls for the antigens tested. Antipneumolysin neutralizing titers increased with the number of episodes of acute OM, but antibody potency did not. Pneumolysin antibody potency was lower in children colonized with pneumococci than in noncarriers, and this was significant for the otitis-prone group (P < 0.05). The production of functional antipneumococcal antibodies in otitis-prone children demonstrates that they respond to the current PCV and are likely to respond to pneumolysin-based vaccines as effectively as healthy children. PMID:28031178
Meerveld-Eggink, A; de Weerdt, O; van Velzen-Blad, H; Biesma, D H; Rijkers, G T
We determined the immunogenicity of conjugated Haemophilus influenzae type b and pneumococcal vaccines by quantitative analysis of the antibody response in asplenic patients. To that end, we vaccinated 92 patients with a conjugated Hib vaccine and 54 received two doses of conjugated pneumococcal vaccine (PCV7), followed at six months by a plain polysaccharide pneumococcal vaccine (PPV23). Antibody concentrations were measured before and three weeks after vaccination. After one dose of pneumococcal conjugate vaccine, 46% of the patients reached the antibody threshold of ≥ 1.0 μg/mL for all 7 tested vaccine serotypes. This percentage rose to 54% after the second dose of PCV7 and did not increase further after PPV23. Over 90% of patients had antibody concentrations ≥ 1.0 μg/mL for at least 5 out of the 7 conjugated pneumococcal serotypes after 2 doses of PCV7. For serotypes, included in the PPV23 vaccine only, 25% (PPS3)-100% (PPS19A) of the patients reached antibody concentrations ≥ 1.0 μg/mL after one dose of PPV23. For Hib, 97% of the patients reached the threshold concentration of ≥ 1.0 μg/mL after one dose of vaccine. It can be concluded that the majority of asplenic patients had a sufficient response to conjugated vaccines against Streptococcus pneumoniae and Hib, reflected by a ≥ 1.0 μg/mL antibody response. Inclusion of conjugated pneumococcal polysaccharide vaccines might be of additional value in the vaccination schedule for asplenic patients because of their high immunogenicity.
Prins-van Ginkel, Annemarijn C.; Berbers, Guy A. M.; Grundeken, Lucienne H.; Tcherniaeva, Irina; Wittenberns, Jelle I.; Elberse, Karin; Mollema, Liesbeth; de Melker, Hester E.; Knol, Mirjam J.
Introduction Introduction of pneumococcal conjugate vaccines (PCVs) for infants decreased overall invasive pneumococcal disease (IPD), while non-vaccine serotype IPD increased. To fully understand this serotype replacement, knowledge about serotype dynamics in the pre-vaccine era is needed. In addition to IPD surveillance and carriage studies, the serotype replacement can be investigated by serosurveillance studies. The current study compared the results of two Dutch serosurveillance studies conducted in 1995–1996 (PIENTER1) and 2006–2007 (PIENTER2). Methods Participants in these studies donated a blood sample and completed a questionnaire. Pneumococcal antibodies of serotypes included in PCV13 were measured with a fluorescent-bead based multiplex immunoassay. Geometric mean antibody concentrations (GMCs) and determinants of pneumococcal antibody levels were investigated. Results GMCs were higher in PIENTER2 for serotypes 1, 6A, 6B, 9V, 18C, 19F and 23F and lower for 3 and 5. Age, day care attendance, household size, vaccination coverage, and urbanisation rate were associated with pneumococcal antibodies in children. Education level, ethnicity, age, low vaccination coverage sample, urbanisation rate, and asthma/COPD were associated with pneumococcal antibodies in elderly. The determinants significantly associated with pneumococcal IgG were slightly different for the elderly in PIENTER1 compared to the elderly in PIENTER2. Conclusion Although most of the serotype antibody levels remained stable, some of the serotype-specific antibody levels varied during the pre-vaccine era, indicating that exposure of certain serotypes changes without interference of PCVs. PMID:26796783
Le Gouëllec, Audrey; Roux, Laure; Fadda, Daniela; Massidda, Orietta; Vernet, Thierry; Zapun, André
DivIB, also known as FtsQ in gram-negative organisms, is a division protein that is conserved in most eubacteria. DivIB is localized at the division site and forms a complex with two other division proteins, FtsL and DivIC/FtsB. The precise function of these three bitopic membrane proteins, which are central to the division process, remains unknown. We report here the characterization of a divIB deletion mutant of Streptococcus pneumoniae, which is a coccus that divides with parallel planes. Unlike its homologue FtsQ in Escherichia coli, pneumococcal DivIB is not required for growth in rich medium, but the ΔdivIB mutant forms chains of diplococci and a small fraction of enlarged cells with defective septa. However, the deletion mutant does not grow in a chemically defined medium. In the absence of DivIB and protein synthesis, the partner FtsL is rapidly degraded, whereas other division proteins are not affected, pointing to a role of DivIB in stabilizing FtsL. This is further supported by the finding that an additional copy of ftsL restores growth of the ΔdivIB mutant in defined medium. Functional mapping of the three distinct α, β, and γ domains of the extracellular region of DivIB revealed that a complete β domain is required to fully rescue the deletion mutant. DivIB with a truncated β domain reverts only the chaining phenotype, indicating that DivIB has distinct roles early and late in the division process. Most importantly, the deletion of divIB increases the susceptibility to β-lactams, more evidently in a resistant strain, suggesting a function in cell wall synthesis. PMID:18441058
Rosendahl, Alva; Bergmann, Simone; Hammerschmidt, Sven; Goldmann, Oliver; Medina, Eva
Streptococcus pneumoniae is a leading cause of bacterial pneumonia worldwide. Given the critical role of dendritic cells (DCs) in regulating and modulating the immune response to pathogens, we investigated here the role of DCs in S. pneumoniae lung infections. Using a well-established transgenic mouse line which allows the conditional transient depletion of DCs, we showed that ablation of DCs resulted in enhanced resistance to intranasal challenge with S. pneumoniae. DCs-depleted mice exhibited delayed bacterial systemic dissemination, significantly reduced bacterial loads in the infected organs and lower levels of serum inflammatory mediators than non-depleted animals. The increased resistance of DCs-depleted mice to S. pneumoniae was associated with a better capacity to restrict pneumococci extrapulmonary dissemination. Furthermore, we demonstrated that S. pneumoniae disseminated from the lungs into the regional lymph nodes in a cell-independent manner and that this direct way of dissemination was much more efficient in the presence of DCs. We also provide evidence that S. pneumoniae induces expression and activation of matrix metalloproteinase-9 (MMP-9) in cultured bone marrow-derived DCs. MMP-9 is a protease involved in the breakdown of extracellular matrix proteins and is critical for DC trafficking across extracellular matrix and basement membranes during the migration from the periphery to the lymph nodes. MMP-9 was also significantly up-regulated in the lungs of mice after intranasal infection with S. pneumoniae. Notably, the expression levels of MMP-9 in the infected lungs were significantly decreased after depletion of DCs suggesting the involvement of DCs in MMP-9 production during pneumococcal pneumonia. Thus, we propose that S. pneumoniae can exploit the DC-derived proteolysis to open tissue barriers thereby facilitating its own dissemination from the local site of infection. PMID:23802100
Wasserstrom, Heather; Bussel, James; Lim, Lony C.-L.; Cunningham-Rundles, Charlotte
Splenectomized patients are susceptible to bloodstream infections with encapsulated bacteria, potentially due to loss of blood filtering but also defective production of anticarbohydrate Ab. Recent studies propose that a lack of Ab is related to reduced numbers of IgM+ CD27+ memory B cells found after splenectomy. To test this, we analyzed CD27+ memory B cell subsets, IgG, and IgM pneumococcal Ab responses in 26 vaccinated splenectomized subjects in comparison to memory B cell subsets and Ab responses in healthy controls. As shown previously, the splenectomized autoimmune subjects had fewer total, isotype switched, and IgM+ CD27+ memory B cells as compared with controls, but there was no difference in memory B cells subsets between controls and splenectomized subjects with spherocytosis. There was no difference between the geometric mean IgG Ab response between normal controls and splenectomized subjects (p = 0.51; p = 0.81). Control subjects produced more IgM Ab than splenectomized autoimmune subjects (p = 0.01) but the same levels as subjects with spherocytosis (p = 0.15.) There was no correlation between memory B cell subsets and IgG or IgM Ab responses for controls or splenectomized subjects. These data suggest that splenectomy alone may not be the sole reason for loss of memory B cells and reduced IgM antipneumococcal Ab. Because subjects with autoimmunity had splenectomy at a significantly older age than participants with spherocytosis, these data suggest that an age-related loss of extra splenic sites necessary for the maintenance or function of memory B cells may lead to impaired immunity in these subjects. PMID:18714044
Background Bacterial meningitis caused by Streptococcus pneumoniae leads to death in up to 30% of patients and leaves up to half of the survivors with neurological sequelae. The inflammatory host reaction initiates the induction of the kynurenine pathway and contributes to hippocampal apoptosis, a form of brain damage that is associated with learning and memory deficits in experimental paradigms. Vitamin B6 is an enzymatic cofactor in the kynurenine pathway and may thus limit the accumulation of neurotoxic metabolites and preserve the cellular energy status. The aim of this study in a pneumococcal meningitis model was to investigate the effect of vitamin B6 on hippocampal apoptosis by histomorphology, by transcriptomics and by measurement of cellular nicotine amide adenine dinucleotide content. Methods and results Eleven day old Wistar rats were infected with 1x106 cfu/ml of S. pneumoniae and randomized for treatment with vitamin B6 or saline as controls. Vitamin B6 led to a significant (p > 0.02) reduction of hippocampal apoptosis. According to functional annotation based clustering, vitamin B6 led to down-regulation of genes involved in processes of inflammatory response, while genes encoding for processes related to circadian rhythm, neuronal signaling and apoptotic cell death were mostly up-regulated. Conclusions Our results provide evidence that attenuation of apoptosis by vitamin B6 is multi-factorial including down-modulation of inflammation, up-regulation of the neuroprotective brain-derived neurotrophic factor and prevention of the exhaustion of cellular energy stores. The neuroprotective effect identifies vitamin B6 as a potential target for the development of strategies to attenuate brain injury in bacterial meningitis. PMID:23977941
Kandasamy, Rama; Gurung, Meeru; Thapa, Anushil; Ndimah, Susan; Adhikari, Neelam; Murdoch, David R.; Kelly, Dominic F.; Waldron, Denise E.; Gould, Katherine A.; Thorson, Stephen; Shrestha, Shrijana; Hinds, Jason; Pollard, Andrew J.
Invasive pneumococcal disease is one of the major causes of death in young children in resource poor countries. Nasopharyngeal carriage studies provide insight into the local prevalence of circulating pneumococcal serotypes. There are very few data on the concurrent carriage of multiple pneumococcal serotypes. This study aimed to identify the prevalence and serotype distribution of pneumococci carried in the nasopharynx of young healthy Nepalese children prior to the introduction of a pneumococcal conjugate vaccine using a microarray-based molecular serotyping method capable of detecting multi-serotype carriage. We conducted a cross-sectional study of healthy children aged 6 weeks to 24 months from the Kathmandu Valley, Nepal between May and October 2012. Nasopharyngeal swabs were frozen and subsequently plated on selective culture media. DNA extracts of plate sweeps of pneumococcal colonies from these cultures were analysed using a molecular serotyping microarray capable of detecting relative abundance of multiple pneumococcal serotypes. 600 children were enrolled into the study: 199 aged 6 weeks to <6 months, 202 aged 6 months to < 12 months, and 199 aged 12 month to 24 months. Typeable pneumococci were identified in 297/600 (49·5%) of samples with more than one serotype being found in 67/297 (20·2%) of these samples. The serotypes covered by the thirteen-valent pneumococcal conjugate vaccine were identified in 44·4% of samples containing typeable pneumococci. Application of a molecular serotyping approach to identification of multiple pneumococcal carriage demonstrates a substantial prevalence of co-colonisation. Continued surveillance utilising this approach following the introduction of routine use of pneumococcal conjugate vaccinates in infants will provide a more accurate understanding of vaccine efficacy against carriage and a better understanding of the dynamics of subsequent serotype and genotype replacement. PMID:25643355
Prediction of Pneumococcal Conjugate Vaccine Effectiveness against Invasive Pneumococcal Disease Using Opsonophagocytic Activity and Antibody Concentrations Determined by Enzyme-Linked Immunosorbent Assay with 22F Adsorption ▿
Schuerman, L.; Wysocki, J.; Tejedor, J. C.; Knuf, M.; Kim, K.-H.; Poolman, J.
We compared the abilities of two serological readouts, antipolysaccharide IgG antibody concentrations and opsonophagocytic activity (OPA) titers, to predict the clinical effectiveness of the 7-valent pneumococcal conjugate vaccine (7vCRM) against invasive pneumococcal disease (IPD). We also assessed the accuracy of the previously established thresholds for GlaxoSmithKline's enzyme-linked immunosorbent assay with 22F adsorption (22F-ELISA) (≥0.2 μg/ml) and OPA assay (titer, ≥8) in predicting effectiveness. We showed that following a 3-dose 7vCRM primary vaccination, the serological response rates as determined using thresholds of ≥0.2 μg/ml IgG and an OPA titer of ≥8 corresponded well with overall effectiveness against IPD. In addition, the OPA assay seemed to better predict serotype-specific effectiveness than enzyme-linked immunoassay. Finally, when applied to post-dose-2 immune responses, both thresholds also corresponded well with the overall IPD effectiveness following a 2-dose 7vCRM primary vaccination. These results support the importance of the OPA assay in evaluating immune responses to pneumococcal conjugate vaccines. PMID:21994351
... HUMAN SERVICES Centers for Disease Control and Prevention Proposed Vaccine Information Materials for Pneumococcal Conjugate Vaccine and Human Papillomavirus Vaccines AGENCY: Centers for Disease Control and...: Under the National Childhood Vaccine Injury Act (NCVIA) (42 U.S.C. 300aa-26), the CDC must...
Ercibengoa, María; Santacatterina, Erica; Alonso, Marta; Pérez-Trallero, Emilio
For pneumococcal disease surveillance, simple and cost-effective methods capable of determining all serotypes are needed. Combining a single-tube multiplex PCR with fluorescently labeled primers followed by amplicon analysis using automated fluorescent capillary electrophoresis, each serotype of 92 reference isolates and 297 recently collected clinical isolates was successfully determined. PMID:27280423
Hermand, Philippe; Vandercammen, Annick; Mertens, Emmanuel; Di Paolo, Emmanuel; Verlant, Vincent; Denoël, Philippe; Godfroid, Fabrice
ABSTRACT The use of protein antigens able to protect against the majority of Streptococcus pneumoniae serotypes is envisaged as stand-alone and/or complement to the current capsular polysaccharide-based pneumococcal vaccines. Pneumolysin (Ply) is a key virulence factor that is highly conserved in amino acid sesec-typsecquence across pneumococcal serotypes, and therefore may be considered as a vaccine target. However, native Ply cannot be used in vaccines due to its intrinsic cytolytic activity. In the present work a completely, irreversibly detoxified pneumolysin (dPly) has been generated using an optimized formaldehyde treatment. Detoxi-fication was confirmed by dPly challenge in mice and histological analysis of the injection site in rats. Immunization with dPly elicited Ply-specific functional antibodies that were able to inhibit Ply activity in a hemolysis assay. In addition, immunization with dPly protected mice against lethal intranasal challenge with Ply, and intranasal immunization inhibited nasopharyngeal colonization after intranasal challenge with homologous or heterologous pneumococcal strain. Our findings supported dPly as a valid candidate antigen for further pneumococcal vaccine development. PMID:27768518
Tavares, Luciana P; Garcia, Cristiana C; Vago, Juliana P; Queiroz-Junior, Celso M; Galvão, Izabela; David, Bruna A; Rachid, Milene A; Silva, Patrícia M R; Russo, Remo C; Teixeira, Mauro M; Sousa, Lirlândia P
Pneumococcal pneumonia is a leading cause of mortality worldwide. The inflammatory response to bacteria is necessary to control infection, but it may also contribute to tissue damage. Phosphodiesterase-4 inhibitors, such as rolipram (ROL), effectively reduce inflammation. Here, we examined the impact of ROL in a pneumococcal pneumonia murine model. Mice were infected intranasally with 10(5)-10(6) CFU of Streptococcus pneumoniae, treated with ROL in a prophylactic or therapeutic schedule in combination, or not, with the antibiotic ceftriaxone. Inflammation and bacteria counts were assessed, and ex vivo phagocytosis assays were performed. ROL treatment during S. pneumoniae infection decreased neutrophil recruitment into lungs and airways and reduced lung injury. Prophylactic ROL treatment also decreased cytokine levels in the airways. Although modulation of inflammation by ROL ameliorated pneumonia, bacteria burden was not reduced. On the other hand, antibiotic therapy reduced bacteria without reducing neutrophil infiltration, cytokine level, or lung injury. Combined ROL and ceftriaxone treatment decreased lethality rates and was more efficient in reducing inflammation, by increasing proresolving protein annexin A1 (AnxA1) expression, and bacterial burden by enhancing phagocytosis. Lack of AnxA1 increased inflammation and lethality induced by pneumococcal infection. These data show that immunomodulatory effects of phosphodiesterase-4 inhibitors are useful during severe pneumococcal pneumonia and suggest their potential benefit as adjunctive therapy during infectious diseases.
Fernández-Tornero, Carlos; García, Ernesto; de Pascual-Teresa, Beatriz; López, Rubens; Giménez-Gallego, Guillermo; Romero, Antonio
The search for new drugs against Streptococcus pneumoniae (pneumococcus) is driven by the 1.5 million deaths it causes annually. Choline-binding proteins attach to the pneumococcal cell wall through domains that recognize choline moieties, and their involvement in pneumococcal virulence makes them potential targets for drug development. We have defined chemical criteria involved in the docking of small molecules from a three-dimensional structural library to the major pneumococcal autolysin (LytA) choline binding domain. These criteria were used to identify compounds that could interfere with the attachment of this protein to the cell wall, and several quinolones that fit this framework were found to inhibit the cell wall-degrading activity of LytA. Furthermore, these compounds produced similar effects on other enzymes with different catalytic activities but that contained a similar choline binding domain; that is, autolysin (LytC) and the phage lytic enzyme (Cpl-1). Finally, we resolved the crystal structure of the complex between the choline binding domain of LytA and ofloxacin at a resolution of 2.6 Angstroms. These data constitute an important launch pad from which effective drugs to combat pneumococcal infections can be developed.
Hirst, Ceri; Owusu-Ofori, Shirley
Background This is an update of a Cochrane Review first published in 2002, and previously updated in 2012. People with sickle cell disease are particularly susceptible to infection. Infants and very young children are especially vulnerable, and the 'Co-operative Study of Sickle Cell Disease' observed an incidence rate of 10 per 100 patient years of pneumococcal septicaemia in children under the age of three.Vaccines, including customary pneumococcal vaccines, may be of limited use in this age group. Therefore, prophylactic penicillin regimens may be advisable for this population.Objectives To assess the effects of prophylactic antibiotic regimens for preventing pneumococcal infection in children with sickle cell disease.Search methods We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Haemoglobinopathies Trials Register, which is comprised of references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Date of the most recent search: 26 June 2014.Selection criteria All randomised or quasi-randomised controlled trials comparing prophylactic antibiotics to prevent pneumococcal infection in children with sickle cell disease with placebo, no treatment or a comparator drug.Data collection and analysis Both authors independently extracted data and assessed trial quality.Main results Five trials were identified by the initial search, of which three trials met the inclusion criteria. All of the included trials showed a reduced incidence of infection in children with sickle cell disease (SS or Sβ0Thal) receiving prophylactic penicillin. In trials which investigated initiation of penicillin on risk of pneumococcal infection, the odds ratio was 0.37 (95% CI 0.16 to 0.86), while for withdrawal the odds ratio was 0.49 (95% CI 0.09 to 2.71). Adverse drug effects were rare and minor. Rates of pneumococcal infection were found to be relatively low in children over the age
Ampofo, Krow; Byington, Carrie L.; Filloux, Francis; Hersh, Adam L.; Blaschke, Anne J.; Cowan, Priscilla; Korgenski, Kent; Mason, Edward O.; Pavia, Andrew T.
BACKGROUND: After licensure of the 7-valent pneumococcal conjugate vaccine (PCV7) in the United States in 2000, the incidence of pediatric pneumococcal meningitis decreased significantly. However, cases continue to occur. It is unknown whether meningitis due to PCV7 and non-PCV7 serotypes causes similar morbidity and mortality. METHODS: We performed a retrospective cohort study of laboratory-confirmed pneumococcal meningitis among Utah children from 1997 to 2010. We reviewed medical records and obtained clinical data during the acute illness and follow-up data on neurologic sequelae. RESULTS: Sixty-eight cases of meningitis were identified. PCV7 serotypes caused 64% of cases before and 25% of cases after licensure of PCV7 (P < .01). The age range was similar before and after PCV7 licensure (P = .5). The overall case fatality rate was 13% and was similar among cases caused by PCV7 and non-PCV7 serotypes (P = .7). Children with PCV7 serotypes were more likely to require mechanical ventilation (68% vs 34%; P < .01). Of all survivors, 63% had neurologic sequelae, and the proportion was similar after infection with PCV7 or non-PCV7 serotypes (P = .1). More than one-half (54%) of all children who developed pneumococcal meningitis in the PCV7 period were eligible for PCV7 and had not been immunized. CONCLUSIONS: Pneumococcal meningitis continues to be associated with high mortality and morbidity; death and neurologic sequelae are common with both PCV7 and non-PCV7 serotype meningitis. The substantial burden of this disease and continued cases among unimmunized children reinforce the need for more effective immunization strategies and continued surveillance in the era of PCV13. PMID:23979090
La Torre, Giuseppe; Mannocci, Alice; Colamesta, Vittoria; D’Egidio, Valeria; Sestili, Cristina; Spadea, Antonietta
Background The risk of getting influenza and pneumococcal disease is higher in cancer patients, and serum antibody levels tend to be lower in patients with hematological malignancy. Objective To assess flu and pneumococcal vaccinations efficacy, effectiveness, and safety in onco-hematological patients. Methods Two systematic reviews and possible meta-analysis were conducted to summarize the results of all primary study in the scientific literature about the flu and pneumococcal vaccine in onco-hematological patients. Literature searches were performed using Pub-Med and Scopus databases. StatsDirect 2.8.0 was used for the analysis. Results 22 and 26 studies were collected respectively for flu and pneumococcal vaccinations. Protection rate of booster dose was 30% (95% CI=6–62%) for H1N1. Pooled prevalence protection rate of H3N2 and B was available for meta-analysis only for first dose, 42.6% (95% CI=23.2 – 63.3 %) and 39.6 % (95% CI=26%–54.1%) for H3N2 and B, respectively. Response rate of booster dose resulted 35% (95% CI=19.7–51.2%) for H1N1, 23% (95% CI=16.6–31.5%) for H3N2, 29% (95% CI=21.3–37%) for B. Conclusion Despite the low rate of response, flu, and pneumococcal vaccines are worthwhile for patients with hematological malignancies. Patients undergoing chemotherapy in particular rituximab, splenectomy, transplant recipient had lower and impaired response. No serious adverse events were reported for both vaccines. PMID:27648207
Kwan-Gett, T. S.; Davis, R. L.; Shay, D. K.; Black, S.; Shinefield, H.; Koepsell, T.
We used microbiology and pharmacy data from health-maintenance organizations to determine whether antibiotic use by a household member increases the risk of penicillin-non-susceptible pneumococcal disease. Though it has been well established that an individual's antibiotic use increases one's risk of antibiotic-resistant infection, it is unclear whether the risk is increased if a member of one's household is exposed to antibiotics. We therefore conducted a case-control study of patients enrolled in health maintenance organizations in Western Washington and Northern California. Cases were defined as individuals with penicillin-non-susceptible pneumococcal infection; controls were individuals with penicillin-susceptible pneumococcal infection. Socioeconomic variables were obtained by linking addresses with 1997 census block group data. One-hundred and thirty-four cases were compared with 798 controls. Individual antibiotic use prior to diagnosis increased the odds of penicillin non-susceptibility, with the strongest effect seen for beta-lactam use within 2 months (OR 1.8, 95% CI 1.2, 2.8). When household antibiotic use by persons other than the patient were considered, at 4 months prior to diagnosis there was a trend towards an association between penicillin non-susceptibility and beta-lactam antibiotic use, and a possible association in a small subgroup of patients with eye and ear isolates. However, no significant overall pattern of association was seen. We conclude that though antibiotic use of any kind within 2 months prior to diagnosis is associated with an increased risk of penicillin-non-susceptible pneumococcal disease, there is no significant overall pattern of association between household antibiotic use and penicillin-non-susceptible pneumococcal infection. PMID:12558332
Vernet, G; Saha, S; Satzke, C; Burgess, D H; Alderson, M; Maisonneuve, J-F; Beall, B W; Steinhoff, M C; Klugman, K P
In view of the increasing use of pneumococcal vaccines, especially in the developing world, there is a need for appropriate diagnostics to understand the aetiology of pneumonia, to define the burden of pneumococcal disease, and to monitor vaccine efficacy and effectiveness. This article summarizes a meeting on the diagnosis, detection and serotyping of pneumococcal disease organized by PATH and Fondation Mérieux (18-20 October 2009, Fondation Mérieux Conference Centre, Les Pensières, France). Workers and experts met to discuss the gaps in the microbiology-based diagnosis of Streptococcus pneumoniae disease, with special emphasis on pneumonia. The meeting was designed to evaluate the state of the art of pneumococcal diagnostics and serotyping methodologies, identify research and development needs, and propose new guidelines to public health authorities to support the introduction of vaccines. Regarding detection, the main recommendations were to encourage chest X-rays and antigen detection in urine. Large-scale studies are needed to evaluate the diagnostic utility of test algorithms that associate chest X-rays, antigen detection in urine, S. pneumoniae quantitative PCR in nasopharyngeal aspirates and sputum, and C-reactive protein or procalcitonin measurement in blood. Efforts should be focused on proteomics to identify pneumococcus-specific antigens in urine or host markers in blood expressed during pneumonia. It was recommended to develop S. pneumoniae typing capacities, to understand the epidemiology of pneumococcal disease, and to evaluate vaccine effectiveness. Simple and effective approaches are encouraged, and new technologies based on beads, microarrays or deep sequencing should be developed to determine, in a single test capsular serotype, resistance profile and genotype.
Savva, Athina; Brouwer, Matthijs C; Roger, Thierry; Valls Serón, Mercedes; Le Roy, Didier; Ferwerda, Bart; van der Ende, Arie; Bochud, Pierre-Yves; van de Beek, Diederik; Calandra, Thierry
Pneumococcal meningitis is the most frequent and critical type of bacterial meningitis. Because cytokines play an important role in the pathogenesis of bacterial meningitis, we examined whether functional polymorphisms of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) were associated with morbidity and mortality of pneumococcal meningitis. Two functional MIF promoter polymorphisms, a microsatellite (-794 CATT5-8; rs5844572) and a single-nucleotide polymorphism (-173 G/C; rs755622) were genotyped in a prospective, nationwide cohort of 405 patients with pneumococcal meningitis and in 329 controls matched for age, gender, and ethnicity. Carriages of the CATT7 and -173 C high-expression MIF alleles were associated with unfavorable outcome (P= 0.005 and 0.003) and death (P= 0.03 and 0.01). In a multivariate logistic regression model, shock [odds ratio (OR) 26.0, P= 0.02] and carriage of the CATT7 allele (OR 5.12,P= 0.04) were the main predictors of mortality. MIF levels in the cerebrospinal fluid were associated with systemic complications and death (P= 0.0002). Streptococcus pneumoniae strongly up-regulated MIF production in whole blood and transcription activity of high-expression MIF promoter Luciferase reporter constructs in THP-1 monocytes. Consistent with these findings, treatment with anti-MIF immunoglogulin G (IgG) antibodies reduced bacterial loads and improved survival in a mouse model of pneumococcal pneumonia and sepsis. The present study provides strong evidence that carriage of high-expression MIF alleles is a genetic marker of morbidity and mortality of pneumococcal meningitis and also suggests a potential role for MIF as a target of immune-modulating adjunctive therapy.
Licciardi, Paul V; Russell, Fiona M; Balloch, Anne; Burton, Robert L; Nahm, Moon H; Gilbert, Gwendolyn; Tang, Mimi L K; Mulholland, Edward K
The impact of prior nasopharyngeal carriage on serotype-specific IgG responses following immunization with pneumococcal conjugate vaccines (PCV) has recently been described. This report extends these findings to describe the attenuation of functional immune responses following 23-valent pneumococcal polysaccharide vaccination (PPS). We report the attenuation of immune responses following booster with the 23-valent pneumococcal polysaccharide vaccination (PPS) in infants with prior nasopharyngeal carriage of Streptococcus pneumoniae. Fijian infants who were part of a phase II randomized, controlled trial of reduced dose PCV7 schedules were the basis of this study. Pneumococcal carriage was determined at 6, 9 and 12 months of age, prior to PPS immunization. Serum samples collected at 18 weeks (post-PCV7), 12 months (pre-PPS), 12.5 months and 17 months (post-PPS) of age were assessed for serotype-specific IgG and opsonophagocytic responses. The most frequently carried serotypes were 6B (N=11), 19F (N=14) and 23F (N=23). Significantly lower serotype-specific IgG for 19F, 23F but not 6B post-PPS were detected in infants with homologous serotype carriage prior to PPS compared with non-carriers (N=230). However, OPA levels for 6B and 23F were lower in infants that carried these serotypes. Pneumococcal carriage with 19F or 23F at any time prior to PPS immunization in infants at 12 months of age who were previously primed with PCV resulted in serotype-specific hyporesponsiveness that persisted until 17 months of age. These results may have implications for the timing of infant vaccine schedules, particularly in high disease burden settings.
Savva, Athina; Brouwer, Matthijs C.; Valls Serón, Mercedes; Le Roy, Didier; Ferwerda, Bart; van der Ende, Arie; Bochud, Pierre-Yves; van de Beek, Diederik; Calandra, Thierry
Pneumococcal meningitis is the most frequent and critical type of bacterial meningitis. Because cytokines play an important role in the pathogenesis of bacterial meningitis, we examined whether functional polymorphisms of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) were associated with morbidity and mortality of pneumococcal meningitis. Two functional MIF promoter polymorphisms, a microsatellite (−794 CATT5–8; rs5844572) and a single-nucleotide polymorphism (−173 G/C; rs755622) were genotyped in a prospective, nationwide cohort of 405 patients with pneumococcal meningitis and in 329 controls matched for age, gender, and ethnicity. Carriages of the CATT7 and −173 C high-expression MIF alleles were associated with unfavorable outcome (P = 0.005 and 0.003) and death (P = 0.03 and 0.01). In a multivariate logistic regression model, shock [odds ratio (OR) 26.0, P = 0.02] and carriage of the CATT7 allele (OR 5.12, P = 0.04) were the main predictors of mortality. MIF levels in the cerebrospinal fluid were associated with systemic complications and death (P = 0.0002). Streptococcus pneumoniae strongly up-regulated MIF production in whole blood and transcription activity of high-expression MIF promoter Luciferase reporter constructs in THP-1 monocytes. Consistent with these findings, treatment with anti-MIF immunoglogulin G (IgG) antibodies reduced bacterial loads and improved survival in a mouse model of pneumococcal pneumonia and sepsis. The present study provides strong evidence that carriage of high-expression MIF alleles is a genetic marker of morbidity and mortality of pneumococcal meningitis and also suggests a potential role for MIF as a target of immune-modulating adjunctive therapy. PMID:26976591
Gonçalves, Viviane M; Dias, Waldely O; Campos, Ivana B; Liberman, Celia; Sbrogio-Almeida, Maria E; Silva, Eliane P; Cardoso, Celso P; Alderson, Mark; Robertson, George; Maisonneuve, Jean-François; Tate, Andrea; Anderson, Porter; Malley, Richard; Fratelli, Fernando; Leite, Luciana C C
Pneumococcal infections impose a large burden of disease on the human population, mainly in developing countries, and the current pneumococcal vaccines offer serotype-specific protection, but do not cover all pathogenic strains, leaving populations vulnerable to disease caused by non-vaccine serotypes. The pneumococcal whole cell vaccine is a low-cost strategy based on non-capsular antigens common to all strains, inducing serotype-independent immunity. Therefore, we developed the process for the cGMP production of this cellular vaccine. Initially, three engineering runs and two cGMP runs were performed in 60-L bioreactors, demonstrating the consistency of the production process, as evaluated by the growth curves, glucose consumption and metabolite formation (lactate and acetate). Cell recovery by tangential filtration was 92 ± 13 %. We optimized the conditions for beta-propiolactone (BPL) inactivation of the bacterial suspensions, establishing a maximum cell density of OD600 between 27 and 30, with a BPL concentration of 1:4000 (v/v) at 150 rpm and 4 °C for 30 h. BPL was hydrolyzed by heating for 2h at 37 °C. The criteria and methods for quality control were defined using the engineering runs and the cGMP Lots passed all specifications. cGMP vaccine Lots displayed high potency, inducing between 80 and 90% survival in immunized mice when challenged with virulent pneumococci. Sera from mice immunized with the cGMP Lots recognized several pneumococcal proteins in the extract of encapsulated strains by Western blot. The cGMP whole cell antigen bulk and whole cell vaccine product lots were shown to be stable for up to 12 and 18 months, respectively, based upon survival assays following i.p. challenge. Our results show the consistency and stability of the cGMP whole cell pneumococcal vaccine lots and demonstrate the feasibility of production in a developing country setting.
