Pneumococcal Serotypes and Mortality following Invasive Pneumococcal Disease: A Population-Based Cohort Study
TL;DR: Analyzing population-based data collected over 30 years in more than 18,000 patients with invasive pneumococcal infection, Zitta Harboe and colleagues find specific pneumococCal serotypes to be associated with increased mortality.
Abstract: Background: Pneumococcal disease is a leading cause of morbidity and mortality worldwide. The aim of this study was to investigate the association between specific pneumococcal serotypes and mortality from invasive pneumococcal disease (IPD). Methods and Findings: In a nationwide population-based cohort study of IPD in Denmark during 1977–2007, 30-d mortality associated with pneumococcal serotypes was examined by multivariate logistic regression analysis after controlling for potential confounders. A total of 18,858 IPD patients were included. Overall 30-d mortality was 18%, and 3% in children younger than age 5 y. Age, male sex, meningitis, high comorbidity level, alcoholism, and early decade of diagnosis were significantly associated with mortality. Among individuals aged 5 y and older, serotypes 31, 11A, 35F, 17F, 3, 16F, 19F, 15B, and 10A were associated with highly increased mortality as compared with serotype 1 (all: adjusted odds ratio $3, p,0.001). In children younger than 5 y, associations between serotypes and mortality were different than in adults but statistical precision was limited because of low overall childhood-related mortality. Conclusions: Specific pneumococcal serotypes strongly and independently affect IPD associated mortality. Please see later in the article for the Editors’ Summary.
Citations
More filters
TL;DR: Evidence supporting the recommendation for PPV to prevent IPD in adults is provided, with strong evidence of PPV efficacy against IPD found, and vaccine efficacy against primary outcomes appeared poorer in adults with chronic illness.
Abstract: Background Diseases caused by Streptococcus pneumoniae (S. pneumoniae) continue to cause substantial morbidity and mortality globally. Whilst pneumococcal polysaccharide vaccines (PPVs) have the potential to prevent disease and death, the degree of protection afforded against various clinical endpoints and within different populations is uncertain. Objectives To assess the efficacy and effectiveness of PPVs in preventing pneumococcal disease or death in adults. We did not assess adverse events. Search methods We searched CENTRAL 2012, Issue 6, MEDLINE (January 1966 to June Week 2, 2012) and EMBASE (1974 to June 2012). Selection criteria We considered randomised controlled trials (RCTs) in adults, provided the study outcome met the definition of the outcome considered in the review. We also considered non-RCTs in adults, where the study assessed PPV effectiveness against culture-confirmed invasive pneumococcal disease (IPD), provided the study controlled for important confounding factors. Data collection and analysis Two review authors assessed trial quality of RCTs and three review authors extracted the data. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using a random-effects model. Two review authors assessed study quality and extracted data for non-RCTs. We calculated ORs and 95% CIs using a random-effects model following the conversion of each study outcome to a log OR and standard error (SE). Main results Twenty-five studies met our inclusion criteria (18 RCTs involving 64,852 participants and seven non-RCTs involving 62,294 participants). Meta-analysis of the RCTs found strong evidence of PPV efficacy against IPD with no statistical heterogeneity (OR 0.26, 95% CI 0.14 to 0.45; random-effects model, I(2) statistic = 0%). There was efficacy against all-cause pneumonia in low-income (OR 0.54, 95% CI 0.43 to 0.67, I(2) statistic = 19%) but not high-income countries in either the general population (OR 0.71, 95% CI 0.45 to 1.12, I(2) statistic = 93%) or in adults with chronic illness (OR 0.93, 95% CI 0.73 to 1.19, I(2) statistic = 10%). PPV was not associated with substantial reductions in all-cause mortality (OR 0.90, 95% CI 0.74 to 1.09; random-effects model, I(2) statistic = 69%). Vaccine efficacy against primary outcomes appeared poorer in adults with chronic illness. Non-RCTs provided evidence for protection against IPD in populations for whom the vaccine is currently utilised (OR 0.48, 95% CI 0.37 to 0.61; random-effects model, I(2) statistic = 31%). This review did not consider adverse events as it was outside the scope of the review. Authors' conclusions This meta-analysis provides evidence supporting the recommendation for PPV to prevent IPD in adults. The evidence from RCTs is less clear with respect to adults with chronic illness. This might be because of lack of effect or lack of power in the studies. The meta-analysis does not provide evidence to support the routine use of PPV to prevent all-cause pneumonia or mortality.
