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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arch Intern Med. Author manuscript; available in PMC Apr 26, 2011.
Published in final edited form as:
PMCID: PMC2946166
NIHMSID: NIHMS159659

The changing role of exposure to children as a risk factor for bacteremic pneumococcal disease in the post conjugate vaccine era

Abstract

Background

The introduction of a pneumococcal conjugate vaccine has been associated with a shift in the serotypes responsible for bacteremic pneumococcal disease. We sought to examine recent trends in serotypes responsible for disease and examine current risk factors among adults.

Methods

48 acute care hospitals in the 5 county region surrounding Philadelphia provided data from 10/1/02-9/30/08 on all hospitalized adult patients with community-acquired bacteremic pneumococcal disease. Isolates were serotyped and patient characteristics were compared to data from a household survey of the adult population in the region.

Results

Over the study period, the annual rate of disease due to vaccine serotypes declined by 29% per year, but the rate of disease due to non-vaccine serotypes increased 13% per year, yielding an overall 7% increase in the annual rate of disease among adults. Advanced age was a risk factor for infection with non-vaccine serotypes compared to vaccine serotypes. Comparing all patients to the source population, African Americans were at increased risk of infection and the presence of additional children in the home was associated with decreased risk of disease. Smoking, advanced age and diabetes mellitus remain important risk factors in adults.

Conclusions

New serotypes are replacing the serotypes covered in the conjugate vaccine. While some risk factors for pneumococcal disease remain unchanged, the observation that exposure to children in the home is associated with lower risk of disease, suggests that the changing epidemiology of pneumococcal disease may be altering the dominant modes of transmission in the community.

In February 2000, the Food and Drug Administration licensed a new conjugate pneumococcal vaccine (Prevnar, Wyeth Lederle Vaccines) which was subsequently recommended by the American Academy of Pediatrics and Advisory Committee on Immunization Practices for use in children 2 years of age and younger as well as older, high risk children.1, 2 The vaccine includes 7 capsular polysaccharide serotypes (4, 6B, 9V,14,18C, 19F and 23F) conjugated to an immunogenic carrier protein.

The conjugate vaccine has been shown to dramatically reduce the risk of invasive pneumococcal disease in infants.3 In addition, the vaccine significantly reduces the carriage of pneumococcal serotypes covered by the vaccine.4, 5 Introduction of the conjugate vaccine has been associated with statistically significant declines in the rates of invasive disease in adults.6, 7 However recent reports are concerning in terms of the emergence of non-vaccine serotypes among children,8, 9 and adults 7 with invasive disease.

Serotype replacement is an important process to study not only because of its impact on the overall benefit of the vaccine but also because different pneumococcal serotypes possess different absolute and relative potentials for establishing the carrier state and causing invasive disease.10 Thus, it is plausible that as serotype replacement occurs, risk factors for infection may change.

The aim of this study was to examine trends in serotypes responsible for bacteremic pneumococcal disease in adults and identify risk factors for disease in the post conjugate vaccine era. We were particularly interested in the role of exposure to children as a risk factor in the post conjugate vaccine era.

METHODS

Study Design

Data were collected as part of population-based surveillance for bacteremic pneumococcal disease within the 5 county region surrounding Philadelphia (Bucks, Chester, Delaware, Montgomery, Philadelphia counties). Adult (age ≥ 18 years) population surveillance was initiated in October 2002. The surveillance network currently encompasses 48 of the 49 acute-care hospitals that serve the 3.7 million residents of the five counties. The one non-participating hospital is a small hospital, closed to external studies and accounting for < 2% of all cases in the region.