Andrade, Ana Lucia; Minamisava, Ruth; Policena, Gabriela; Cristo, Elier B; Domingues, Carla Magda S; de Cunto Brandileone, Maria Cristina; Almeida, Samanta Cristine Grassi; Toscano, Cristiana Maria; Bierrenbach, Ana Luiza
Routine infant immunization with 10-valent pneumococcal conjugate vaccine (PCV-10) began in Brazil in 2010. The impact of the PCV-10 on rates of invasive pneumococcal disease (IPD) at the population level was not yet evaluated. Serotype-specific IPD changes after PCV-10 introduction is still to be determined. Data from national surveillance system for notifiable diseases (SINAN) and national reference laboratory for S. pneumoniae in Brazil (IAL) were linked to enhance case ascertainment of IPD. An interrupted time-series analysis was conducted to predict trends in the postvaccination IPD rates in the absence of PCV-10 vaccination, taking into consideration seasonality and secular trends. PCVs serotype-specific distribution were assessed before (2008–2009) and after (2011–2013) the introduction of PCV-10 in the immunization program. A total of 9,827 IPD cases were identified from 2008–2013 when combining SINAN and IAL databases. Overall, PCV-10 types decreased by 41.3% after PCV-10 vaccination period, mostly in children aged 2–23 months, while additional PCV-13 serotypes increased by 62.8% mainly in children under 5-year of age. For children aged 2–23 months, targeted by the immunization program, we observed a 44.2% (95%CI, 15.8–72.5%) reduction in IPD rates. In contrast, significant increase in IPD rates were observed for adults aged 18–39 y (18.9%, 95%CI 1.1–36.7%), 40–64 y (52.5%, 95%CI 24.8–80.3%), and elderly ≥ 65 y (79.3%, 95%CI 62.1–96.5%). This is the first report of a time-series analysis for PCV impact in IPD conducted at national level data in a developing country. We were able to show significant impact of PCV-10 on IPD for age groups targeted by vaccination in Brazil, 3 y after its introduction. No impact on other age groups was demonstrated. PMID:26905679
Andrade, Ana Lucia; Minamisava, Ruth; Policena, Gabriela; Cristo, Elier B; Domingues, Carla Magda S; de Cunto Brandileone, Maria Cristina; Almeida, Samanta Cristine Grassi; Toscano, Cristiana Maria; Bierrenbach, Ana Luiza
Routine infant immunization with 10-valent pneumococcal conjugate vaccine (PCV-10) began in Brazil in 2010. The impact of the PCV-10 on rates of invasive pneumococcal disease (IPD) at the population level was not yet evaluated. Serotype-specific IPD changes after PCV-10 introduction is still to be determined. Data from national surveillance system for notifiable diseases (SINAN) and national reference laboratory for S. pneumoniae in Brazil (IAL) were linked to enhance case ascertainment of IPD. An interrupted time-series analysis was conducted to predict trends in the postvaccination IPD rates in the absence of PCV-10 vaccination, taking into consideration seasonality and secular trends. PCVs serotype-specific distribution were assessed before (2008-2009) and after (2011-2013) the introduction of PCV-10 in the immunization program. A total of 9,827 IPD cases were identified from 2008-2013 when combining SINAN and IAL databases. Overall, PCV-10 types decreased by 41.3% after PCV-10 vaccination period, mostly in children aged 2-23 months, while additional PCV-13 serotypes increased by 62.8% mainly in children under 5-year of age. For children aged 2-23 months, targeted by the immunization program, we observed a 44.2% (95%CI, 15.8-72.5%) reduction in IPD rates. In contrast, significant increase in IPD rates were observed for adults aged 18-39 y (18.9%, 95%CI 1.1-36.7%), 40-64 y (52.5%, 95%CI 24.8-80.3%), and elderly ≥ 65 y (79.3%, 95%CI 62.1-96.5%). This is the first report of a time-series analysis for PCV impact in IPD conducted at national level data in a developing country. We were able to show significant impact of PCV-10 on IPD for age groups targeted by vaccination in Brazil, 3 y after its introduction. No impact on other age groups was demonstrated.
Keller, Lance E; Luo, Xiao; Thornton, Justin A; Seo, Keun-Seok; Moon, Bo Youn; Robinson, D Ashley; McDaniel, Larry S
Current vaccinations are effective against encapsulated strains of Streptococcus pneumoniae, but they do not protect against nonencapsulated Streptococcus pneumoniae (NESp), which is increasing in colonization and incidence of pneumococcal disease. Vaccination with pneumococcal proteins has been assessed for its ability to protect against pneumococcal disease, but several of these proteins are not expressed by NESp. Pneumococcal surface protein K (PspK), an NESp virulence factor, has not been assessed for immunogenic potential or host modulatory effects. Mammalian cytokine expression was determined in an in vivo mouse model and in an in vitro cell culture system. Systemic and mucosal mouse immunization studies were performed to determine the immunogenic potential of PspK. Murine serum and saliva were collected to quantitate specific antibody isotype responses and the ability of antibody and various proteins to inhibit epithelial cell adhesion. Host cytokine response was not reduced by PspK. NESp was able to colonize the mouse nasopharynx as effectively as encapsulated pneumococci. Systemic and mucosal immunization provided protection from colonization by PspK-positive (PspK(+)) NESp. Anti-PspK antibodies were recovered from immunized mice and significantly reduced the ability of NESp to adhere to human epithelial cells. A protein-based pneumococcal vaccine is needed to provide broad protection against encapsulated and nonencapsulated pneumococci in an era of increasing antibiotic resistance and vaccine escape mutants. We demonstrate that PspK may serve as an NESp target for next-generation pneumococcal vaccines. Immunization with PspK protected against pneumococcal colonization, which is requisite for pneumococcal disease.
... HPV (Human Papillomavirus) Influenza (Flu) Measles Meningococcal Disease Mumps Pertussis (Whooping Cough) Pneumococcal Disease Rubella (German Measles) ... HPV (Human Papillomavirus) Influenza (Flu) Measles Meningococcal Disease Mumps Pertussis (Whooping Cough) Pneumococcal Disease Rubella (German Measles) ...
... HPV (Human Papillomavirus) Influenza (Flu) Measles Meningococcal Disease Mumps Pertussis (Whooping Cough) Pneumococcal Disease Rubella (German Measles) ... HPV (Human Papillomavirus) Influenza (Flu) Measles Meningococcal Disease Mumps Pertussis (Whooping Cough) Pneumococcal Disease Rubella (German Measles) ...
Croney, Christina M.; Coats, Mamie T.; Nahm, Moon H.; Briles, David E.
Pneumococcal conjugate vaccines (PCVs) are recommended for the prevention of invasive pneumococcal disease (IPD) in young children. Since the introduction of the heptavalent pneumococcal vaccine (PCV7) in 2000, IPD caused by serotypes in the vaccine has almost been eliminated, and previously uncommon capsular serotypes now cause most cases of pediatric IPD in the United States. One way to protect against these strains would be to add cross-reactive protein antigens to new vaccines. One such protein is pneumococcal surface protein A (PspA). Prior to 2000, PspA families 1 and 2 were expressed by 94% of isolates. Because PCV7 vaccine pressure has resulted in IPD caused by capsular serotypes that were previously uncommon and unstudied for PspA expression, it was possible that many of the new strains expressed different PspA antigens or even lacked PspA. Of 157 pediatric invasive pneumococcal isolates collected at a large pediatric hospital in Alabama between 2002 and 2010, only 60.5% had capsular serotypes included in PCV13, which came into general use in Alabama after our strains were collected. These isolates included 17 serotypes that were not covered by PCV13. Nonetheless, pneumococcal capsular serotype replacement was not associated with changes in PspA expression; 96% of strains in this collection expressed PspA family 1 or 2. Continued surveillance will be critical to vaccine strategies to further reduce IPD. PMID:22539473
Moorthy, Anandi Narayana; Rai, Prashant; Jiao, Huipeng; Wang, Shi; Tan, Kong Bing; Qin, Liang; Watanabe, Hiroshi; Zhang, Yongliang; Teluguakula, Narasaraju; Chow, Vincent Tak Kwong
Neutrophil extracellular traps (NETs) are released by activated neutrophils to ensnare and kill microorganisms. NETs have been implicated in tissue injury since they carry cytotoxic components of the activated neutrophils. We have previously demonstrated the generation of NETs in infected murine lungs during both primary pneumococcal pneumonia and secondary pneumococcal pneumonia after primary influenza. In this study, we assessed the correlation of pneumococcal capsule size with pulmonary NETs formation and disease severity. We compared NETs formation in the lungs of mice infected with three pneumococcal strains of varying virulence namely serotypes 3, 4 and 19F, as well as a capsule-deficient mutant of serotype 4. In primary pneumonia, NETs generation was strongly associated with the pneumococcal capsule thickness, and was proportional to the disease severity. Interestingly, during secondary pneumonia after primary influenza infection, intense pulmonary NETs generation together with elevated myeloperoxidase activity and cytokine dysregulation determined the disease severity. These findings highlight the crucial role played by the size of pneumococcal capsule in determining the extent of innate immune responses such as NETs formation that may contribute to the severity of pneumonia. PMID:27034012
Kim, Kyung-Hyo; Hong, Jung Yun; Lee, Hyunju; Kwak, Ga Young; Nam, Chan Hee; Lee, Soo Young; Oh, Eunsang; Yu, Jigui; Nahm, Moon H; Kang, Jin Han
To confirm the effect of 7-valent pneumococcal conjugate vaccine (PCV7), pneumococcal nasopharyngeal (NP) carriage was compared between vaccinated (3 + 1 doses PCV7) and non-vaccinated children. Vaccinated subjects were recruited from highly vaccinated regions (≥ 60%), Seoul and Incheon whereas control subjects were recruited from Jeju Island where vaccination rates are low (< 15%). NP swabs were obtained from 400 children aged 18-59 months. Serotype and antibiotic susceptibility was analyzed. Pneumococcal carriage rate was 18.0% (36/200) and 31.5% (63/200) for the vaccinated and control group, respectively. Among those vaccinated, 41.7% (15/36) of the serotypes were vaccine-related type (VRT: 6A, 6C, 19A) with the most common serotype 6C. The next common type was non-typable/non-capsule 30.6% (11/36) followed by non-vaccine type 16.7% (6/36) and vaccine type (VT) serotypes were found in only 11.1% (4/36). In contrast, 52.4% (33/63) of the isolates in the control group were VT. Resistance rates for penicillin and erythromycin were lower in the vaccine group (vaccine vs control; penicillin 45.2% vs 71.4%, erythromycin 74.2% vs 90.5%, P < 0.05). Multi-drug resistance was also lower in vaccinated subjects (vaccine vs control; 45.2% vs 69.8%, P < 0.05). PCV7 reduces carriage in VT which leads to replacement of pneumococci by antibiotic susceptible VRT or non-vaccine type strains.
Hausdorff, William P; Hoet, Bernard; Adegbola, Richard A
Streptococcus pneumoniae is a major cause of childhood morbidity and mortality worldwide. A heptavalent polysaccharide-protein conjugate vaccine (PCV) has proven highly effective in preventing pneumococcal disease in industrialized countries. Two higher-valent pneumococcal conjugate vaccines are now widely available, even in the poorest countries. These differ from each other in the number of serotypes and carrier proteins used for their conjugation. Some have assumed that the only meaningful clinical difference between PCV formulations is a function of the number of serotypes each contains. A careful review of recent clinical data with these and several unlicensed PCV formulations points to important similarities but also that some key properties of each vaccine likely differ from one another.
Sugiyama, Takashi; Uchiyama, Tsuyoshi; Takashima, Hirotsugu; Yamamoto, Daisuke; Sato, Keishiro; Shimizu, Takako; Otsuki, Yoshiro; Ohashi, Toshihiko
One explanation for cerebral infarctions that occur as a complication of pneumococcal meningitis is blood coagulation abnormalities. We investigated the clinical features, laboratory test results, magnetic resonance imaging (MRI) findings, and pathological features of 10 patients with pneumococcal meningitis between 2006 and 2013 to examine the abnormal findings that may be associated with prognosis. Five patients (50%) that had Glasgow Outcome Scale scores between 1 and 4 were classified as the poor outcome group. In this group, the MRI revealed a high signal intensity on the diffusion-weighted image (DWI), and there was an abnormal signal along the cerebral cortex and Virchow-Robin spaces, which were characterized pathologically by ischemic changes. The plasma thrombin-antithrombin complex (TAT) levels showed greater differences between the poor and good prognosis groups than platlet and D-dimer levels; this suggested that high plasma TAT levels indicate a poor prognosis.
Kuipers, Kirsten; Diavatopoulos, Dimitri A; van Opzeeland, Fred; Simonetti, Elles; van den Kieboom, Corné H; Kerstholt, Mariska; Borczyk, Malgorzata; van IngenSchenau, D; Brandsma, Eelke T; Netea, Mihai G; de Jonge, Marien I
For many bacterial respiratory infections, development of (severe) disease is preceded by asymptomatic colonization of the upper airways. For Streptococcus pneumoniae, the transition to severe lower respiratory tract infection is associated with an increase in nasopharyngeal colonization density. Insight into how the mucosal immune system restricts colonization may provide new strategies to prevent clinical symptoms. Several studies have provided indirect evidence that the mucosal adjuvant cholera toxin subunit B (CTB) may confer nonspecific protection against respiratory infections. Here, we show that CTB reduces the pneumococcal load in the nasopharynx, which required activation of the caspase-1/11 inflammasome, mucosal T cells, and macrophages. Our findings suggest that CTB-dependent activation of the local innate response synergizes with noncognate T cells to restrict bacterial load. Our study not only provides insight into the immunological components required for containment and clearance of pneumococcal carriage, but also highlights an important yet often understudied aspect of adjuvants.
Grewal, Prabhjit K; Aziz, Peter V; Uchiyama, Satoshi; Rubio, Gabriel R; Lardone, Ricardo D; Le, Dzung; Varki, Nissi M; Nizet, Victor; Marth, Jamey D
The endocytic Ashwell-Morell receptor (AMR) of hepatocytes detects pathogen remodeling of host glycoproteins by neuraminidase in the bloodstream and mitigates the lethal coagulopathy of sepsis. We have investigated the mechanism of host protection by the AMR during the onset of sepsis and in response to the desialylation of blood glycoproteins by the NanA neuraminidase of Streptococcus pneumoniae. We find that the AMR selects among potential glycoprotein ligands unmasked by microbial neuraminidase activity in pneumococcal sepsis to eliminate from blood circulation host factors that contribute to coagulation and thrombosis. This protection is attributable in large part to the rapid induction of a moderate thrombocytopenia by the AMR. We further show that neuraminidase activity in the blood can be manipulated to induce the clearance of AMR ligands including platelets, thereby preactivating a protective response in pneumococcal sepsis that moderates the severity of disseminated intravascular coagulation and enables host survival.
Sinisalo, Marjatta; Vilpo, Juhani; Itälä, Maija; Väkeväinen, Merja; Taurio, Jyrki; Aittoniemi, Janne
Chronic lymphocytic leukaemia (CLL) is a common adulthood mature B-cell neoplasm. Infections are the most important cause of mortality in this condition, and Streptococcus pneumoniae has been considered the most important single pathogen. We investigated the immunogenicity of 7-valent pneumococcal conjugate vaccine in patients with CLL. The study material comprised 52 patients with CLL and 25 age- and sex-matched controls. The subjects were vaccinated with Prevenar pneumococcal conjugate vaccine. Serum samples were taken for antibody determinations before and four weeks after vaccination. Antibody response rates to vaccine antigens were lower in patients with CLL compared to controls. However, if the vaccine had been administered at an early stage of the disease, i.e. before commencement of chemotherapy and the development of hypogammaglobulinaemia, a significant vaccination response to at least six antigens was obtained in almost 40% of the CLL patients. Our results indicate that early administration of conjugate vaccine may be beneficial in CLL.
Alsina, Laia; Basteiro, Maria G.; de Paz, Hector D.; Iñigo, Melania; de Sevilla, Mariona F.; Triviño, Miriam; Juan, Manel; Muñoz-Almagro, Carmen
Purpose Clinical, immunological and microbiological characteristics of recurrent invasive pneumococcal disease (IPD) in children were evaluated, differentiating relapse from reinfection, in order to identify specific risk factors for both conditions. Methods All patients <18 years-old with recurrent IPD admitted to a tertiary-care pediatric center from January 2004 to December 2011 were evaluated. An episode of IPD was defined as the presence of clinical findings of infection together with isolation and/or pneumococcal DNA detection by Real-Time PCR in any sterile body fluid. Recurrent IPD was defined as 2 or more episodes in the same individual at least 1 month apart. Among recurrent IPD, we differentiated relapse (same pneumococcal isolate) from reinfection. Results 593 patients were diagnosed with IPD and 10 patients died. Among survivors, 23 episodes of recurrent IPD were identified in 10 patients (1.7%). Meningitis was the most frequent form of recurrent IPD (10 episodes/4 children) followed by recurrent empyema (8 episodes/4 children). Three patients with recurrent empyema caused by the same pneumococcal clone ST306 were considered relapses and showed high bacterial load in their first episode. In contrast, all other episodes of recurrent IPD were considered reinfections. Overall, the rate of relapse of IPD was 0.5% and the rate of reinfection 1.2%. Five out of 7 patients with reinfection had an underlying risk factor: cerebrospinal fluid leak (n = 3), chemotherapy treatment (n = 1) and a homozygous mutation in MyD88 gene (n = 1). No predisposing risk factors were found in the remainder. Conclusions recurrent IPD in children is a rare condition associated with an identifiable risk factor in case of reinfection in almost 80% of cases. In contrast, recurrent IPD with pleuropneumonia is usually a relapse of infection. PMID:25738983
Sanal, Ozden; Ersoy, Fugen; Tezcan, Ilhan; Metin, Ayse; Turul, Tuba; Gariboglu, Semra; Yel, Leman
Immunodeficiency is a characteristic feature of ataxia-telangiectasia (A-T). Humoral immunodeficiency generally consists of hypogammaglobulinemia and impaired antibody response to bacterial and viral antigens. We previously observed defective antibody response to 23-valent pneumococcal polysaccharide vaccine (PPV) in 96% of 29 patients with A-T. In this study, we investigated the antibody response to a seven-valent pneumococcal conjugate vaccine, PCV7, in 14 patients with A-T. IgG antibody levels to four pneumococcal serotypes, 6B, 14, 19F, 23F, which were included in PCV7, were measured by ELISA in pre- and postimmunization serum samples. Antibody titers against each individual Streptococcus pneumoniae serotype was considered to be positive when serotype specific pneumococcal antibody titer was higher than 10% (>10 U/mL) of the reference plasma pool level. However, when the fold increase (FI) in postimmunization antibody titer was less than two, the subject was determined to be unresponsive to the given serotype. The values were compared with the results obtained in age- and ethnic-matched children after one dose of PPV. Only two patients produced antibodies to one serotype each; one to serotype 19 with a fold increase of <2, and the other to serotype 23F with a fold increase of 5.7 based on the above criteria, although the differences between pre- and postvaccine antibody titers for serotypes 14, 19, and 23 appeared to be statistically significant. In conclusion, A-T patients failed to respond to one dose of PCV7 vaccine. Two or more doses of conjugated vaccine may be required to recruit the help of T lymphocytes in A-T patients.
Schirm, Sibylle; Ahnert, Peter; Wienhold, Sandra; Mueller-Redetzky, Holger; Nouailles-Kursar, Geraldine; Loeffler, Markus; Witzenrath, Martin; Scholz, Markus
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. PMID:27196107
Pope, Caroline; Oliver, Elizabeth H; Ma, Jiangtao; Langton Hewer, Claire; Mitchell, Tim J; Finn, Adam
Streptococcus pneumoniae colonises the upper respiratory tract and can cause pneumonia, meningitis and otitis media. Existing pneumococcal conjugate vaccines are expensive to produce and only protect against 13 of the 90+ pneumococcal serotypes; hence there is an urgent need for the development of new vaccines. We have shown previously in mice that pneumolysin (Ply) and a non-toxic variant (Δ6Ply) enhance antibody responses when genetically fused to pneumococcal surface adhesin A (PsaA), a potentially valuable effect for future vaccines. We investigated this adjuvanticity in human paediatric mucosal primary immune cell cultures. Adenoidal mononuclear cells (AMNC) from children aged 0-15 years (n=46) were stimulated with conjugated, admixed or individual proteins, cell viability and CD4+ T-cell proliferative responses were assessed using flow cytometry and cytokine secretion was measured using multiplex technology. Proliferation of CD4+ T-cells in response to PsaAPly, was significantly higher than responses to individual or admixed proteins (p=0.002). In contrast, an enhanced response to PsaAΔ6Ply compared to individual or admixed proteins only occurred at higher concentrations (p<0.01). Evaluation of cytotoxicity suggested that responses occurred when Ply-induced cytolysis was inhibited, either by fusion or mutation, but importantly an additional toxicity independent immune enhancing effect was also apparent as a result of fusion. Responses were MHC class II dependent and had a Th1/Th17 profile. Genetic fusion of Δ6Ply to PsaA significantly modulates and enhances pro-inflammatory CD4+ T-cell responses without the cytolytic effects of some other pneumolysoids. Membrane binding activity of such proteins may confer valuable adjuvant properties as fusion may assist Δ6Ply to deliver PsaA to the APC surface effectively, contributing to the initiation of anti-pneumococcal CD4+ T-cell immunity.
Greene, Christopher J.; Marks, Laura R.; Hu, John C.; Reddinger, Ryan; Mandell, Lorrie; Roche-Hakansson, Hazeline; King-Lyons, Natalie D.
Streptococcus pneumoniae commonly inhabits the nasopharynx as a member of the commensal biofilm. Infection with respiratory viruses, such as influenza A virus, induces commensal S. pneumoniae to disseminate beyond the nasopharynx and to elicit severe infections of the middle ears, lungs, and blood that are associated with high rates of morbidity and mortality. Current preventive strategies, including the polysaccharide conjugate vaccines, aim to eliminate asymptomatic carriage with vaccine-type pneumococci. However, this has resulted in serotype replacement with, so far, less fit pneumococcal strains, which has changed the nasopharyngeal flora, opening the niche for entry of other virulent pathogens (e.g., Streptococcus pyogenes, Staphylococcus aureus, and potentially Haemophilus influenzae). The long-term effects of these changes are unknown. Here, we present an attractive, alternative preventive approach where we subvert virus-induced pneumococcal disease without interfering with commensal colonization, thus specifically targeting disease-causing organisms. In that regard, pneumococcal surface protein A (PspA), a major surface protein of pneumococci, is a promising vaccine target. Intradermal (i.d.) immunization of mice with recombinant PspA in combination with LT-IIb(T13I), a novel i.d. adjuvant of the type II heat-labile enterotoxin family, elicited strong systemic PspA-specific IgG responses without inducing mucosal anti-PspA IgA responses. This response protected mice from otitis media, pneumonia, and septicemia and averted the cytokine storm associated with septic infection but had no effect on asymptomatic colonization. Our results firmly demonstrated that this immunization strategy against virally induced pneumococcal disease can be conferred without disturbing the desirable preexisting commensal colonization of the nasopharynx. PMID:27001538
Bacterial infections are common in patients with nephrotic syndrome, including peritonitis, sepsis, meningitis, urinary tract infection, and cellulitis. An 8-year-old boy presented with colicky abdominal pain, vomiting, swollen and painful erythematous lesions around the umbilicus and in anterior surface of left thigh (cellulitis), mild generalized edema, and ascites. The microorganism isolated from peritoneal fluid and blood cultures was Pneumococcus. Association of pneumococcal sepsis, peritonitis, and cellulitis has been rarely reported in nephrotic syndrome.
Capsular serotypes and antimicrobial susceptibilities of Streptococcus pneumoniae causing invasive pneumococcal disease from 2009-2012 with an emphasis on serotype 19A in bacteraemic pneumonia and empyema and β-lactam resistance.
Lee, Meng-Rui; Chen, Chung-Ming; Chuang, Tzu-Yi; Huang, Yu-Tsung; Hsueh, Po-Ren
Capsular serotypes and antimicrobial susceptibilities of Streptococcus pneumoniae isolates that cause invasive pneumococcal disease (IPD) were studied and the role of serotype 19A in the development of bacteraemic pneumonia and empyema was investigated. Subjects comprised 98 patients (56 adults and 42 children) who were treated for IPD at a university-affiliated tertiary referral centre in Taiwan during 2009-2012. Serotypes of the isolates were identified using the latex agglutination method. In vitro susceptibilities of the isolates to 13 antimicrobial agents were determined using the broth microdilution method and were interpreted as recommended by the Clinical and Laboratory Standards Institute. During the study period, bacteraemic pneumonia was the most common type of infection (43/98; 43.9%), followed by primary bacteraemia (30/98; 30.6%). Serotype 19A was the most common serotype (23/98; 23.5%) in all patients. Fourteen (70.0%) of 20 children (47.6% of all children) with serotype 19A infection had pneumonia with empyema, whilst eight patients had concomitant bacteraemia. 7-valent pneumococcal conjugated vaccine (PCV-7), PCV-10, PCV-13 and 23-valent pneumococcal polysaccharide vaccine (PPV-23) had coverage rates of 37.8%, 38.8%, 79.6% and 77.6%, respectively. A substantial increase in the proportion of serotype 15A (6.1%) and 6A (8.2%) was found. In addition, there was a significant reduction in rates of susceptibility of serotype 19A isolates to penicillin, cefotaxime and ceftriaxone but not to azithromycin or any quinolone tested compared with those of non-19A isolates. The prevalence of serotypes 19A, 15A and 6A in patients with IPD increased markedly during the period, especially in children with bacteraemic pneumonia and empyema.
Farnworth, Sarah L.; Henderson, Neil C.; MacKinnon, Alison C.; Atkinson, Kirsten M.; Wilkinson, Tom; Dhaliwal, Kevin; Hayashi, Katsutoshi; Simpson, A. John; Rossi, Adriano G.; Haslett, Christopher; Sethi, Tariq
The Gram-positive Streptococcus pneumoniae is the leading cause of community-acquired pneumonia worldwide, resulting in high mortality. Our in vivo studies show that galectin-3−/− mice develop more severe pneumonia after infection with S. pneumoniae, as demonstrated by increased bacteremia and lung damage compared to wild-type mice and that galectin-3 reduces the severity of pneumococcal pneumonia in part by augmenting neutrophil function. Specifically, we show that 1) galectin-3 directly acts as a neutrophil-activating agent and potentiates the effect of fMLP, 2) exogenous galectin-3 augments neutrophil phagocytosis of bacteria and delays neutrophil apoptosis, 3) phagocytosis of apoptotic neutrophils by galectin-3−/− macrophages is less efficient compared to wild type, and 4) galectin-3 demonstrates bacteriostatic properties against S. pneumoniae in vitro. Furthermore, ad-back of recombinant galectin-3 in vivo protects galectin-3-deficient mice from developing severe pneumonia. Together, these results demonstrate that galectin-3 is a key molecule in the host defense against pneumococcal infection. Therapeutic strategies designed to augment galectin-3 activity may both enhance inflammatory cell function (by directly affecting neutrophil responsiveness and prolonging neutrophil longevity) and have direct bacteriostatic activity, improving clinical outcomes after severe pneumococcal infection. PMID:18202191
Lee, C J
The maternal transfer of pneumococcal polysaccharides to foetus, as well as the antibody formation and metabolic response were studied in mice exposed to pneumococcal polysaccharides during pregnancy. Type 19 and type 57 pneumococcal polysaccharides display cross-placental transfer to foetus. These polysaccharides also transfer through mother's milk to neonates. Maternal immunization of type 19 polysaccharide during pregnancy induced higher antibody formation in the offspring than the group from non-immunized mothers. Young mice, which received a second dose of polysaccharide at 2 weeks of age, showed a higher antibody response than those which did not receive polysacharide. Treatment of mothers with anti-lymphocyte serum, following by administration of polysaccharide, significantly increased the neonatal immune response to the polysaccharide. Treatment of the mother with a high dose of type 19 or type 57 polysaccharide did not cause significant changes in neonatal growth and organ weights. The offspring from mothers treated with high doses of these polysaccharides did not exhibit abnormalities in chemical contents of their tissues. PMID:7429553
Apiwattanakul, Nopporn; Thomas, Paul G; Kuhn, Raymond E; Herbert, De'Broski R; McCullers, Jonathan A
Pneumonia is the leading killer of children worldwide. Here, we report that helminth-infected mice develop fatal pneumonia when challenged with Streptococcus pneumoniae. Mice were chronically infected with either the flatworm Taenia crassiceps or the roundworm Heligmosomoides polygyrus. Upon challenge with a pneumonic type 3 strain of S. pneumoniae (A66.1), the worm-infected mice developed pneumonia at a rate and to a degree higher than age-matched control mice as measured by bioluminescent imaging and lung titers. This predisposition to pneumonia appears to be specific to S. pneumoniae, as worm-infected mice did not show evidence of increased morbidity when challenged with a lethal dose of influenza virus or sublethal doses of Staphylococcus aureus or Listeria monocytogenes. The defect was also present when worm-infected mice were challenged with a type 2 sepsis-causing strain (D39); an increased rate of pneumonia, decreased survival, and increased lung and blood titers were found. Pneumococcal colonization and immunity against acute otitis media were unaffected. Anti-helminthic treatment in the H. polygyrus model reversed this susceptibility. We conclude that helminth coinfection predisposes mice to fatal pneumococcal pneumonia by promoting increased outgrowth of bacteria in the lungs and blood. These data have broad implications for the prevention and treatment for pneumonia in the developing world, where helminth infections are endemic and pneumococcal pneumonia is common.
van der Gaast—de Jongh, Christa E.; Diavatopoulos, Dimitri A.; de Jonge, Marien I.