835 citations
TL;DR: Improvements in capabilities will greatly enhance future investigations of pneumococcal epidemiology and diseases and the biology of colonization and innate immunity to pneumococcas capsules, and more-precise and -efficient serotypes that directly detect polysaccharide structures are emerging.
Abstract: 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.
532 citations
TL;DR: A systematic review and meta-analysis of serotype-specific disease outcomes for patients with pneumonia and meningitis suggests that IPD outcome, like other epidemiologic measures, is a stable serotypes-associated property.
Abstract: Streptococcus pneumoniae, or pneumococcus, is an important cause of pneumonia, meningitis, otitis media, and septicemia and is associated with significant morbidity and mortality worldwide. There are 92 known pneumococcal serotypes, and each produces a unique polysaccharide capsule that protects the bacterium against host immune effectors [1].
Serotype affects many aspects of pneumococcal epidemiology. The rank orders of serotypes found in nasopharyngeal carriage [2] and invasive disease [3, 4] are similar worldwide with a few exceptions. Likewise, the invasiveness of a serotype, or the frequency with which it causes invasive disease per carriage episode, is a stable property [5]. There is an inverse relationship between the carriage prevalence of a serotype and its invasiveness [5] and between disease severity and invasiveness [6].
The outcome of a case of invasive pneumococcal disease (IPD) can be affected both by bacterial factors, such as serotype, and by host characteristics, such as old age, very young age, low socioeconomic status, quality of care, alcoholism, immunodeficiency, and other underlying conditions[7–10]. Some studies have found that even after controlling for relevant host factors, certain serotypes are independently associated with more severe outcomes [11–13]. Likewise, experimental studies in mice have shown that serotypes differ in their ability to cause severe disease [14], and strains with larger capsules are more virulent in animals than strains of the same serotype with smaller capsules [15, 16]. It was long ago noted that differences in polysaccharide production between types 1, 2, and 3 correlated with the case-fatality ratios (CFR) for these serotypes in humans [7, 17].
While a number of studies have investigated the relationship between serotype and disease outcome, they differ in the kinds of clinical syndromes included, the age of the populations studied, and the covariates included when deriving effect estimates. As a result, published studies differ in the magnitude and direction of effect estimates for certain serotypes, and these studies have not previously been compared to determine whether stable patterns of virulence exist. We performed a systematic review and meta-analysis of IPD outcome by serotype to evaluate the stability of these estimates between studies. We found that clinical outcome in bacteremic pneumonia, like carriage prevalence and invasiveness, is a stable serotype-associated property, and we hypothesize about the biological reasons for these patterns.
317 citations
Cites result from "Pneumococcal Serotypes and Mortalit..."
...However, Denmark has extremely low levels of antimicrobial resistance (2%–5%) [11], and we see similar mortality patterns in the Danish study and in the other datasets....
[...]
...We found that adjusting for age did not greatly affect the odds ratio in the 2 studies we examined (Appendix [available online], ), suggesting that serotype independently affects disease outcome, which is consistent with published findings [11]....
[...]
TL;DR: The incidence of adult bacterial meningitis has decreased substantially, which is partly explained by herd protection by paediatric conjugate vaccines.
Abstract: Summary Background We studied causative pathogens, clinical characteristics, and outcome of adult community-acquired bacterial meningitis after the introduction of adjunctive dexamethasone treatment and nationwide implementation of paediatric conjugate vaccines. Methods In this cohort study, we prospectively assessed adults (age >16 years) with community-acquired bacterial meningitis in the Netherlands, identified through the National Reference Laboratory for Bacterial Meningitis or individual physicians between Jan 1, 2006, and July 1, 2014. We identified independent predictors of an unfavourable outcome (Glasgow Outcome Scale score 1–4) by logistic regression. Findings We assessed 1412 episodes of community-acquired bacterial meningitis. Incidence declined from 1·72 cases per 100 000 adults per year in 2007–08, to 0·94 per 100 000 per year in 2013–14. Streptococcus pneumoniae caused 1017 (72%) of 1412 episodes. Rates of adult bacterial meningitis decreased most sharply among pneumococcal serotypes included in paediatric conjugate vaccine, and in meningococcal meningitis. We found no evidence of serotype or serogroup replacement. The overall case fatality rate was 244 (17%) of 1412 episodes and unfavourable outcome occurred in 531 (38%) of 1412 episodes. Predictors of unfavourable outcome were advanced age, absence of otitis or sinusitis, alcoholism, tachycardia, lower score on the Glasgow Coma Scale, cranial nerve palsy, a cerebrospinal fluid white-cell count lower than 1000 cells per μL, a positive blood culture, and a high serum C-reactive protein concentration. Adjunctive dexamethasone was administered for 1234 (89%) of 1384 assessed episodes. The multivariable adjusted odds ratio of dexamethasone treatment for unfavourable outcome was 0·54 (95% CI 0·39–0·73). Interpretation The incidence of adult bacterial meningitis has decreased substantially, which is partly explained by herd protection by paediatric conjugate vaccines. Adjunctive dexamethasone treatment was associated with substantially improved outcome. Funding European Research Council, National Institute of Public Health and the Environment, European Union, Academic Medical Center, and Netherlands Organization for Health Research and Development.
