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1.  Serotype-Specific Effect of Influenza on Adult Invasive Pneumococcal Pneumonia 
The Journal of Infectious Diseases  2013;208(8):1274-1280.
Background. Influenza affects host susceptibility to pneumococcus. We sought to evaluate whether this relationship varies by pneumococcal serotype using a large epidemiological database covering 3 decades.
Methods. Weekly rates of invasive pneumococcal pneumonia (IPP) were obtained from the Danish National Laboratory Surveillance System, and influenza-like illness (ILI) data were collected from Danish sentinel surveillance, Statens Serum Institut, 1977–2007. We fit Poisson regression models for each age and comorbidity group, with predictors for seasonality and secular changes, ILI activity, and serotype.
Results. Among individuals with low levels of comorbidities, influenza had the largest impact on IPP incidence among low-invasiveness serotypes (influenza attributable percent: 17.9%, 95% confidence interval [CI], 13.6–21.9) as compared with high-invasiveness serotypes (6.7%, 95% CI, 3.8%–11.7%). Among those with higher levels of comorbidities, the effect of influenza was smaller, but high-invasiveness serotypes increased more than low-invasiveness serotypes (8.9% [95% CI, 6.6–11.8] vs 1.3% [95% CI, −1.6–5.4].
Conclusions. Influenza was associated with the greatest increases in the incidence of disease caused by serotypes with lower invasive potential and among individuals with low levels of comorbid conditions. The importance of influenza for adult IPP varies by serotype and host comorbidity.
doi:10.1093/infdis/jit375
PMCID: PMC3888281  PMID: 23901093
pneumococcus; influenza; coinfection; comorbidity; interaction; regression
2.  Prediction of serotypes causing invasive pneumococcal disease in unvaccinated and vaccinated populations 
Epidemiology (Cambridge, Mass.)  2011;22(2):199-207.
Introduction
Before the introduction of the heptavalent pneumococcal conjugate vaccine (Prevnar-7), the relative prevalence of serotypes of Streptococcus pneumoniae was fairly stable worldwide. We sought to develop a statistical tool to predict the relative frequency of different serotypes among disease isolates in the pre- and post-Prevnar-7 eras using the limited amount of data that is widely available.
Methods
We initially used pre-Prevnar-7 carriage prevalence and estimates of invasiveness derived from case-fatality data as predictors for the relative abundance of serotypes causing invasive pneumococcal disease during the pre- and post-Prevnar-7 eras, using negative binomial regression. We fit the model to pre-Prevnar-7 invasive pneumococcal disease data from England and Wales and used these data to (1) evaluate the performance of the model using several datasets and (2) evaluate the utility of the country-specific carriage data. We then fit an alternative model that used polysaccharide structure, a correlate of prevalence that does not require country-specific information and could be useful in determining the post-vaccine population structure, as a predictor.
Results
Predictions from the initial model fit data from several pediatric populations in the pre-Prevnar-7 era. Following the introduction of Prevnar-7, the model still had a good negative predictive value, though substantial unexplained variation remained. The alternative model had a good negative predictive value but poor positive predictive value. Both models demonstrate that the pneumococcal population follows a somewhat predictable pattern even after vaccination.
Conclusions
This approach provides a preliminary framework to evaluate the potential patterns and impact of serotypes causing invasive pneumococcal disease.
doi:10.1097/EDE.0b013e3182087634
PMCID: PMC3142570  PMID: 21646962
3.  Pediatric Invasive Pneumococcal Disease Caused by Vaccine Serotypes following the Introduction of Conjugate Vaccination in Denmark 
PLoS ONE  2013;8(1):e51460.
A seven-valent pneumococcal conjugate vaccine (PCV7) was introduced in the Danish childhood immunization program (2+1 schedule) in October 2007, followed by PCV13 starting from April 2010. The nationwide incidence of IPD among children younger than 5 years nearly halved after the introduction of PCV7 in the program, mainly due to a decline in IPD caused by PCV7-serotypes. We report the results from a nationwide population-based cohort study of laboratory confirmed IPD cases in children younger than 5 years during October 1, 2007 to December 31, 2010 and describe the characteristics of children suspected to present with a vaccine failure. The period between April 19 and December 31, 2010 was considered a PCV7/PCV13 transitional period, where both vaccines were offered. We identified 45 episodes of IPD caused by a PCV7 serotype (23% of the total number) and 105 (55%) caused by one of the 6 additional serotypes in PCV13. Ten children had received at least one PCV7 dose before the onset of IPD caused by a PCV7 serotype. Seven children were considered to be incompletely vaccinated before IPD, but only three cases fulfilled the criteria of vaccine failure (caused by serotypes 14, 19F and 23F). One case of vaccine failure was observed in a severely immunosuppressed child following three PCV7 doses, and two cases were observed in immunocompetent children following two infant doses before they were eligible for their booster. None of the IPD cases caused by the additional PCV13 serotypes had been vaccinated by PCV13 and there were therefore no PCV13-vaccine failures in the first 8-months after PCV13 introduction in Denmark.