The respiratory pathogen Streptococcus pneumoniae is a major cause of diseases such as otitis media, pneumonia, sepsis and meningitis. The first step towards infection is colonization of the nasopharynx. Recently, it was shown that agglutinating antibodies play an important role in the prevention of mucosal colonization with S. pneumoniae. Here, we present a novel method to quantify antibody-dependent pneumococcal agglutination in a high-throughput manner using flow cytometry. We found that the concentration of agglutinating antibodies against pneumococcal capsule are directly correlated with changes in the size and complexity of bacterial aggregates, as measured by flow cytometry and confirmed by light microscopy. Using the increase in size, we determined the agglutination index. The cutoff value was set by measuring a series of non-agglutinating antibodies. With this method, we show that not only anti-polysaccharide capsule antibodies are able to induce agglutination but that also anti-PspA protein antibodies have agglutinating capabilities. In conclusion, we have described and validated a novel method to quantify pneumococcal agglutination, which can be used to screen sera from murine or human vaccination studies, in a high-throughput manner. PMID:28288168
Nelson, George E; Gershman, Kenneth A; Swerdlow, David L; Beall, Bernard W; Moore, Matthew R
Pneumococcal pneumonia was a complication during previous influenza pandemics but was not evident initially during pandemic (H1N1) 2009. During October 2009 in Denver, Colorado, USA, invasive pneumococcal disease (IPD) and pandemic (H1N1) 2009 peaked simultaneously, which suggests a link. We compared cases of IPD in October 2009 with cases in February 2009, the most recent peak month of seasonal influenza. During October 2009, we observed 58 IPD cases, which was 3× the average number of IPD cases that usually occur in October in Denver. Patients with IPD in October 2009 were younger and more likely to have chronic lung disease than patients who had IPD in February 2009; a total of 10/47 patients had influenza, and 33/53 patients had influenza-like illness. Thus, ≈17%-62% cases of IPD may have been associated with pandemic (H1N1) 2009. Pneumococcal disease prevention strategies should be emphasized during future influenza pandemics.
Bloom, H G; Bloom, J S; Krasnoff, L; Frank, A D
This study compared three interventions designed to increase acceptance of influenza and pneumococcal vaccines among elderly hospitalized patients. All individuals 65 and older able to give informed consent (73 patients) who were admitted to one medical floor of an acute care hospital were randomized to one of three groups. All groups received informational pamphlets explaining influenza and pneumococcal disease, their respective vaccines, and indications for their use. The first group received pamphlets only, the second received nursing follow-up, and the third received trained volunteer follow-up. Patients on another medical floor served as controls. The results showed a significant improvement in vaccine acceptance in all three study groups compared to controls for both influenza (78% vs 0%) and pneumococcal (75% vs 0%) vaccines. The differences among the three groups were not significant. No significant differences were found among patients accepting or refusing vaccination with regard to diagnosis, age, length of stay, sex, or having a private physician. We conclude that a simple educational program followed by offering vaccination before hospital discharge can be easily implemented, and dramatically increase immunization rates in this high risk group.
Mahdi, Layla K; Higgins, Melanie A; Day, Christopher J; Tiralongo, Joe; Hartley-Tassell, Lauren E; Jennings, Michael P; Gordon, David L; Paton, Adrienne W; Paton, James C; Ogunniyi, Abiodun D
Streptococcus pneumoniae (the pneumococcus) is a major human pathogen, causing a broad spectrum of diseases including otitis media, pneumonia, bacteraemia and meningitis. Here we examined the role of a potential pneumococcal meningitis vaccine antigen, alpha-glycerophosphate oxidase (SpGlpO), in nasopharyngeal colonization. We found that serotype 4 and serotype 6A strains deficient in SpGlpO have significantly reduced capacity to colonize the nasopharynx of mice, and were significantly defective in adherence to human nasopharyngeal carcinoma cells in vitro. We also demonstrate that intranasal immunization with recombinant SpGlpO significantly protects mice against subsequent nasal colonization by wild type serotype 4 and serotype 6A strains. Furthermore, we show that SpGlpO binds strongly to lacto/neolacto/ganglio host glycan structures containing the GlcNAcβ1-3Galβ disaccharide, suggesting that SpGlpO enhances colonization of the nasopharynx through its binding to host glycoconjugates. We propose that SpGlpO is a promising vaccine candidate against pneumococcal carriage, and warrants inclusion in a multi-component protein vaccine formulation that can provide robust, serotype-independent protection against all forms of pneumococcal disease.
Yamamoto, Natsuo; Kerfoot, Steven M; Hutchinson, Andrew T; Dela Cruz, Charles S; Nakazawa, Naomi; Szczepanik, Marian; Majewska-Szczepanik, Monika; Nazimek, Katarzyna; Ohana, Noboru; Bryniarski, Krzysztof; Mori, Tsutomu; Muramatsu, Masamichi; Kanemitsu, Keiji; Askenase, Philip W
We describe a protective early acquired immune response to pneumococcal pneumonia that is mediated by a subset of B1a cells. Mice deficient in B1 cells (xid), or activation-induced cytidine deaminase (AID(-/-) ), or invariant natural killer T (iNKT) cells (Jα18(-/-) ), or interleukin-13 (IL-13(-/-) ) had impaired early clearance of pneumococci in the lung, compared with wild-type mice. In contrast, AID(-/-) mice adoptively transferred with AID(+/+) B1a cells, significantly cleared bacteria from the lungs as early as 3 days post infection. We show that this early bacterial clearance corresponds to an allergic contact sensitivity-like cutaneous response, probably due to a subpopulation of initiating B1a cells. In the pneumonia model, these B1a cells were found to secrete higher affinity antigen-specific IgM. In addition, as in contact sensitivity, iNKT cells were required for the anti-pneumococcal B1a cell initiating response, probably through early production of IL-13, given that IL-13(-/-) mice also failed to clear infection. Our study is the first to demonstrate the importance of AID in generating an appropriate B1a cell response to pathogenic bacteria. Given the antibody affinity and pneumonia resistance data, natural IgM produced by conventional B1a cells are not responsible for pneumonia clearance compared with the AID-dependent subset.
Blum, M D; Dagan, R; Mendelman, P M; Pinsk, V; Giordani, M; Li, S; Bohidar, N; McNeely, T B
Children who had been randomized to receive one dose of either heptavalent pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine (PCV) or 23-valent pneumococcal polysaccharide vaccine (PN23) at 12, 15, or 18 months of age were subsequently randomized to receive a booster injection of either PCV or PN23 12 months later. For those children who received a priming dose of PCV (N=75) compared to PN23 (N=48) at 12, 15, or 18 months of age, higher serum antibody concentrations were achieved 1 month following a booster injection of either PCV or PN23 for all serotypes tested (p<0.001). Within the group of children receiving a priming dose of PCV, those children who received a booster dose of PN23 developed higher serum antibody concentrations for four of the seven serotypes tested and similar opsonic antibody titers to serotype 6B, yet more frequent erythema (p=0.030) and pain or soreness (p=0.024) at the injection site compared to those boosted with PCV. In conclusion, a single dose of PCV at 12-18 months of age primed for responses to booster doses of either PCV or PN23 12 months later. For those children who received a priming dose of PCV, boosting with PN23 resulted in more frequent injection site pain and erythema than boosting with PCV, yet higher antibody concentrations for most of the serotypes tested.
[Statement of the Advisory Immunization Committee of the Chilean Society of Infectious Diseases on the emergence of serotype 19A pneumococcal infection and the use of pneumococcal conjugated vaccine in Chilean children].
Potin, Marcela; Fica, Alberto; Wilhem, Jan; Cerda, Jaime; Contreras, Lily; Escobar, Carola; Moreno, Gabriela; Muñoz, Alma; Véliz, Liliana
Inclusion of the 10-valent pneumococcal conjugated vaccine (PCV10) in the Chilean infant vaccination Program in 2011 was followed by a reduction of hospital admissions and pneumonia-related deaths in this age group. However, a progressive increase of serotype 19A pneumococcal isolates (not included in PCV10) has been observed. According to the analysis of pneumococcal strains performed by the national reference laboratory of the Institute of Public Health as part of a national surveillance on invasive pneumococcal infections, the relative proportion of serotype 19A isolates increased from <5% before 2010 to 12-23% in years 2014-2015. Serotype 19A represented 4-8% of the isolates in the pre-vaccine era among children less than 2 years, increasing to 25% during 2014. This increase has been documented in two-thirds of the national territory. Aimong children <5 years of age, 25% of 19A serotype isolates from non-meningeal infections were penicillin resistant wheras from meningeal infections near 100% were penicillin resistant. Genetic analysis indicates that 48% of these 19A strains belong to clonal complex 320, recognized for its pandemic potential and high antimicrobial resistance. Among children, most invasive infections secondary to serotype 19A have occurred in patients fully vaccinated with PCV10. These epidemiological changes indicate an increase in invasive pneumococcal infections by serotype 19A in Chile and the need to control this problem by changing the current PCV10 for the PCV13 vaccine containing serotype 19A.
Background The clinical and economic burden associated with invasive and non-invasive pneumococcal and non-typeable Haemophilus influenzae (NTHi) diseases is substantial in the Latin America and Caribbean region, where pneumococcal vaccines have only been introduced to a few countries. This study analyzed the cost-effectiveness and cost utility of three different pneumococcal conjugate vaccines (PCVs) for Peru. Methods A Markov model that simulated the disease processes in a birth cohort over a lifetime, within 1,128 month cycles was used to evaluate the cost-effectiveness of 10-valent pneumococcal NTHi protein D conjugate vaccine (PHiD-CV) and 7- and 13-valent PCVs (PCV-7 and PCV-13). Expected quality-adjusted life years (QALYs), cost-savings and incremental cost-effectiveness ratios (ICERs) were calculated. Results Without vaccination, pneumonia was associated with the greatest health economic burden (90% of QALYs lost and 63% of lifetime direct medical costs); while acute otitis media (AOM) was responsible for 1% of QALYs lost and 25% of direct medical costs. All vaccines were predicted to be cost-effective for Peru, with PHiD-CV being most cost-effective. PHiD-CV was predicted to generate 50 more QALYs gained and required a reduced investment (−US$ 3.4 million) versus PCV-13 (discounted data), and was therefore dominant and cost saving. The probabilistic sensitivity analysis showed that PHiD-CV generated more QALYs gained at a reduced cost than PCV-13 in 84% of the simulations and less QALYs gains at a reduced cost in 16%. Additional scenarios using different assumptions on vaccine efficacies based on previous evidence were explored, but no significant change in the overall cost-effective results were observed. Conclusions The results of this modeling study predict that PCVs are likely to be a cost-effective strategy to help relieve the epidemiological and economic burden associated with pediatric pneumococcal and NTHi diseases for Peru. PHiD-CV is likely
Evaluation of components of X-ray irradiated 7-valent pneumococcal conjugate vaccine and pneumococcal vaccine polyvalent and X-ray and gamma-ray irradiated acellular pertussis component of DTaP vaccine products
May, J. C.; Rey, L.; Lee, Chi-Jen; Arciniega, Juan
Samples of pneumococcal vaccine polyvalent, 7-valent pneumococcal conjugate vaccine, and two different diphtheria and tetanus toxoids and acellular pertussis vaccines adsorbed were irradiated with X-rays and/or gamma-rays (Co-60). Mouse IgG and IgM antibody responses (ELISA) for types 9V, 14, 18C, and 19F pneumococcal polysaccharides and conjugates indicated that the polysaccharides were more tolerant of the radiation than the conjugates. The mouse antibody response for the detoxified pertussis toxin (PT) antigen, filamentous hemagglutinin antigen (FHA), pertactin (PRN), and fimbriae types 2 and 3 (FIM) antigens for the appropriate vaccine type indicated that the antibody response was not significantly changed in the 25 kGy X-ray irradiated vaccines frozen in liquid nitrogen compared to the control vaccine.
Levofloxacin-Ceftriaxone Combination Attenuates Lung Inflammation in a Mouse Model of Bacteremic Pneumonia Caused by Multidrug-Resistant Streptococcus pneumoniae via Inhibition of Cytolytic Activities of Pneumolysin and Autolysin
Majhi, Arnab; Adhikary, Rana; Bhattacharyya, Aritra; Mahanti, Sayantika
In this study, our objective was to determine whether a synergistic antimicrobial combination in vitro would be beneficial in the downregulation of pneumococcal virulence genes and whether the associated inflammation of the lung tissue induced by multidrug-resistant Streptococcus pneumoniae infection in vivo needs to be elucidated in order to consider this mode of therapy in case of severe pneumococcal infection. We investigated in vivo changes in the expression of these virulence determinants using an efficacious combination determined in previous studies. BALB/c mice were infected with 106 CFU of bacteria. Intravenous levofloxacin at 150 mg/kg and/or ceftriaxone at 50 mg/kg were initiated 18 h postinfection; the animals were sacrificed 0 to 24 h after the initiation of treatment. The levels of cytokines, chemokines, and C-reactive protein (CRP) in the serum and lungs, along with the levels of myeloperoxidase and nitric oxide the inflammatory cell count in bronchoalveolar lavage fluid (BALF), changes in pneumolysin and autolysin gene expression and COX-2 and inducible nitric oxide synthase (iNOS) protein expression in the lungs were estimated. Combination therapy downregulated inflammation and promoted bacterial clearance. Pneumolysin and autolysin expression was downregulated, with a concomitant decrease in the expression of COX-2 and iNOS in lung tissue. Thus, the combination of levofloxacin and ceftriaxone can be considered for therapeutic use even in cases of pneumonia caused by drug-resistant isolates. PMID:24957840
Levofloxacin-ceftriaxone combination attenuates lung inflammation in a mouse model of bacteremic pneumonia caused by multidrug-resistant Streptococcus pneumoniae via inhibition of cytolytic activities of pneumolysin and autolysin.
Majhi, Arnab; Adhikary, Rana; Bhattacharyya, Aritra; Mahanti, Sayantika; Bishayi, Biswadev
In this study, our objective was to determine whether a synergistic antimicrobial combination in vitro would be beneficial in the downregulation of pneumococcal virulence genes and whether the associated inflammation of the lung tissue induced by multidrug-resistant Streptococcus pneumoniae infection in vivo needs to be elucidated in order to consider this mode of therapy in case of severe pneumococcal infection. We investigated in vivo changes in the expression of these virulence determinants using an efficacious combination determined in previous studies. BALB/c mice were infected with 10(6) CFU of bacteria. Intravenous levofloxacin at 150 mg/kg and/or ceftriaxone at 50 mg/kg were initiated 18 h postinfection; the animals were sacrificed 0 to 24 h after the initiation of treatment. The levels of cytokines, chemokines, and C-reactive protein (CRP) in the serum and lungs, along with the levels of myeloperoxidase and nitric oxide the inflammatory cell count in bronchoalveolar lavage fluid (BALF), changes in pneumolysin and autolysin gene expression and COX-2 and inducible nitric oxide synthase (iNOS) protein expression in the lungs were estimated. Combination therapy downregulated inflammation and promoted bacterial clearance. Pneumolysin and autolysin expression was downregulated, with a concomitant decrease in the expression of COX-2 and iNOS in lung tissue. Thus, the combination of levofloxacin and ceftriaxone can be considered for therapeutic use even in cases of pneumonia caused by drug-resistant isolates.
Boelsen, Laura K; Dunne, Eileen M; Lamb, Karen E; Bright, Kathryn; Cheung, Yin Bun; Tikoduadua, Lisi; Russell, Fiona M; Mulholland, E Kim; Licciardi, Paul V; Satzke, Catherine
Previously, the Fiji Pneumococcal Project (FiPP) evaluated reduced dose immunization schedules that incorporated pneumococcal protein conjugate and/or polysaccharide vaccine (PCV7 and 23vPPV, respectively). Immune hyporesponsiveness was observed in children vaccinated with 23vPPV at 12 months of age compared with children who did not receive 23vPPV. Here we assess the long-term impact of 23vPPV vaccination on nasopharyngeal carriage rates and densities of Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus and Moraxella catarrhalis. Nasopharyngeal swabs (n=194) were obtained from healthy children who participated in FiPP (now aged 5-7 years). S. pneumoniae were isolated and identified by standard culture-based methods, and serotyped using latex agglutination and the Quellung reaction. Carriage rates and densities of S. pneumoniae, H. influenzae, S. aureus and M. catarrhalis were determined using real-time quantitative PCR. There were no differences in the rate or density of S. pneumoniae, H. influenzae or M. catarrhalis carriage by PCV7 dose or 23vPPV vaccination in the vaccinated participants overall. However, differences were observed between the two main ethnic groups: Fijian children of Indian descent (Indo-Fijian) were less likely to carry S. pneumoniae, H. influenzae and M. catarrhalis, and there was evidence of a higher carriage rate of S. aureus compared with indigenous Fijian (iTaukei) children. Polysaccharide vaccination appeared to have effects that varied between ethnic groups, with 23vPPV vaccination associated with a higher carriage rate of S. aureus in iTaukei children, while there was a lower carriage rate of S. pneumoniae associated with 23vPPV vaccination in Indo-Fijian children. Overall, polysaccharide vaccination had no long-term impact on pneumococcal carriage, but may have impacted on S. aureus carriage and have varying effects in ethnic groups, suggesting current WHO vaccine schedule recommendations against the use of 23v
Shibl, Atef M; Memish, Ziad A; Al-Kattan, Khaled M
Streptococcus pneumoniae is one of the most common bacterial causes of morbidity and mortality worldwide, causing life threatening infections such as meningitis, pneumonia and febrile bacteremia, particular among young children. The severity and frequency of S. pneumoniae infection and emergence of drug-resistant isolates have highlighted the need for prevention of invasive pneumococcal disease (IPD) as the best method for controlling disease; to better achieve this, more information is needed about serotype distribution and patterns of antibiotic resistance in children in the Kingdom of Saudi Arabia (KSA). Cases of pneumococcal infections in children aged <5 years, recorded in hospitals throughout KSA from 2005 to 2010 were reviewed for serotyping and for antibiotic susceptibility. This covers the time period just before limited introduction of 7-valent pneumococcal conjugate vaccine (PCV7) in 2006, to its introduction into the national immunization program in 2008, until right after a switch to PCV13 in 2010. Case definition required isolation of S. pneumoniae from blood, cerebrospinal fluid, or any sterile biological fluid. Isolates from 311 eligible cases were collected from different regions across KSA, 250 from blood and 61 from cerebrospinal fluid. The most frequently isolated IPD serotypes were 23F, 19F, 6B, 5 and 1. Over the course of the study, there was significant rise of serotype 19A (covered by PCV13 but not PCV7), which accounted for 20% of isolates of IPD in Western and 5% in Central regions in the last 2 years in KSA. There was a notable decrease in serotype 18C over this period, one of the PCV7 serotypes. Serotype coverage for PCV7, PCV10, PCV13 in children <5 years was 53%, 80%, and 91%, respectively across the Kingdom from 2005 to 2010. A total of 66% of IPD isolates were penicillin-resistant, and 62% were erythromycin-resistant. Continued surveillance is critical to measure the emerging of new serotypes and antibiotic resistance strain, and the
Mallet, Eric; Brachet, Elisabeth; Fernsten, Philip; Laudat, France; Razmpour, Ahmad; Gruber, William C
Streptococcus pneumoniae and Neisseria meningitidis cause invasive disease in children aged <2 years. While individual conjugate vaccines are available to protect this age group against these pathogens, availability of a vaccine combining these antigens into a single injection is desirable. This study randomized 467 healthy infants to receive 4 doses of combination 9-valent pneumococcal and meningococcal serogroup C conjugate vaccine (9vPnC-MnCC) or 9-valent pneumococcal conjugate vaccine (9vPnC). Percentages of subjects achieving immunoglobulin G (IgG) antibody concentrations ≥0.35μg/mL and geometric mean IgG concentrations for each pneumococcal serotype in the 9vPnC-MnCC group were noninferior compared to the 9vPnC group. Both vaccines were well-tolerated.
Huijts, Susanne M.; Wu, Kangjian; Souza, Victor; Passador, Sherry; Tinder, Chunyan; Song, Esther; Elfassy, Arik; McNeil, Lisa; Menton, Ronald; French, Roger; Callahan, Janice; Webber, Chris; Gruber, William C.; Bonten, Marc J. M.; Jansen, Kathrin U.
To improve the clinical diagnosis of pneumococcal infection in bacteremic and nonbacteremic community-acquired pneumonia (CAP), a Luminex technology-based multiplex urinary antigen detection (UAD) diagnostic assay was developed and validated. The UAD assay can simultaneously detect 13 different serotypes of Streptococcus pneumoniae by capturing serotype-specific S. pneumoniae polysaccharides (PnPSs) secreted in human urine. Assay specificity is achieved by capturing the polysaccharides with serotype-specific monoclonal antibodies (MAbs) on spectrally unique microspheres. Positivity for each serotype was based on positivity cutoff values calculated from a standard curve run on each assay plate together with positive- and negative-control urine samples. The assay is highly specific, since significant signals are detected only when each PnPS was paired with its homologous MAb-coated microspheres. Validation experiments demonstrated excellent accuracy and precision. The UAD assay and corresponding positivity cutoff values were clinically validated by assessing 776 urine specimens obtained from patients with X-ray-confirmed CAP. The UAD assay demonstrated 97% sensitivity and 100% specificity using samples obtained from patients with bacteremic, blood culture-positive CAP. Importantly, the UAD assay identified Streptococcus pneumoniae (13 serotypes) in a proportion of individuals with nonbacteremic CAP, a patient population for which the pneumococcal etiology of CAP was previously difficult to assess. Therefore, the UAD assay provides a specific, noninvasive, sensitive, and reproducible tool to support vaccine efficacy as well as epidemiological evaluation of pneumococcal disease, including CAP, in adults. PMID:22675155
Pride, Michael W; Huijts, Susanne M; Wu, Kangjian; Souza, Victor; Passador, Sherry; Tinder, Chunyan; Song, Esther; Elfassy, Arik; McNeil, Lisa; Menton, Ronald; French, Roger; Callahan, Janice; Webber, Chris; Gruber, William C; Bonten, Marc J M; Jansen, Kathrin U
To improve the clinical diagnosis of pneumococcal infection in bacteremic and nonbacteremic community-acquired pneumonia (CAP), a Luminex technology-based multiplex urinary antigen detection (UAD) diagnostic assay was developed and validated. The UAD assay can simultaneously detect 13 different serotypes of Streptococcus pneumoniae by capturing serotype-specific S. pneumoniae polysaccharides (PnPSs) secreted in human urine. Assay specificity is achieved by capturing the polysaccharides with serotype-specific monoclonal antibodies (MAbs) on spectrally unique microspheres. Positivity for each serotype was based on positivity cutoff values calculated from a standard curve run on each assay plate together with positive- and negative-control urine samples. The assay is highly specific, since significant signals are detected only when each PnPS was paired with its homologous MAb-coated microspheres. Validation experiments demonstrated excellent accuracy and precision. The UAD assay and corresponding positivity cutoff values were clinically validated by assessing 776 urine specimens obtained from patients with X-ray-confirmed CAP. The UAD assay demonstrated 97% sensitivity and 100% specificity using samples obtained from patients with bacteremic, blood culture-positive CAP. Importantly, the UAD assay identified Streptococcus pneumoniae (13 serotypes) in a proportion of individuals with nonbacteremic CAP, a patient population for which the pneumococcal etiology of CAP was previously difficult to assess. Therefore, the UAD assay provides a specific, noninvasive, sensitive, and reproducible tool to support vaccine efficacy as well as epidemiological evaluation of pneumococcal disease, including CAP, in adults.
Ramos-Sevillano, Elisa; Urzainqui, Ana; de Andrés, Belén; González-Tajuelo, Rafael; Domenech, Mirian; González-Camacho, Fernando; Sánchez-Madrid, Francisco; Brown, Jeremy S.; García, Ernesto; Yuste, Jose
Bacterial uptake by phagocytic cells is a vital event in the clearance of invading pathogens such as Streptococcus pneumoniae. A major role of the P-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes against invasive pneumococcal disease is described in this study. Phagocytosis experiments using different serotypes demonstrated that PSGL-1 is involved in the recognition, uptake and killing of S. pneumoniae. Co-localization of several clinical isolates of S. pneumoniae with PSGL-1 was demonstrated, observing a rapid and active phagocytosis in the presence of PSGL-1. Furthermore, the pneumococcal capsular polysaccharide and the main autolysin of the bacterium ―the amidase LytA― were identified as bacterial ligands for PSGL-1. Experimental models of pneumococcal disease including invasive pneumonia and systemic infection showed that bacterial levels were markedly increased in the blood of PSGL-1−/− mice. During pneumonia, PSGL-1 controls the severity of pneumococcal dissemination from the lung to the bloodstream. In systemic infection, a major role of PSGL-1 in host defense is to clear the bacteria in the systemic circulation controlling bacterial replication. These results confirmed the importance of this receptor in the recognition and clearance of S. pneumoniae during invasive pneumococcal disease. Histological and cellular analysis demonstrated that PSGL-1−/− mice have increased levels of T cells migrating to the lung than the corresponding wild-type mice. In contrast, during systemic infection, PSGL-1−/− mice had increased numbers of neutrophils and macrophages in blood, but were less effective controlling the infection process due to the lack of this functional receptor. Overall, this study demonstrates that PSGL-1 is a novel receptor for S. pneumoniae that contributes to protection against invasive pneumococcal disease. PMID:26975045
Briles, D E; Forman, C; Horowitz, J C; Volanakis, J E; Benjamin, W H; McDaniel, L S; Eldridge, J; Brooks, J
Antibodies to pneumococcal capsular polysaccharides are well known for their ability to protect against pneumococcal infection. Recent studies indicate that antibodies to cell wall antigens, including pneumococcal surface protein A and the phosphocholine (PC) determinant of teichoic acids as well as human C-reactive protein (which also binds to PC), can protect mice against pneumococcal infection. In the present study we compared the protective effects of these agents as measured by mouse protection, the blood bactericidal assay, and clearance of pneumococci from the blood and peritoneal cavity. Our findings extend previous results indicating that human C-reactive protein and antibodies to noncapsular antigens are generally less protective than anticapsular antibodies. The new results obtained indicate the following: (i) mouse protection studies with intraperitoneal and intravenous infections provide very similar results; (ii) monoclonal immunoglobulin G2a (IgG2a) antibodies to PC, like IgG1, IgG2b, and IgG3 antibodies to PC, are highly protective against pneumococcal infection in mice; (iii) human antibody to PC is able to protect against pneumococcal infection in mice; (iv) antibodies to PspA are effective at mediating blood and peritoneal clearance of pneumococci; (v) complement is required for the in vivo protective effects of both IgG and IgM antibodies to PC; (vi) IgG1, IgG2b, and IgG3 anti-PC antibodies all mediate complement-dependent lysis of PC-conjugated erythrocytes; and (vii) antibodies and human C-reactive proteins that are reactive with capsular antigens but not cell wall antigens are able to mediate significant antibacterial activity in the blood bactericidal assay. PMID:2707854
Pneumococcal surface protein A (PspA), a cell-surface protein present on all strains of pneumococci, has been shown to elicit protective antibody responses in mice in the absence of capsular polysaccharide. Whereas PspA is polymorphic, considerable cross-reactivity and cross- protection have been demonstrated among PspA proteins of pneumococci exhibiting different capsular and PspA serotypes. A gene segment encoding the nonrepetitive variable NH2-terminal portion of PspA has been cloned into three distinct recombinant Bacille Calmette-Guerin (rBCG) vectors, allowing for expression of PspA as a cytoplasmic or secreted protein, or a chimeric exported membrane-associated lipoprotein. All rBCG-PspA strains elicited comparable anti-PspA ELISA titers, ranging from 10(4) to 10(5) (reciprocal titers) in both BALB/c and C3H/HeJ mice. However, protective responses were observed only in animals immunized with the rBCG-PspA vaccines expressing PspA as a secreted protein or chimeric exported lipoprotein. In addition, anti- PspA immune sera elicited by the rBCG vaccines passively protected X- linked immunodeficient mice from lethal challenge with the highly virulent, encapsulated WU2 strain of Streptococcus pneumoniae and two additional virulent strains exhibiting heterologous PspA and capsular serotypes. These studies confirm previous PspA immunization studies showing cross-protection against heterologous serotypes of S. pneumoniae and demonstrate a potential for rBCG-based PspA vaccines to elicit protective humoral responses against pneumococcal disease in humans. PMID:7964500
Comparison of immunogenicity and safety of an influenza vaccine administered concomitantly with a 13-valent pneumococcal conjugate vaccine or 23-valent polysaccharide pneumococcal vaccine in the elderly
Purpose Previous studies have demonstrated the immunogenicity and safety of the co-administration of the trivalent inactivated influenza vaccine (IIV3) with the polysaccharide pneumococcal vaccine (PPV) or pneumococcal conjugate vaccine (PCV). However, there is no direct comparison study that evaluates the immunogenicity and safety of IIV3 given concomitantly with PCV13 or PPV23 in the elderly. Materials and Methods During the 2012-2013 influenza vaccination period, 224 healthy elderly volunteers aged 65 years and older randomly received IIV3 given concomitantly with either PCV13 (PCV13+IIV3) or PPV23 (PPV23+IIV3) in a 1:1 ratio. Serum hemagglutination-inhibiting antibodies for IIV3 were measured at the time of vaccination and 1 month after vaccination. Adverse events were recorded prospectively in a clinical diary during a 7-day period. Results A total of 220 participants blood samples for analysis of immunogenicity and kept a clinical diary for safety analysis (PCV13+IIV3, n=110; PPV23+IIV3, n=110). One month after vaccination, both groups satisfied the Committee for Medical Products for Human Use criteria for A/H1N1, A/H3N2 and B strains, showing comparable seroprotection rates, seroconversion rates and geometric mean titer fold. The assessments of immunogenicity were similar in both groups. The most common local and systemic reactions were pain at the injection site and generalized myalgia. They were generally mild or moderate in intensity. The adverse events were not statistically different between the two groups. Conclusion PCV13+IIV3 and PPV23+IIV3 demonstrated similar immunogenicity and safety in the elderly. PMID:28168172
Insight Into Resistance Phenotypes of Emergent Non 13-valent Pneumococcal Conjugate Vaccine Type Pneumococci Isolated From Invasive Disease After 13-valent Pneumococcal Conjugate Vaccine Implementation in France
Janoir, Claire; Lepoutre, Agnès; Gutmann, Laurent; Varon, Emmanuelle
Background. In 2010, the pneumococcal 13-valent conjugate vaccine (PCV13), containing 6 additional serotypes including the multidrug-resistant 19A, replaced the PCV7 in France. This study aimed at analyzing trends in antibiotic resistance in invasive pneumococcal disease (IPD) isolates in France after PCV13 introduction. Methods. A total of 5243 pneumococci isolated from IPD in 2008–2009 (late PCV7 era) and 2011–2012 (PCV13 era) were studied according to their serotype and antibiotic resistance profile. Multilocus sequence typing analysis was performed on strains of the predominant serotypes (12F and 24F) isolated from young children. Results. Overall, the prevalence of antibiotic resistance decreased in France (−21.5% for penicillin from 2008–2009 to 2011–2012), mainly driven by the decline of the 19A serotype. Among non-PCV13 serotypes that concomitantly emerged, serotypes 12F, 24F, 15A, and 35B were consistently associated with resistance to 1 or more antibiotics. In children under 2 years, serotypes 15A, 35B, and 24F accounted together for 37.8% and 31.9% of penicillin-nonsusceptible and erythromycin-resistant isolates, respectively. Chloramphenicol and cotrimoxazole resistance were mainly associated with serotypes 12F and 24F, respectively. Genetic analysis showed that although emergence of serotype 12F pneumococci resulted from the expansion of various pre-existing lineages, increase in serotype 24F was related to the clonal expansion of the ST162 penicillin-susceptible cotrimoxazole-resistant lineage. Conclusions. We showed that decline of PCV13-related IPD was associated with a decline in antibiotic resistance in France, but that it likely favored the spread of several resistant nonvaccine serotypes. However, antibiotic resistance does not seem to be the only element that may drive this phenomenon. PMID:26955644
Buchwald, Ulrike K; Lees, Andrew; Steinitz, Michael; Pirofski, Liise-Anne
Increasing antibiotic resistance and a rising patient population at risk for infection due to impaired immunity underscore the importance of vaccination against pneumococci. However, available capsular polysaccharide vaccines are often poorly immunogenic in patients at risk for pneumococcal disease. The goal of this study was to explore the potential of peptide mimotopes to function as alternative vaccine antigens to elicit a type-specific antibody response to pneumococci. We used a human monoclonal immunoglobulin A (IgA) antibody (NAD) to type 8 Streptococcus pneumoniae capsular polysaccharide (type 8 PS) to screen a phage display library, and the phage PUB1 displaying the peptide FHLPYNHNWFAL was selected after three rounds of biopanning. Inhibition studies with phage-displayed peptide or the peptide PUB1 and type 8 PS showed that PUB1 is a mimetic of type 8 PS. PUB1 conjugated to tetanus toxoid (PUB1-TT) induced a type 8 PS-specific antibody response in BALB/c mice, further defining it as a mimotope of type 8 PS. The administration of immune sera obtained from PUB1-TT-immunized mice earlier (days 14 and 21) and later (days 87 and 100) after primary and reimmunization resulted in a highly significant prolongation of the survival of naive mice after pneumococcal challenge compared to controls. The survival of PUB1-TT-immunized mice was also prolonged after pneumococcal challenge nearly 4 months after primary immunization. The efficacy of PUB1-TT-induced immune sera provides proof of principle that a mimotope-induced antibody response can protect against pneumococci and suggests that peptide mimotopes selected by type-specific human antibodies could hold promise as immunogens for pneumococci.
