Invasive Pneumococcal Isolates from Danish Infants (0 - 90 Days) during the Years 1943 to 2013

Background

The seven-valent pneumococcal conjugate vaccine (PCV-7) was introduced in the Danish childhood immunization program (at 3, 5 and 12 months of age) in 2007 and was replaced with PCV-13 in 2010 without changes to the schedule. After the introduction of these vaccines the incidence of invasive pneumococcal disease (IPD) due to vaccine types (VTs) declined markedly in children aged 0–2 years; however, cases among infants too young to be protected by vaccination have not been studied in detail. We present data on IPD in infants less than 90 days from 1943 until 2013.

Study design

The study included all infants younger than 90 days born from 1943 through 2013, who had not been PCV vaccinated and from whom a pneumococcus isolate from blood or cerebrospinal fluid had been submitted to the Danish national reference laboratory. All isolates were serotyped using Pneumotest Latex and Quellung reaction.

Results

A total of 216 IPD cases were identified. The age group specific incidence (total number of IPD cases per 100,000 live births) varied from 0 to 16 in the period 1943 to 2007 and from 1.7 to 9.2 in the period 2008 to 2013. IPD cases due to PCV-7 serotypes were not observed later than 2009.

Conclusion

In Danish infants younger than 90 days, IPD due to PCV-7 serotypes has decreased and has not been observed since 2009, but the total incidence of IPD has not changed.     

Epidemiology of invasive pneumococcal disease in older people in Spain (2007-2009): implications for future vaccination strategies

Background

Recently, the 13-valent pneumococcal conjugate vaccine (PCV13) has been recommended for adults. We analyzed the epidemiology of invasive pneumococcal disease (IPD) in older adults in Spain before PCV13 introduction.

Methodology/Principal Findings

IPD episodes, defined as clinical findings together with an invasive pneumococcal isolate, were prospectively collected from patients aged over 65 years in three hospitals in Spain from 2007 to 2009. A total of 335 IPD episodes were collected. Pneumonia was the main clinical syndrome, while chronic obstructive pulmonary disease, diabetes mellitus and cancer were the main underlying diseases. Pneumococcal isolates were serotyped and the molecular typing was performed by PFGE/MLST. PCV13 serotypes accounted for 59.3% of isolates, the most prevalent being serotypes 19A (15.1%), 3 (9.6%), 7F (7.5%), 14 (6.9%) and 1 (5.4%). The most frequent non-PCV13 serotypes were serotypes 16F (4.5%), 22F (3.6%), 24F (3.3%) and 6C (2.1%). The most common genotypes were CC230 (8.5%, serotypes 19A and 24F), CC156 (8.2%, serotypes 9V and 14), ST191 (7.9%, serotype 7F), CC260 (6.6%, serotype 3), ST306 (5.2%, serotype 1), CC30 (4.6%, serotype 16F) and ST433 (3.6%, serotype 22F). Comparing the 335 IPD isolates to 174 invasive pneumococci collected at the same hospitals in 1999–2000, PCV7 serotypes decreased (45.4% vs 18.4%,p<0.001), non-PCV7 serotypes included in PCV13 increased (26.4% vs 41.0%,p = 0.001) and two non-PCV13 serotypes increased (serotype 6C 0% vs 2.1%, p = 0.05; serotype 24F 0.6% vs 3.3%, p = 0.04,).

Conclusion

In our older adult population two serotypes (19A and 3) included in PCV13 accounted for about a quarter of IPD episodes in people ≥65 years. Non-PCV13 emerging serotypes should be carefully monitored in future surveillance studies.     

Serotype Distribution and Antimicrobial Resistance of Streptococcus pneumoniae Isolates Causing Invasive Diseases from Shenzhen Children’s Hospital

Objective

To provide guidance for clinical disease prevention and treatment, this study examined the epidemiology, antibiotic susceptibility, and serotype distribution of Streptococcus pneumoniae (S. pneumoniae) associated with invasive pneumococcal diseases (IPDs) among children less than 14 years of age in Shenzhen, China.

Materials and Methods

All the clinical strains were isolated from children less than 14 years old from January 2009 to August 2012. The serotypes and antibiotic resistance of strains of S. pneumoniae were determined using the capsular swelling method and the E-test.

