Pneumococcal Conjugate Vaccine Era Research Articles

Predictors for Bacteremia in Febrile Sickle Cell Disease Children in the Post-7-Valent Pneumococcal Conjugate Vaccine Era

The objective of this study was to determine the incidence of bacteremia in febrile sickle cell disease (SCD) children before and after the 7-valent pneumococcal vaccine (PCV7), and to determine clinical factors associated with bacteremia following PCV7. We reviewed all febrile events in SCD children from 1993 to 2009 at a tertiary care pediatric center, comparing general bacteremia and pneumococcal bacteremia incidence for 3 time periods around the PCV7. Univariate analysis and stepwise logistic regression identified clinical factors most associated with bacteremia in this population. Of 466 SCD children identified, there were 2504 febrile events. We found 84 cases of bacteremia; 8 were pneumococcal. The general bacteremia incidence decreased significantly from 5.60% to 2.44% (P<0.001) over time. Pneumococcal bacteremia incidence did not decrease (P=0.13). Following PCV7, we identified 4 significant independent risk factors associated with general bacteremia: the presence of a central venous line, higher absolute band count, toxic appearance, and older age. In febrile SCD children, the incidence of general bacteremia decreased over time. No decrease in pneumococcal bacteremia was found. The presence of a central venous line, absolute band count, clinical appearance, and age may help predict bacteremia in this population.

Update of Pneumococcal PCR Serotyping Assay for Detection of a Commonly Occurring Type 19F wzy Variant in Brazil

In this era of effective pneumococcal conjugate vaccines, simple and inexpensive methods are desirable for determining capsular serotype (st) distributions. Although a multiplexed conventional PCR (cmPCR) approach is generally reliable ([1][1][–][2][4][3]) (updates at [www.cdc.gov/ncidod/biotech/

Do community-level predictors of pneumococcal carriage continue to play a role in the conjugate vaccine era?

This paper examined whether previously identified community-level factors (high proportion of crowded households and/or persons below the poverty level) remained associated with childhood pneumococcal carriage in the heptavalent pneumococcal conjugate vaccine (PCV7) era. Using logistic regression, individual factors were used to develop base models to which community-level factors were added to evaluate impact on pneumococcal carriage within two paediatric study cohorts from Massachusetts (urban Boston, outside Boston). Six years after introduction of universal childhood PCV7 vaccination, we found no consistent evidence that census tract characteristics (e.g. population size and density, age and race distribution, percent participating in group childcare, parental education, percent lacking in-unit plumbing, poverty, and community stability) affected odds of pneumococcal carriage when added to individual predictors (e.g. younger age, current respiratory tract infections, and attendance in group childcare). How community-level factors influence pneumococcal carriage continues to change in the era of increasing immunization coverage.

Serotype and Clonal Evolution of Penicillin-Nonsusceptible Invasive Streptococcus pneumoniae in the 7-Valent Pneumococcal Conjugate Vaccine Era in Italy

Serotype and Clonal Evolution of Penicillin-Nonsusceptible Invasive Streptococcus pneumoniae in the 7-Valent Pneumococcal Conjugate Vaccine Era in Italy

Incidence of pneumococcal infections among children under 15 years in southern Catalonia throughout the heptavalent conjugate vaccine era, 2002–2009

Updating epidemiological studies to document current incidences of pneumococcal diseases are greatly needed in the current era of new pneumococcal conjugate vaccines (PCVs). The aim of this study is to analyze the incidence and distribution of different serotypes causing pneumococcal infections among the pediatric population in southern Catalonia, Spain, throughout the 2002-2009 PCV7 eras. A population-based surveillance study was conducted among children aged ≤ 14 years in the region of Tarragona (Catalonia, Spain) during the period 2002-2009. All cases of pneumococcal infections (invasive and non-invasive cases) were included in the study. Incidence rates (per 100,000 population-year) and prevalence of infections caused by serotypes included in different PCV formulations were calculated for the 2002-2005 and 2006-2009 periods. Globally, across the total 2002-2009 period, the incidence of pneumococcal infections was 48.2 per 100,000 children-year (22.4 and 25.8 for invasive and non-invasive infections, respectively). Between 2002-2005 and 2006-2009, the incidence rates largely decreased among children aged <2 years (from 171 to 111 per 100,000 children-year; p = 0.059), but they did not substantially vary among children aged 2-14 years. The percentages of cases caused by serotypes included in PCV7 (60.0 vs. 16.7 %; p < 0.001), PCV10 (75.0 vs. 47.4 %; p = 0.028), and PCV13 (85.0 vs. 70.5 %; p = 0.190) decreased in both periods. In this study, which was conducted in a setting with intermediate PCV7 uptakes, a considerable protective direct effect of vaccination occurred among young infants, but an indirect protective effect did not emerge in the rest of the pediatric population. Despite new PCVs with higher serotype coverage, an important proportion of pneumococcal infections is still not covered by these vaccines.