Vivas, M; Force, E; Tubau, F; El Haj, C; Ariza, J; Cabellos, C
This study aimed to determine the effect of dexamethasone in combination with low-dose or high-dose daptomycin for the treatment of penicillin- and cephalosporin-resistant pneumococcal meningitis. Efficacy (ΔCFU/mL) and cerebrospinal fluid (CSF) levels of daptomycin at 15mg/kg and 25mg/kg were studied in a rabbit model of pneumococcal meningitis, comparing them with the same doses in combination with dexamethasone at 0.125mg/kg every 12h over a 26-h period against two different Streptococcus pneumoniae strains, HUB 2349 and ATCC 51916 with daptomycin minimum inhibitory concentrations (MICs) of 0.09mg/L and 0.19mg/L, respectively. Daptomycin levels in CSF were lower when dexamethasone was given concurrently. Against strain HUB 2349, therapeutic failure occurred with daptomycin 15mg/kg+dexamethasone; daptomycin 25mg/kg+dexamethasone was better at reducing bacterial counts than the lower dose throughout treatment. Against the highly cephalosporin-resistant ATCC 51916 strain, daptomycin 15mg/kg+dexamethasone achieved a lower bacterial decrease than daptomycin 15mg/kg alone, and therapeutic failure at 24h occurred in the daptomycin 15mg/kg+dexamethasone group. Addition of dexamethasone to a 25mg/kg daptomycin dose did not affect the efficacy of daptomycin: it remained bactericidal throughout treatment. In conclusion, against the studied strains, low-dose (15mg/kg/day) daptomycin is affected by concomitant use of dexamethasone: CSF levels are reduced and its bacterial efficacy is affected. At a higher daptomycin dose (25mg/kg/day), however, the use of dexamethasone does not alter efficacy; the combination appears to be a good choice for the treatment of pneumococcal meningitis.
Background PspA is recognized as a major pneumococcal virulence factor and a possible vaccine candidate. The aim of this study was to analyze the PspA family and clade distribution among 112 Spanish pneumococci representatives of dominant clones among patients with invasive disease (n = 66) and nasopharyngeal healthy carriage in children (n = 46). Results PspA family 2 was predominant among invasive (63.6%) and carriage (54.3%) pneumococcal isolates. No PspA family 3 isolates were detected and only one strain was PspA negative. Although four clonal complexes contained strains of different clades, a clear association between clade and multi locus sequence typing results was found. Clades 1, 3 and 4 were associated with a wide variety of sequence types (ST) related to multiresistant and antibiotic-susceptible worldwide-disseminated clones. Clade 1 was associated with Spain6B-ST90, Spain14-ST18, Colombia5-ST289, Sweden1-ST306, Denmark14-ST230 and Sweden1-ST304 clones. Clade 3 was associated with Spain23F-ST81, Spain9V-ST156, Tennessee14-ST67, Netherlands3-ST180 and Netherlands7F-ST191 clones. Clade 4 was related to Sweden15A-ST63, Netherlands18C-ST113 and Greece21-ST193 clones. In contrast, PspA clade was not related to serotype, age or clinical origin of the isolates. Conclusion PspA clades were associated with genotypes. PspA family 2 and family 1 were dominant among major Spanish pneumococcal clones isolated from patients with invasive disease and nasopharyngeal carriage in children. PMID:19419534
Gao, Fang; Lockyer, Kay; Burkin, Karena; Crane, Dennis T; Bolgiano, Barbara
Physico-chemical analysis of pneumococcal polysaccharide (PS)-protein conjugate vaccine components used for two commercially licensed vaccines was performed to compare the serotype- and carrier protein-specific stabilities of these vaccines. Nineteen different monovalent pneumococcal conjugates from commercial vaccines utilizing CRM197, diphtheria toxoid (DT), Protein D (PD) or tetanus toxoid (TT) as carrier proteins were incubated at temperatures up to 56°C for up to eight weeks or were subjected to freeze-thawing (F/T). Structural stability was evaluated by monitoring their size, integrity and carrier protein conformation. The molecular size of the vaccine components was well maintained for Protein D, TT and DT conjugates at -20°C, 4°C and F/T, and for CRM197 conjugates at 4°C and F/T. It was observed that four of the eight serotypes of Protein D conjugates tended to form high molecular weight complexes at 37°C or above. The other conjugated carrier proteins also appeared to form oligomers or ‘aggregates’ at elevated temperatures, but rarely when frozen and thawed. There was evidence of degradation in some of the conjugates as evidenced by the formation of lower molecular weight materials which correlated with measured free saccharide. In conclusion, pneumococcal-Protein D/TT/DT and most CRM197 bulk conjugate vaccines were stable when stored at 2–8°C, the recommended temperature. In common between the conjugates produced by the two manufacturers, serotypes 1, 5, and 19F were relatively less stable and 6B was the most stable, with types 7F and 23F also showing good stability. PMID:25483488
Buey, Rubén M; Monterroso, Begoña; Menéndez, Margarita; Diakun, Greg; Chacón, Pablo; Hermoso, Juan Antonio; Díaz, J Fernando
Phosphocholine moieties decorating the pneumococcal surface are used as a docking station for a family of modular proteins, the so-called choline binding proteins or CBPs. Choline recognition is essential for CBPs function and may also be a determinant for their quaternary structure. There is little knowledge about modular arrangement or oligomeric structures in this family. Therefore, we have used the small angle X-ray scattering (SAXS) technique combined with analytical ultracentrifugation in order to model the three-dimensional envelope of two highly different CBPs: the phage encoded Cpl-1 lysozyme and the pneumococcal phosphorylcholine esterase Pce. Both enzymes have an N-terminal catalytic module and a C-terminal choline-binding module (CBM) that attaches them to the bacterial surface and comprises six and ten sequence repeats in Cpl-1 and Pce, respectively. SAXS experiments have shown an inherent conformational plasticity in Cpl-1 that accounts for the different relative position of these regions in the solution and crystal structures. Dimerization of Cpl-1 upon choline binding has been also visualised for the first time, and monomer-monomer interactions take place through the first CBR where a non-canonical choline binding site has now been identified. This mode of association seems to be independent of the absence or presence of the Cpl-1 catalytic module and reveals that the arrangement of the monomers differs from that previously found in the isolated CBM dimer of pneumococcal LytA amidase. In contrast, Pce displays the same modular disposition in the solution and crystal structures, and remains almost invariant upon choline binding. The present results suggest that protein dimerization and duplication of CBRs may be alternative but not equivalent ways of improving cell wall recognition by CBPs, since they provide different interaction geometries for choline residues present in (lipo)teichoic acids.
Background After the implementation of 7-valent pneumococcal conjugate vaccine (PCV7), in several countries, serotype 19A is now the serotype most frequently involved in pneumococcal diseases and carriage. To determine factors potentially related to 19A nasopharyngeal (NP) carriage we analyzed data from an ongoing prospective French national surveillance study of pneumococcal NP carriage in young children. Methods NP swabs were obtained from children aged 6 to 24 months, either during routine check-ups with normal findings, or when they presented with acute otitis media (AOM). The swabs were sent for analysis to the French National Reference Centre for Pneumococci. Factors influencing pneumococcal carriage and carriage of penicillin non-susceptible (PNSP), 19A and PNS-19A were investigated by multivariate logistic regression. Results From 2006 to 2009, 66 practitioners enrolled 3507 children (mean age 13.6 months), of whom, 98.3% of children had been vaccinated with PCV7 and 33.4% of children attended daycare centres (DCC). Serotype 19A was found in 10.4% of the overall population, 20.5% of S. pneumoniae carriers (n = 1780) and 40.8% of PNSP carriers (n = 799). Among 19A strains, 10.7% were penicillin-susceptible, 80% intermediate and 9.3% fully resistant. Logistic regression analysis showed that the main factors associated with PNSP carriage were AOM (OR = 3.09, 95% CI [2.39;3.98]), DCC (OR = 1.70, 95% CI [1.42;2.03]), and recent antibiotic use (OR = 1.24, 95% CI [1.05;1.47]. The main factors predictive of 19A carriage were recent antibiotic use (OR = 1.81, 95% CI [1.42;2.30]), AOM (OR = 1.67, 95% CI [1.11;2.49]), DCC (OR = 1.56, 95% CI [1.21;2.2] and young age, <12 months (OR = 1.51, 95% CI [1.16;1.97]). Conclusion In a population of children aged from 6 to 24 months with a high rate of PCV7 vaccination coverage, we found that antibiotic exposure, DCC attendance and AOM were linked to 19A carriage. PMID:21501471
McBride, J S; Micklem, H S; Ure, J M
Acute Plasmodium yoelii yoelii and chronic Plasmodium berghei malaria infections of CBA mice were accompanied by a reduced capacity to give an antibody response to type III pneumococcal polysaccharide (SIII). The depression of response initiated by acute malaria persisted for several weeks after recovery from clinical infection. During chronic infection, and at the peak of acute parasitaemia, virtually no response to SIII was detected. A substance which crossreacted serologically with SIII was found in blood cells of infected mice. The results suggest that antigen-specific, as well as non-specific, factors may contribute to the depression of the response to this antigen. PMID:67996
Rodgers, Gail L; Klugman, Keith P
Infection due to Streptococcus pneumoniae is a leading cause of morbidity and mortality in young children, especially in developing countries. With the support of Gavi, the Vaccine Alliance, the majority of these countries have introduced pneumococcal conjugate vaccines (PCV) into their national immunization programs and early data demonstrate a high degree of effectiveness, translating to enormous public health benefit through both direct and indirect (herd) effects. Future vaccination strategy may be focused on maintaining herd effects rather than individual protection. Evaluation of vaccine-type carriage, particularly in pneumonia cases, may be an easy, feasible way of measuring continued vaccine impact.
Ramdani-Bouguessa, N.; Ziane, H.; Bekhoucha, S.; Guechi, Z.; Azzam, A.; Touati, D.; Naim, M.; Azrou, S.; Hamidi, M.; Mertani, A.; Laraba, A.; Annane, T.; Kermani, S.; Tazir, M.
Pneumococcal infections are a major cause of morbidity and mortality in developing countries. The introduction of pneumococcal conjugate vaccines (PCVs) has dramatically reduced the incidence of pneumococcal diseases. PCVs are not currently being used in Algeria. We conducted a prospective study from 2005 to 2012 in Algeria to determine antimicrobial drug resistance and serotype distribution of Streptococcus pneumoniae from children with pneumococcal disease. Among 270 isolated strains from children, 97 (36%) were invasive disease; of these, 48% were not susceptible to penicillin and 53% not susceptible to erythromycin. A high rate of antimicrobial nonsusceptibility was observed in strains isolated from children with meningitis. The serotype distribution from pneumococci isolated from children with invasive infections was (by order of prevalence): 14, 1, 19F, 19A, 6B, 5, 3, 6A and 23F. Multidrug resistance was observed in serotypes 14, 19F, 19A and 6B. The vaccine coverage of serotypes isolated from children aged <5 years was 55.3% for PCV7, 71.1% for PCV10 and 86.8% for PCV13. Our results highlight the burden of pneumococcal disease in Algeria and the increasing S. pneumoniae antibiotic resistance. The current pneumococcal vaccines cover a high percentage of the circulating strains. Therefore, vaccination would reduce the incidence of pneumococcal disease in Algeria. PMID:26106481
McLaughlin, John M; McGinnis, Justin J; Tan, Litjen; Mercatante, Annette; Fortuna, Joseph
Low uptake of routinely recommended adult immunizations is a public health concern. Using data from the peer-reviewed literature, government disease-surveillance programs, and the US Census, we developed a customizable model to estimate human and economic burden caused by four major adult vaccine-preventable diseases (VPD) in 2013 in the United States, and for each US state individually. To estimate the number of cases for each adult VPD for a given population, we multiplied age-specific incidence rates obtained from the literature by age-specific 2013 Census population data. We then multiplied the estimated number of cases for a given population by age-specific, estimated medical and indirect (non-medical) costs per case. Adult VPDs examined were: (1) influenza, (2) pneumococcal disease (both invasive disease and pneumonia), (3) herpes zoster (shingles), and (4) pertussis (whooping cough). Sensitivity analyses simulated the impact of various epidemiological scenarios on the total estimated economic burden. Estimated US annual cost for the four adult VPDs was $26.5 billion (B) among adults aged 50 years and older, $15.3B (58 %) of which was attributable to those 65 and older. Among adults 50 and older, influenza, pneumococcal disease, herpes zoster, and pertussis made up $16.0B (60 %), $5.1B (19 %), $5.0B (19 %), and $0.4B (2 %) of the cost, respectively. Among those 65 and older, they made up $8.3B (54 %), $3.8B (25 %), $3.0B (20 %), and 0.2B (1 %) of the cost, respectively. Most (80-85 %) pneumococcal costs stemmed from nonbacteremic pneumococcal pneumonia (NPP). Cost attributable to adult VPD in the United States is substantial. Broadening adult immunization efforts beyond influenza only may help reduce the economic burden of adult VPD, and a pneumococcal vaccination effort, primarily focused on reducing NPP, may constitute a logical starting place. Sensitivity analyses revealed that a pandemic influenza season or change in size of the US elderly population
Campos, Ivana B; Herd, Muriel; Moffitt, Kristin L; Lu, Ying-Jie; Darrieux, Michelle; Malley, Richard; Leite, Luciana C C; Gonçalves, Viviane M
The pneumococcal whole cell vaccine (PWCV) has been investigated as an alternative to polysaccharide-based vaccines currently in use. It is a non-encapsulated killed vaccine preparation that induces non-capsular antibodies protecting mice against invasive pneumococcal disease (IPD) and reducing nasopharyngeal (NP) carriage via IL-17A activation of mouse phagocytes. Here, we show that PWCV induces antibody and IL-17A production to protect mice against challenge in a fatal aspiration-sepsis model after only one dose. We observed protection even with a boiled preparation, attesting to the stability and robustness of the vaccine. PWCV antibodies were shown to bind to different encapsulated strains, but complement deposition on the pneumococcal surface was observed only on serotype 3 strains; using flow cytometer methodology, variations in PWCV quality, as in the boiled vaccine, were detected. Moreover, anti-PWCV induces phagocytosis of different pneumococcal serotypes by murine peritoneal cells in the presence of complement or IL-17A. These findings suggest that complement and IL-17A may participate in the process of phagocytosis induced by PWCV antibodies. IL-17A can stimulate phagocytic cells to kill pneumococcus and this is enhanced in the presence of PWCV antibodies bound to the bacterial cell surface. Our results provide further support for the PWCV as a broad-range vaccine against all existing serotypes, potentially providing protection for humans against NP colonization and IPD. Additionally, we suggest complement deposition assay as a tool to detect subtle differences between PWCV lots.
McEllistrem, M Catherine; Scott, Jennifer R; Zuniga-Castillo, Jacobo; Khan, Saleem A
Otitis, pneumonia, and meningitis are tissue-based pneumococcal infections that can be associated with biofilms. The emergence of phenotypic rough variants, also known as acapsular small-colony variants, is essential for pneumococcal biofilm formation. These rough variants can increase nearly 100-fold in biofilms over time and can arise through single nucleotide polymorphisms (SNPs), deletions, or tandem duplications in the first gene of the capsular operon, cps3D. We detected a 100-fold increase in rifampin-resistant (Rif(r)) mutants in biofilms compared to planktonic cultures using a nonvaccine serotype 3 strain, which is causing an increasing number of cases of otitis in the 7-valent pneumococcal conjugate vaccine era. Since both rough variants and Rif(r) strains can arise through SNPs, they could emerge due to alteration of the mismatch repair (MMR) system. The Hex system, a pneumococcal MMR system, repairs mismatches during replication and transformation. In this study, no mutations were detected in the hexAB gene sequences among several rough variants with unique mutations in the cps3D gene. Within a hexA null mutant grown in broth, we detected only a 17.5-fold increase in rough variants compared to the wild-type parental strain. Taken together, these data suggest that mutations in the hex genes and modulation of hexA activity are unlikely to account for the generation of biofilm-derived rough variants.
Denoël, Philippe; Philipp, Mario T; Doyle, Lara; Martin, Dale; Carletti, Georges; Poolman, Jan T
Infections caused by Streptococcus pneumoniae are a major cause of mortality throughout the world. Protein-based pneumococcal vaccines are envisaged to replace or complement the current polysaccharide-based vaccines. In this context, detoxified pneumolysin (dPly) and pneumococcal histidine triad protein D (PhtD) are two potential candidates for incorporation into pneumococcal vaccines. In this study, the protective efficacy of a PhtD-dPly vaccine was evaluated in a rhesus macaque (Macaca mulatta) model of pneumonia. The animals were immunized twice with 10 μg of PhtD and 10 μg of dPly formulated in the Adjuvant System AS02 or with AS02 alone, before they were challenged with a 19F pneumococcal strain. The survival was significantly higher in the protein-vaccinated group and seemed to be linked to the capacity to greatly reduce bacterial load within the first week post-challenge. Vaccination elicited high concentrations of anti-PhtD and anti-Ply antibodies and a link was found between survival and antibody levels. In conclusion, AS02-adjuvanted PhtD-dPly vaccine protects against S. pneumoniae-induced pneumonia. It is probable that the protection is at least partially mediated by PhtD- and Ply-specific antibodies.
Martynova, A V; Turkutiukov, V B
Despite modern achievements in diagnostics and treatment, invasive and non-invasive pneumococcal infections remain a topical public health problem. To a large extent, it is connected with the absence or inconsistence of evidence-based information on this kind of infection. In this paper, retrospective analysis of the incidence of pneumococcal infections was performed on the basis of medical records available today in every health institution; the peculiarities of their nosologic structure were revealed. Among invasive forms, pneumococcal pneumonias prevailed (50.06%); apparent hypodiagnostics of pneumococcal meningitis was noted (only 4.02%). Among non-invasive forms, acute otitis with various complications prevailed (47.5%), acute sinusitis was registered in 37.5% of cases, and other ENT diseases (sphenoiditis, frontitis, ethmoiditis, etc.) were registered in 15% of cases. The study found that the main risk factors in these patients had been different ENT diseases which the patients had suffered from during the previous three months before the actual illness. Thus, the necessity for the development and perfection of techniques of microbiological diagnostics and the development of epidemiological control methods on their basis are obvious.
Background This study aimed to assess the costs and clinical benefits of the 13-valent pneumococcal conjugate vaccine (PCV13) administered annually to the 65-year-old cohort in Spain versus the alternative of not vaccinating patients and treating them only when infected. Methods Cases of pneumococcal disease avoided were calculated through a dynamic model based on the work of Anderson and May (1999). Sixty-six percent of the 65-year-old cohort was assumed to have been vaccinated with one PCV13 dose (304,492 subjects). Base-case estimated vaccine effectiveness and serotype coverage were 58% and 60%, respectively. Disease-related costs were calculated based on published data. Results Over the 5-year period, a total of 125,906 cases of pneumococcal disease would be avoided. Net savings of €102 million would be obtained. The cost-saving distribution was not homogeneous, starting in the 2nd year and increasing through the 5th. To demonstrate model robustness, an additional scenario analysis was performed using extreme values of model parameters (vaccination programme coverage, vaccine effectiveness, discount rate and disease costs). Under those scenarios, net savings were always achieved. Conclusions Based on the assumptions of the model, the 65-year-cohort pneumococcal vaccination campaign appears to be a cost-saving intervention in the Spanish population under different scenarios. PMID:23578307
Wu, Kaifeng; Yao, Run; Wang, Hong; Pang, Dan; Liu, Yusi; Xu, Hongmei; Zhang, Shuai; Zhang, Xuemei; Yin, Yibing
Despite the availability of effective vaccines, Streptococcus pneumoniae is still one of the major infectious diseases causing substantial morbidity and mortality in children under 5 years old. In this study, we demonstrate the protective efficacy of S. pneumoniae SPY1, a novel live attenuated vaccine strain against pneumococcal infection in murine models. This strain was characterized by defects in three important pneumococcal virulence factors including capsule, teichoic acids and pneumolysin. The lactate dehydrogenase assays and in vivo animal experiments demonstrated a significantly attenuated virulence and a reduced nasopharyngeal colonization for the SPY1 strain. We also show that mucosal and systemic immunization with the live SPY1 strain induced protective immune responses against pneumococci. Mucosal immunization with SPY1 offered better protection against colonization challenge with strains TIGR4 and serotype 19F than systemic SPY1 immunization. In invasive infection models, mucosal vaccination with the SPY1 strain conferred complete protection against D39 and clinical serotype 6B and 3 strains. Notably, intranasal vaccination with the SPY1 strain conferred superior protection against pneumococcal invasive disease compared with the commercial available vaccines. SPY1 strain was shown to elicit high levels of serotype-independent antibodies and a mixed cellular immune response. Besides, the SPY1 serum was able to passively protect mice against invasive challenge with D39 strain, indicating the protective effect of the antibody-mediated responses. Together, the SPY1 strain may be a promising live vaccine strain to protect pneumococcal infection.
Adibkia, Khosro; Khorasani, Golrokh; Payab, Shahriar; Lotfipour, Farzaneh
Purpose: Bacterial pneumonia is a common lung infection caused by different types of bacteria. Azithromycin (AZI), an azalide antibiotic, is widely used to manage pneumococcal infections. Studies have shown that antibiotics in nanocarriers may lead to increased antibacterial activity and reduced toxicity. The aim of this work was to valuate in vitro antibacterial performance azithromycin-Eudragit RS100 nano-formulations against Streptococcus pneumoniae and Staphylococcus aureus. Methods: AZI-Eudragit RS100 nanoparticles were prepared via electrospinning technique and the in vitro antibacterial performance against S. pneumoniae and S. aureus were assessed using agar dilution method. Results: Nanofibers in the sizes about 100-300 nm in diameter and micro scale in length and nanobeads in the range of 100-500 nm were achieved. The Minimum Inhibitory Concentrations (MIC) showed an enhancement in the antimicrobial effect of AZI-Eudragit RS100 nanofibers (40 µg/ml) compare to untreated AZI solution (>160 µg/ml) against S. pneumonia. The MIC value for AZI-Eudragit RS100 nanofibers against S. aureus was >128 µg/ml, same as that of the untreated AZI solution. Conclusion: The enhanced efficiency of AZI in nanofibers could be related to the more adsorption opportunity of nanofibers to S. pneumonia capsulated cell wall which provides an antibiotic depot on the bacterial surface compared to S. aureus. AZI-Eudragit RS100 nanofibers with enhanced antimicrobial effect against S. pneumonia can be considered as a candidate for in vivo evaluations in antibiotic therapy of Pneumococcal infections. PMID:27766231
Sabharwal, Vishakha; Stevenson, Abbie; Figueira, Marisol; Orthopoulos, George; Trzciński, Krzysztof; Pelton, Stephen I
We hypothesized that capsular switch event, in which pneumococcus acquires a new capsule operon by horizontal gene transfer, may result in emergence of strains with increased virulence in acute otitis media. Using serotype 6A strain from a patient with invasive pneumococcal disease and clonally distant serotype 6C strain isolated from asymptomatic carrier we created 6A:6C (6A background with 6C capsule) capsular transformants and applied whole genome macro-restriction analysis to assess conservation of the 6A chassis. Next, we assessed complement (C3) and antibodies deposition on surface of pneumococcal cells and tested capsule recipient, capsule donor and two 6A:6C transformants for virulence in chinchilla experimental otitis media model. Both 6A:6C(1 or 2) transformants bound less C3 compared to 6C capsule-donor strain but more compared to serotype 6A capsule-recipient strain. Pneumococci were present in significantly higher proportion of ears among animals challenged with either of two 6A:6C(1 or 2) transformants compared to chinchillas infected with 6C capsule-donor strain [p < 0.001] whereas a significantly decreased proportion of ears were infected with 6A:6C(1 or 2) transformants as compared to 6A capsule-recipient strain. Our observations though limited to two serotypes demonstrate that capsular switch events can result in Streptococcus pneumoniae strains of enhanced virulence for respiratory tract infection.
Ocampo, Thad F; Le, Tuan; Matthews, Peter E; Okulicz, Jason F
Streptococcus pneumoniae infection is a predominant cause of bacterial infection in HIV-infected individuals. However, reported rates of pneumococcal vaccination with 23-valent polysaccharide vaccine (PPV23) are variable. We evaluated uptake of PPV23 in patients diagnosed with HIV between 1996 and 2012 (n = 507) in the United States Air Force, a centralized HIV program with free access to care including vaccines and medications. A total of 411 (81.1%) patients received at least 1 PPV23 dose. The PPV23 vaccination within 1 year of diagnosis was greater for those diagnosed between 2004 and 2012 (n = 184, 86%) compared with 1996 to 2003 (n = 104, 56.5%; P < .001). For those with ≥6 years of follow-up, receipt of a second recommended PPV23 dose was greater for those diagnosed between 1996 and 2003 (n = 52, 57.8%) compared with 2004 to 2012 (n = 9, 28.1%; P = .004). Although first PPV23 vaccination was high in recent years, process improvement efforts are underway to overcome barriers and improve uptake of pneumococcal vaccines in our program.
Subramanian, Karthik; Bergman, Peter; Henriques-Normark, Birgitta
Streptococcus pneumoniae is a major human pathogen and a leading cause of pneumonia, septicemia, and meningitis worldwide. Despite clinical studies linking vitamin D deficiency and pneumonia, molecular mechanisms behind these observations remain unclear. In particular, the effects of vitamin D on neutrophil responses remain unknown. Using pneumococcal strains, primary neutrophils isolated from human blood, and sera from patients with frequent respiratory tract infections (RTIs), we investigated the effects of vitamin D on neutrophil bactericidal and inflammatory responses, including pattern recognition receptors, antimicrobial peptides, and cytokine regulation. We found that vitamin D upregulated pattern recognition receptors, TLR2, and NOD2, and induced the antimicrobial human neutrophil peptides (HNP1-3) and LL-37, resulting in increased killing of pneumococci in a vitamin D receptor-dependent manner. Antibodies targeting HNP1-3 inhibited bacterial killing. Vitamin D supplementation of serum from patients with bacterial RTIs enhanced neutrophil killing. Moreover, vitamin D lowered inflammatory cytokine production by infected neutrophils via IL-4 production and the induction of suppressor of cytokine signaling (SOCS) proteins SOCS-1 and SOCS-3, leading to the suppression of NF-κB signaling. Thus, vitamin D enhances neutrophil killing of S. pneumoniae while dampening excessive inflammatory responses and apoptosis, suggesting that vitamin D could be used alongside antibiotics when treating pneumococcal infections.
von Mollendorf, Claire; Cohen, Cheryl; Tempia, Stefano; Meiring, Susan; de Gouveia, Linda; Quan, Vanessa; Lengana, Sarona; Karstaedt, Alan; Dawood, Halima; Seetharam, Sharona; Lekalakala, Ruth; Madhi, Shabir A; Klugman, Keith P; von Gottberg, Anne
In South Africa, 7-valent pneumococcal conjugate vaccine (PCV) was introduced in April 2009 and replaced with 13-valent PCV in April 2011. We describe the epidemiology of serotype 1 Streptococcus pneumoniae disease during the pre- and post-PCV eras (2003-2013). Using laboratory-based invasive pneumococcal disease (IPD) surveillance, we calculated annual incidences, identified IPD clusters, and determined serotype 1-associated factors. Of 46,483 IPD cases, 4,544 (10%) were caused by serotype 1. Two clusters of serotype 1 infection were detected during 2003-2004 and 2008-2012, but incidence decreased after 2011. Among children <5 years of age, those who had non-serotype 1 IPD had shorter hospital stays, fewer cases of penicillin-nonsusceptible disease, and lower HIV prevalence and in-hospital death rates than did those with serotype 1 IPD; similar factors were noted for older patients. Serotype 1 IPD had distinctive clinical features in South Africa, and annual incidences fluctuated, with decreases noted after the introduction of PCV13.
Li, Yi; Beitelshees, Marie; Fang, Lei; Hill, Andrew; Ahmadi, Mahmoud Kamal; Chen, Mingfu; Davidson, Bruce A.; Knight, Paul; Smith, Randall J.; Andreadis, Stelios T.; Hakansson, Anders P.; Jones, Charles H.; Pfeifer, Blaine A.
The type and potency of an immune response provoked during vaccination will determine ultimate success in disease prevention. The basis for this response will be the design and implementation of antigen presentation to the immune system. Whereas direct antigen administration will elicit some form of immunological response, a more sophisticated approach would couple the antigen of interest to a vector capable of broad delivery formats and designed for heightened response. New antigens associated with pneumococcal disease virulence were used to test the delivery and adjuvant capabilities of a hybrid biological-biomaterial vector consisting of a bacterial core electrostatically coated with a cationic polymer. The hybrid design provides (i) passive and active targeting of antigen-presenting cells, (ii) natural and multicomponent adjuvant properties, (iii) dual intracellular delivery mechanisms, and (iv) a simple formulation mechanism. In addition, the hybrid format enables device-specific, or in situ, antigen production and consolidation via localization within the bacterial component of the vector. This capability eliminates the need for dedicated antigen production and purification before vaccination efforts while leveraging the aforementioned features of the overall delivery device. We present the first disease-specific utilization of the vector toward pneumococcal disease highlighted by improved immune responses and protective capabilities when tested against traditional vaccine formulations and a range of clinically relevant Streptococcus pneumoniae strains. More broadly, the results point to similar levels of success with other diseases that would benefit from the production, delivery, and efficacy capabilities offered by the hybrid vector. PMID:27419235
Park, Chulmin; Kwon, Eun-Young; Choi, Su-Mi; Cho, Sung-Yeon; Byun, Ji-Hyun; Park, Jung Yeon; Lee, Dong-Gun; Kang, Jin Han; Shin, Jinhwan; Kim, Hun
Animal models facilitate evaluation of vaccine efficacy at relatively low cost. This study was a comparative evaluation of the immunogenicity and protective efficacy of a new 13-valent pneumococcal conjugate vaccine (PCV13) with a control vaccine in a mouse model. After vaccination, anti-capsular antibody levels were evaluated by pneumococcal polysaccharide (PnP) enzyme-linked immunosorbent assay (ELISA) and opsonophagocytic killing assay (OPA). Also, mice were challenged intraperitoneally with 100-fold of the 50% lethal dose of Streptococcus pneumoniae. The anti-capsular IgG levels against serotypes 1, 4, 7F, 14, 18C, 19A, and 19F were high (quartile 2 >1,600), while those against the other serotypes were low (Q2 ≤ 800). Also, the OPA titres were similar to those determined by PnP ELISA. Comparative analysis between new PCV13 and control vaccination group in a mouse model exhibited significant differences in serological immunity of a few serotypes and the range of anti-capsular IgG in the population. Challenge of wild-type or neutropenic mice with serotypes 3, 5, 6A, 6B, and 9V showed protective immunity despite of induced relatively low levels of anti-capsular antibodies. With comparison analysis, a mouse model should be adequate for evaluating serological efficacy and difference in the population level as preclinical trial.