Results

A total of 89 strains were isolated and 87 isolates were included. The five prevailing serotypes were 19F (28.7%), 14 (16.1%), 23F (11.5%), 19A (9.2%) and 6B (6.9%). The most common sequence types (ST) were ST271 (21.8%), ST876 (18.4%), ST320 (8.0%) and ST81 (6.9%) which were mainly related to 19F, 14, 19A and 23F, respectively. The potential coverage by 7-, 10-, and 13-valent pneumococcal conjugate vaccine were 77.0%, 77.0%, and 89.7%, respectively. Among the 87 isolates investigated, 11.5% were resistant to penicillin, and for meningitis isolates, the resistance rate was 100%. Multi-drug resistance (MDR) was exhibited by 49 (56.3%) isolates. Eighty-four isolates were resistance to erythromycin, among which, 56 (66.7%) carried the ermB gene alone and 28 (33.3%) expressed both the ermB and mefA/E genes.

Conclusions

The potential coverage of PCV13 is higher than PCV7 and PCV10 because high rates of serotypes 19A and 6A in Shenzhen. The clinical treatment of IPD needs a higher drug concentration of antibiotics. Continued surveillance of the antimicrobial susceptibility and serotypes distribution of IPD isolates may be necessary.     

Population-Based Surveillance for Invasive Pneumococcal Disease in Homeless Adults in Toronto

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 other program to reduce transmission in shelters, harm reduction programs to reduce rates of smoking, alcohol abuse and infection with bloodborne pathogens, and improved treatment programs for HIV infection may all be effective in reducing the risk.     

7-Valent Pneumococcal Conjugate Vaccination in England and Wales: Is It Still Beneficial Despite High Levels of Serotype Replacement?

Background

The UK introduced the 7-valent pneumococcal conjugate vaccine (PCV7) into the national vaccination program in September 2006. Previous modelling assumed that the likely impact of PCV7 on invasive pneumococcal disease (IPD) would be similar to the US experience with PCV7. However, recent surveillance data show a more rapid replacement of PCV7 IPD cases by non-PCV7 IPD cases than was seen in the US.

Methods and Findings

A previous model of pneumococcal vaccination was re-parameterised using data on vaccine coverage and IPD from England and Wales between 2006 and 2009. Disease incidence was adjusted for the increasing trend in reported IPD cases prior to vaccination. Using this data we estimated that individuals carrying PCV7 serotypes have much higher protection (96%;95% CI 72%-100%) against acquisition of NVT carriage than the 15% previously estimated from US data, which leads to greater replacement. However, even with this level of replacement, the annual number of IPD cases may be 560 (95% CI, -100 to 1230) lower ten years after vaccine introduction compared to what it may have been without vaccination. A particularly marked fall of 39% in children under 15 years by 2015/6 is predicted.

Conclusion

Our model suggests that PCV7 vaccination could result in a decrease in overall invasive pneumococcal disease, particularly in children, even in an environment of rapid replacement with non-PCV7 serotypes within 5 years of vaccine introduction at high coverage.     

Ten years of surveillance for invasive Streptococcus pneumoniae during the era of antiretroviral scale-up and cotrimoxazole prophylaxis in Malawi

Objective

To document trends in invasive pneumococcal disease (IPD) in a central hospital in Malawi during the period of national scale-up of antiretroviral therapy (ART) and cotrimoxazole prophylaxis.

Methods

Between 1 January 2000 and 31 December 2009 almost 100,000 blood cultures and 40,000 cerebrospinal fluid (CSF) cultures were obtained from adults and children admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi with suspected severe bacterial infection.

Results

4,445 pneumococcal isolates were obtained over the 10 year period. 1,837 were from children: 885 (19.9%) from blood and 952 (21.4%) from CSF. 2,608 were from adults: 1,813 (40.8%) from blood and 795 (17.9%) from CSF. At the start of the surveillance period cotrimoxazole resistance was 73.8% and at the end was 92.6%. Multidrug resistance (MDR) was present in almost one third of isolates and was constant over time. Free ART was introduced in Malawi in 2004. From 2005 onwards there was a decline in invasive pneumococcal infections with a negative correlation between ART scale-up and the decline in IPD (Pearson''s correlation r = −0.91; p<0.001).

Conclusion

During 2004–2009, national ART scale-up in Malawi was associated with a downward trend in IPD at QECH. The introduction of cotrimoxazole prophylaxis in HIV-infected groups has not coincided with a further increase in pneumococcal cotrimoxazole or multidrug resistance. These data highlight the importance of surveillance for high disease burden infections such as IPD in the region, which will be vital for monitoring pneumococcal conjugate vaccine introduction into national immunisation programmes.     