Pneumococcal carriage in children attending a hospital outpatient clinic in the era of pneumococcal conjugate vaccines in Barcelona

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.

Serotype and Clonal Evolution of Penicillin-Nonsusceptible Invasive Streptococcus pneumoniae in the 7-Valent Pneumococcal Conjugate Vaccine Era in Italy

The percentage of invasive penicillin-nonsusceptible pneumococci (PNSSP) isolated in Italy in the seven-valent pneumococcal conjugate vaccine (PCV7) era moderately increased in comparison to the pre-PCV7 era. Increase of nonvaccine serotypes was observed among PNSSP. The most frequent PNSSP clones were the same as those identified in the pre-PCV7 era, although they were present in different proportions. Clonal expansion, emergence of new clones, and acquisition of penicillin resistance by established clones contributed to the maintenance of penicillin resistance.

Pediatric Invasive Pneumococcal Disease in the United States in the Era of Pneumococcal Conjugate Vaccines

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.

Pneumococcal Bacteremia in a Vaccinated Pediatric Sickle Cell Disease Population

The incidence of pneumococcal disease in sickle cell disease declined significantly with penicillin prophylaxis as well as with the pneumococcal polysaccharide and heptavalent conjugate vaccines. In this report, we describe our experience with pneumococcal bacteremia in pediatric patients with sickle cell disease in the post-heptavalent pneumococcal conjugate vaccine era. Despite established prophylactic strategies, pneumococcal bacteremia continues to occur in patients with sickle cell disease.

Invasive bacterial infections in a paediatric emergency department in the era of the heptavalent pneumococcal conjugate vaccine

To describe the characteristics of patients diagnosed with invasive bacterial infections (IBIs) in a Paediatric Emergency Department (PED) following the introduction of the heptavalent pneumococcal conjugated vaccine (PCV7). Descriptive retrospective study of children under 14 years of age diagnosed with IBIs in a PED of a tertiary hospital between January 2008 and December 2009. In this period we registered 123 396 episodes and 59 patients who were diagnosed with IBIs (22 patients under 1 year of age, 37.2%). Of these, 11 (18.6%) had some severe underlying condition and 38 (64.4%) were stable on arrival. The most common diagnoses were sepsis with/without meningitis (23, 38.9%) and bacteraemia (14, 23.7%), while the pathogens most frequently isolated were Streptococcus pneumoniae (23, 38.9%) and Neisseria meningitidis (18, 30.5%). Pathogens were isolated from blood in 57 patients and from the cerebrospinal fluid in eight (in these, the same bacterial species was isolated in the blood, except for two cases with S. pneumoniae). Of the pneumococci isolated, 80% corresponded to serotypes included in the 13-valent PCV13. In seven cases, pathogens were detected using only PCR analysis (N. meningitidis, four; S. pneumoniae, three). Twenty-five patients were admitted to the Paediatric Intensive Care Unit. No patient died but two had sequelae. In the era of PCV7, pneumococcus is the leading cause of IBI in PED. The introduction of PCV13 may lead to a very significant decrease in the IBI rate and meningococcus may become the leading cause of IBI.