283 citations
TL;DR: Following usage of the pneumococcal conjugate vaccine in children, the incidence of invasive pneumitis disease declined in both children and adults (reflecting herd immunity), however, emergence of serotypes not encompassed in the vaccine is worrisome, and may be associated with heightened antimicrobial resistance and virulence.
Abstract: Purpose of review Streptococcus pneumoniae (pneumococcus) remains an important cause of pneumonia, meningitis, bacteremias, and acute otitis media worldwide. Antimicrobial resistance among pneumococci has escalated dramatically over the past three decades, and is influenced by patterns of antibiotic use, population density, and spread of a few international clones. Recent findings Globally, antimicrobial resistance among pneumococci spread rapidly in the 1990s, reflecting dissemination of a few clones. The incidence of resistance varies considerably among different geographic regions and is influenced by patterns of antibiotic use, population density, and local prevalence of resistant strains. The use of specific antibiotic classes not only predisposes to resistance to that class but also may facilitate emergence of resistance to unrelated antibiotic classes. Judicious usage of antibiotics may reduce the incidence of antibiotic-resistant pneumococci. Summary Following usage of the pneumococcal conjugate vaccine in children, the incidence of invasive pneumococcal disease declined in both children and adults (reflecting herd immunity). However, emergence of serotypes not encompassed in the vaccine is worrisome, and may be associated with heightened antimicrobial resistance and virulence. Continued vigilance for emergence of novel serotypes and development of vaccines with expanded coverage and immunogenicity will be critical for optimal prevention of pneumococcal infections.
274 citations
References
More filters
TL;DR: The method of classifying comorbidity provides a simple, readily applicable and valid method of estimating risk of death fromComorbid disease for use in longitudinal studies and further work in larger populations is still required to refine the approach.
39,961 citations
"Pneumococcal Serotypes and Mortalit..." refers methods in this paper
...Comorbidity was assessed by computing the Charlson index score for each patient by using ICD codes from all available discharge diagnoses, as previously described [36,37]....
[...]
TL;DR: The Danish Civil Registration System (CRS) in connection with other registers and biobanks will continue to provide the basis for significant knowledge relevant to the aetiological understanding and possible prevention of human diseases.
Abstract: Introduction: The Danish Civil Registration System (CRS) was established in 1968, and all persons alive and living in Denmark were registered for administrative use. Content: CRS includes individual information on the unique personal identification number, name, gender, date of birth, place of birth, citizenship, identity of parents and continuously updated information on vital status, place of residence and spouses. Validity and coverage: Since 1968, CRS has recorded current and historical information on all persons living in Denmark. Among persons born in Denmark in 1960 or later it contains complete information on maternal identity. For women born in Denmark in April 1935 or later it contains complete information on all their children. CRS contains complete information on immigrations and emigrations from 1969 onwards, permanent residence in a Danish municipality from 1971 onwards, and full address in Denmark from 1977 onwards. Conclusion: CRS in connection with other registers and biobanks will continue to provide the basis for significant knowledge relevant to the aetiological understanding and possible prevention of human diseases.
3,724 citations
Journal Article•
TL;DR: The Danish National Hospital Register is well suited to contribute to international comparative studies with relevance for evidence-based medicine, and how researchers may get access to the Register is described.