Effect of Pneumococcal Conjugate Vaccination in Uruguay,a Middle-Income Country

Background

In 2008, a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced into the routine childhood immunization program in Uruguay, with a 2+1 schedule. In 2010, PCV13 replaced PCV7, and the same 2+1 schedule was used. The effect of these pneumococcal vaccines on the incidence of invasive pneumococcal infections (IPD) and on serotype distribution was analyzed retrospectively, based on passive national laboratory surveillance.

Methods

Data from 1,887 IPD isolates from 5 years before and 5 years after PCV7 introduction (7 before and 3 after PCV13 introduction) was examined to assess the incidence rate per 100,000 age-specific population of all IPD, PCV7-serotypes, and PCV13-serotypes associated IPD among children <2 years and 2 to 4 years old, and patients ≥5 years old. Trends of frequency for each serotype were also analyzed.

Results

Comparison of pre-vaccination (2003–2007) and post-vaccination (2008–2012) periods showed a significant decrease in IPD incidence among children <2 years old (IR 68.7 to IR 29.6, p<0.001) and children 2 to 4 years (p<0.04). IPD caused by serotypes in PCV7 was reduced by 95.6% and IPD caused by 6 serotypes added in PCV13 was reduced by 83.9% in children <5 years old. Indirect effects of both conjugate vaccines were observed among patients ≥5 years old one year after the introduction of each vaccine, in 2010 for PCV7 and in 2012 for PCV13. Nevertheless, for reasons that still need to be explained, perhaps due to ascertainment bias, total IPD in this group increased after 2007. In 2012, the relative frequency of vaccine serotypes among vaccinated and unvaccinated population declined, except for serotype 3. Non vaccine serotypes with increasing frequency were identified, in rank order: 12F, 8, 24F, 22F, 24A, 15C, 9N, 10A and 33.

Conclusion

Consecutive immunization with PCV7 and PCV13 has significantly reduced IPD in children <5 years of age in Uruguay.     

Recurrent Invasive Pneumococcal Disease in Children: Underlying Clinical Conditions,and Immunological and Microbiological Characteristics

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.     

Persistent high burden of invasive pneumococcal disease in South African HIV-infected adults in the era of an antiretroviral treatment program

Background

Highly active antiretroviral treatment (HAART) programs have been associated with declines in the burden of invasive pneumococcal disease (IPD) in industrialized countries. The aim of this study was to evaluate trends in IPD hospitalizations in HIV-infected adults in Soweto, South Africa, associated with up-scaling of the HAART program from 2003 to 2008.

Methods

Laboratory-confirmed IPD cases were identified from 2003 through 2008 through an existing surveillance program. The period 2003-04 was designated as the early-HAART era, 2005–06 as the intermediate-HAART era and 2007–08 as the established-HAART era. The incidence of IPD was compared between the early-HAART and established-HAART eras in HIV-infected and–uninfected individuals.

Results

A total of 2,567 IPD cases among individuals older than 18 years were reported from 2003 through 2008. Overall incidence of IPD (per 100,000) did not change during the study period in HIV-infected adults (207.4 cases in the early-HAART and 214.0 cases in the established-HAART era; p = 0.55). IPD incidence, actually increased 1.16-fold (95% CI: 1.01; 1.62) in HIV-infected females between the early-and established-HAART eras (212.1 cases and 246.2 cases, respectively; p = 0.03). The incidence of IPD remained unchanged in HIV-uninfected adults across the three time periods.

Conclusion

Despite a stable prevalence of HIV and the increased roll-out of HAART for treatment of AIDS patients in our setting, the burden of IPD has not decreased among HIV-infected adults. The study indicates a need for ongoing monitoring of disease and HAART program effectiveness to reduce opportunistic infections in African adults with HIV/AIDS, as well as the need to consider alternate strategies including pneumococcal conjugate vaccine immunization for the prevention of IPD in HIV-infected adults.     

Serotypes and Patterns of Antibiotic Resistance in Strains Causing Invasive Pneumococcal Disease in Children Less than 5 Years of Age

Objective

The serotypes and patterns of antibiotic resistance of Streptococcus pneumoniae (S. pneumoniae) strains that cause invasive pneumococcal disease (IPD) in infants were analyzed to provide guidance for clinical disease prevention and treatment.