Chen, Jing Jing; Yuan, Lin; Huang, Zhen; Shi, Nian Min; Zhao, Yu Liang; Xia, Sheng Li; Li, Guo Hua; Li, Rong Cheng; Li, Yan Ping; Yang, Shu Yuan; Xia, Jie Lai
Introduction The invasive pneumococcal diseases (IPDs) caused by Streptococcus pneumoniae pose an enormous threat to children under 5 years of age. However, routine use of pneumococcal conjugate vaccines could aid in reducing the incidence of IPDs. The purpose of this clinical trial is to assess the non-inferiority of the investigational 13-valent pneumococcal conjugate vaccine (PCV13) to the currently licensed 7-valent pneumococcal conjugate vaccine (PCV7). Methods and analysis 1040 infants will receive a three-dose series of either PCV13 or PCV7 at ages 3, 4 and 5 months, respectively, and a booster dose at 12–15 months. Primary end points are the percentage of participants reaching a serotype-specific IgG concentration of ≥0.35 µg/mL and the IgG antibody geometric mean concentrations (GMCs) measured 30 days after the primary immunisation. Secondary end points include the percentage of vaccine recipients reaching a serotype-specific IgG concentration threshold of 1.0 µg/mL, the percentage of participants reaching the pneumococcal opsonophagocytic assay (OPA) titre threshold of 1:8, and the geometric mean titres (GMTs) of OPA measured 30 days after primary and booster doses. The number of standard IgG responders and IgG GMCs measured 30 days after the booster immunisation will also be determined. To evaluate differences between two groups, the sequential testing of the non-inferiority of PCV13 for the seven common serotypes and its effectiveness in treating the six additional serotypes will be performed. Ethics and dissemination Ethics approvals have been granted by the Ethics Committees at the three provinces involved in this study: Shanxi, Henan and Hebei. The trial will be reported in accordance with the CONSORT guidance. Trial registration number NCT02736240. PMID:27798013
Altun, Hatice Uludag; Hascelik, Gülsen; Gür, Deniz; Eser, Özgen Köseoglu
This study evaluates the antimicrobial susceptibilities and serotype distributions of invasive Streptococcus pneumoniae (SP) isolates identified in a Turkish hospital before the introduction of the 7-valent pneumococcal conjugate vaccine (PCV7). The susceptibilities of all isolates were determined by evaluating six antibiotics: penicillin (PEN), ceftriaxone (CRO), levofloxacin (LEV), erythromycin (ERY), clindamycin (CD), and vancomycin (VAN). Serotyping and amplification of macrolide resistance genes were performed. Sixteen (50%) and four (2%) isolates were resistant to PEN and LEV, respectively. No isolates demonstrated VAN resistance. Intermediate resistance to CRO was found in 4% of all invasive isolates. Twenty-three (12.6%) isolates were resistant to ERY. Four (2%) invasive SP isolates demonstrated multidrug resistance. Serogroups 3, 5, 6, 8, 9, and 23 were the most common in both age groups. The potential coverage rates of PCV7 and PCV13 were 44.1 and 66.1% in children and 39.8 and 71.5% in adults, respectively. Continuous surveillance of antimicrobial resistance is required.
Ingels, Helene Andrea Sinclair
Streptococcus pneumoniae is still a leading cause of septicaemia, pneumonia and meningitis in young children world-wide with over half a million children dying annually from pneumococcal disease. Some children are prone to repeated episodes of invasive pneumococcal disease (IPD) because of an underlying predisposing disease. Recurrent IPD (rIPD) is a rarity and published reports on rIPD are limited by having few children included, selected groups of patients or short follow-up periods. Deficiencies in the innate or adaptive immune system have been described in children with rIPD, but the frequency of immunodeficiency among such patients is unknown. The aim of this PhD thesis was to examine paediatric cases of laboratory-confirmed rIPD, over a 33-year period in Denmark, to determine risk factors and study aspects of the immunological background for this problem in children. In October 2007, a seven-valent pneumococcal conjugate vaccine (PCV7) was implemented in the Danish infant immunization programme. An additional aim of the thesis was to examine the impact of vaccination on a population level, following the first three years of general PCV7 vaccination in Denmark. The thesis consists of three papers, which are all directly or indirectly based on data retrieved from the National Streptococcus Pneumoniae Registry. This registry is nationwide and dates back to 1938. The registry contains data from all laboratory-confirmed cases of IPD in Denmark and is continually updated for national surveillance. In Paper 1, we conducted a 33-year retrospective nationwide study of paediatric rIPD. By using data from the National Streptococcus Pneumoniae Registry combined with clinical data from hospital records, we could describe one of the largest known cohorts of children (n:59) with rIPD . We covered epidemiological, microbiological, and clinical features of this clinical entity. Of all children experiencing rIPD, 47% had a known predisposing underlying disease at the time of
Francis, J P; Richmond, P C; Strickland, D; Prescott, S L; Pomat, W S; Michael, A; Nadal-Sims, M A; Edwards-Devitt, C J; Holt, P G; Lehmann, D; van den Biggelaar, A H J
In areas where Streptococcus pneumoniae is highly endemic, infants experience very early pneumococcal colonization of the upper respiratory tract, with carriage often persisting into adulthood. We aimed to explore whether newborns in high-risk areas have pre-existing pneumococcal-specific cellular immune responses that may affect early pneumococcal acquisition. Cord blood mononuclear cells (CBMC) of 84 Papua New Guinean (PNG; high endemic) and 33 Australian (AUS; low endemic) newborns were stimulated in vitro with detoxified pneumolysin (dPly) or pneumococcal surface protein A (PspA; families 1 and 2) and compared for cytokine responses. Within the PNG cohort, associations between CBMC dPly and PspA-induced responses and pneumococcal colonization within the first month of life were studied. Significantly higher PspA-specific interferon (IFN)-γ, tumour necrosis factor (TNF)-α, interleukin (IL)-5, IL-6, IL-10 and IL-13 responses, and lower dPly-IL-6 responses were produced in CBMC cultures of PNG compared to AUS newborns. Higher CBMC PspA-IL-5 and PspA-IL-13 responses correlated with a higher proportion of cord CD4 T cells, and higher dPly-IL-6 responses with a higher frequency of cord antigen-presenting cells. In the PNG cohort, higher PspA-specific IL-5 and IL-6 CBMC responses were associated independently and significantly with increased risk of earlier pneumococcal colonization, while a significant protective effect was found for higher PspA-IL-10 CBMC responses. Pneumococcus-specific cellular immune responses differ between children born in pneumococcal high versus low endemic settings, which may contribute to the higher risk of infants in high endemic settings for early pneumococcal colonization, and hence disease.
Johnston, Calum; Martin, Bernard; Granadel, Chantal; Polard, Patrice; Claverys, Jean-Pierre
In bacteria, transformation and restriction-modification (R-M) systems play potentially antagonistic roles. While the former, proposed as a form of sexuality, relies on internalized foreign DNA to create genetic diversity, the latter degrade foreign DNA to protect from bacteriophage attack. The human pathogen Streptococcus pneumoniae is transformable and possesses either of two R-M systems, DpnI and DpnII, which respectively restrict methylated or unmethylated double-stranded (ds) DNA. S. pneumoniae DpnII strains possess DpnM, which methylates dsDNA to protect it from DpnII restriction, and a second methylase, DpnA, which is induced during competence for genetic transformation and is unusual in that it methylates single-stranded (ss) DNA. DpnA was tentatively ascribed the role of protecting internalized plasmids from DpnII restriction, but this seems unlikely in light of recent results establishing that pneumococcal transformation was not evolved to favor plasmid exchange. Here we validate an alternative hypothesis, showing that DpnA plays a crucial role in the protection of internalized foreign DNA, enabling exchange of pathogenicity islands and more generally of variable regions between pneumococcal isolates. We show that transformation of a 21.7 kb heterologous region is reduced by more than 4 logs in dpnA mutant cells and provide evidence that the specific induction of dpnA during competence is critical for full protection. We suggest that the integration of a restrictase/ssDNA-methylase couplet into the competence regulon maintains protection from bacteriophage attack whilst simultaneously enabling exchange of pathogenicicy islands. This protective role of DpnA is likely to be of particular importance for pneumococcal virulence by allowing free variation of capsule serotype in DpnII strains via integration of DpnI capsule loci, contributing to the documented escape of pneumococci from capsule-based vaccines. Generally, this finding is the first evidence for a
PspA is a cell surface protein of Streptococcus pneumoniae that is present on a number of clinical isolates as well as the nonencapsulated laboratory strain Rx1. In a previous report we have shown that mAbs directed against PspA can protect mice from at least some of the pneumococcal strains bearing this protein. In our present report we have produced insertional inactivation mutants that lack PspA and have used these mutants to demonstrate that PspA can play a role in pneumococcal virulence and that anti-PspA immunity can lead to protection against pneumococcal infection. PspA- mutants were obtained using derivatives of plasmid pVA891 carrying chromosomal fragments from Rx1. From one of the mutants, we cloned a 550 bp fragment of the pneumococcal gene into pVA891 and transferred this chimeric plasmid, designated pKSD300, into Escherichia coli. After transformation of pKSD300 into Rx1, PspA production is not detected. In colony hybridization experiments, the 550 bp fragment hybridizes specifically to pneumococcal isolates in a pattern consistent with the hypothesis that the fragment is a portion of the pspA structural gene that is different from the portions coding for the antigenic determinants detected by mAbs Xi64 or Xi126. When X-linked immunodeficient (xid) CBA/N mice were immunized with wild-type Rx1, they were resistant to challenge with type 3 strain WU2. However, when these mice were immunized with a PspA- mutant of Rx1, they failed to survive the subsequent challenge, indicating that immunity to PspA can contribute to the resistance to pneumococcal infection. Using pKSD300 we insertionally inactivated pspA in D39, a virulent strain of S. pneumoniae. When injected intravenously there was a 10-fold greater reduction of the mutant pneumococci in the blood, as compared to the wild-type D39. PMID:3546575
Patel, Hiren; Patel, Charmi; Soni, Mrugesh; Patel, Amit; Banda, Venkat
Bacterial pericarditis is a rapidly progressive and highly fatal infection, and is often diagnosed postmortem in half of the cases. Even with drainage and antibiotics, the mortality rate is high. Gram-positive cocci, specifically Streptococcus penumoniae, have been the most common cause of bacterial pericarditis with a preceding primary site of infection. Following the introduction of antibiotics in the 1940s and more recently the pneumococcal conjugate vaccine, the incidence has drastically decreased.We describe an extremely rare case of primary streptococcus pneumoniae purulent pericarditis that presented with cardiac tamponade. The patient was successfully treated with broad-spectrum antibiotics and urgent pericardiocentesis.Due to the high mortality rate with purulent pericarditis, a high index of suspicion is needed when acute pericarditis is suspected for early diagnosis to instate appropriate therapy with antibiotics and drainage.
Seshadri, Srividya; Kirwan, John; Neal, Tim
BACKGROUND: Genital tract infections in females secondary to Streptococcus pneumoniae (pneumococcus) are unusual. Tubo-ovarian abscess resulting from such an infection is a rare occurrence and diagnosis is not always easy. This report demonstrates the problems of recognizing this condition and summarizes the pathomechanism, investigations leading to a diagnosis and the subsequent management. CASE: A rare case of a tubo-ovarian abscess caused by pneumococcus, occurring in a previously healthy 48-year-old woman, is presented. The tubo-ovarian abscess may have developed insidiously and probably had an acute exacerbation prior to presentation. CONCLUSION: This case is unusual in that there were no identifiable initiating events for the source of the pneumococcal infection. Early recognition of a tubo-ovarian abscess is important in order to prevent the associated morbidity and mortality. This condition has the propensity to mimic a neoplasm. PMID:15460193
Siber, G R; Ambrosino, D M; Gorgone, B C
A platelet transfusion from a blood group O donor, immunized 1 month before with Pneumovax, caused a hemolytic reaction in a blood group A recipient. Forty-five of 59 group O donors (76%) and all of nine group B donors immunized with Pneumovax had a fourfold or higher anti-A response. Half of the anti-A antibody in high titered donors was in the IgG fraction. Pneumovax contained approximately 30 micrograms of an A-like substance per dose; polyvalent pneumococcal vaccines prepared by two other manufactures contained very low and probably subimmunogenic concentrations. Several culture media prepared from animal tissues contained as antigen of similar physical, immunologic, and chemical properties, and were the most likely source of the contaminant. Manufacturing procedures have since been revised to eliminate A-like substances.
Hamm, Melissa; Ha, Sha; Rustandi, Richard R
Simple Western is a new technology that allows for the separation, blotting, and detection of proteins similar to a traditional Western except in a capillary format. Traditionally, identity assays for biological products are performed using either an enzyme-linked immunosorbent assay (ELISA) or a manual dot blot Western. Both techniques are usually very tedious, labor-intensive, and complicated for multivalent vaccines, and they can be difficult to transfer to other laboratories. An advantage this capillary Western technique has over the traditional manual dot blot Western method is the speed and the automation of electrophoresis separation, blotting, and detection steps performed in 96 capillaries. This article describes details of the development of an automated identity assay for a 15-valent pneumococcal conjugate vaccine, PCV15-CRM197, using capillary Western technology.
Foo, Ning-Hui; Chen, Chun-Ta; Chow, Julie Chi
A 1-year-5-months-old female who had cough, rhinorrhea and prolonged fever for 19 days was admitted to the intensive care unit due to exertional dyspnea. She was intubated promptly in virtue of hypotension and cyanosis. The physical examination demonstrated diminished breathing sound over the right lung and distant heart sound; echocardiogram showed cardiac tamponade. Further X ray study showed right hydropneumothorax and cardiomegaly. Pericardiocentesis and chest thoracostomy were performed, and subsequently all the cultures showed growth of Streptococcus pneumoniae. Antibiotics therapy was started promptly after admission. Further investigation indicated osteomyelitis of the right ilium, so that surgical debridement was done. The patient was discharged 54 days later with complete recovery. After following up for 18 months, no restrictive heart disease developed. Purulent pericarditis with cardiac tamponade is an extremely rare complication of pneumococcal infection.
Wu, David Bin-Chia; Roberts, Craig; Lee, Vivian Wing Yan; Hong, Li-Wen; Tan, Kah Kee; Mak, Vivienne; Lee, Kenneth Kwing Chin
Pneumococcal disease causes large morbidity, mortality and health care utilization and medical and non-medical costs, which can all be reduced by effective infant universal routine immunization programs with pneumococcal conjugate vaccines (PCV). We evaluated the clinical and economic benefits of such programs with either 10- or 13-valent PCVs in Malaysia and Hong Kong by using an age-stratified Markov cohort model with many country-specific inputs. The incremental cost per quality-adjusted life year (QALY) was calculated to compare PCV10 or PCV13 against no vaccination and PCV13 against PCV10 over a 10-year birth cohort's vaccination. Both payer and societal perspectives were used. PCV13 had better public health and economic outcomes than a PCV10 program across all scenarios considered. For example, in the base case scenario in Malaysia, PCV13 would reduce more cases of IPD (+2,296), pneumonia (+705,281), and acute otitis media (+376,967) and save more lives (+6,122) than PCV10. Similarly, in Hong Kong, PCV13 would reduce more cases of IPD cases (+529), pneumonia (+172,185), and acute otitis media (+37,727) and save more lives (+2,688) than PCV10. During the same time horizon, PCV13 would gain over 74,000 and 21,600 additional QALYs than PCV10 in Malaysia and Hong Kong, respectively. PCV13 would be cost saving when compared against similar program with PCV10, under both payer and societal perspective in both countries. PCV13 remained a better choice over PCV10 in multiple sensitivity, scenario, and probabilistic analyses. PCV13s broader serotype coverage in its formulation and herd effect compared against PCV10 were important drivers of differences in outcomes.
Scicluna, Brendon P; van Lieshout, Miriam H; Blok, Dana C; Florquin, Sandrine; van der Poll, Tom
Streptococcus pneumoniae (Spneu) remains the most lethal bacterial pathogen and the dominant agent of community-acquired pneumonia. Treatment has perennially focused on the use of antibiotics, albeit scrutinized due to the occurrence of antibiotic-resistant Spneu strains. Immunomodulatory strategies have emerged as potential treatment options. Although promising, immunomodulation can lead to improper tissue functions either at steady state or upon infectious challenge. This argues for the availability of tools to enable a detailed assessment of whole pulmonary functions during the course of infection, not only those functions biased to the defense response. Thus, through the use of an unbiased tissue microarray and bioinformatics approach, we aimed to construct a comprehensive map of whole-lung transcriptional activity and cellular pathways during the course of pneumococcal pneumonia. We performed genome-wide transcriptional analysis of whole lungs before and 6 and 48 h after Spneu infection in mice. The 4,000 most variable transcripts across all samples were used to assemble a gene coexpression network comprising 13 intercorrelating modules (clusters of genes). Fifty-four percent of this whole-lung transcriptional network was altered 6 and 48 h after Spneu infection. Canonical signaling pathway analysis uncovered known pathways imparting protection, including IL17A/IL17F signaling and previously undetected mechanisms that included lipid metabolism. Through in silico prediction of cell types, pathways were observed to enrich for distinct cell types such as a novel stromal cell lipid metabolism pathway. These cellular mechanisms were furthermore anchored at functional hub genes of cellular fate, differentiation, growth and transcription. Collectively, we provide a benchmark unsupervised map of whole-lung transcriptional relationships and cellular activity during early and late pneumococcal pneumonia.
Olsen, Keith M; Gentry-Nielsen, Martha; Yue, Mei; Snitily, Mary U; Preheim, Laurel C
This investigation compared the effect of ethanol on fluoroquinolone antibiotic efficacy and pharmacodynamics in an ethanol-fed rat model of pneumococcal pneumonia. Male Sprague-Dawley rats received a liquid diet containing 36% of total calories as ethanol. Paired controls (pair-fed controls) were fed a liquid diet without ethanol or received rat chow. Diets began 7 days before and continued for 10 days after transtracheal infections with 10 times the 50% lethal dose of type 3 Streptococcus pneumoniae. Beginning 18 h after infection, the rats received once daily subcutaneous phosphate-buffered saline, levofloxacin, moxifloxacin, or trovafloxacin at 50 or 100 mg/kg of body weight. White blood cell counts were determined, blood samples were collected for culture, and mortality was recorded. Additional rats were killed on day 5 for pharmacodynamic studies and quantitative cultures of bronchoalveolar lavage fluid. Bacteremia occurred by day 3 in 20 of 22 untreated rats. All 22 untreated rats died by day 9. Moxifloxacin treatment was effective in all diet groups at both the 50- and 100-mg/kg doses. In contrast, 50-mg/kg doses of levofloxacin and trovafloxacin improved survival in ethanol-fed rats but were ineffective in chow-fed rats. High-dose trovafloxacin at 100 mg/kg was associated with increased mortality in pair-fed rats. The free-fraction area under the concentration-time curve/MIC ratio exceeded 50 with all antibiotics in the ethanol group but dropped below 30 with levofloxacin and trovafloxacin in the pair- and chow-fed rats, with higher mortality. Achievement of adequate antibiotic-free fraction area under the concentration-time curve/MIC ratios helps overcome ethanol-induced immune defects induced in experimental pneumococcal pneumonia.
Pawlowski, A; Källenius, G; Svenson, S B
There is a global urgent need for a new efficient and inexpensive vaccine to combat pneumococcal disease, which should also be affordable in developing countries. In view of this need a simple low-cost technique to prepare such a vaccine was developed. The preparation of serotype 14 and 23F pneumococcal capsular polysaccharide (PnPS)-protein conjugates to be included in a forthcoming multivalent PnPS conjugate vaccine is described. Commercial lots of PnPSs produced according to Good Manufacturing Practice from Streptococcus pneumoniae serotype 14 (PS14) and 23F (PS23F) were partially depolymerized by sonication or irradiation in an electron beam accelerator. The PnPS fragments were conjugated to tetanus toxoid (TT) using a recently developed conjugation chemistry. The application of these new simple, efficient and inexpensive fragmentation and conjugation technologies allowed the synthesis of several PnPS-protein conjugates containing PnPS fragments of preselected sizes and differing in the degree of substitution. The PS14TT and PS23FTT conjugate vaccine candidates were characterized chemically and their immunogenicity was evaluated in rabbits and mice. All PnPS conjugate vaccines, unlike the corresponding plain polysaccharides, produced high IgG titres in both animal species. The PS14TT conjugates tended to be more immunogenic than the PS23FTT conjugates. The immune response to the PS14TT conjugates, but not to the PS23FTT conjugates, was related to the size of the conjugated polysaccharide hapten. Both types of conjugates elicited strong booster effects upon secondary immunizations, resulting in high IgG1, IgG2a and IgG2b titres.
In Japan, the 7-valent pneumococcal conjugate vaccine (PCV-7) became commercially available as a voluntary vaccine in March 2010. It was included in the routine immunization schedule in April 2013 and was replaced by PCV-13 in November 2013. We evaluated 146 cases of invasive pneumococcal disease (IPD) in 142 children (2 developed the disease twice, and 1 developed it three times) treated in the northern district of Hokkaido, Japan from April 2000 to March 2015, before and after the introduction of PCV-7. The incidence rate per 100,000 people aged <5 years showed an increasing trend between April 2000 and March 2010, and reached 87.5 per 100,000 people per year between April 2009 and March 2010, which was immediately before the introduction of PCV-7. Subsequently, the incidence rate started to show a decreasing trend and reached as low as 9.5 per 100,000 people per year between April 2013 and March 2014. However, the incidence rate showed an increasing trend again between April 2014 and March 2015, reaching 33.4 per 100,000 people per year. Serotyping was performed for the 77 strains collected between April 2000 and March 2010. The most frequently isolated serotype was 6B (31.2%), followed by 23F (14.3%) and 19F (13.0%). Among them, 55 strains were covered by PCV-7 (71.4%), and 64 strains were covered by PCV-13 (83.1%). Of the 33 strains collected between April 2010 and March 2015, 14 were covered by PCV-7 (42.4%) and 16 were covered by PCV-13 (48.4%), showing a significant decrease (p < 0.01).
Maricic, Natalie; Dawid, Suzanne
Streptococcus pneumoniae colonizes the highly diverse polymicrobial community of the nasopharynx where it must compete with resident organisms. We have shown that bacterially produced antimicrobial peptides (bacteriocins) dictate the outcome of these competitive interactions. All fully-sequenced pneumococcal strains harbor a bacteriocin-like peptide (blp) locus. The blp locus encodes for a range of diverse bacteriocins and all of the highly conserved components needed for their regulation, processing, and secretion. The diversity of the bacteriocins found in the bacteriocin immunity region (BIR) of the locus is a major contributor of pneumococcal competition. Along with the bacteriocins, immunity genes are found in the BIR and are needed to protect the producer cell from the effects of its own bacteriocin. The overlay assay is a quick method for examining a large number of strains for competitive interactions mediated by bacteriocins. The overlay assay also allows for the characterization of bacteriocin-specific immunity, and detection of secreted quorum sensing peptides. The assay is performed by pre-inoculating an agar plate with a strain to be tested for bacteriocin production followed by application of a soft agar overlay containing a strain to be tested for bacteriocin sensitivity. A zone of clearance surrounding the stab indicates that the overlay strain is sensitive to the bacteriocins produced by the pre-inoculated strain. If no zone of clearance is observed, either the overlay strain is immune to the bacteriocins being produced or the pre-inoculated strain does not produce bacteriocins. To determine if the blp locus is functional in a given strain, the overlay assay can be adapted to evaluate for peptide pheromone secretion by the pre-inoculated strain. In this case, a series of four lacZ-reporter strains with different pheromone specificity are used in the overlay.
Tashani, Mohamed; Jayasinghe, Sanjay; Harboe, Zitta B; Rashid, Harunor; Booy, Robert
AIM To investigate evidence of clinical protection in infants after one dose of 7-valent pneumococcal conjugate vaccine (7vPCV) owing to carrier priming. METHODS Using Australian National Notifiable Diseases Surveillance System data, we conducted a descriptive analysis of cases of vaccine type invasive pneumococcal disease (VT-IPD) during “catch-up” years, when 7vPCV was carrier primed by prior administration of DTPa vaccine. We compared the number of VT-IPD cases occurring 2-9 wk after a single dose of 7vPCV (carrier primed), with those < 2 wk post vaccination, when no protection from 7vPCV was expected yet. Further comparison was conducted to compare the occurrence of VT-IPD cases vs non-VT-IPD cases after a single carrier-primed dose of 7vPCV. RESULTS We found four VT-IPD cases occurring < 2 wk after one carrier primed dose of 7vPCV while only one case occurred 2-9 wk later. Upon further comparison with the non-VT-IPD cases that occurred after one carrier primed dose of 7vPCV, two cases were detected within 2 wk, whereas seven occurred within 2-9 wk later; suggesting a substantial level of protection from VT-IPD occurring from 2 wk after carrier-primed dose of 7vPCV. CONCLUSION This data suggest that infants may benefit from just one dose of 7vPCV, likely through enhanced immunity from carrier priming effect. If this is proven, an adjusted 2-dose schedule (where the first dose of PCV is not given until after DTPa) may be sufficient and more cost-effective. PMID:27610348
Olarte, Liset; Kaplan, Sheldon L; Barson, William J; Romero, José R; Lin, Philana Ling; Tan, Tina Q; Hoffman, Jill A; Bradley, John S; Givner, Laurence B; Mason, Edward O; Hultén, Kristina G
Streptococcus pneumoniae serotype 35B is a nonvaccine serotype associated with high rates of penicillin nonsusceptibility. An increase in the proportion of multidrug-resistant (MDR) 35B isolates has recently been reported. The genetic events contributing to the emergence of MDR serotype 35B are unknown. The sequence type (ST) composition of 78 serotype 35B isolates obtained from pediatric patients with invasive pneumococcal disease from 1994 to 2014 and 48 isolates from pediatric patients with otitis media (noninvasive) from 2011 to 2014 was characterized by multilocus sequence typing (MLST). The most common STs were ST558 (69.2%), ST156 (10.3%), and ST452 (3.8%). Two major clonal complexes (CC), CC558 and CC156, were identified by eBURST analysis. Overall, 91% (71/78) of isolates were penicillin nonsusceptible and 16.7% (13/78) were MDR. Among all invasive serotype 35B isolates, MDR isolates increased significantly, from 2.9% (1/35) to 27.9% (12/43) (P = 0.004), after the 13-valent pneumococcal conjugate vaccine (PCV13) was introduced. All CC156 isolates were identified after the introduction of PCV13 (0/35 [0%] before versus 9/43 [20.9%] after; P = 0.003) and were MDR. All CC156 isolates had similar antimicrobial susceptibility patterns; in contrast, high variability in antimicrobial susceptibility was observed among CC558 isolates. The distributions of CC558 and CC156 among invasive and noninvasive isolates were not different. The increased prevalence of MDR serotype 35B after the introduction of PCV13 was directly associated with the emergence of ST156. Genotyping suggests that capsular switching has occurred between MDR vaccine serotypes belonging to ST156 (e.g., 9V, 14, and 19A) and serotype 35B.
Effect of the different 13-valent pneumococcal conjugate vaccination uptakes on the invasive pneumococcal disease in children: Analysis of a hospital-based and population-based surveillance study in Madrid, Spain, 2007-2015
Picazo, Juan; Ruiz-Contreras, Jesús; Casado-Flores, Juan; Negreira, Sagrario; Baquero, Fernando; Hernández-Sampelayo, Teresa; Otheo, Enrique; Méndez, Cristina
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. PMID:28207888
Thisyakorn, Usa; Chokephaibulkit, Kulkanya; Kosalaraksa, Pope; Benjaponpitak, Suwat; Pancharoen, Chitsanu; Chuenkitmongkol, Sunate
The current study examined the safety and immunogenicity of 23-valent pneumococcal capsular polysaccharide vaccine (Pneumo23(®) [PPV23], Sanofi Pasteur) as a booster dose in 12- to 18-month-old children primed with heptavalent pneumococcal vaccine (PCV7; Prevnar(®), Pfizer). This was a randomized, observer-blinded, 2-arm, controlled, multicenter phase III study performed in Thailand to assess and describe the immunogenicity and safety of PPV23 as a booster dose in children who had received the 3 primary doses of PCV7, the pneumococcal vaccine available during the study period. Children primed with 3 doses of PCV7 were randomized 1:1 to receive a booster immunization with PPV23 or PCV7. Pneumococcal antibody concentrations were measured by enzyme-linked immunosorbent assay and functional antibody levels by multiplex opsonophagocytosis assay on day 30. A total of 339 children were enrolled. Geometric mean serum antibody concentrations against serotypes common to PCV7 and PPV23 (4, 6B, 9V, 14, 18C, 19F, and 23F) increased in both groups but they were higher for serotypes 4, 9V, 18C, and 19F in the PPV23 group. Opsonization indices increased in both groups for all measured serotypes (1, 6B, 14, 19A, and 23F) and were higher for serotypes 6B, 14, and 23F in the PCV7 group and for serotypes 1 and 19A in PPV23 group. Solicited reactions and unsolicited adverse events were similar in the 2 groups and generally mild and transient. No treatment-related serious adverse events were reported. These results confirm that boosting with PPV23 is immunogenic and well tolerated in healthy toddlers primed with PCV7.
Thisyakorn, Usa; Chokephaibulkit, Kulkanya; Kosalaraksa, Pope; Benjaponpitak, Suwat; Pancharoen, Chitsanu; Chuenkitmongkol, Sunate
The current study examined the safety and immunogenicity of 23-valent pneumococcal capsular polysaccharide vaccine (Pneumo23® [PPV23], Sanofi Pasteur) as a booster dose in 12- to 18-month-old children primed with heptavalent pneumococcal vaccine (PCV7; Prevnar®, Pfizer). This was a randomized, observer-blinded, 2-arm, controlled, multicenter phase III study performed in Thailand to assess and describe the immunogenicity and safety of PPV23 as a booster dose in children who had received the 3 primary doses of PCV7, the pneumococcal vaccine available during the study period. Children primed with 3 doses of PCV7 were randomized 1:1 to receive a booster immunization with PPV23 or PCV7. Pneumococcal antibody concentrations were measured by enzyme-linked immunosorbent assay and functional antibody levels by multiplex opsonophagocytosis assay on day 30. A total of 339 children were enrolled. Geometric mean serum antibody concentrations against serotypes common to PCV7 and PPV23 (4, 6B, 9V, 14, 18C, 19F, and 23F) increased in both groups but they were higher for serotypes 4, 9V, 18C, and 19F in the PPV23 group. Opsonization indices increased in both groups for all measured serotypes (1, 6B, 14, 19A, and 23F) and were higher for serotypes 6B, 14, and 23F in the PCV7 group and for serotypes 1 and 19A in PPV23 group. Solicited reactions and unsolicited adverse events were similar in the 2 groups and generally mild and transient. No treatment-related serious adverse events were reported. These results confirm that boosting with PPV23 is immunogenic and well tolerated in healthy toddlers primed with PCV7. PMID:25424793
Amerighi, Fulvia; Valeri, Maria; Donnarumma, Danilo; Maccari, Silvia; Moschioni, Monica; Taddei, Annarita; Lapazio, Lucia; Pansegrau, Werner; Buccato, Scilla; De Angelis, Gabriella; Ruggiero, Paolo; Masignani, Vega; Soriani, Marco; Pezzicoli, Alfredo
The adhesion of Streptococcus pneumoniae is a key step during colonization of human respiratory tract mucosae. Here we demonstrate that pneumococcal type I pilus significantly increases the adhesiveness of poorly adhering highly capsulated strains in vitro. Interestingly, preincubation of bacteria with antibodies against the major pilus backbone subunit (RrgB) or the adhesin component (RrgA) impaired pneumococcal association to human epithelial cells. Screening for anti-RrgA monoclonal antibodies specifically affecting the adhesive capacity of S. pneumoniae led to the identification of the monoclonal 11B9/61 antibody, which greatly reduced pilus-dependent cell contact. Proteomic-based epitope mapping of 11B9/61 monoclonal antibody revealed a well-exposed epitope on the D2 domain of RrgA as the target of this functional antibody. The data presented here confirm the importance of pilus I for S. pneumoniae pathogenesis and the potential use of antipilus antibodies to prevent bacterial colonization.
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... well as emerging forms capable of causing a global pandemic. To learn about risk factors for the flu and current prevention and treatment strategies visit the MedlinePlus flu site . Credit: NIAID A ...