The Changing Epidemiology of Invasive Pneumococcal Disease at a Tertiary Children's Hospital Through the 7-valent Pneumococcal Conjugate Vaccine Era

In 2000, a 7-valent pneumococcal conjugate vaccine (PCV7) was licensed for use among US children. Many sites have since reported changes in invasive pneumococcal disease (IPD). We recognized an opportunity to describe the changes in epidemiology, clinical syndromes, and serotype distribution during a 14-year period including 4 years before vaccine introduction and spanning the entire PCV7 era. Cases were defined as children <18 years of age who were cared for at Primary Children's Medical Center for culture-confirmed IPD. We defined the prevaccine period as the time frame spanning from 1997 to 2000 and the postvaccine period from 2001 to 2010. Demographics, clinical data, and outcomes were collected through electronic query and chart review. Streptococcus pneumoniae serotyping was performed using the capsular swelling method. The median age of children with IPD increased from 19 months during the prevaccine period to 27 months during postvaccine period (P = 0.02), with a larger proportion of IPD among children older than 5 years. The proportion of IPD associated with pneumonia increased substantially from 29% to 50% (P < 0.001). This increase was primarily attributable to an increase in complicated pneumonia (17% to 33%, P < 0.001). Nonvaccine serotypes 7F, 19A, 22F, and 3 emerged as the dominant serotypes in the postvaccine period. In children with IPD who were younger than 5 years, for whom vaccine is recommended, 67% of the cases were caused by serotypes in 13-valent PCV during 2005 to 2010. After PCV7 was introduced, significant changes in IPD were noted. One-third of IPD occurred in children older than 5 years, who were outside the age-group for which PCV is recommended. Continued surveillance is warranted to identify further evolution of the epidemiology, clinical syndromes, and serotype distribution of S. pneumoniae after 13-valent PCV licensure.

Clinical Presentation of Invasive Pneumococcal Disease in Spain in the Era of Heptavalent Conjugate Vaccine

The aim of this study was to analyze the rate of incidence, clinical presentation, serotype, and clonal distribution of invasive pneumococcal disease (IPD) in the era of heptavalent pneumococcal conjugate vaccine (PCV7) in Barcelona, Spain. This was a prospective study comprising all children <5 years with IPD who were managed in 2 tertiary-care, pediatric hospitals between January 2007 and December 2009. IPD was defined as the presence of clinical findings of infection together with isolation or detection of DNA of Streptococcus pneumoniae in a sterile fluid sample. In this study, 319 patients (53.3% male), mean age 29.6 months, were included. Comparing rates in 2007 and 2009 (76.2 and 109.9 episodes/100,000 population, respectively), an increase of 44% (95% confidence interval, 10%-89%) was observed. The main clinical presentation was pneumonia (254 episodes, 79.6%), followed by meningitis (29, 9.1%), and bacteremia (25, 7.8%).The diagnosis was made by positive culture in 123 (38.6%) patients and in 196 (61.4%) by real-time polymerase chain reaction. Serotype study was performed in 300 episodes, and 273 (91%) were non-PCV7 serotypes. The most frequent serotypes were 1 (20.7%), 19A (15.7%), and 3 (12.3%). A minimal inhibitory concentration ≥0.12 μg/mL to penicillin was detected in 34.4% of isolates. Sequence type 306 expressing serotype 1 was the most frequent clonal type detected (20.3% of studied strains). IPD continues to increase in Barcelona, and the rate is higher than previously reported as a result of low sensitivity of bacterial culture. Non-PCV7 serotypes were responsible for 91% of episodes and pneumonia was the main clinical presentation.

Evolution of the Epidemiology of Pneumococcal Disease Among Utah Children Through the Vaccine Era

From 1996 to 2009, we analyzed changes in pneumococcal disease (PD) in Utah children aged <18 years using International Classification of Diseases, ninth revision coded hospital discharges. We observed a sustained decrease in the incidence of PD among children <5 years in 2001-2004 (-36%) and 2005-2009 (-34%) compared with 1996-2000 (pre-7-valent pneumococcal conjugate vaccine). Decreases were primarily in bacteremia, uncomplicated pneumonia, and meningitis. In contrast, significant increases in complicated pneumonia/empyema were noted in children <5 years (+95% and +85%) and 5 to 17 years (+2% and +70%). Despite decreases in PD among Utah children, complicated pneumonia/empyema has increased during the 7-valent pneumococcal conjugate vaccine era.