Abstract: The Danish National Hospital Register (LPR) has collected nationwide data on all somatic hospital admissions since 1977, and since 1995 data on outpatients and emergency patients have been included as well. Numerous research projects have been undertaken in the national Danish context as well as in collaboration with international teams, and the LPR is truly a valuable source of data for health sciences, especially in epidemiology, health services research and clinical research. Nearly complete registration of somatic hospital events in Denmark is combined with ideal conditions for longterm follow-up due to the existence of a national system of unique person identification in a population of relative demographic stability. Examples of studies are provided for illustration within three main areas: I: Using LPR for surveillance of the occurrence of diseases and of surgical procedures, II: Using the Register as a sampling frame for longitudinal population based and clinical research, and III: Using the Register as a data source for monitoring outcomes. Data available from the Register as well as studies of the validity of the data are mentioned, and it is described how researchers may get access to the Register. The Danish National Hospital Register is well suited to contribute to international comparative studies with relevance for evidence-based medicine.
2,033 citations
"Pneumococcal Serotypes and Mortalit..." refers background in this paper
...The Danish National Hospital Register contains data on all hospitalizations since 1977 and on all outpatient visits since 1995 [35]....
[...]
Journal Article•
TL;DR: Data from the CRS is an important research tool in epidemiological research, which enables Danish researchers to carry out representative population-based studies on e.g. the potential clustering of disease and death in families and the potential association between residence and disease andDeath.
Abstract: Background The Danish Civil Registration System (CRS) was established in 1968, where all persons alive and living in Denmark were registered. Among many other variables, it includes individual information on personal identification number, gender, date of birth, place of birth, place of residence, citizenship, continuously updated information on vital status, and the identity of parents and spouses. Methods To evaluate the quality and completeness of the information recorded on persons in the CRS, we considered all persons registered on November 4, 2005, i.e. all persons who were alive and resident in Denmark at least one day from April 2, 1968 to November 4, 2005, or in Greenland from May 1, 1972 to November 4, 2005. Results A total of 8,176,097 persons were registered. On November 4, 2005, 5,427,687 (66.4%) were alive and resident in Denmark, 56,920 (0.7%) were alive and resident in Greenland, 2,141,373 (26.2%) were dead, 21,160 (0.3%) had disappeared, and 528,957 (6.5%) had emigrated. Among persons born in Denmark 1960 or later the CRS contains complete information on maternal identity. Among persons born in Denmark 1970 or later the CRS contains complete information on paternal identity. Among women born in Denmark April 1935 or later the CRS contains complete information on all their children. Among males born in Denmark April 1945 or later the CRS contains complete information on all their children. The CRS contains complete information on: a) immigrations and emigrations from 1971 onwards, b) permanent residence in a Danish municipality from 1971 onwards, c) permanent residence in a municipality in Greenland from May 1972 onwards, and d) full address in Denmark from 1977 onwards. Conclusion Data from the CRS is an important research tool in epidemiological research, which enables Danish researchers to carry out representative population-based studies on e.g. the potential clustering of disease and death in families and the potential association between residence and disease and death.
1,561 citations
"Pneumococcal Serotypes and Mortalit..." refers methods in this paper
...Laboratory surveillance in Denmark is based on the voluntary submission of S. pneumoniae isolates cultured from a normally sterile site from all local departments of clinical microbiology to the NSR [30]....
[...]
...Because there is universal health coverage in Denmark, we probably identified nearly all IPD episodes requiring hospitalization....
[...]
...Isolates were routinely serotyped by pneumotest latex and Quellung reaction using type-specific pneumococcal rabbit antisera from SSI as previously described (SSI-Diagnostica, Copenhagen, Denmark) [28,29]....
[...]
...An estimate of the proportion of the uptake of PCV7, based on the number of doses sold in Denmark (and assuming that all vaccines were given in a three-dose series to children younger than 2 y), ranges from 0.6 to 1.4 per 1,000 children between 2001 and 2006....
[...]
...Linkage between data sources was done by using the unique ten-digit identification number provided to all residents in Denmark [27]....
[...]
TL;DR: Twenty-five years have elapsed since the subject of pneumococcal bacteremia has been reviewed, and in that period many changes have taken place both in the treatment of this disorder and in the research into its causes.
Abstract: Excerpt Twenty-five years have elapsed since the subject of pneumococcal bacteremia has been reviewed (1, 2). In that period many changes have taken place both in the treatment of this disorder and...
917 citations
"Pneumococcal Serotypes and Mortalit..." refers background or result in this paper
...Epidemiological and experimental studies have identified serotype 3 and 11A and serotypes included in serogroup 9 as serotypes that are more likely to cause severe disease [16,19,20,41]....
[...]
...Few other population-based studies have investigated confounder-adjusted serotype-specific mortality, and they produced conflicting results and explored a relatively limited number of serotypes [10,19,21,24,25,41,42]....
[...]