doi:10.1371/journal.pone.0051460
PMCID: PMC3554759  PMID: 23365635
4.  A Pneumococcal Carriage Study in Danish Pre-school Children before the Introduction of Pneumococcal Conjugate Vaccination 
We present data on pneumococcal carriage before the introduction of the heptavalent-pneumococcal conjugated vaccine (PCV7) in Denmark. In the pre-PCV7 period, the incidence of invasive pneumococcal disease (IPD) among children younger than 5 years was approximately 25 per 100.000 population, with the highest incidence rates observed in children younger than 2 years of age. The study included 437 children aged 12-72 months attending day care centres (DCC) and was conducted during 48 months. In total, 56% (n=247) of children were pneumococcal carriers with the highest prevalence in children aged 12–23 months (69%), the proportion significantly declining with increasing age. PCV7 serotypes accounted for 33%, PCV10 for 34%, and PCV13 for 57% of all carried isolates. The proportion of serotypes included in the three conjugate vaccines was higher among IPD isolates compared to carrier isolates (range 35– 90%). We found that the frequency of carriage was high among Danish pre-school children attending DCC and serotypes were not frequently covered by PCV7 in the pre-PCV7 period.
doi:10.2174/1874285801206010040
PMCID: PMC3355352  PMID: 22611459
Children; nasopharyngeal carriage; Streptococcus pneumoniae; serotypes; vaccine.
5.  Risk of death from pneumococcal pneumonia is a stable serotype-associated property: a meta-analysis 
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.
doi:10.1086/655828
PMCID: PMC2927802  PMID: 20715907
Serotype; pneumococcus; case-fatality ratio; mortality; capsule; meta-analysis
6.  Robustness of genome-wide scanning using archived dried blood spot samples as a DNA source 
BMC Genetics  2011;12:58.
Background
The search to identify disease-susceptible genes requires access to biological material from numerous well-characterized subjects. Archived residual dried blood spot (DBS) samples, also known as Guthrie cards, from national newborn screening programs may provide a DNA source for entire populations. Combined with clinical information from medical registries, DBS samples could provide a rich source for productive research. However, the amounts of DNA which can be extracted from these precious samples are minute and may be prohibitive for numerous genotypings. Previously, we demonstrated that DBS DNA can be whole-genome amplified and used for reliable genetic analysis on different platforms, including genome-wide scanning arrays. However, it remains unclear whether this approach is workable on a large sample scale. We examined the robustness of using DBS samples for whole-genome amplification following genome-wide scanning, using arrays from Illumina and Affymetrix.
Results
This study is based on 4,641 DBS samples from the Danish Newborn Screening Biobank, extracted for three separate genome-wide association studies. The amount of amplified DNA was significantly (P < 0.05) affected by the year of storage and storage conditions. Nine (0.2%) DBS samples failed whole-genome amplification. A total of 4,586 (98.8%) samples met our criterion of success of a genetic call-rate above 97%. The three studies used different arrays, with mean genotyping call-rates of 99.385% (Illumina Infinium Human610-Quad), 99.722% (Illumina Infinium HD HumanOmni1-Quad), and 99.206% (Affymetrix Axiom Genome-Wide CEU). We observed a concordance rate of 99.997% in the 38 methodological replications, and 99.999% in the 27 technical replications. Handling variables such as time of storage, storage conditions and type of filter paper were shown too significantly (P < 0.05) affect the genotype call-rates in some of the arrays, although the effect was minimal.
Conclusion
Our study indicates that archived DBS samples from the Danish Newborn Screening Biobank represent a reliable resource of DNA for whole-genome amplification and subsequent genome-wide association studies. With call-rates equivalent to high quality DNA samples, our results point to new opportunities for using the neonatal biobanks available worldwide in the hunt for genetic components of disease.
doi:10.1186/1471-2156-12-58
PMCID: PMC3142526  PMID: 21726430
7.  Seroprevalence of Pertussis among Danish Patients with Cough of Unknown Etiology▿ †  
Clinical and Vaccine Immunology : CVI  2010;17(12):2016-2023.