Multiple-Locus Variable Number Tandem Repeat Analysis for Streptococcus pneumoniae: Comparison with PFGE and MLST

In the era of pneumococcal conjugate vaccines, surveillance of pneumococcal disease and carriage remains of utmost importance as important changes may occur in the population. To monitor these alterations reliable genotyping methods are required for large-scale applications. We introduced a high throughput multiple-locus variable number tandem repeat analysis (MLVA) and compared this method with pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). The MLVA described here is based on 8 BOX loci that are amplified in two multiplex PCRs. The labeled PCR products are sized on an automated DNA sequencer to accurately determine the number of tandem repeats. The composite of the number of repeats of the BOX loci makes up a numerical profile that is used for identification and clustering. In this study, MLVA was performed on 263 carriage isolates that were previously characterized by MLST and PFGE. MLVA, MLST and PFGE (cut-off of 80%) yielded 164, 120, and 87 types, respectively. The three typing methods had Simpson's diversity indices of 98.5% or higher. Congruence between MLST and MLVA was high. The Wallace of MLVA to MLST was 0.874, meaning that if two strains had the same MLVA type they had an 88% chance of having the same MLST type. Furthermore, the Wallace of MLVA to clonal complex of MLST was even higher: 99.5%. For some isolates belonging to a single MLST clonal complex although displaying different serotypes, MLVA was more discriminatory, generating groups according to serotype or serogroup. Overall, MLVA is a promising genotyping method that is easy to perform and a relatively cheap alternative to PFGE and MLST. In the companion paper published simultaneously in this issue we applied the MLVA to assess the pneumococcal population structure of isolates causing invasive disease in the Netherlands before the introduction of the 7-valent conjugate vaccine.

Pediatric acute mastoiditis in the post–pneumococcal conjugate vaccine era

To determine whether the characteristics of acute mastoiditis in children have changed in the post-heptavalent pneumococcal conjugate vaccine (PCV7) era. Case series. Clinical data for all patients admitted for acute mastoiditis at an urban tertiary children's hospital from July 1, 1996, to June 30, 2009, were reviewed. Patients with a known immune deficiency or cholesteatoma were excluded. Patients were divided into pre-PCV7 (July 1996 to December 2002; n = 38) and post-PCV7 (January 2003 to June 2009; n = 58) groups. Statistical analyses were used to compare the two groups. Ninety-six children met the inclusion criteria. There was a 53% increase in admission for acute mastoiditis in the post-PCV7 era. The pre- and post-PCV7 groups had similar demographic features, presenting history, signs and symptoms, laboratory study results, and medical management. Computed tomography scan abnormalities seen in the two groups were similar except for subperiosteal abscess, which was seen more frequently in the post-PCV7 group. Streptococcus pneumoniae was the most common pathogen isolated in both groups. The patients in the post-PCV7 group had shorter hospital stays, despite undergoing more extensive surgery to address their disease. The number of acute mastoiditis admissions did not decrease with the widespread use of PCV7. Computed tomography findings and surgical procedures required to address acute mastoiditis indicate that the post-PCV7 group had more advanced disease. S pneumoniae remains the main pathogen in acute mastoiditis, and its nonsusceptibility to penicillin and ceftriaxone may be increasing.

Risk Factors for Invasive Pneumococcal Disease in Children in the Era of Conjugate Vaccine Use

We conducted a case-control study to evaluate risk factors for invasive pneumococcal disease (IPD) among children who were aged 3 to 59 months in the era of pneumococcal conjugate vaccine (PCV7). IPD cases were identified through routine surveillance during 2001-2004. We matched a median of 3 control subjects to each case patient by age and zip code. We calculated odds ratios for potential risk factors for vaccine-type and non-vaccine-type IPD by using multivariable conditional logistic regression. We enrolled 782 case patients (45% vaccine-type IPD) and 2512 matched control subjects. Among children who received any PCV7, children were at increased risk for vaccine-type IPD when they had underlying illnesses, were male, or had no health care coverage. Vaccination with PCV7 did not influence the risk for non-vaccine-type IPD. Presence of underlying illnesses increased the risk for non-vaccine-type IPD, particularly among children who were not exposed to household smoking. Non-vaccine-type case patients were more likely than control subjects to attend group child care, be male, live in low-income households, or have asthma; case patients were less likely than control subjects to live in households with other children. Vaccination with PCV7 has reduced the risk for vaccine-type IPD that is associated with race and group child care attendance. Because these factors are still associated with non-vaccine-type IPD risk, additional reductions in disparities should be expected with new, higher valency conjugate vaccines.