Methods

The clinical features of confirmed IPD were evaluated in 61 patients, less than 5 years of age, who were admitted to our hospital between January 2009 and December 2011. The serotypes and antibiotic resistance of strains of S.pneumoniae were determined using the capsular swelling method and the E-test.

Results

A total of 61 invasive strains were isolated. The serotype distribution of those isolates were 19A (41.0%), 14 (19.7%), 19F (11.5%), 23F (9.8%), 8 (4.9%), 9V (4.9%), 1 (3.3%), and 4, 6B, and 20 (each 1.6%). The percentage of S. pneumoniae strains resistant to erythromycin, clindamycin, and cotrimoxazole were 100%, 86.9%, and 100%, respectively. The percentage of S. pneumoniae strains resistant to penicillin, amoxicillin/clavulanic acid, cefuroxime, ceftriaxone, cefotaxime, cefepime, and meropenem were 42.6%, 18.0%, 82.0%, 18.0%, 13.1%, 13.1%, and 36.1%, respectively. The percentage of multidrug-resistant strains was 95.6%. Strains of all serotypes isolated in this study were highly resistant to erythromycin, cotrimoxazole, and clindamycin. Strains with serotype 19A had the highest rates of resistance.

Conclusions

Serotype 19A strains were most frequently isolated from children with IPD treated in our hospital. The strains causing IPD are highly resistant to antibiotics.     

Invasive Pneumococcal Disease in Healthy Adults: Increase of Empyema Associated with the Clonal-Type Sweden(1)-ST306

Background

Adult invasive pneumococcal disease (IPD) occurs mainly in the elderly and patients with co-morbidities. Little is known about the clinical characteristics, serotypes and genotypes causing IPD in healthy adults.

Methods

We studied 745 culture-proven cases of IPD in adult patients aged 18–64 years (1996–2010). Patients were included in two groups: 1.) adults with co-morbidities, and 2.) healthy adults, who had no prior or coincident diagnosis of a chronic or immunosuppressive underlying disease. Microbiological studies included pneumococcal serotyping and genotyping.

Results

Of 745 IPD episodes, 525 (70%) occurred in patients with co-morbidities and 220 (30%) in healthy adults. The healthy adults with IPD were often smokers (56%) or alcohol abusers (18%). As compared to patients with co-morbidities, the healthy adults had (P<0.05): younger age (43.5+/−13.1 vs. 48.7+/−11.3 years); higher proportions of women (45% vs. 24%), pneumonia with empyema (15% vs. 7%) and infection with non-PCV7 serotypes including serotypes 1 (25% vs. 5%), 7F (13% vs. 4%), and 5 (7% vs. 2%); and lower mortality (5% vs. 20%). Empyema was more frequently caused by serotype 1. No death occurred among 79 patients with serotype 1 IPD. There was an emergence of virulent clonal-types Sweden¹-ST306 and Netherlands^7F-ST191. The vaccine serotype coverage with the PCV13 was higher in healthy adults than in patients with co-morbidities: 82% and 56%, respectively, P<0.001.

Conclusion

In this clinical study, one-third of adults with IPD had no underlying chronic or immunosuppressive diseases (healthy adults). They were often smokers and alcohol abusers, and frequently presents with pneumonia and empyema caused by virulent clones of non-PCV7 serotypes such as the Sweden¹-ST306. Thus, implementing tobacco and alcohol abuse-cessation measures and a proper pneumococcal vaccination, such as PCV13 policy, in active smokers and alcohol abusers may diminish the burden of IPD in adults.     

Pneumococcal Serotypes and Mortality following Invasive Pneumococcal Disease: A Population-Based Cohort Study

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.     

Impact of Preceding Flu-Like Illness on the Serotype Distribution of Pneumococcal Pneumonia

Background

Even though the pathogenicity and invasiveness of pneumococcus largely depend on capsular types, the impact of serotypes on post-viral pneumococcal pneumonia is unknown.