Dupont, Damien; Mahjoub-Messai, Farah; François, Martine; Doit, Catherine; Mariani-Kurkdjian, Patricia; Bidet, Philippe; Bonacorsi, Stéphane; Carol, Agnès; Bingen, Edouard
We compare the microbiology of otopathogens causing recurrent acute otitis media (AOM) or AOM treatment failure in 600 children during 2000 to 2008 before and after the introduction of 7-valent pneumococcal conjugate vaccine (PCV-7). Streptococcus pneumoniae predominated before PCV-7 introduction and during 2007 to 2008, whereas Haemophilus influenzae predominated during 2005 to 2006. S. pneumoniae 19A became the most frequent serotype after PCV-7 introduction.
van Tonder, Andries J.; Bray, James E.; Quirk, Sigríður J.; Haraldsson, Gunnsteinn; Jolley, Keith A.; Maiden, Martin C. J.; Hoffmann, Steen; Bentley, Stephen D.; Haraldsson, Ásgeir; Erlendsdóttir, Helga; Kristinsson, Karl G.; Brueggemann, Angela B.
The pneumococcus is a leading global pathogen and a key virulence factor possessed by the majority of pneumococci is an antigenic polysaccharide capsule (‘serotype’), which is encoded by the capsular (cps) locus. Approximately 100 different serotypes are known, but the extent of sequence diversity within the cps loci of individual serotypes is not well understood. Investigating serotype-specific sequence variation is crucial to the design of sequence-based serotyping methodology, understanding pneumococcal conjugate vaccine (PCV) effectiveness and the design of future PCVs. The availability of large genome datasets makes it possible to assess population-level variation among pneumococcal serotypes and in this study 5405 pneumococcal genomes were used to investigate cps locus diversity among 49 different serotypes. Pneumococci had been recovered between 1916 and 2014 from people of all ages living in 51 countries. Serotypes were deduced bioinformatically, cps locus sequences were extracted and variation was assessed within the cps locus, in the context of pneumococcal genetic lineages. Overall, cps locus sequence diversity varied markedly: low to moderate diversity was revealed among serogroups/types 1, 3, 7, 9, 11 and 22; whereas serogroups/types 6, 19, 23, 14, 15, 18, 33 and 35 displayed high diversity. Putative novel and/or hybrid cps loci were identified among all serogroups/types apart from 1, 3 and 9. This study demonstrated that cps locus sequence diversity varied widely between serogroups/types. Investigation of the biochemical structure of the polysaccharide capsule of major variants, particularly PCV-related serotypes and those that appear to be novel or hybrids, is warranted. PMID:28133541
Hoogendoorn, E H; Oyen, W J G; van Dijk, A P J; van der Meer, J W M
We describe an 82-year-old male with pneumococcal aortitis of the descending aorta, visualized by echocardiography and positron emission tomography using fluorinated deoxyglucose (FDG-PET). Computed tomography is considered to be the best diagnostic imaging modality in infected aortic lesions; in this case, the use of FDG-PET, which gives the opportunity to distinguish between inflammatory and non-inflammatory aortic aneurysms, made an important contribution to the diagnosis.
Saleh, Malek; Abdullah, Mohammed R; Schulz, Christian; Kohler, Thomas; Pribyl, Thomas; Jensch, Inga; Hammerschmidt, Sven
Pneumonia is one of the major health care problems in developing and industrialized countries and is associated with considerable morbidity and mortality. Despite advances in knowledge of this illness, the availability of intensive care units (ICU), and the use of potent antimicrobial agents and effective vaccines, the mortality rates remain high(1). Streptococcus pneumoniae is the leading pathogen of community-acquired pneumonia (CAP) and one of the most common causes of bacteremia in humans. This pathogen is equipped with an armamentarium of surface-exposed adhesins and virulence factors contributing to pneumonia and invasive pneumococcal disease (IPD). The assessment of the in vivo role of bacterial fitness or virulence factors is of utmost importance to unravel S. pneumoniae pathogenicity mechanisms. Murine models of pneumonia, bacteremia, and meningitis are being used to determine the impact of pneumococcal factors at different stages of the infection. Here we describe a protocol to monitor in real-time pneumococcal dissemination in mice after intranasal or intraperitoneal infections with bioluminescent bacteria. The results show the multiplication and dissemination of pneumococci in the lower respiratory tract and blood, which can be visualized and evaluated using an imaging system and the accompanying analysis software.
Barthelemy, Adeline; Ivanov, Stoyan; Hassane, Maya; Fontaine, Josette; Heurtault, Béatrice; Frisch, Benoit; Faveeuw, Christelle; Paget, Christophe
ABSTRACT Influenza A virus infection can predispose to potentially devastating secondary bacterial infections. Invariant natural killer T (iNKT) cells are unconventional, lipid-reactive T lymphocytes that exert potent immunostimulatory functions. Using a mouse model of postinfluenza invasive secondary pneumococcal infection, we sought to establish whether α-galactosylceramide (α-GalCer [a potent iNKT cell agonist that is currently in clinical development]) could limit bacterial superinfection. Our results highlighted the presence of a critical time window during which α-GalCer treatment can trigger iNKT cell activation and influence resistance to postinfluenza secondary pneumococcal infection. Intranasal treatment with α-GalCer during the acute phase (on day 7) of influenza virus H3N2 and H1N1 infection failed to activate (gamma interferon [IFN-γ] and interleukin-17A [IL-17A]) iNKT cells; this effect was associated with a strongly reduced number of conventional CD103+ dendritic cells in the respiratory tract. In contrast, α-GalCer treatment during the early phase (on day 4) or during the resolution phase (day 14) of influenza was associated with lower pneumococcal outgrowth and dissemination. Less intense viral-bacterial pneumonia and a lower morbidity rate were observed in superinfected mice treated with both α-GalCer (day 14) and the corticosteroid dexamethasone. Our results open the way to alternative (nonantiviral/nonantibiotic) iNKT-cell-based approaches for limiting postinfluenza secondary bacterial infections. PMID:27803187
da Silva, Sandra Rodrigues; de Mello, Luane Marques; da Silva, Anderson Soares; Nunes, Altacílio Aparecido
Abstract Objective: To describe and analyze the occurrence of hospitalizations for community-acquired pneumonia in children before and after the pneumococcal 10-valent conjugate vaccine implementation into the National Immunization Program. Methods: This is an ecological study that includes records of children younger than one year old, vaccinated and not vaccinated with the pneumococcal 10-valent conjugate vaccine in the periods pre- and post-inclusion of the vaccine in the National Immunization Program in the area covered by the Regional Health Superintendence of Alfenas, state of Minas Gerais, Brazil. Vaccination was considered as the exposure factor and hospitalization for community-acquired pneumonia as the endpoint, using secondary annual data by municipality. The prevalence ratio and its 95% confidence interval (95%CI) were used to verify the association between variables. The Z test was used to calculate the difference between proportions. Results: Considering the 26 municipalities of the Regional Health Superintendence of Alfenas, there was a significant reduction in hospitalizations for community-acquired pneumonia in children younger than one year of age, with prevalence ratio (PR)=0.81 (95%CI: 0.74-0.89; p<0.05), indicating a 19% lower prevalence of hospitalization for community-acquired pneumonia in the post-vaccination period. Conclusions: The results suggest the effectiveness of the pneumococcal 10-valent conjugate vaccine in preventing severe cases of community-acquired pneumonia in children younger than one year of age. PMID:27108092
Hommes, Tijmen J; van Lieshout, Miriam H; van 't Veer, Cornelis; Florquin, Sandrine; Bootsma, Hester J; Hermans, Peter W; de Vos, Alex F; van der Poll, Tom
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.
Satman, Ilhan; Akalin, Sema; Cakir, Bekir; Altinel, Serdar
We aimed to examine the effect of increased physician awareness on the rate and determinants of influenza and pneumococcal vaccinations in diabetic patients. Diabetic patients (n = 5682, mean [SD] age: 57.3 [11.6] years, 57% female) were enrolled by 44 physicians between Sept 2010 and Jan 2011. The physicians were initially questioned regarding vaccination practices, and then, they attended a training program. During the last five years, the physicians recommended influenza and pneumococcal vaccinations to 87.9% and 83.4% of the patients, respectively; however; only 27% of the patients received the influenza and 9.8% received the pneumococcal vaccines. One year after the training, the vaccination rates increased to 63.3% and 40.7%, respectively. The logistic regression models revealed that variables which increased the likelihood of having been vaccinated against influenza were: longer duration of diabetes, presence of hyperlipidemia and more use of concomitant medications whereas more use of anti-hyperglycemic medications was associated with increased odds of vaccination. On the other hand, older age, longer duration of diabetes and presence of a cardiovascular disease were variables which decreased the likelihood of having been vaccinated against pneumococcal disease during the past five years. However, during the study period, variables which decreased the odds of having been vaccinated included: older age and anti-hyperglycemic medications for influenza, and presence of hyperlipidemia and a family history of hypertension for pneumococcal disease. While variables which increased the likelihood of vaccination in the same period were: increased number of co-morbidities for influenza, and family history of diabetes for pneumococcal disease. We conclude that increased awareness of physicians may help improve vaccination rates against influenza and pneumococcal disease. However, diabetic patients with more severe health conditions are less likely to having been
Pasiarski, Marcin; Rolinski, Jacek; Grywalska, Ewelina; Stelmach-Goldys, Agnieszka; Korona-Glowniak, Izabela; Gozdz, Stanislaw; Hus, Iwona; Malm, Anna
Background Chronic lymphocytic leukemia (CLL) leads to significant immune system dysfunction. The predominant clinical presentation in 50% of patients involves recurrent, often severe, infections. Infections are also the most common (60–80%) cause of deaths in CLL patients. The scope of infections varies with the clinical stage of the disease. Treatment-naive patients typically present with respiratory tract infections caused by encapsulated bacteria Streptococcus pneumoniae and Haemophilus influenzae. Since 2012, the 13-valent pneumococcal conjugate vaccine (PCV13) has been recommended in the United States and some EU countries for pneumococcal infection prevention in patients with CLL (besides the long-standing standard, 23-valent pneumococcal polysaccharide vaccine, PPV23). The aim of this study was to compare the immune response to PCV13 in 24 previously untreated CLL patients and healthy subjects. Methods Both groups were evaluated for: the levels of specific pneumococcal antibodies, the levels of IgG and IgG subclasses and selected peripheral blood lymphocyte subpopulations including the frequency of plasmablasts before and after immunization. Results Adequate response to vaccination, defined as an at least two-fold increase in specific pneumococcal antibody titers versus pre-vaccination baseline titers, was found in 58.3% of CLL patients and 100% of healthy subjects. Both the CLL group and the control group demonstrated a statistically significant increase in the IgG2 subclass levels following vaccination (P = 0.0301). After vaccination, the frequency of plasmablasts was significantly lower (P<0.0001) in CLL patients in comparison to that in controls. Patients who responded to vaccination had lower clinical stage of CLL as well as higher total IgG, and IgG2 subclass levels. No significant vaccine-related side effects were observed. Conclusions PCV13 vaccination in CLL patients is safe and induces an effective immune response in a considerable
[Recommendations for prevention of community-acquired pneumonia with bacteremia as the leading form of invasive pneumococcal infections in the population of people over 50 years of age and risk groups above 19 years of age].
Albrecht, Piotr; Antczak, Adam; Hryniewicz, Waleria; Skoczyńska, Anna; Radzikowski, Andrzej; Kedziora-Kornatowska, Kornelia; Bernatowska, Ewa; Stompór, Tomasz; Grodzicki, Tomasz; Gyrczuk, Ewa; Imiela, Jacek; Jedrzejczak, Wiesław; Windak, Adam
Invasive pneumococcal disease (IPD) is a main cause of mortality associated with pneumococcal infections. Although, IPD is regarding mainly small children and persons in the age > 65 years, the investigations showed that because of IPD exactly sick persons are burdened with the greatest mortality in the older age, rather than of children. The most frequent form of IPD is community acquired pneumonia (CAP) with the bacteremia. The presence of even a single additional risk factor is increasing the probability of the unfavorable descent of pneumococcal infection. The risk factors for IPD and/or pneumonia with bacteremia apart from the age are among others asthma (> 2 x), chronic obstructive pulmonary disease (COPD), sarcoidosis (4 x), idiopathic pulmonary fibrosis (5 x), bronchiectases (2 x), allergic alveolitis (1.9 x) and pneumoconiosis (2 x), type 1 diabetes (4.4 x), type 2 diabetes (1.2 x), autoimmune diseases (e.g. rheumatoid arthritis (4.2 to 14.9 x), kidney failure with the necessity to dialysis (12 x), immunosuppression, cardiovascular disease, alcoholism and cancers. Examinations show that the best method of IPD and CAP preventing are pneumococcal vaccinations. On the market for ages 23-valent polysaccharide vaccine (PPV23) is available covering close the 90% of IPD triggering stereotypes. Her role in preventing CAP is uncertain and the immunological answer after vaccination at older persons and after revaccination is weak. Widely discussed disadvantageous effects of growing old of the immunological system show on the benefit from applying the immunization inducing the immunological memory, i.e. of conjugated vaccines which are activating the T-dependent reply and are ensuring the readiness for the effective secondary response. Examinations so far conducted with conjugated 7-valent and 13-valent (PCV13) vaccines at persons in the age > 50 years are confirming these expectations. Also sick persons can take benefits from PCV13 applying back from so-called IPD
Gallo, Tolinda; Furlan, Patrizia; Romor, Pierantonio; Bertoncello, Chiara; Buja, Alessandra; Baldovin, Tatjana
Background Community-acquired pneumonia (CAP) is an important cause of illness and death worldwide, particularly among the elderly. Previous studies on the factors associated with mortality in patients hospitalized for CAP revealed a direct association between the type of microorganism involved, the characteristics of the patient and mortality. Vaccination status against pneumococcal disease was not considered. We conducted a retrospective analysis on the mortality rates after a first hospitalization for CAP in north-east Italy with a view to examining especially the role of anti-pneumococcal vaccination as a factor associated with pneumonia-related mortality at one year. Method Between 2012–2013, patients aged 65+ hospitalized with a primary diagnosis of CAP, identified based on International Classification of Diseases, Ninth Revision, Clinical Modification codes 481–486, were enrolled in the study only once. Patients were divided into three groups by pneumococcal vaccination status: 1) 13-valent pneumococcal conjugate vaccine (PCV13) prior to their hospitalization; 2) 23-valent pneumococcal polysaccharide vaccine (PPV23) within 5 years before hospitalization and 3) unvaccinated or PPV23 more than 5 years prior to admission. Gender, age, length of hospital stay and influenza vaccination were considered. Comorbidities were ascertained by means of a properly coded diagnosis. Every patient was followed up for 1 year and the outcome investigated was mortality for any cause and for pneumonia. Results A total of 4,030 patient were included in the study; mean age at the time of admission to hospital was 84.3±7.7; 50.9% were female. 74.2% of subjects had at least one comorbidity; 73.7% has been vaccinated against influenza. Regard to pneumococcal vaccine, 80.4% of patients were not vaccinated, 14.5% vaccinated with PPV23 and 5.1% with PCV13. The 1-year survival rates after hospitalization for pneumonia were 83.6%, 85.9% and 89.3% in the unvaccinated, PPV23 and PCV13
Herbert, Jenny A; Mitchell, Andrea M; Mitchell, Timothy J
The pneumococcal serine threonine protein kinase (StkP) acts as a global regulator in the pneumococcus. Bacterial mutants deficient in StkP are less virulent in animal models of infection. The gene for this regulator is located adjacent to the gene for its cognate phosphatase in the pneumococcal genome. The phosphatase dephosphorylates proteins phosphorylated by StkP and has been shown to regulate a number of key pneumococcal virulence factors and to modulate adherence to eukaryotic cells. The role of StkP in adherence of pneumococci to human cells has not previously been reported. In this study we show StkP represses the pneumococcal pilus, a virulence factor known to be important for bacterial adhesion. In a serotype 4 strain regulation of the pilus by StkP modulates adherence to human brain microvascular endothelial cells (HBMEC) and human lung epithelial cells. This suggests that the pneumococcal pilus may play a role in adherence during infections such as meningitis and pneumonia. We show that regulation of the pilus occurs at the population level as StkP alters the number of pili-positive cells within a single culture. As far as we are aware this is the first gene identified outside of the pilus islet that regulates the biphasic expression of the pilus. These findings suggest StkPs role in cell division may be linked to regulation of expression of a cell surface adhesin.
Zon, G; Szu, S C; Egan, W; Robbins, J D; Robbins, J B
The hydrolyses of the immunologically cross-reactive and constitutionally isomeric group 6 pneumococcal polysaccharides, types 6A and 6B, were investigated by 31P nuclear magnetic resonance spectroscopy, gel filtration through Sepharose 4B, reducing-sugar analysis, and rocket immunoelectrophoresis. Phosphorus nuclear magnetic resonance spectroscopy showed that cleavage of the repeating-unit phosphodiester linkages at pH 10, 60 degrees C was considerably faster (greater than 10(3) ) for the type 6A than the type 6B polysaccharide. Under these reaction conditions, 31P nuclear magnetic resonance kinetic measurements showed that the Na+ form of the type 6A polysaccharide underwent phosphodiester-linkage hydrolysis two times slower than the corresponding Ca+2 form; a stoichiometrically excess amount of Ca+2 caused a 30-fold enhancement of the latter hydrolysis rate. The spectroscopic characterization of phosphorus-containing end groups resulting from hydrolysis of the type 6A polymer provided additional mechanistic information. Heating the type 6A and 6B polysaccharides at 56 degrees C for various times led to gel filtration coefficients of distribution (Kd values) which indicated that the type 6A material underwent size reductions considerably faster than did the type 6B antigen; these increased Kd values qualitatively correlated with the loss of immunochemical reactivity measured by rocket immunoelectrophoresis. The application of a statistical theory to the depolymerization of the type 6A and 6B polysaccharides was consistent with random bond cleavage, as evidenced by the calculated versus measured gel filtration patterns. Although the molecular changes causing the size reductions were not fully elaborated, it was established that the acetal linkages of the type 6A and 6B polysaccharides were comparatively resistant to hydrolysis and that depolymerization by hydrolysis of the phosphodiester linkage was a major factor only in the type 6A structure. It was concluded
Kohler, Thomas P.; Scholz, Annemarie; Kiachludis, Delia; Hammerschmidt, Sven
Streptococcus pneumoniae is a widespread colonizer of the mucosal epithelia of the upper respiratory tract of human. However, pneumococci are also responsible for numerous local as well as severe systemic infections, especially in children under the age of five and the elderly. Under certain conditions, pneumococci are able to conquer the epithelial barrier, which can lead to a dissemination of the bacteria into underlying tissues and the bloodstream. Here, specialized macrophages represent an essential part of the innate immune system against bacterial intruders. Recognition of the bacteria through different receptors on the surface of macrophages leads thereby to an uptake and elimination of bacteria. Accompanied cytokine release triggers the migration of leukocytes from peripheral blood to the site of infection, where monocytes differentiate into mature macrophages. The rearrangement of the actin cytoskeleton during phagocytosis, resulting in the engulfment of bacteria, is thereby tightly regulated by receptor-mediated phosphorylation cascades of different protein kinases. The molecular cellular processes including the modulation of central protein kinases are only partially solved. In this study, the human monocytic THP-1 cell line was used as a model system to examine the activation of Fcγ and complement receptor-independent signal cascades during infection with S. pneumoniae. Pneumococci cultured either in chemically defined or complex medium showed no significant differences in pneumococcal phagocytosis by phorbol 12-myristate 13-acetate (PMA) differentiated THP-1 cells. Double immuno-fluorescence microscopy and antibiotic protection assays demonstrated a time-dependent uptake and killing of S. pneumoniae 35A inside of macrophages. Infections of THP-1 cells in the presence of specific pharmacological inhibitors revealed a crucial role of actin polymerization and importance of the phosphoinositide 3-kinase (PI3K) and Protein kinase B (Akt) as well during
Zon, G; Szu, S C; Egan, W; Robbins, J D; Robbins, J B
The hydrolyses of the immunologically cross-reactive and constitutionally isomeric group 6 pneumococcal polysaccharides, types 6A and 6B, were investigated by 31P nuclear magnetic resonance spectroscopy, gel filtration through Sepharose 4B, reducing-sugar analysis, and rocket immunoelectrophoresis. Phosphorus nuclear magnetic resonance spectroscopy showed that cleavage of the repeating-unit phosphodiester linkages at pH 10, 60 degrees C was considerably faster (greater than 10(3) ) for the type 6A than the type 6B polysaccharide. Under these reaction conditions, 31P nuclear magnetic resonance kinetic measurements showed that the Na+ form of the type 6A polysaccharide underwent phosphodiester-linkage hydrolysis two times slower than the corresponding Ca+2 form; a stoichiometrically excess amount of Ca+2 caused a 30-fold enhancement of the latter hydrolysis rate. The spectroscopic characterization of phosphorus-containing end groups resulting from hydrolysis of the type 6A polymer provided additional mechanistic information. Heating the type 6A and 6B polysaccharides at 56 degrees C for various times led to gel filtration coefficients of distribution (Kd values) which indicated that the type 6A material underwent size reductions considerably faster than did the type 6B antigen; these increased Kd values qualitatively correlated with the loss of immunochemical reactivity measured by rocket immunoelectrophoresis. The application of a statistical theory to the depolymerization of the type 6A and 6B polysaccharides was consistent with random bond cleavage, as evidenced by the calculated versus measured gel filtration patterns. Although the molecular changes causing the size reductions were not fully elaborated, it was established that the acetal linkages of the type 6A and 6B polysaccharides were comparatively resistant to hydrolysis and that depolymerization by hydrolysis of the phosphodiester linkage was a major factor only in the type 6A structure. It was concluded
Lloyd-Puryear, M A; Ball, L K; Benor, D
In 1996, the National Vaccine Advisory Committee (NVAC) asked for a review of the pros and cons of including adult influenza and pneumococcal vaccines in the Vaccine Injury Compensation Program (VICP). The authors, as staff to the subcommittees charged with undertaking this assessment, looked at the following questions: (a) Would inclusion in VICP of these two vaccines, used primarily for adults, increase adult vaccination levels? (b) Is this Federal involvement warranted based on the liability burden for these vaccines? (c) Does the risk of adverse events following vaccinations warrant inclusion of these vaccines? (d) Is there a consensus among stakeholders favoring their inclusion? To address these questions, the authors reviewed information on adult vaccines, including data on l lawsuits filed and reports of injuries, and sought input from interested groups. They found no evidence that the use of influenza and pneumococcal vaccines would increase if they were included in VICP. They found a low liability burden for these vaccines, that serious adverse events were rare, and that no consensus existed among stakeholders. After considering the staff report, NVAC chose, in 1996, not to advise the Department of Health and Human Services to include adult vaccines in VICP.
Song, Meng; Li, Li; Li, Meng; Cha, Yonghong; Deng, Xuming; Wang, Jianfeng
Streptococcus pneumoniae is an important human pathogenic bacterium that can cause various life-threatening infections. Pneumolysin (PLY), the pore-forming toxin that forms large pores in the cell membrane, is a key virulence factor secreted by S. pneumoniae that penetrates the physical defenses of the host and plays an important role in the pathogenesis of pneumococcal diseases, such as pneumonia, meningitis, bacteremia and otitis media. This study showed that apigenin, one of the bioflavonoids widely found in herbs, inhibits PLY-induced hemolysis by inhibiting the oligomerization of PLY and has no anti-S. pneumoniae activity. In addition, when PLY was incubated with human alveolar epithelial (A549) cells, apigenin could effectively alleviate PLY-mediated cell injury. In vivo studies further demonstrated that apigenin could protect mice against S. pneumoniae pneumonia. These results imply that apigenin could directly interact with PLY to decrease the pathogenicity of S. pneumoniae and that novel therapeutics against S. pneumoniae PLY might provide greater effectiveness in combatting S. pneumoniae pneumonia.
Hanage, William P.; Harris, Simon R.; Bentley, Stephen; Fraser, Christophe
The bacterium Streptococcus pneumoniae (pneumococcus) is one of the most important human bacterial pathogens, and a leading cause of morbidity and mortality worldwide. The pneumococcus is also known for undergoing extensive homologous recombination via transformation with exogenous DNA. It has been shown that recombination has a major impact on the evolution of the pathogen, including acquisition of antibiotic resistance and serotype-switching. Nevertheless, the mechanism and the rates of recombination in an epidemiological context remain poorly understood. Here, we proposed several mathematical models to describe the rate and size of recombination in the evolutionary history of two very distinct pneumococcal lineages, PMEN1 and CC180. We found that, in both lineages, the process of homologous recombination was best described by a heterogeneous model of recombination with single, short, frequent replacements, which we call micro-recombinations, and rarer, multi-fragment, saltational replacements, which we call macro-recombinations. Macro-recombination was associated with major phenotypic changes, including serotype-switching events, and thus was a major driver of the diversification of the pathogen. We critically evaluate biological and epidemiological processes that could give rise to the micro-recombination and macro-recombination processes. PMID:24786281
Prudhomme, Marc; Berge, Mathieu; Martin, Bernard; Polard, Patrice
Bacteria have evolved various inducible genetic programs to face many types of stress that challenge their growth and survival. Competence is one such program. It enables genetic transformation, a major horizontal gene transfer process. Competence development in liquid cultures of Streptococcus pneumoniae is synchronized within the whole cell population. This collective behavior is known to depend on an exported signaling Competence Stimulating Peptide (CSP), whose action generates a positive feedback loop. However, it is unclear how this CSP-dependent population switch is coordinated. By monitoring spontaneous competence development in real time during growth of four distinct pneumococcal lineages, we have found that competence shift in the population relies on a self-activated cell fraction that arises via a growth time-dependent mechanism. We demonstrate that CSP remains bound to cells during this event, and conclude that the rate of competence development corresponds to the propagation of competence by contact between activated and quiescent cells. We validated this two-step cell-contact sensing mechanism by measuring competence development during co-cultivation of strains with altered capacity to produce or respond to CSP. Finally, we found that the membrane protein ComD retains the CSP, limiting its free diffusion in the medium. We propose that competence initiator cells originate stochastically in response to stress, to form a distinct subpopulation that then transmits the CSP by cell-cell contact. PMID:27355362
Johnson, Michael D L; Kehl-Fie, Thomas E; Klein, Roger; Kelly, Jacqueline; Burnham, Corinna; Mann, Beth; Rosch, Jason W
In bacteria, the intracellular levels of metals are mediated by tightly controlled acquisition and efflux systems. This is particularly true of copper, a trace element that is universally toxic in excess. During infection, the toxic properties of copper are exploited by the mammalian host to facilitate bacterial clearance. To better understand the role of copper during infection, we characterized the contribution of the cop operon to copper homeostasis and virulence in Streptococcus pneumoniae. Deletion of either the exporter, encoded by copA, or the chaperone, encoded by cupA, led to hypersensitivity to copper stress. We further demonstrated that loss of the copper exporter encoded by copA led to decreased virulence in pulmonary, intraperitoneal, and intravenous models of infection. Deletion of copA resulted in enhanced macrophage-mediated bacterial clearance in vitro. The attenuation phenotype of the copA mutant in the lung was found to be dependent on pulmonary macrophages, underscoring the importance of copper efflux in evading immune defenses. Overall, these data provide insight into the role of the cop operon in pneumococcal pathogenesis.
Lopez, P; Espinosa, M; Greenberg, B; Lacks, S A
The pneumococcal recombinant plasmid pLS70, which contains two strong promoters for transcription of the malM and malX genes, is unstable when transferred to Bacillus subtilis, and it gives rise to deleted derivatives. Analysis of proteins produced by the deleted plasmids and restriction mapping of 29 different deletions showed that stabilization in B. subtilis was accompanied by deletions affecting both promoters. Plasmids containing even a single strong promoter were at a selective disadvantage. Nucleotide sequences surrounding the deletions in 10 plasmids were determined. Six different deletions occurred between directly repeated sequences of 3-13 base pairs in length, presumably by a recombination mechanism involving short homologies. Four deletions occurred between sites not contained within repeated sequences. A weak but significant similarity of an 11-base sequence was found surrounding these deletions and the corresponding points of junction in the progenitor plasmids. It is suggested that this sequence may be the recognition site for a topoisomerase-like enzyme that can produce deletions. Images PMID:6089185
van den Boogaard, Florry E; van 't Veer, Cornelis; Roelofs, Joris J T H; Meijers, Joost C M; Schultz, Marcus J; Broze, George J; van der Poll, Tom
Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia. Coagulation and inflammation interact in the host response to infection. Tissue factor pathway inhibitor (TFPI) is a natural anticoagulant protein that inhibits tissue factor (TF), the main activator of inflammation-induced coagulation. It was the objective of this study to investigate the effect of endogenous TFPI levels on coagulation, inflammation and bacterial growth during S. pneumoniae pneumonia in mice. The effect of low endogenous TFPI levels was studied by administration of a neutralising anti-TFPI antibody to wild-type mice, and by using genetically modified mice expressing low levels of TFPI, due to a genetic deletion of the first Kunitz domain of TFPI (TFPIK1(-/-)) rescued with a human TFPI transgene. Pneumonia was induced by intranasal inoculation with S. pneumoniae and samples were obtained at 6, 24 and 48 hours after infection. Anti-TFPI reduced TFPI activity by ~50 %. Homozygous lowTFPI mice and heterozygous controls had ~10 % and ~50 % of normal TFPI activity, respectively. TFPI levels did not influence bacterial growth or dissemination. Whereas lung pathology was unaffected in all groups, mice with ~10 % (but not with ~50 %) of TFPI levels displayed elevated lung cytokine and chemokine concentrations 24 hours after infection. None of the groups with low TFPI levels showed an altered procoagulant response in lungs or plasma during pneumonia. These data argue against an important role for endogenous TFPI in the antibacterial, inflammatory and procoagulant response during pneumococcal pneumonia.
García-Suárez, María del Mar; Flórez, Noelia; Astudillo, Aurora; Vázquez, Fernando; Villaverde, Roberto; Fabrizio, Kevin; Pirofski, Liise-Anne; Méndez, Francisco J
Background Intranasal inoculation of Streptococcus pneumoniae D39 serotype 2 causes fatal pneumonia in mice. The cytotoxic and inflammatory properties of pneumolysin (PLY) have been implicated in the pathogenesis of pneumococcal pneumonia. Methods To examine the role of PLY in this experimental model we performed ELISA assays for PLY quantification. The distribution patterns of PLY and apoptosis were established by immunohistochemical detection of PLY, caspase-9 activity and TUNEL assay on tissue sections from mice lungs at various times, and the results were quantified with image analysis. Inflammatory and apoptotic cells were also quantified on lung tissue sections from antibody treated mice. Results In bronchoalveolar lavages (BAL), total PLY was found at sublytic concentrations which were located in alveolar macrophages and leukocytes. The bronchoalveolar epithelium was PLY-positive, while the vascular endothelium was not PLY reactive. The pattern and extension of cellular apoptosis was similar. Anti-PLY antibody treatment decreased the lung damage and the number of apoptotic and inflammatory cells in lung tissues. Conclusion The data strongly suggest that in vivo lung injury could be due to the pro-apoptotic and pro-inflammatory activity of PLY, rather than its cytotoxic activity. PLY at sublytic concentrations induces lethal inflammation in lung tissues and is involved in host cell apoptosis, whose effects are important to pathogen survival. PMID:17257395
Al-Bayati, Firas A. Y.; Kahya, Hasan F. H.; Damianou, Andreas; Shafeeq, Sulman; Kuipers, Oscar P.; Andrew, Peter W.; Yesilkaya, Hasan
Catabolism of galactose by Streptococcus pneumoniae alters the microbe’s metabolism from homolactic to mixed acid fermentation, and this shift is linked to the microbe’s virulence. However, the genetic basis of this switch is unknown. Pyruvate formate lyase (PFL) is a crucial enzyme for mixed acid fermentation. Functional PFL requires the activities of two enzymes: pyruvate formate lyase activating enzyme (coded by pflA) and pyruvate formate lyase (coded by pflB). To understand the genetic basis of mixed acid fermentation, transcriptional regulation of pflA and pflB was studied. By microarray analysis of ΔpflB, differential regulation of several transcriptional regulators were identified, and CcpA, and GlnR’s role in active PFL synthesis was studied in detail as these regulators directly interact with the putative promoters of both pflA and pflB, their mutation attenuated pneumococcal growth, and their expression was induced on host-derived sugars, indicating that these regulators have a role in sugar metabolism, and multiple regulators are involved in active PFL synthesis. We also found that the influence of each regulator on pflA and pflB expression was distinct in terms of activation and repression, and environmental condition. These results show that active PFL synthesis is finely tuned, and feed-back inhibition and activation are involved. PMID:28240278
Mostowy, Rafal; Croucher, Nicholas J; Hanage, William P; Harris, Simon R; Bentley, Stephen; Fraser, Christophe
The bacterium Streptococcus pneumoniae (pneumococcus) is one of the most important human bacterial pathogens, and a leading cause of morbidity and mortality worldwide. The pneumococcus is also known for undergoing extensive homologous recombination via transformation with exogenous DNA. It has been shown that recombination has a major impact on the evolution of the pathogen, including acquisition of antibiotic resistance and serotype-switching. Nevertheless, the mechanism and the rates of recombination in an epidemiological context remain poorly understood. Here, we proposed several mathematical models to describe the rate and size of recombination in the evolutionary history of two very distinct pneumococcal lineages, PMEN1 and CC180. We found that, in both lineages, the process of homologous recombination was best described by a heterogeneous model of recombination with single, short, frequent replacements, which we call micro-recombinations, and rarer, multi-fragment, saltational replacements, which we call macro-recombinations. Macro-recombination was associated with major phenotypic changes, including serotype-switching events, and thus was a major driver of the diversification of the pathogen. We critically evaluate biological and epidemiological processes that could give rise to the micro-recombination and macro-recombination processes.