Surveillance of invasive pneumococcal disease in 30 EU countries: Towards a European system?

In this era of new pneumococcal conjugate vaccines (PCV), we described and compared surveillance of invasive pneumococcal disease (IPD) and PCV policies in 30 European countries to provide guidance for Europe-wide surveillance. We confirmed the heterogeneity of surveillance systems and case definitions across countries but identified elements common to all countries, such as the availability of serotyping and the surveillance of pneumococcal meningitis. PCV impact was monitored in 11/15 countries using it. We propose steps for the monitoring of incidence rates and serotype distribution at EU level, to assess the need to introduce PCV and monitor its impact once introduced.

Marked Increase in Biofilm-Derived Rough Pneumococcal Variants and Rifampin-Resistant Strains Not Due tohexGene Mutations

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.

Prevalence of Occult Bacteremia in Children Aged 3 to 36 Months Presenting to the Emergency Department with Fever in the Postpneumococcal Conjugate Vaccine Era

The goal of this study was to identify the prevalence of occult bacteremia (OB) in well-appearing, previously healthy children aged 3 to 36 months who present to the emergency department (ED) with fever without source in the post-pneumococcal conjugate vaccine (PCV) era. This was a retrospective cohort study of children presenting to an urban pediatric ED between July 1, 2004, and June 30, 2007. Children were included if they were aged 3 to 36 months, febrile, and previously healthy; had no source of infection on examination; had a blood culture drawn; and were discharged from the ED. Outcome measures were rates of OB and contaminant rates. A total of 8,408 children met all inclusion criteria. There were 21 true-positives, yielding an OB rate of 0.25% (95% confidence interval [CI] = 0.16% to 0.37%). There were 159 contaminant cultures yielding a contaminant rate of 1.89% (95% CI = 1.61% to 2.19%), or a ratio of 7.6 contaminants for each true-positive. There were 14 included patients who grew Streptococcus pneumoniae from the blood, for a rate of 0.17% (95% CI = 0.09% to 0.27%). Given the current rate of OB in the post-PCV era, it may no longer be cost-effective to send blood cultures on well-appearing, previously healthy children aged 3 to 36 months who have fever without source.

Seasonal Invasive Pneumococcal Disease in Children: Role of Preceding Respiratory Viral Infection

Our objective was to demonstrate correlations between invasive pneumococcal disease in children and circulating respiratory viruses. This retrospective study included 6 winter respiratory viral seasons (2001-2007) in Intermountain Healthcare, an integrated health system in the Intermountain West, including Primary Children's Medical Center in Salt Lake City, Utah. Children <18 years of age who were hospitalized with either invasive pneumococcal disease in any Intermountain Healthcare facility or culture-confirmed invasive pneumococcal disease at Primary Children's Medical Center were included. We analyzed the correlation between invasive pneumococcal disease and circulating respiratory viruses. A total of 435 children with invasive pneumococcal disease and 203 with culture-confirmed invasive pneumococcal disease were hospitalized in an Intermountain Healthcare facility or Primary Children's Medical Center during the study period. During the same period, 6963 children with respiratory syncytial virus, 1860 with influenza virus, 1459 with parainfluenza virus, and 818 with adenoviruses were evaluated at Primary Children's Medical Center. A total of 253 children with human metapneumovirus were identified during the last 5 months of the study. There were correlations between invasive pneumococcal disease and seasonal respiratory syncytial virus, influenza virus, and human metapneumovirus activity. The correlation with invasive pneumococcal disease was strong up to 4 weeks after respiratory syncytial virus activity. For influenza virus and human metapneumovirus, the correlations were strong at 2 weeks after activity of these viruses. Pneumonia was the most common clinical disease associated with culture-confirmed invasive pneumococcal disease, mostly attributable to serotypes 1, 19A, 3, and 7F. In the post-pneumococcal conjugate vaccine era, seasonal increases in respiratory syncytial virus, influenza virus, and human metapneumovirus infections in children were associated with increased pediatric admissions with invasive pneumococcal disease, especially pneumonia caused by nonvaccine serotypes.