Methods and Findings

This study was performed to evaluate the impact of capsular serotypes on the development of pneumococcal pneumonia after preceding respiratory viral infections. Patients with a diagnosis of pneumococcal pneumonia were identified. Pneumonia patients were divided into two groups (post-viral pneumococcal pneumonia versus primary pneumococcal pneumonia), and then their pneumococcal serotypes were compared. Nine hundred and nineteen patients with pneumococcal pneumonia were identified during the study period, including 327 (35.6%) cases with post-viral pneumococcal pneumonia and 592 (64.4%) cases with primary pneumococcal pneumonia. Overall, serotypes 3 and 19A were the most prevalent, followed by serotypes 19F, 6A, and 11A/11E. Although relatively uncommon (33 cases, 3.6%), infrequently colonizing invasive serotypes (4, 5, 7F/7A, 8, 9V/9A, 12F, and 18C) were significantly associated with preceding respiratory viral infections (69.7%, P<0.01). Multivariate analysis revealed several statistically significant risk factors for post-viral pneumococcal pneumonia: immunodeficiency (OR 1.66; 95% CI, 1.10–2.53), chronic lung diseases (OR 1.43; 95% CI, 1.09–1.93) and ICI serotypes (OR 4.66; 95% CI, 2.07–10.47).

Conclusions

Infrequently colonizing invasive serotypes would be more likely to cause pneumococcal pneumonia after preceding respiratory viral illness, particularly in patients with immunodeficiency or chronic lung diseases.     

Streptococcus pneumoniae serotype-2 childhood meningitis in Bangladesh: a newly recognized pneumococcal infection threat

Background

Streptococcus pneumoniae is a leading cause of meningitis in countries where pneumococcal conjugate vaccines (PCV) targeting commonly occurring serotypes are not routinely used. However, effectiveness of PCV would be jeopardized by emergence of invasive pneumococcal diseases (IPD) caused by serotypes which are not included in PCV. Systematic hospital based surveillance in Bangladesh was established and progressively improved to determine the pathogens causing childhood sepsis and meningitis. This also provided the foundation for determining the spectrum of serotypes causing IPD. This article reports an unprecedented upsurge of serotype 2, an uncommon pneumococcal serotype, without any known intervention.

Methods and Findings

Cases with suspected IPD had blood or cerebrospinal fluid (CSF) collected from the beginning of 2001 till 2009. Pneumococcal serotypes were determined by capsular swelling of isolates or PCR of culture-negative CSF specimens. Multicenter national surveillance, expanded from 2004, identified 45,437 patients with suspected bacteremia who were blood cultured and 10,618 suspected meningitis cases who had a lumber puncture. Pneumococcus accounted for 230 culture positive cases of meningitis in children <5 years. Serotype-2 was the leading cause of pneumococcal meningitis, accounting for 20.4% (45/221; 95% CI 15%–26%) of cases. Ninety eight percent (45/46) of these serotype-2 strains were isolated from meningitis cases, yielding the highest serotype-specific odds ratio for meningitis (29.6; 95% CI 3.4–256.3). The serotype-2 strains had three closely related pulsed field gel electrophoresis types.

Conclusions

S. pneumoniae serotype-2 was found to possess an unusually high potential for causing meningitis and was the leading serotype-specific cause of childhood meningitis in Bangladesh over the past decade. Persisting disease occurrence or progressive spread would represent a major potential infection threat since serotype-2 is not included in PCVs currently licensed or under development.     

High Nasopharyngeal Carriage of Non-Vaccine Serotypes in Western Australian Aboriginal People Following 10 Years of Pneumococcal Conjugate Vaccination

Background

Invasive pneumococcal disease (IPD) continues to occur at high rates among Australian Aboriginal people. The seven-valent pneumococcal conjugate vaccine (7vPCV) was given in a 2-4-6-month schedule from 2001, with a 23-valent pneumococcal polysaccharide vaccine (23vPPV) booster at 18 months, and replaced with 13vPCV in July 2011. Since carriage surveillance can supplement IPD surveillance, we have monitored pneumococcal carriage in western Australia (WA) since 2008 to assess the impact of the 10-year 7vPCV program.

Methods

We collected 1,500 nasopharyngeal specimens from Aboriginal people living in varied regions of WA from August 2008 until June 2011. Specimens were cultured on selective media. Pneumococcal isolates were serotyped by the quellung reaction.

Results

Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis were carried by 71.9%, 63.2% and 63.3% respectively of children <5 years of age, and 34.6%, 22.4% and 27.2% of people ≥5 years. Of 43 pneumococcal serotypes identified, the most common were 19A, 16F and 6C in children <5 years, and 15B, 34 and 22F in older people. 7vPCV serotypes accounted for 14.5% of all serotypeable isolates, 13vPCV for 32.4% and 23vPPV for 49.9%, with little variation across all age groups. Serotypes 1 and 12F were rarely identified, despite causing recent IPD outbreaks in WA. Complete penicillin resistance (MIC ≥2µg/ml) was found in 1.6% of serotype 19A (5.2%), 19F (4.9%) and 16F (3.2%) isolates and reduced penicillin susceptibility (MIC ≥0.125µg/ml) in 24.9% of isolates, particularly 19F (92.7%), 19A (41.3%), 16F (29.0%). Multi-resistance to cotrimoxazole, tetracycline and erythromycin was found in 83.0% of 23F isolates. Among non-serotypeable isolates 76.0% had reduced susceptibility and 4.0% showed complete resistance to penicillin.