Täuber, M. G.; Kennedy, S. L.; Tureen, J. H.; Lowenstein, D. H.
We examined whether experimental pneumococcal meningitis induced the 72-kd heat shock protein (HSP72), a sensitive marker of neuronal stress in other models of central nervous system (CNS) injury. Brain injury was characterized by vasculitis, cerebritis, and abscess formation in the cortex of infected animals. The extent of these changes correlated with the size of the inoculum (P less than 0.003) and with pathophysiologic parameters of disease severity, i.e., cerebrospinal fluid (CSF) lactate (r = 0.61, P less than 0.0001) and CSF glucose concentrations (r = -0.55, P less than 0.0001). Despite the presence of numerous cortical regions having morphologic evidence of injury, HSP72 was not detected in most animals. When present, only rare neurons were HSP72 positive. Western blot analysis of brain samples confirmed the paucity of HSP72 induction. The lack of neuronal HSP72 expression in this model suggests that at least some of the events leading to neuronal injury in meningitis are unique, when compared with CNS diseases associated with HSP72 induction. Images Figure 1 Figure 2 Figure 3 PMID:1632471
Hammerschmidt, S; Bethe, G; Remane, P H; Chhatwal, G S
Lactoferrin (Lf), an iron-sequestering glycoprotein, predominates in mucosal secretions, where the level of free extracellular iron (10(-18) M) is not sufficient for bacterial growth. This represents a mechanism of resistance to bacterial infections by prevention of colonization of the host by pathogens. In this study we were able to show that Streptococcus pneumoniae specifically recognizes and binds the iron carrier protein human Lf (hLf). Pretreatment of pneumococci with proteases reduced hLf binding significantly, indicating that the hLf receptor is proteinaceous. Binding assays performed with 63 clinical isolates belonging to different serotypes showed that 88% of the tested isolates interacted with hLf. Scatchard analysis showed the existence of two hLf-binding proteins with dissociation constants of 5.7 x 10(-8) and 2.74 x 10(-7) M. The receptors were purified by affinity chromatography, and internal sequence analysis revealed that one of the S. pneumoniae proteins was homologous to pneumococcal surface protein A (PspA). The function of PspA as an hLf-binding protein was confirmed by the ability of purified PspA to bind hLf and to competitively inhibit hLf binding to pneumococci. S. pneumoniae may use the hLf-PspA interaction to overcome the iron limitation at mucosal surfaces, and this might represent a potential virulence mechanism.
Pearson, Amber L; Kingham, Simon; Mitchell, Peter; Apparicio, Philippe
The etiology of pneumococcal pneumonia (PP) is well-known. Yet, some events may increase its incidence. Natural disasters may worsen air quality, a risk factor for PP. We investigated spatial/spatio-temporal clustering of PP pre- and post-earthquakes in Christchurch, New Zealand. The earthquakes resulted in deaths, widespread damage and liquefaction ejecta (a source of air-borne dust). We tested for clusters and associations with ejecta, using 97 cases (diagnosed 10/2008-12/2011), adjusted for age and area-level deprivation. The strongest evidence to support the potential role of ejecta in clusters of PP cases was the: (1) geographic shift in the spatio-temporal cluster after deprivation adjustment to match the post-earthquake clusters and; (2) increased relative risk in the fully-adjusted post-earthquake compared to the pre-earthquake cluster. The application of spatial statistics to study PP and ejecta are novel. Further studies to assess the long-term impacts of ejecta inhalation are recommended particularly in Christchurch, where seismic activity continues.
West, Devin M; McCauley, Lindsay M; Sorensen, Jeffrey S; Jephson, Al R; Dean, Nathan C
The pneumocococcal urine antigen test increases specific microbiological diagnosis over conventional culture methods in pneumonia patients. Data are limited regarding its yield and effect on antibiotic prescribing among patients with community-onset pneumonia in clinical practice. We performed a secondary analysis of 2837 emergency department patients admitted to seven Utah hospitals over 2 years with international diagnostic codes version 9 codes and radiographic evidence of pneumonia. Mean age was 64.2 years, 47.2% were male and all-cause 30-day mortality was 9.6%. Urinary antigen testing was performed in 1110 (39%) patients yielding 134 (12%) positives. Intensive care unit patients were more likely to undergo testing, and have a positive result (15% versus 8.8% for ward patients; p<0.01). Patients with risk factors for healthcare-associated pneumonia had fewer urinary antigen tests performed, but 8.4% were positive. Physicians changed to targeted antibiotic therapy in 20 (15%) patients, de-escalated antibiotic therapy in 76 patients (57%). In 38 (28%) patients, antibiotics were not changed. Only one patient changed to targeted therapy suffered clinical relapse. Length of stay and mortality were lower in patients receiving targeted therapy. Pneumococcal urinary antigen testing is an inexpensive, noninvasive test that favourably influenced antibiotic prescribing in a "real world", multi-hospital observational study.
West, Devin M.; McCauley, Lindsay M.; Sorensen, Jeffrey S.; Jephson, Al R.
The pneumocococcal urine antigen test increases specific microbiological diagnosis over conventional culture methods in pneumonia patients. Data are limited regarding its yield and effect on antibiotic prescribing among patients with community-onset pneumonia in clinical practice. We performed a secondary analysis of 2837 emergency department patients admitted to seven Utah hospitals over 2 years with international diagnostic codes version 9 codes and radiographic evidence of pneumonia. Mean age was 64.2 years, 47.2% were male and all-cause 30-day mortality was 9.6%. Urinary antigen testing was performed in 1110 (39%) patients yielding 134 (12%) positives. Intensive care unit patients were more likely to undergo testing, and have a positive result (15% versus 8.8% for ward patients; p<0.01). Patients with risk factors for healthcare-associated pneumonia had fewer urinary antigen tests performed, but 8.4% were positive. Physicians changed to targeted antibiotic therapy in 20 (15%) patients, de-escalated antibiotic therapy in 76 patients (57%). In 38 (28%) patients, antibiotics were not changed. Only one patient changed to targeted therapy suffered clinical relapse. Length of stay and mortality were lower in patients receiving targeted therapy. Pneumococcal urinary antigen testing is an inexpensive, noninvasive test that favourably influenced antibiotic prescribing in a “real world”, multi-hospital observational study. PMID:28053969
Mouneimne, H; Juvin, M; Beretti, J L; Azoulay-Dupuis, E; Vallee, E; Geslin, P; Petitpretz, P; Berche, P; Gaillard, J L
To detect new antigen candidates for serological tests, we studied the antibody response to pneumococcal protein antigens in mice infected intratracheally with various Streptococcus pneumoniae strains. Sera were tested by Western blotting against whole-cell protein extracts. Mice developed a detectable immunoglobulin G-type response against a small number of polypeptides. The antibody response was strain dependent: sera from individuals infected with the same strain gave similar banding patterns on immunoblots. The banding patterns varied with the strain used for infection. However, a band at 36 to 38 kDa was recognized by all reactive sera. This band appeared to correspond to a polypeptide that was antigenically well conserved among the different S. pneumoniae serotypes. An antibody response to this antigen developed in mice irrespective of the capsular type, the virulence, and the susceptibility to penicillin G of the infecting strain. Thus, this 36- to 38-kDa protein antigen may be of value for the development of a serological test for humans. PMID:9384307
Goldblatt, David; Ramakrishnan, Meena; O'Brien, Katherine
An international consultation was convened in March 2012 to provide feedback on the Case for Carriage, a summary statement by the Pneumococcal Carriage Consortium (PneumoCarr) proposing nasopharyngeal (NP) colonization as a supplementary or alternative endpoint in vaccine licensure. PneumoCarr members provided information to vaccine manufacturers, regulators and the WHO on the evidence for NP carriage as a precursor to pneumococcal disease, standardization of laboratory methods for the detection of multiple serotype carriage, definition and estimation of pneumococcal vaccine efficacy against carriage (VE-col), and the direct and indirect impact of vaccination on carriage. Manufacturers and regulators had the opportunity to respond to the information compiled by PneumoCarr and share their perspectives. VE-col as a licensure endpoint may be more useful for the next generation pneumococcal vaccine products, particularly those for which the immunological correlate of protection is not established, whereas it may be less needed for pneumococcal conjugate vaccines which have an established licensure pathway. The consultation supported the importance of NP carriage data as a critical element linking vaccine impact on the individual direct risk of disease to the population-level impact: indirect effects such as herd protection and serotype replacement. The indirect effects of vaccination, however, are not currently established as part of the licensure process and to include them would be a paradigm shift for regulatory agencies who currently consider this information in the post-licensure setting. More discussion and consensus-building is needed around the rationale and optimal mechanism to include carriage data in the licensure pathway for new pneumococcal vaccines. The WHO and national advisory groups on immunization policy may have an important role in considering the evidence for the indirect benefit of vaccination as informed by its impact on NP carriage.
Muema, D M; Nduati, E W; Uyoga, M; Bashraheil, M; Scott, J A G; Hammitt, L L; Urban, B C
Memory B cells are long-lived and could contribute to persistence of humoral immunity by maintaining the plasma-cell pool or making recall responses upon re-exposure to an antigen. We determined the ability of a pneumococcal conjugate vaccine to induce anti-pneumococcal memory B cells. Frequencies of memory B cells against pneumococcal capsular polysaccharides from serotypes 1, 6B, 14, 19F and 23F were determined by cultured B cell enzyme-linked immunospot (ELISPOT) in 35 children aged 12-23 months who received pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV). The relationships between plasma antibodies and memory B cell frequencies were also assessed. After two doses of PHiD-CV, the proportion of subjects with detectable memory B cells against pneumococcal capsular polysaccharides increased significantly for serotypes 1 (3-45%; P < 0·01), 19F (21-66%; P < 0·01) and 23F (13-36%; P = 0·02), but not serotypes 6B (24-42%; P = 0·24) and 14 (21-40%; P = 0·06). Correlations between antibodies and memory B cells were weak. Carriage of serotype 19F at enrolment was associated with poor memory B cell responses against this serotype at subsequent time-points (day 30: non-carriers, 82% versus carriers, 0%, P < 0·01; day 210: non-carriers, 72% versus carriers, 33%, P = 0·07). PHiD-CV is capable of inducing memory B cells against some of the component pneumococcal capsular polysaccharides.
Johansson, Kjell Arne; Memirie, Solomon Tessema; Pecenka, Clint; Jamison, Dean T.; Verguet, Stéphane
Background Pneumonia and pneumococcal disease cause a large disease burden in resource-constrained settings. We pursue an extended cost-effectiveness analysis (ECEA) of two fully publicly financed interventions in Ethiopia: pneumococcal vaccination for newborns and pneumonia treatment for under-five children in Ethiopia. Methods We apply ECEA methods and estimate the program impact on: (1) government program costs; (2) pneumonia and pneumococcal deaths averted; (3) household expenses related to pneumonia/pneumococcal disease treatment averted; (4) prevention of household medical impoverishment measured by an imputed money-metric value of financial risk protection; and (5) distributional consequences across the wealth strata of the country population. Available epidemiological and cost data from Ethiopia are applied and the two interventions are assessed separately at various incremental coverage levels. Results Scaling-up pneumococcal vaccines at around 40% coverage would cost about $11.5 million and avert about 2090 child deaths annually, while a 10% increase of pneumonia treatment to all children under 5 years of age would cost about $13.9 million and avert 2610 deaths annually. Health benefits of the two interventions publicly financed would be concentrated among the bottom income quintile, where 30–40% of all deaths averted would be expected to occur in the poorest quintile. In sum, the two interventions would eliminate a total of $2.4 million of private household expenditures annually, where the richest quintile benefits from around 30% of the total private expenditures averted. The financial risk protection benefits would be largely concentrated among the bottom income quintile. The results are most sensitive to variations in vaccine price, population size, number of deaths due to pneumonia, efficacy of interventions and out-of-pocket copayment share. Conclusions Vaccine and treatment interventions for children, as shown with the illustrative examples of
Steinbakk, Martin; Aaberge, Ingeborg S.; Caugant, Dominique A.
Serotype replacement in invasive pneumococcal disease has been observed after widespread use of the 7-valent pneumococcal conjugate vaccine (PCV7). Replacement is dominated by penicillin-nonsusceptible serotype 19A in several countries. Antibiotic selection pressure has been proposed to interact with immunization, leading to rapid replacement. In Norway, where prescription of antibiotics is limited, post-PCV7 replacement by serotype 19A is dominated by penicillin-susceptible clones. Hence, serotype 19A replacement occurs, although it is not driven by antibiotic selection pressure. PMID:22237889
Tseng, Hung Fu; Smith, Ning; Sy, Lina S; Jacobsen, Steven J
In 2009, a revision to the zoster vaccine package insert was approved stating that the zoster vaccine and the pneumococcal vaccine should not be given concurrently because concomitant use resulted in reduced immunogenicity of the zoster vaccine. We conducted an observational study to evaluate if concomitant vaccination reduces the protective effect of the zoster vaccine. The study was conducted in Kaiser Permanente Southern California. Incidence of herpes zoster (HZ) after vaccination with a zoster vaccine in the population receiving both vaccines on the same day was compared to that in the population receiving a pneumococcal vaccine within one year to 30 days prior to zoster vaccine. Vaccinations and incident HZ cases were identified by electronic health records. The hazard ratio for incident HZ associated with concomitant vs. nonconcomitant vaccination was estimated using the Cox proportional hazard model. There were 56 incident HZ cases in the concomitant vaccination cohort and 58 in the nonconcomitant vaccination cohort, yielding a HZ incidence of 4.54 (95% confidence interval [CI], 3.43-5.89) and 4.51 (95% CI, 3.42-5.83) per 1000 person-years, respectively. The hazard ratio comparing the incidence rate of HZ in the two cohorts was 1.19 (95% CI, 0.81-1.74) in the adjusted analysis. In this study, we found no evidence of an increased risk of HZ in the population receiving zoster vaccine and pneumococcal vaccine concomitantly. The revision of the product information needs to be carefully assessed to avoid introducing barriers to patients and providers who are interested in these two important vaccines.
Sury, Matthias D; Vorlet-Fawer, Lorianne; Agarinis, Claudia; Yousefi, Shida; Grandgirard, Denis; Leib, Stephen L; Christen, Stephan
Pneumococcal meningitis causes apoptosis of developing neurons in the dentate gyrus of the hippocampus. The death of these cells is accompanied with long-term learning and memory deficits in meningitis survivors. Here, we studied the role of the PI3K/Akt (protein kinase B) survival pathway in hippocampal apoptosis in a well-characterized infant rat model of pneumococcal meningitis. Meningitis was accompanied by a significant decrease of the PI3K product phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) and of phosphorylated (i.e., activated) Akt in the hippocampus. At the cellular level, phosphorylated Akt was decreased in both the granular layer and the subgranular zone of the dentate gyrus, the region where the developing neurons undergo apoptosis. Protein levels and activity of PTEN, the major antagonist of PI3K, were unaltered by infection, suggesting that the observed decrease in PIP(3) and Akt phosphorylation is a result of decreased PI3K signaling. Treatment with the PTEN inhibitor bpV(pic) restored Akt activity and significantly attenuated hippocampal apoptosis. Co-treatment with the specific PI3K inhibitor LY294002 reversed the restoration of Akt activity and attenuation of hippocampal apoptosis, while it had no significant effect on these parameters on its own. These results indicate that the inhibitory effect of bpV(pic) on apoptosis was mediated by PI3K-dependent activation of Akt, strongly suggesting that bpV(pic) acted on PTEN. Treatment with bpV(pic) also partially inhibited the concentration of bacteria and cytokines in the CSF, but this effect was not reversed by LY294002, indicating that the effect of bpV(pic) on apoptosis was independent of its effect on CSF bacterial burden and cytokine levels. These results indicate that the PI3K/Akt pathway plays an important role in the death and survival of developing hippocampal neurons during the acute phase of pneumococcal meningitis.
Sugino, Hirotoshi; Tsumura, Shigeru; Kunimoto, Masaru; Noda, Masuhiro; Chikuie, Daisuke; Noda, Chieko; Yamashita, Mariko; Watanabe, Hiroshi; Ishii, Hidemasa; Tashiro, Toru; Iwata, Kazuhiro; Kono, Takashi; Tsumura, Kaoru; Sumiya, Takahiro; Takeno, Sachio; Hirakawa, Katsuhiro
The Japanese guidelines for acute otitis media in children recommend classifying acute otitis media by age, manifestations and local findings, and also recommend myringotomy for moderate-grade cases with severe local findings, severe-grade cases, and treatment-resistant cases. The heptavalent pneumococcal conjugate vaccine was released in Japan in February 2010. In Hiroshima City, public funding allowing free inoculation with this vaccine was initiated from January 2011, and the number of vaccinated individuals has since increased dramatically. This study investigated changes in the number of myringotomies performed to treat acute otitis media during the 5-year period from January 2008 to December 2012 at two hospitals and five clinics in the Asa Area of Hiroshima City, Japan. A total of 3,165 myringotomies for acute otitis media were performed. The rate of procedures per child-year performed in <5-year-old children decreased by 29.1% in 2011 and by 25.2% in 2012 compared to the mean rate performed in the 3 years prior to the introduction of public funding. A total of 895 myringotomies were performed for 1-year-old infants. The rate of myringotomies per child-year performed for acute otitis media in 1-year-old infants decreased significantly in the 2 years after the introduction of public funding for heptavalent pneumococcal conjugate vaccine compared to all years before introduction (p<0.000001). Our results suggest a benefit of heptavalent pneumococcal conjugate vaccine for acute otitis media in reducing the financial burden of myringotomy. In addition, this vaccine may help prevent acute otitis media with severe middle ear inflammation in 1-year-old infants.
Lai, Zengzu; Schreiber, John R
Bacterial polysaccharides (PS) are T cell-independent antigens that do not induce immunologic memory and are poor immunogens in infants. Conjugate vaccines in which the PS is covalently linked to a carrier protein have enhanced immunogenicity that resembles that of T cell-dependent antigens. The Haemophilus influenzae type b (Hib) conjugate vaccine, which uses the outer membrane protein complex (OMPC) from meningococcus as a carrier protein, elicits protective levels of anti-capsular PS antibody (Ab) after a single dose, in contrast to other conjugate vaccines, which require multiple doses. We have previously shown that OMPC robustly engages Toll-like receptor 2 (TLR2) and enhances the early anti-Hib PS Ab titer associated with an increase in TLR2-mediated induction of cytokines. We now show that the addition of OMPC to the 7-valent pneumococcal PS-CRM₁₉₇ conjugate vaccine during immunization significantly increases the anti-PS IgG and IgM responses to most serotypes of pneumococcus contained in the vaccine. The addition of OMPC also increased the likelihood of anti-PS IgG3 production against serotypes 4, 6B, 9V, 18C, 19F, and 23F. Splenocytes from mice who had received OMPC with the pneumococcal conjugate vaccine produced significantly more interleukin-2 (IL-2), IL-4, IL-6, IL-10, tumor necrosis factor alpha (TNF-α), and gamma interferon (IFN-γ) than splenocytes from mice who received phosphate-buffered saline (PBS) plus the conjugate vaccine. We conclude that OMPC enhances the anti-PS Ab response to pneumococcal PS-CRM₁₉₇ conjugate vaccine, an effect associated with a distinct change in cytokine profile. It may be possible to reduce the number of conjugate vaccine doses required to achieve protective Ab levels by priming with adjuvants that are TLR2 ligands.
Beadsworth, Mike B J; Wooton, Dan; Chenzbraun, Adrian; Beeching, Nick J
We describe the first reported case of Austrian's syndrome in an injecting drug user (IDU). The triad of endocarditis, meningitis and pneumonia caused by invasive pneumococcal disease (IPD) is most commonly associated with excess alcohol. Injecting drug use is a recognised risk factor for IPD, whose prevalence and resistance continue to rise. We propose that injecting drug use is associated with Austrian's syndrome and that it should at least be considered in 'at risk' groups presenting with IPD. Furthermore, IDU presenting with IPD, meningitis and pneumonia should be considered for echocardiography.
Liechti, Fabian D.; Grandgirard, Denis; Leppert, David
Pneumococcal meningitis (PM) results in high mortality rates and long-lasting neurological deficits. Hippocampal apoptosis and cortical necrosis are histopathological correlates of neurofunctional sequelae in rodent models and are frequently observed in autopsy studies of patients who die of PM. In experimental PM, inhibition of matrix metalloproteinases (MMPs) and/or tumor necrosis factor (TNF)-converting enzyme (TACE) has been shown to reduce brain injury and the associated impairment of neurocognitive function. However, none of the compounds evaluated in these studies entered clinical development. Here, we evaluated two second-generation MMP and TACE inhibitors with higher selectivity and improved oral availability. Ro 32-3555 (Trocade, cipemastat) preferentially inhibits collagenases (MMP-1, -8, and -13) and gelatinase B (MMP-9), while Ro 32-7315 is an efficient inhibitor of TACE. PM was induced in infant rats by the intracisternal injection of live Streptococcus pneumoniae. Ro 32-3555 and Ro 32-7315 were injected intraperitoneally, starting at 3 h postinfection. Antibiotic (ceftriaxone) therapy was initiated at 18 h postinfection, and clinical parameters (weight, clinical score, mortality rate) were recorded. Myeloperoxidase activities, concentrations of cytokines and chemokines, concentrations of MMP-2 and MMP-9, and collagen concentrations were measured in the cerebrospinal fluid. Animals were sacrificed at 42 h postinfection, and their brains were assessed by histomorphometry for hippocampal apoptosis and cortical necrosis. Both compounds, while exhibiting disparate MMP and TACE inhibitory profiles, decreased hippocampal apoptosis and cortical injury. Ro 32-3555 reduced mortality rates and cerebrospinal fluid TNF, interleukin-1β (IL-1β) and collagen levels, while Ro 32-7315 reduced weight loss and cerebrospinal fluid TNF and IL-6 levels. PMID:24491581
Veber, B; Vallée, E; Desmonts, J M; Pocidalo, J J; Azoulay-Dupuis, E
The correlation between the pharmacokinetics of erythromycin, roxithromycin, clarithromycin, spiramycin and azithromycin and their efficacy was investigated in two pneumococcal pneumonia models. Female Swiss and C57B1/6 mice were infected with Streptococcus pneumoniae strain P4241 by the intratracheal per oral route. This virulent strain produces acute pneumonia with death within 3-4 days (Swiss mice), or subacute pneumonia with death within 10 days (C57B1/6 mice) in untreated mice and the outcome of the disease is closely related to progressive weight loss. Swiss mice received three doses of each macrolide 50 mg/kg bd beginning 18 h post-infection. C57B1/6 mice received three doses of each macrolide 25 mg/kg, bd (except azithromycin was 12.5 mg/kg bd) beginning 48 h post-infection. Cure rates were evaluated on the basis of body weight variations recorded daily after the end of treatment. Pharmacokinetic parameters were determined in infected and non-infected mice after a single dose of each macrolide 50 mg/kg sc. The pharmacokinetics of azithromycin was also determined in leucopenic Swiss mice. We observed a hierarchy of in-vivo efficacy as follows: azithromycin > spiramycin = clarithromycin > roxithromycin = erythromycin which did not correlate with in-vitro MIC or MBC. The same hierarchy was found in terms of the lung T1/2. Lung T1/2s of macrolides could thus be predictive of their efficacy in respiratory tract infections. A reduced tissue AUC of azithromycin was seen in leucopenic mice suggesting leucocytes may help transport macrolides to sites of infection.
Fliegauf, Manfred; Sonnen, Andreas F-P; Kremer, Bernhard; Henneke, Philipp
Mucociliary airway clearance is an innate defense mechanism that protects the lung from harmful effects of inhaled pathogens. In order to escape mechanical clearance, airway pathogens including Streptococcus pneumoniae (pneumococcus) are thought to inactivate mucociliary clearance by mechanisms such as slowing of ciliary beating and lytic damage of epithelial cells. Pore-forming toxins like pneumolysin, may be instrumental in these processes. In a murine in vitro airway infection model using tracheal epithelial cells grown in air-liquid interface cultures, we investigated the functional consequences on the ciliated respiratory epithelium when the first contact with pneumococci is established. High-speed video microscopy and live-cell imaging showed that the apical infection with both wildtype and pneumolysin-deficient pneumococci caused insufficient fluid flow along the epithelial surface and loss of efficient clearance, whereas ciliary beat frequency remained within the normal range. Three-dimensional confocal microscopy demonstrated that pneumococci caused specific morphologic aberrations of two key elements in the F-actin cytoskeleton: the junctional F-actin at the apical cortex of the lateral cell borders and the apical F-actin, localized within the planes of the apical cell sides at the ciliary bases. The lesions affected the columnar shape of the polarized respiratory epithelial cells. In addition, the planar architecture of the entire ciliated respiratory epithelium was irregularly distorted. Our observations indicate that the mechanical supports essential for both effective cilia strokes and stability of the epithelial barrier were weakened. We provide a new model, where--in pneumococcal infection--persistent ciliary beating generates turbulent fluid flow at non-planar distorted epithelial surface areas, which enables pneumococci to resist mechanical cilia-mediated clearance.
Fabrizio, Kevin; Manix, Catherine; Tian, Haijun; van Rooijen, Nico; Pirofski, Liise-anne
The efficacy of antibody immunity against Streptococcus pneumoniae stems from the ability of opsonic, serotype (ST)-specific antibodies to pneumococcal capsular polysaccharide (PPS) to facilitate killing of the homologous ST by host phagocytes. However, PPS-specific antibodies have been identified that are protective in mice, but do not promote opsonic killing in vitro, raising the question of how they mediate protection in vivo. To probe this question, we investigated the dependence of antibody efficacy against lethal systemic (intraperitoneal, i.p.) infection with Streptococcus pneumoniae serotype 3 (ST3) on macrophages and neutrophils for the following PPS3-specific monoclonal antibodies (MAbs) in survival experiments in mice using a non-opsonic human IgM (A7), a non-opsonic mouse IgG1 (1E2) and an opsonic mouse IgG1 (5F6). The survival of A7- and PPS3-specific and isotype control MAb-treated neutrophil-depleted and neutrophil-sufficient and macrophage-depleted and macrophage-sufficient mice were determined after i.p. challenge with ST3 strains 6303 and WU2. Neutrophils were dispensable for A7 and the mouse MAbs to mediate protection in this model, but macrophages were required for the efficacy of A7 and optimal mouse MAb-mediated protection. For A7-treated mice, macrophage-depleted mice had higher blood CFU, cytokines and peripheral neutrophil levels than macrophage-sufficient mice, and macrophage-sufficient mice had lower tissue bacterial burdens than control MAb-treated mice. These findings demonstrate that macrophages contribute to opsonic and non-opsonic PPS3-specific MAb-mediated protection against ST3 infection by enhancing bacterial clearance and suggest that neutrophils do not compensate for the absence of macrophages in the model used in this study.
García-Suárez, María del Mar; Cima-Cabal, María Dolores; Flórez, Noelia; García, Pilar; Cernuda-Cernuda, Rafael; Astudillo, Aurora; Vázquez, Fernando; De los Toyos, Juan R; Méndez, F Javier
Pneumolysin (PLY) is an important virulence factor of Streptococcus pneumoniae. We examined the ability of three murine monoclonal antibodies (MAbs) to PLY (PLY-4, PLY-5, and PLY-7) to affect the course of pneumococcal pneumonia in mice. The intravenous administration of antibodies PLY-4 and PLY-7 protected the mice from the lethal effect of the purified toxin. Mice treated with PLY-4 before intranasal inoculation of S. pneumoniae type 2 survived longer (median survival time, 100 h) than did untreated animals (median survival time, 60 h) (P < 0.0001). The median survival time for mice treated with a combination of PLY-4 and PLY-7 was 130 h, significantly longer than that for mice given isotype-matched indifferent MAbs (P = 0.0288) or nontreated mice (P = 0.0002). The median survival time for mice treated with a combination of three MAbs was significantly longer (>480 h) than that for mice treated with PLY-5 (48 h; P < 0.0001), PLY-7 (78 h; P = 0.0007), or PLY-4 (100 h; P = 0.0443) alone. Similarly, the survival rate for mice treated with three MAbs (10 of 20 mice) was significantly higher than the survival rate obtained with PLY-5 (1 of 20; P = 0.0033), PLY-4 (2 of 20; P = 0.0138), or PLY-7 (3 of 20; P = 0.0407) alone. These results suggest that anti-PLY MAbs act with a synergistic effect. Furthermore, MAb administration was associated with a significant decrease in bacterial lung colonization and lower frequencies of bacteremia and tissue injury with respect to the results for the control groups.
Dowling, David J.; van Haren, Simon D.; Scheid, Annette; Bergelson, Ilana; Kim, Dhohyung; Mancuso, Christy J.; Foppen, Willemina; Fresh, Lynn; Theriot, Terese B.; Lackner, Andrew A.; Fichorova, Raina N.; Smirnov, Dmitri; Vasilakos, John P.; Beaurline, Joe M.; Tomai, Mark A.; Midkiff, Cecily C.; Alvarez, Xavier; Blanchard, James L.; Gilbert, Margaret H.; Aye, Pyone Pyone
Infection is the most common cause of mortality in early life, and immunization is the most promising biomedical intervention to reduce this burden. However, newborns fail to respond optimally to most vaccines. Adjuvantation is a key approach to enhancing vaccine immunogenicity, but responses of human newborn leukocytes to most candidate adjuvants, including most TLR agonists, are functionally distinct. Herein, we demonstrate that 3M-052 is a locally acting lipidated imidazoquinoline TLR7/8 agonist adjuvant in mice, which, when properly formulated, can induce robust Th1 cytokine production by human newborn leukocytes in vitro, both alone and in synergy with the alum-adjuvanted pneumococcal conjugate vaccine 13 (PCV13). When admixed with PCV13 and administered i.m. on the first day of life to rhesus macaques, 3M-052 dramatically enhanced generation of Th1 CRM-197–specific neonatal CD4+ cells, activation of newborn and infant Streptococcus pneumoniae polysaccharide–specific (PnPS-specific) B cells as well as serotype-specific antibody titers, and opsonophagocytic killing. Remarkably, a single dose at birth of PCV13 plus 0.1 mg/kg 3M-052 induced PnPS-specific IgG responses that were approximately 10–100 times greater than a single birth dose of PCV13 alone, rapidly exceeding the serologic correlate of protection, as early as 28 days of life. This potent immunization strategy, potentially effective with one birth dose, could represent a new paradigm in early life vaccine development. PMID:28352660
Niedermeier, Katharina; Braun, Susanne; Fauser, Claudius; Straubinger, Reinhard K; Stark, Thomas
In 2002 an increased number of cochlear implant related meningitis cases was reported by the U. S. Food and Drug Administration (FDA). The most commonly identified causative agent was Streptococcus pneumoniae. Although most cases of meningitis were related to a special electrode design, the risk for post-operative pneumococcal meningitis might nonetheless be enhanced by opening of the cochlea during implantation. In the present study, a threshold model for middle ear inoculation of S. pneumoniae was established in the guinea pig after cochlear implantation to assess the post-operative risk of meningitis. Guinea pigs were implanted unilaterally with a silicone cochlear implant electrode dummy. Five weeks after implantation, animals were challenged via the middle ear with a clinically relevant strain of S. pneumoniae and monitored over a period of five days for signs of meningitis. Meningitis was confirmed by clinical outcome in the animals, histological investigation of brains, as well as by pleocytosis and presence of bacteria in cerebrospinal fluid (CSF). By inoculation of varying numbers of bacteria (between 1 × 10(4) and 1 × 10(9) CFU/ml in 10 μl), a threshold model was established. The attack rate, pattern and onset of meningitis depended on number of inoculated bacteria. An increased meningitis rate in different experimental groups shows that greater bacterial burden leads to an increased attack rate after intratympanal inoculation. The established animal model provides a potential tool to assess the meningitis risk after cochlear implantation. Its implementation in future studies will allow the investigation of existing and newly developed prostheses for postoperatively infection risk.