The common perception that pertussis is only a childhood disease is not correct. Vaccination or infection with Bordetella pertussis provides only short-lived protection against pertussis—and the majority of the population is consequently at risk of contracting pertussis. We evaluated the seroprevalence of pertussis antibodies (IgG against pertussis toxin) in serum samples from 265 Danish patients, aged 8 years and older, with coughs of unknown etiology. Depending on the cutoff chosen, we found that 2.6% to 10.9% of these patients were seropositive for pertussis. Of 178 patients with a reported duration of cough between 2 weeks and 3 months, 3.4% to 12.4% were seropositive for pertussis, indicating recent infection. Our study indicates that B. pertussis infection may be underdiagnosed among older children and adults with coughs in Denmark.
doi:10.1128/CVI.00270-10
PMCID: PMC3008190  PMID: 20926698
8.  Pneumococcal Serotypes and Mortality following Invasive Pneumococcal Disease: A Population-Based Cohort Study 
PLoS Medicine  2009;6(5):e1000081.
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.
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.
Editors' Summary
Background
Pneumococcal diseases—illnesses caused by Streptococcus pneumoniae bacteria—are leading causes of illness and death around the world. S. pneumoniae is transmitted through contact with infected respiratory secretions and usually causes noninvasive diseases such as ear infections and bronchitis. Sometimes, however, the bacteria invade the lungs (where they cause pneumonia), the bloodstream (where they cause bacteremia), or the covering of the brain (where they cause meningitis). These invasive pneumococcal diseases (IPDs) are often fatal. One million children die annually from pneumococcal disease, many of them in developing countries. In the developed world, however, IPDs mainly affect elderly people and patients with chronic conditions such as diabetes and alcoholism. Although pneumococcal diseases can sometimes be treated successfully with antibiotics, many patients die or develop long-term complications. Consequently, vaccination with “pneumococcal polysaccharide vaccine” (PPV) is recommended for everyone over 65 years old and for people between 2 and 65 years old who are at high risk of developing IPD; vaccination with “pneumococcal conjugate vaccine” (PCV) is recommended for children younger than 2 years old who are at high risk of IPDs.
Why Was This Study Done?
S. pneumoniae is not a single organism. There are actually more than 90 S. pneumoniae variants or “serotypes.” These variants are coated with different polysaccharides (complex sugar molecules) that are, in part, responsible for the deleterious effects of S. pneumonia infections. The same molecules also trigger the human immune response that kills the bacteria. Consequently, pneumococcal vaccines contain polysaccharide mixtures isolated from the S. pneumoniae serotypes responsible for most pneumococcal disease. But are these serotypes also responsible for most of the deaths caused by IPD? Until now, the few studies that have investigated the association between S. pneumoniae serotypes and death from IPD have yielded conflicting results. Here, therefore, the researchers undertook a large population-based study to discover whether there is an association between specific pneumococcal serotypes and death following IPD.
What Did the Researchers Do and Find?
The researchers linked data on the serotype of S. pneumoniae isolates sent to the Danish National Neisseria and Streptococcus Reference Center between 1977 and 2007 with clinical data from national medical databases. After allowing for other factors that might affect a person's likelihood of dying from IPD (for example, age and other illnesses), the researchers used multivariate logistic regression analysis (a statistical approach) to look for associations between S. pneumoniae serotypes and death within 30 days of admission to hospital for pneumococcal bacteremia or meningitis. Overall, 18% of the nearly 19,000 people included in this analysis died within 30 days of hospital admission; among the children younger than 5 years included in the study, the death rate was 3%. Among patients 5 years old or older, nine S. pneumoniae serotypes were associated with a more than 3-fold higher death rate (mostly from bacteremia) than serotype 1, the most common serotype isolated during the study. Interestingly, in young children, a different set of serotypes seemed to be associated with death. However, because so few children died from IPD, this result is statistically uncertain. The researchers' results also show that age, gender, having meningitis, having other illnesses, and alcoholism all affected a patient's chances of dying from IPD.
What Do These Findings Mean?
These findings show that specific pneumococcal serotypes strongly affect the likelihood that a person aged 5 years or over will die within 30 days of admission to hospital with IPD. Importantly, unlike previous studies, this study was large and comprehensive—the Danish surveillance center covers more than 90% of the Danish population—and the researchers carefully took other factors into account that might have affected a patient's chances of dying from IPD. Thus, these new insights into which pneumococcal serotypes are most deadly could help in the design of new pneumococcal vaccines, at least for people aged 5 years or older. For younger children, however, the results are not as informative and a similar study now needs to be done in developing countries, where more young people die from IPD.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000081.
The US Centers for Disease Control and Prevention provides information for patients and health professionals on all aspects of pneumococcal disease and pneumococcal vaccination
The US National Foundation for Infectious Diseases has a fact sheet on pneumococcal disease
The UK Health Protection Agency also provides background information on pneumococcal disease
The GAVI's Pneumococcal Vaccines Accelerated Development and Introduction Plan focuses on pneumococcal vaccines for children
doi:10.1371/journal.pmed.1000081
PMCID: PMC2680036  PMID: 19468297

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