Conclusions

Ten years after introduction of 7vPCV for Aboriginal Australian children, 7vPCV serotypes account for a small proportion of carried pneumococci. A large proportion of circulating serotypes are not covered by any currently licensed vaccine.     

Systematic Evaluation of Serotypes Causing Invasive Pneumococcal Disease among Children Under Five: The Pneumococcal Global Serotype Project

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     

Antimicrobial Resistance among Isolates Causing Invasive Pneumococcal Disease before and after Licensure of Heptavalent Conjugate Pneumococcal Vaccine

Background

The impact of the pneumococcal conjugate vaccine (PCV-7) on antibiotic resistance among pneumococcal strains causing invasive pneumococcal disease (IPD) has varied in different locales in the United States. We assessed trends in IPD including trends for IPD caused by penicillin non-susceptible strains before and after licensure of PCV-7 and the impact of the 2008 susceptibility breakpoints for penicillin on the epidemiology of resistance.

Methodology/Principal Findings

We performed a retrospective review of IPD cases at Morgan Stanley Children''s Hospital of NewYork-Presbyterian, Columbia University Medical Center. Subjects were ≤18 years of age with Streptococcus pneumoniae isolated from sterile body sites from January 1995–December 2006. The rate of IPD from 1995–1999 versus 2002–2006 significantly decreased from 4.1 (CI₉₅ 3.4, 4.8) to 1.7 (CI₉₅ 1.3, 2.2) per 1,000 admissions. Using the breakpoints in place during the study period, the proportion of penicillin non-susceptible strains increased from 27% to 49% in the pre- vs. post-PCV-7 era, respectively (p = 0.001), although the rate of IPD caused by non-susceptible strains did not change from 1995–1999 (1.1 per 1,000 admissions, CI₉₅ 0.8, 1.5) when compared with 2002–2006 (0.8 per 1,000 admissions, CI₉₅ 0.6, 1.2). In the multivariate logistic regression model controlling for the effects of age, strains causing IPD in the post-PCV-7 era were significantly more likely to be penicillin non-susceptible compared with strains in the pre-PCV-7 era (OR 2.46, CI₉₅ 1.37, 4.40). However, using the 2008 breakpoints for penicillin, only 8% of strains were non-susceptible in the post-PCV-7 era.

Conclusions/Significance

To date, there are few reports that document an increase in the relative proportion of penicillin non-susceptible strains of pneumococci causing IPD following the introduction of PCV-7. Active surveillance of pneumococcal serotypes and antibiotic resistance using the new penicillin breakpoints is imperative to assess potential changes in the epidemiology of IPD.     

Monitoring the long-term molecular epidemiology of the pneumococcus and detection of potential 'vaccine escape' strains

Background

While the pneumococcal protein conjugate vaccines reduce the incidence in invasive pneumococcal disease (IPD), serotype replacement remains a major concern. Thus, serotype-independent protection with vaccines targeting virulence genes, such as PspA, have been pursued. PspA is comprised of diverse clades that arose through recombination. Therefore, multi-locus sequence typing (MLST)-defined clones could conceivably include strains from multiple PspA clades. As a result, a method is needed which can both monitor the long-term epidemiology of the pneumococcus among a large number of isolates, and analyze vaccine-candidate genes, such as pspA, for mutations and recombination events that could result in ‘vaccine escape’ strains.

Methodology

We developed a resequencing array consisting of five conserved and six variable genes to characterize 72 pneumococcal strains. The phylogenetic analysis of the 11 concatenated genes was performed with the MrBayes program, the single nucleotide polymorphism (SNP) analysis with the DNA Sequence Polymorphism program (DnaSP), and the recombination event analysis with the recombination detection package (RDP).