Grenón, Sandra L; Salvi Grabulosa, Marcelo C; Regueira, Mabel M; Fossati, María S; von Specht, Martha H
We report the results of pneumococcal meningitis surveillance conducted at the Provincial Pediatric Hospital of Posadas, Misiones (Argentina), before the conjugate vaccine was introduced into the national vaccination schedule. Between January 1994 and December 2009, 167 cases of Streptococcus pneumoniae meningitis were diagnosed in children aged 1 month to 15 years. The attack rate/100,000 children ranged from 19.2 (1997) to 4.3 (2009), with a mean of 10.6 and a tendency to decrease (y=-0.689x+16.52). The number of cases per 100,000 children decreased from 146.6 to 34.8 and particularly involved the group of children aged 1 to 11 months (94/167, 56%). Thirty point seven percent (30.7%) (46/150) of the isolates were resistant to penicillin whereas 16.7% (25/150) were non-susceptible to cefotaxime. β-lactam resistance increased as from 1997 and began to decline in 2005. Nineteen serotypes were detected; type 14 was predominant and accounted for 32% (40/125). Eighty four point eight percent (84.8%) of the isolates were circumscribed to nine serotypes: 14, 5, 1, 7F, 18C, 6B, 9N, 9V and 4. Theoretical coverage for patients aged <2 years and >2 years was 84.1% (74/88) and 83.8% (31/37) for the 10-valent vaccine and 89.8 % (79/88) and 83.8% (31/37) for the 13-valent vaccine respectively. Penicillin resistance was restricted to 8 serotypes (14, 6B, 6A, 9V, 4, 23B, 19A1) and nonsusceptibility to cefotaxime was circumscribed to 3 serotypes (14, 9V and 1). This study will allow to evaluate the impact of the implementation of conjugate vaccines on our area.
Stolberg, Valerie R.; McCubbrey, Alexandra L.; Freeman, Christine M.; Brown, Jeanette P.; Crudgington, Sean W.; Taitano, Sophina H.; Saxton, Bridget L.; Mancuso, Peter; Curtis, Jeffrey L.
Inhaled corticosteroid(s) (ICS) increase community-acquired pneumonia (CAP) incidence in patients with chronic obstructive pulmonary disease (COPD) by unknown mechanisms. Apoptosis is increased in the lungs of COPD patients. Uptake of apoptotic cells (AC) (“efferocytosis”) by alveolar macrophages (AMø) reduces their ability to combat microbes, including Streptococcus pneumoniae, the most common cause of CAP in COPD patients. Having shown that ICS significantly increase AMø efferocytosis, we hypothesized that this process, termed glucocorticoid-augmented efferocytosis (GCAE), might explain the association of CAP with ICS therapy in COPD. To test this hypothesis, we studied the effects of fluticasone, AC or both on AMø of C57BL/6 mice in vitro and in an established model of pneumococcal pneumonia. Fluticasone plus AC significantly reduced TLR4-stimulated AMø IL-12 production, relative to either treatment alone, and decreased TNF-α, CCL3, CCL5 and KC, relative to AC. Mice treated with fluticasone plus AC before infection with viable pneumococci developed significantly more lung CFU at 48 h. However, none of the pretreatments altered inflammatory cell recruitment to the lungs at 48 h post-infection, and fluticasone plus AC less markedly reduced in vitro mediator production to heat-killed pneumococci. Fluticasone plus AC significantly reduced in vitro AMø killing of pneumococci, relative to other conditions, in part by delaying phagolysosome acidification without affecting production of reactive oxygen or nitrogen species. These results support GCAE as a potential explanation for the epidemiological association of ICS therapy of COPD patients with increased risk of CAP, and establish murine experimental models to dissect underlying molecular mechanisms. PMID:25987742
Saumyaa; Pujanauski, Lindsey; Colino, Jesus; Flora, Michael; Torres, Raul M; Tuomanen, Elaine; Snapper, Clifford M
Intact, inactivated Streptococcus pneumoniae [including the unencapsulated S. pneumoniae, serotype 2 strain (R36A)] markedly inhibits the humoral immune response to coimmunized heterologous proteins, a property not observed with several other intact Gram-positive or Gram-negative bacteria. In this study, we determined the nature of this immunosuppressive property. Because phosphorylcholine (PC), a major haptenic component of teichoic acid in the S. pneumoniae cell wall, and lipoteichoic acid in the S. pneumoniae membrane were previously reported to be immunosuppressive when derived from filarial parasites, we determined whether R36A lacking PC (R36A(pc-)) was inhibitory. Indeed, although R36A(pc-) exhibited a markedly reduced level of inhibition of the IgG response to coimmunized chicken OVA (cOVA), no inhibition was observed when using several other distinct PC-expressing bacteria or a soluble, protein-PC conjugate. Further, treatment of R36A with periodate, which selectively destroys PC residues, had no effect on R36A-mediated inhibition. Because R36A(pc-) also lacks choline-binding proteins (CBPs) that require PC for cell wall attachment, and because treatment of R36A with trypsin eliminated its inhibitory activity, we incubated R36A in choline chloride, which selectively strips CBPs from its surface. R36A lacking CBPs lost most of its inhibitory property, whereas the supernatant of choline chloride-treated R36A, containing CBPs, was markedly inhibitory. Coimmunization studies using cOVA and various S. pneumoniae mutants, each genetically deficient in one of the CBPs, demonstrated that only S. pneumoniae lacking the CBP pneumococcal surface protein A lost its ability to inhibit the IgG anti-cOVA response. These results strongly suggest that PspA plays a major role in mediating the immunosuppressive property of S. pneumoniae.
Madhi, Shabir A.; Koen, Anthonet; Jose, Lisa; van Niekerk, Nadia; Adrian, Peter V.; Cutland, Clare; François, Nancy; Ruiz-Guiñazú, Javier; Yarzabal, Juan-Pablo; Moreira, Marta; Borys, Dorota; Schuerman, Lode
Abstract Background: Phase III, open-label, single-center, controlled study in South Africa (ClinicalTrials.gov: NCT00829010) to evaluate immunogenicity, reactogenicity, and safety of the 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in human immunodeficiency virus (HIV)-infected (HIV+), HIV-exposed-uninfected (HEU), and HIV-unexposed-uninfected (HUU) children. Methods: Children stratified by HIV status received PHiD-CV primary vaccination (age 6/10/14 weeks; coadministered with routine childhood vaccines) and booster dose (age 9–10 months). Immune responses, assessed using enzyme-linked immunosorbent and functional assays, and safety were evaluated up to 14 months post-booster. Results: Of 83, 101, and 100 children enrolled in HIV+, HEU, and HUU groups, 70, 91, and 93 were included in according-to-protocol immunogenicity cohort. For each vaccine-serotype, percentages of children with antibody concentrations ≥0.2 μg/mL were ≥97% 1 month post-primary vaccination and ≥98.5% 1 month post-booster (except for 6B and 23F at both timepoints). Post-primary vaccination, functional antibody responses were lower in HIV+ children: for each vaccine-serotype, percentages of children with opsonophagocytic activity (OPA) titres ≥8 were ≥72%, ≥81%, and ≥79% for HIV+, HEU, and HUU children. Post-booster, ≥87% of children in each group had OPA titres ≥8. Reactogenicity was similar across groups. Thirty one (37%) HIV+, 25 (25%) HEU, and 20 (20%) HUU children reported ≥1 serious adverse event. Five HIV+ and 4 HEU children died. One death (sudden infant death syndrome; HEU group; 3 days post-dose 1) was considered potentially vaccine-related. Conclusion: PHiD-CV was immunogenic and well-tolerated in HIV+, HEU, and HUU children, and has the potential to provide substantial benefit irrespective of HIV infection status. PMID:28079828
Nishi, Junichiro; Tokuda, Koichi; Imuta, Naoko; Minami, Taketsugu; Kawano, Yoshifumi
Haemophilus influenzae type b (Hib) conjugate vaccine (PRP-T) and heptavalent pneumococcal conjugate vaccine (PCV7) were introduced in Japan in December 2008 and February 2010, respectively. The concurrent administration of these vaccines is routinely performed worldwide. However, the safety of the simultaneous administration of these vaccines has not been fully evaluated in Japan, because it has rarely been performed thus far. We conducted a 2-year prospective, observational, multicenter study on PRP-T and PCV7 safety from February 2009 through January 2011 in 29 facilities located in Kagoshima Prefecture, Japan. Objective severe adverse events included anaphylactoid reaction, encephalitis/encephalopathy, neurological events, severe focal reactions, systemic eruption/urticaria, fever above 39℃ within 2 days after inoculation, and other complications requiring hospitalization. The incidences of these events for PRP-T and PCV7 administration were 0.68% (76/11,197) and 0.92% (28/3,049), respectively. No deaths or subsequent complications were reported during the course of the study. There was no significant difference in the incidence of severe adverse events between the single and co-administration groups for both vaccines: PRP-T, 0.55% (31/5,662) versus 0.81% (45/5,535; P = 0.11); PCV7, 0.88% (11/1,247) versus 0.94% (17/1,802; P = 0.86). These results suggest that the simultaneous administration of vaccines including PRP-T and/or PCV7 does not increase the incidence of severe adverse events in Japanese children.
Braeye, Toon; Verheagen, Jan; Mignon, Annick; Flipse, Wim; Pierard, Denis; Huygen, Kris; Schirvel, Carole; Hens, Niel
Introduction Surveillance networks are often not exhaustive nor completely complementary. In such situations, capture-recapture methods can be used for incidence estimation. The choice of estimator and their robustness with respect to the homogeneity and independence assumptions are however not well documented. Methods We investigated the performance of five different capture-recapture estimators in a simulation study. Eight different scenarios were used to detect and combine case-information. The scenarios increasingly violated assumptions of independence of samples and homogeneity of detection probabilities. Belgian datasets on invasive pneumococcal disease (IPD) and pertussis provided motivating examples. Results No estimator was unbiased in all scenarios. Performance of the parametric estimators depended on how much of the dependency and heterogeneity were correctly modelled. Model building was limited by parameter estimability, availability of additional information (e.g. covariates) and the possibilities inherent to the method. In the most complex scenario, methods that allowed for detection probabilities conditional on previous detections estimated the total population size within a 20–30% error-range. Parametric estimators remained stable if individual data sources lost up to 50% of their data. The investigated non-parametric methods were more susceptible to data loss and their performance was linked to the dependence between samples; overestimating in scenarios with little dependence, underestimating in others. Issues with parameter estimability made it impossible to model all suggested relations between samples for the IPD and pertussis datasets. For IPD, the estimates for the Belgian incidence for cases aged 50 years and older ranged from 44 to58/100,000 in 2010. The estimates for pertussis (all ages, Belgium, 2014) ranged from 24.2 to30.8/100,000. Conclusion We encourage the use of capture-recapture methods, but epidemiologists should preferably
Guevara, Marcela; Barricarte, Aurelio; Torroba, Luis; Herranz, Mercedes; Gil-Setas, Alberto; Gil, Francisco; Bernaola, Enrique; Ezpeleta, Carmen; Castilla, Jesús
We estimated the direct, indirect and total effects of the 13-valent pneumococcal conjugate vaccine (PCV13) on invasive pneumococcal disease (IPD) in children. A population-based cohort study followed children aged between 2.5 and 59 months between 2001 and 2014 in Navarra, Spain. IPD incidence was compared by PCV status and period. All cases diagnosed from July 2010 to December 2014 and eight matched controls per case were analysed to estimate the adjusted direct effect of PCV13. A total of 120,980 children were followed and 206 IPD cases were detected. Compared with unvaccinated children in the baseline period (2001-2004), overall IPD incidence in 2011-2014 (76% average PCV coverage) declined equally in vaccinated (total effect: 76%; hazard ratio (HR): 0.24; 95% confidence interval (CI): 0.14-0.40) and unvaccinated children (indirect effect: 78%; HR: 0.22; 95% CI: 0.09-0.55). IPD incidence from non-PCV13 serotypes increased among vaccinated children (HR: 2.84; 95% CI: 1.02-7.88). The direct effect of one or more doses of PCV13 against vaccine serotypes was 95% (odds ratio: 0.05; 95% CI: 0.01-0.55). PCV13 was highly effective in preventing vaccine-serotype IPD. The results suggest substantial and similar population-level vaccine benefits in vaccinated and unvaccinated children through strong total and indirect effects.
Detection of antibody responses against Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis proteins in children with community-acquired pneumonia: effects of combining pneumococcal antigens, pre-existing antibody levels, sampling interval, age, and duration of illness.
Borges, I C; Andrade, D C; Vilas-Boas, A-L; Fontoura, M-S H; Laitinen, H; Ekström, N; Adrian, P V; Meinke, A; Cardoso, M-R A; Barral, A; Ruuskanen, O; Käyhty, H; Nascimento-Carvalho, C M
We evaluated the effects of combining different numbers of pneumococcal antigens, pre-existing antibody levels, sampling interval, age, and duration of illness on the detection of IgG responses against eight Streptococcus pneumoniae proteins, three Haemophilus influenzae proteins, and five Moraxella catarrhalis proteins in 690 children aged <5 years with pneumonia. Serological tests were performed on acute and convalescent serum samples with a multiplexed bead-based immunoassay. The median sampling interval was 19 days, the median age was 26.7 months, and the median duration of illness was 5 days. The rate of antibody responses was 15.4 % for at least one pneumococcal antigen, 5.8 % for H. influenzae, and 2.3 % for M. catarrhalis. The rate of antibody responses against each pneumococcal antigen varied from 3.5 to 7.1 %. By multivariate analysis, pre-existing antibody levels showed a negative association with the detection of antibody responses against pneumococcal and H. influenzae antigens; the sampling interval was positively associated with the detection of antibody responses against pneumococcal and H. influenzae antigens. A sampling interval of 3 weeks was the optimal cut-off for the detection of antibody responses against pneumococcal and H. influenzae proteins. Duration of illness was negatively associated with antibody responses against PspA. Age did not influence antibody responses against the investigated antigens. In conclusion, serological assays using combinations of different pneumococcal proteins detect a higher rate of antibody responses against S. pneumoniae compared to assays using a single pneumococcal protein. Pre-existing antibody levels and sampling interval influence the detection of antibody responses against pneumococcal and H. influenzae proteins. These factors should be considered when determining pneumonia etiology by serological methods in children.
Lee, Chung-Hsun; Lee, Ching-Chi; Hsieh, Chih-Chia; Hong, Ming-Yuan; Chi, Chih-Hsien
Enterobacteriaceae is a leading pathogen of community-onset bacteremia. This study aims to establish a predictive scoring algorithm to identify adults with community-onset Enterobacteriaceae bacteremia who are at risk for abscesses. Of the total 1262 adults, 152 (12.0%) with abscess occurrence were noted. The 6 risk factors significantly associated with abscess occurrence-liver cirrhosis, diabetes mellitus, thrombocytopenia and high C-reactive protein (>100 mg/L) at bacteremic onset, delayed defervescence, and bacteremia-causing Klebsiella pneumoniae-were each assigned +1 point to form the scoring algorithm. In contrast, the elderly, fatal comorbidity (McCabe classification), and bacteremia-causing Escherichia coli were each assigned -1 point, owing to their negative associations with abscess occurrence. Using the proposed scoring algorithm, a cut-off value of +1 yielded a high sensitivity (85.5%) and an acceptable specificity (60.4%). Although the proposed predictive model needs further validation, this simple scoring algorithm may be useful for the early identification of abscesses by clinicians.
Barichello, T; Generoso, J S; Silvestre, C; Costa, C S; Carrodore, M M; Cipriano, A L; Michelon, C M; Petronilho, F; Dal-Pizzol, F; Vilela, M C; Teixeira, A L
Pneumococcal meningitis is a severe infectious illness of the central nervous system (CNS), with high rates of lethality and morbidity, being that the microorganism and the host's inflammatory response are responsible for cerebral complications. Moreover, the blood–brain barrier (BBB) itself secretes cytokines and, because of the bipolar nature of the BBB, these substances can be secreted into either the CNS compartment or in the blood, so patients with acute bacterial meningitis frequently develop sepsis. Therefore, the aim of this study was to evaluate the cytokine/chemokine levels in different vessels and the BBB integrity after pneumococcal meningitis induction. Wistar rats were infected with Streptococcus pneumoniae, and the BBB integrity was investigated using Evan's blue dye. Also, blood from the carotid artery and jugular vein was collected in order to perform tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-60 and cytokine-induced neutrophil chemoattractant-1 (CINC-1) analyses by enzyme-linked immunosorbent assay (ELISA). CINC-1 levels were increased at 6 h in the arterial plasma and at 3 and 6 h in the jugular plasma. We observed BBB breakdown between 12 and 24 h in the hippocampus and at 12 and 18 h in the cortex after pneumococcal meningitis induction. The increase of CINC-1 occurred prior to the BBB breakdown. CINC-1 is a neutrophil chemoattractant and it may be related to early events in the pneumococcal meningitis pathophysiology.
Valls Serón, Mercedes; Ferwerda, Bart; Engelen-Lee, JooYeon; Geldhoff, Madelijn; Jaspers, Valery; Zwinderman, Aeilko H; Tanck, Michael W; Baas, Frank; van der Ende, Arie; Brouwer, Matthijs C; van de Beek, Diederik
Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Here, we have performed a prospective nationwide genetic association study using the Human Exome BeadChip and identified gene variants in encoding dynactin 4 (DCTN4), retinoic acid early transcript 1E (RAET1E), and V-akt murine thymoma viral oncogene homolog 3 (AKT3) to be associated with unfavourable outcome in patients with pneumococcal meningitis. No clinical replication cohort is available, so we validated the role of one of these targets, AKT3, in a pneumococcal meningitis mouse model. Akt3 deficient mice had worse survival and increased histopathology scores for parenchymal damage (infiltration) and vascular infiltration (large meningeal artery inflammation) but similar bacterial loads, cytokine responses, compared to wild-type mice. We found no differences in cerebrospinal fluid cytokine levels between patients with risk or non-risk alleles. Patients with the risk genotype (rs10157763, AA) presented with low scores on the Glasgow Coma Scale and high rate of epileptic seizures. Thus, our results show that AKT3 influences outcome of pneumococcal meningitis.
[Advice of the French Superior Council on Public Health (section on transmissible diseases) relative to vaccination by heptavalent pneumococcal conjugate vaccine (Prevanar). Meeting of March 8, 2002].
This article is the full-length text (including arguments and recommendations) written by the Conseil Supérieur d'Hygiène Publique de France, in its session of march 8th 2002, expressing its opinion on the immunization policy with the heptavalent pneumococcal conjugate vaccine (Prevenar).
Marchisio, Paola; Esposito, Susanna; Picca, Marina; Baggi, Elena; Terranova, Leonardo; Orenti, Annalisa; Biganzoli, Elia; Principi, Nicola
In 177 children living in an area with high 13-valent pneumococcal conjugate vaccine (PCV13) coverage who had acute otitis media (AOM) complicated with spontaneous tympanic membrane perforation (STMP), Streptococcus pneumoniae was identified in the middle ear fluid of 48 (27.1%) subjects, with 37 (77.1%) cases caused by non-PCV13 serotypes.
Introduction Adjuvants (for example, aluminum salts) are frequently incorporated in licensed vaccines to enhance the host immune response. Such vaccines include the pneumococcal conjugate, combinations of diphtheria–tetanus/acellular pertussis, tetanus– diphtheria/acellular pertussis, hepatitis B, some Haemophilus influenzae type b, hepatitis A, and human papillomavirus. These preparations have been associated with complicated local adverse events, especially if administered subcutaneously or intradermally in comparison to deep intramuscular injection. We describe a severe inflammatory reaction at the site of an injection of 13-valent pneumococcal conjugate vaccine. Case presentation A 4-month-old Arab baby boy developed dermal necrotizing granulomatous giant cell reaction at the injection site (right anterior thigh) of the second dose of 13-valent pneumococcal conjugate vaccine. Ziehl–Neelsen and periodic-acid Schiff were negative. This reaction probably resulted from improper intramuscular administration because the first (at 2 months of age) and third (at 10 months of age) doses were uneventful. Conclusions Dermal necrotizing granulomatous reactions are a serious complication of the 13-valent pneumococcal conjugate vaccine. Health care providers need to administer this preparation deeply into a muscle mass. Completing the vaccine series is an acceptable option. Physicians are encouraged to report their experience with completing vaccine series following adverse events. PMID:25152179
Boccalini, Sara; Varone, Ornella; Chellini, Martina; Pieri, Luca; Sala, Antonino; Berardi, Cesare; Bonanni, Paolo; Bechini, Angela
Streptococcus pneumoniae is the main causative organism of acute media otitis in children and meningitis and bacterial pneumonia in the community. Since 2008 in Tuscany, central Italy, the pneumococcal conjugate vaccine (7-valent vaccine, switched to 13-valent vaccine in 2010) was actively offered free of charge to all newborns. Aim of the study is to evaluate the impact of pneumococcal pediatric vaccination in the Tuscan population on hospitalizations potentially caused by S. pneumoniae, during pre-vaccination (PVP, 2002-2007) and vaccination period (VP, 2009-2014). We analyzed hospital discharge records (HDRs) of all hospitals in Tuscany from 2002 to 2014. Hospitalizations potentially due to pneumococcal diseases were 347, 221. The general hospitalization rate was 716/100,000 inhabitants during PVP and 753/100,000 in VP, with a decrease of 29.1% in the age-group 0-9 y ("target" of the vaccination program) and an increase of 75.7% in subjects >64 y of age. During VP, admission days and hospitalization costs increased (6.2% and 24.2%, respectively), especially in patients >64 y (12.9% and 33.8%, respectively); in children <10 y decreased by 21.2% and 12.8%, respectively. The pneumococcal pediatric vaccination resulted in the decrease of hospitalizations in younger but the expected indirect effect in the elderly was not reported, justifying the Tuscan recommendation to extend the vaccination to subjects > 64 y.
Background Compared to the civilian population, military trainees are often at increased risk for respiratory infections. We investigated an outbreak of radiologically-confirmed pneumonia that was recognized after 2 fatal cases of serotype 7F pneumococcal meningitis were reported in a 303-person military trainee company (Alpha Company). Methods We reviewed surveillance data on pneumonia and febrile respiratory illness at the training facility; conducted chart reviews for cases of radiologically-confirmed pneumonia; and administered surveys and collected nasopharyngeal swabs from trainees in the outbreak battalion (Alpha and Hotel Companies), associated training staff, and trainees newly joining the battalion. Results Among Alpha and Hotel Company trainees, the average weekly attack rates of radiologically-confirmed pneumonia were 1.4% and 1.2% (most other companies at FLW: 0-0.4%). The pneumococcal carriage rate among all Alpha Company trainees was 15% with a predominance of serotypes 7F and 3. Chlamydia pneumoniae was identified from 31% of specimens collected from Alpha Company trainees with respiratory symptoms. Conclusion Although the etiology of the outbreak remains unclear, the identification of both S. pneumoniae and C. pneumoniae among trainees suggests that both pathogens may have contributed either independently or as cofactors to the observed increased incidence of pneumonia in the outbreak battalion and should be considered as possible etiologies in outbreaks of pneumonia in the military population. PMID:21635754
Terra, Vanessa Sofia; Zhi, Xiangyun; Kahya, Hasan F.; Andrew, Peter W.
For the generation of energy, the important human pathogen Streptococcus pneumoniae relies on host-derived sugars, including β-glucoside analogs. The catabolism of these nutrients involves the action of 6-phospho-β-glucosidase to convert them into usable monosaccharaides. In this study, we characterized a 6-phospho-β-glucosidase (BglA3) encoded by SPD_0247. We found that this enzyme has a cell membrane localization and is active only against a phosphorylated substrate. A mutated pneumococcal ΔSPD0247 strain had reduced 6-phospho-glucosidase activity and was attenuated in growth on cellobiose and hyaluronic acid compared to the growth of wild-type D39. ΔSPD0247-infected mice survived significantly longer than the wild-type-infected cohort, and the colony counts of the mutant were lower than those of the wild type in the lungs. The expression of SPD_0247 in S. pneumoniae harvested from infected tissues was significantly increased relative to its expression in vitro on glucose. Additionally, ΔSPD0247 is severely impaired in its attachment to an abiotic surface. These results indicate the importance of β-glucoside metabolism in pneumococcal survival and virulence. PMID:26527213
Rautanen, Anna; Pirinen, Matti; Mills, Tara C; Rockett, Kirk A; Strange, Amy; Ndungu, Anne W; Naranbhai, Vivek; Gilchrist, James J; Bellenguez, Céline; Freeman, Colin; Band, Gavin; Bumpstead, Suzannah J; Edkins, Sarah; Giannoulatou, Eleni; Gray, Emma; Dronov, Serge; Hunt, Sarah E; Langford, Cordelia; Pearson, Richard D; Su, Zhan; Vukcevic, Damjan; Macharia, Alex W; Uyoga, Sophie; Ndila, Carolyne; Mturi, Neema; Njuguna, Patricia; Mohammed, Shebe; Berkley, James A; Mwangi, Isaiah; Mwarumba, Salim; Kitsao, Barnes S; Lowe, Brett S; Morpeth, Susan C; Khandwalla, Iqbal; Blackwell, Jenefer M; Bramon, Elvira; Brown, Matthew A; Casas, Juan P; Corvin, Aiden; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S; Mathew, Christopher G; Palmer, Colin N A; Plomin, Robert; Sawcer, Stephen J; Trembath, Richard C; Viswanathan, Ananth C; Wood, Nicholas W; Deloukas, Panos; Peltonen, Leena; Williams, Thomas N; Scott, J Anthony G; Chapman, Stephen J; Donnelly, Peter; Hill, Adrian V S; Spencer, Chris C A
Bacteremia (bacterial bloodstream infection) is a major cause of illness and death in sub-Saharan Africa but little is known about the role of human genetics in susceptibility. We conducted a genome-wide association study of bacteremia susceptibility in more than 5,000 Kenyan children as part of the Wellcome Trust Case Control Consortium 2 (WTCCC2). Both the blood-culture-proven bacteremia case subjects and healthy infants as controls were recruited from Kilifi, on the east coast of Kenya. Streptococcus pneumoniae is the most common cause of bacteremia in Kilifi and was thus the focus of this study. We identified an association between polymorphisms in a long intergenic non-coding RNA (lincRNA) gene (AC011288.2) and pneumococcal bacteremia and replicated the results in the same population (p combined = 1.69 × 10(-9); OR = 2.47, 95% CI = 1.84-3.31). The susceptibility allele is African specific, derived rather than ancestral, and occurs at low frequency (2.7% in control subjects and 6.4% in case subjects). Our further studies showed AC011288.2 expression only in neutrophils, a cell type that is known to play a major role in pneumococcal clearance. Identification of this novel association will further focus research on the role of lincRNAs in human infectious disease.
Link-Gelles, Ruth; Westreich, Daniel; Aiello, Allison E; Shang, Nong; Weber, David J; Holtzman, Corinne; Scherzinger, Karen; Reingold, Arthur; Schaffner, William; Harrison, Lee H; Rosen, Jennifer B; Petit, Susan; Farley, Monica; Thomas, Ann; Eason, Jeffrey; Wigen, Christine; Barnes, Meghan; Thomas, Ola; Zansky, Shelley; Beall, Bernard; Whitney, Cynthia G; Moore, Matthew R
In 2010, 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in the US for prevention of invasive pneumococcal disease in children. Individual-level socioeconomic status (SES) is a potential confounder of the estimated effectiveness of PCV13 and is often controlled for in observational studies using zip code as a proxy. We assessed the utility of zip code matching for control of SES in a post-licensure evaluation of the effectiveness of PCV13 (calculated as [1-matched odds ratio]*100). We used a directed acyclic graph to identify subsets of confounders and collected SES variables from birth certificates, geo-coding, a parent interview, and follow-up with medical providers. Cases tended to be more affluent than eligible controls (for example, 48.3% of cases had private insurance vs. 44.6% of eligible controls), but less affluent than enrolled controls (52.9% of whom had private insurance). Control of confounding subsets, however, did not result in a meaningful change in estimated vaccine effectiveness (original estimate: 85.1%, 95% CI 74.8-91.9%; adjusted estimate: 82.5%, 95% CI 65.6-91.1%). In the context of a post-licensure vaccine effectiveness study, zip code appears to be an adequate, though not perfect, proxy for individual SES.
Rudolph, Karen; Bruce, Michael; Bruden, Dana; Zulz, Tammy; Wenger, Jay; Reasonover, Alisa; Harker-Jones, Marcella; Hurlburt, Debby; Hennessy, Thomas
We investigated serotype 6A/6C invasive pneumococcal disease (IPD) incidence, genetic diversity, and carriage before and after 7-valent pneumococcal conjugate vaccine (PCV7) introduction in Alaska. IPD cases (1986–2009) were identified through population-based laboratory surveillance. Isolates were initially serotyped by conventional methods, and 6C isolates were differentiated from 6A by polymerase chain reaction. Among invasive and carriage isolates initially typed as 6A, 35% and 50% were identified as 6C, respectively. IPD rates caused by serotype 6A or 6C among children <5 years did not change from the pre- to post-PCV7 period (P = 0.71 and P = 0.09, respectively). Multilocus sequence typing of IPD isolates revealed 28 sequence types. The proportion of serotype 6A carriage isolates decreased from 7.4% pre-PCV7 to 1.8% (P < 0.001) during 2008–2009; the proportion of serotype 6C carriage isolates increased from 3.0% to 8.4% (P = 0.004) among children <5 years. Continued surveillance is warranted to monitor changes in serotype distribution and prevalence. PMID:23276772
Ernst, J D; Hartiala, K T; Goldstein, I M; Sande, M A
Experiments were performed to identify the chemoattractant for polymorphonuclear leukocytes that appears in the cerebrospinal fluid of rabbits with experimental pneumococcal meningitis. Meningitis was induced in anesthetized New Zealand white rabbits by injecting 10(4) cells of stationary-phase Streptococcus pneumoniae type III intracisternally. Before bacteria were injected, cerebrospinal fluid contained neither polymorphonuclear leukocytes nor chemotactic activity. Significant chemotactic activity for rabbit polymorphonuclear leukocytes was detected 12 h after inoculation with bacteria and was maximal after 18 to 20 h. Chemotactic activity appeared in cerebrospinal fluid while concentrations of pneumococci and total protein were increasing but before there was any accumulation of polymorphonuclear leukocytes. The chemotactic activity in cerebrospinal fluid was heat stable (56 degrees C for 30 min), eluted from Sephadex G-75 with a profile identical to that of the chemotactic activity in zymosan-activated rabbit serum, and was inhibited by treatment with antibodies to