Results

The phylogenetic analysis correlated with MLST, and identified clonal strains with unique PspA clades. The DnaSP analysis correlated with the serotype-specific diversity detected using MLST. Serotypes associated with more than one ST complex had a larger degree of sequence polymorphism than a serotype associated with one ST complex. The RDP analysis confirmed the high frequency of recombination events in the pspA gene.

Conclusions

The phylogenetic tree correlated with MLST, and detected multiple PspA clades among clonal strains. The genetic diversity of the strains and the frequency of recombination events in the mosaic gene, pspA were accurately assessed using the DnaSP and RDP programs, respectively. These data provide proof-of-concept that resequencing arrays could play an important role within research and clinical laboratories in both monitoring the molecular epidemiology of the pneumococcus and detecting ‘vaccine escape’ strains among vaccine-candidate genes.     

Effect of serotype on focus and mortality of invasive pneumococcal disease: coverage of different vaccines and insight into non-vaccine serotypes

Background

Differences in pathogenicity between pneumococcal serotypes are important when assessing the potential benefit of different valency vaccines. We investigated the effect of serotype on clinical presentation, outcome, and quality of life lost from invasive pneumococcal disease (IPD) in the context of the 7, 10, and 13 valent pneumococcal conjugate vaccines (PCV7, PCV10, PCV13).

Method

Serotyped IPD cases in England were linked to the national dataset of hospital admissions for April 2002 to March 2011. Based on patients’ diagnostic codes and vital status at the end of the admission, disease focus (meningitis, empyema, sepsis, or respiratory disease) and case fatality rates by serotype and age group (5, 5–64, and 65 years and over) were obtained. Using these data the quality adjusted life years (QALY) lost from the IPD remaining when use of PCV7 stopped in 2010 was estimated for the serotypes covered by higher valency vaccines.

Results

The linked dataset contained 23,688 cases with information on diagnosis, mortality, and serotype. There were significant differences between serotypes in the propensity to cause meningitis, death, and QALY loss in each of the investigated age groups. As a result, vaccines’ coverage of disease burden differed by endpoint. For example, in children under 5 years in 2009/10, PCV10 covered 39% of meningitis, 19% of deaths and 28% of the QALY loss of attributable to IPD, whereas the respective percentages for PCV13 were 65%, 67%, and 66%. The highest QALY loss per serotype in this age group was for 6A. Non-PCV serotypes causing the highest QALY loss were 22F and 33F in <5 year olds and 31 in older individuals.

Conclusion

Marked differences exist between serotypes in clinical presentation and outcome, and these should be considered when evaluating the potential impact of higher valency vaccines on overall disease burden and associated QALY loss.     

Evaluation of coseasonality of influenza and invasive pneumococcal disease: results from prospective surveillance

Background

The wintertime co-occurrence of peaks in influenza and invasive pneumococcal disease (IPD) is well documented, but how and whether wintertime peaks caused by these two pathogens are causally related is still uncertain. We aimed to investigate the relationship between influenza infection and IPD in Ontario, Canada, using several complementary methodological tools.

Methods and Findings

We evaluated a total number of 38,501 positive influenza tests in Central Ontario and 6,191 episodes of IPD in the Toronto/Peel area, Ontario, Canada, between 1 January 1995 and 3 October 2009, reported through population-based surveillance. We assessed the relationship between the seasonal wave forms for influenza and IPD using fast Fourier transforms in order to examine the relationship between these two pathogens over yearly timescales. We also used three complementary statistical methods (time-series methods, negative binomial regression, and case-crossover methods) to evaluate the short-term effect of influenza dynamics on pneumococcal risk. Annual periodicity with wintertime peaks could be demonstrated for IPD, whereas periodicity for influenza was less regular. As for long-term effects, phase and amplitude terms of pneumococcal and influenza seasonal sine waves were not correlated and meta-analysis confirmed significant heterogeneity of influenza, but not pneumococcal phase terms. In contrast, influenza was shown to Granger-cause pneumococcal disease. A short-term association between IPD and influenza could be demonstrated for 1-week lags in both case-crossover (odds ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.10 [1.02–1.18]) and negative binomial regression analysis (incidence rate ratio [95% confidence interval] for one case of IPD per 100 influenza cases  = 1.09 [1.05–1.14]).

Conclusions

Our data support the hypothesis that influenza influences bacterial disease incidence by enhancing short-term risk of invasion in colonized individuals. The absence of correlation between seasonal waveforms, on the other hand, suggests that bacterial disease transmission is affected to a lesser extent. Please see later in the article for the Editors'' Summary