Study Subjects

Subjects were initially identified through the microbiology laboratories at all hospitals. Hospital personnel were contacted by study personnel on a regular basis throughout the surveillance period in order to assure complete capture of new cases. We confirmed the total number of eligible cases through contact with laboratory directors and review of their log books on an annual basis, as well as comparison with data from the City of Philadelphia Health Department under a mandatory reporting of cases of pneumococcal bacteremia.11

Eligible patients were hospitalized adults residing in the five county region, with at least one set of blood cultures positive for S. pneumoniae drawn within 48 hours of hospitalization, and no prior hospitalization within ten days of the episode of pneumococcal bacteremia. Laboratory personnel provided the study with the name of the treating physician and physician permission was obtained to contact eligible patients and conduct a telephone interview.

Telephone Interview

Trained telephone interviewers completed a telephone interview with each subject (or a proxy in the case of impaired subjects or children) covering demographic and clinical areas as previously reported.12 In particular, subjects reported the number and age of children living in the household prior to the onset of illness, as well as additional information on race/ethnicity, and underlying chronic illnesses. Because we were unable to validate self-reported vaccine histories, we did not include vaccine history in these analyses. The interview instrument is provided in an Appendix. Twelve percent of all adults identified with bacteremic pneumococcal disease died prior to contact for this study. In these cases, interviews were attempted with a family member and if they were not available, we were granted a waiver of authorization to abstract data from the medical record. Forty-one percent of these patients had their medical records reviewed and in 33% we completed an interview with a family member or caregiver.

Medical Record Review

We obtained a waiver of authorization to abstract information from the hospital record for those eligible subjects who could not be contacted by telephone (35% of all eligible subjects including deceased patients as noted above). Trained medical record abstractors collected information parallel to the telephone interview, including demographic variables and medical comorbitidies.

Population Data

For the analysis of overall population trends in disease rates, we used adult population estimates from the U.S. Census population intercensal estimates for 2002, 2003, 2004, 2005, 2006 and 2007. These county-level population estimates are based on the 2000 decennial Census, with annual population adjustments based on sampling and boundary adjustments (http://www.census.gov/popest/archives/2000s/vintage_2007/). Since our analyses focused on October 1 through September 30 analysis periods, we used the estimated population denominator of the year at the start of the observation period for each annual incidence rate calculation. For the analysis of population risk groups for the 10/05–9/08 period, we estimated population denominator counts based on a 5-county random digit dial survey of the surveillance region. The Philadelphia Health Management Corporation (PHMC) conducts a biannual weighted probabilistic survey of the population in the 5 county region, called the Southeastern Pennsylvania Household Health Survey (SPHHS).13 We used population estimates from the 2006 SPHHS for these analyses.

The 2006 survey included 10,100 adults age ≥ 18 years. Each individual in the dataset (or their proxy) was contacted by telephone interview and data were collected that included information on basic demographic and household factors, along withchronic health information, such as whether participants had ever been diagnosed with diabetes, or asthma, or were currently smoking.

Microbiological Analysis

All pneumococcal isolates were transported to the central laboratory at the Hospital of the University of Pennsylvania. Serotyping of all pneumococcal isolates was performed according to standard methods using the Quellung reaction.14, 15 All sera were purchased from the Statens Serum Institut (WHO Collaborating Centre for Reference and Research on Pneumococci) and constitute 14 pooled sera, 62 factor sera and 22 type sera. A total of 5.5% of all pneumococcal isolates could not be serotyped (3.7% were not viable after shipping and 1.7% were untypable). In order to account for untyped isolates, rates of disease by vaccine and non-vaccine serotypes were proportionally inflated in each year in order to match the total rate of disease in that year.

Statistical Analysis

We calculated overall and serotype specific rates of disease in each year (October 1 through September 30) from October 1, 2002 through September 30, 2008. We analyzed secular trends using Poisson regression using annual count data and fitting linear terms for each surveillance year. To adjust for overdispersion in the Poisson regression model, Pearson scale adjustment was applied. We explored higher order terms for year and also attempted to fit cubic splines but the simple linear model was the best fit for the data. We categorized all isolates with serotype results into vaccine serotypes (one of the seven included in the conjugate vaccine) vs. non-vaccine serotypes (all remaining serotypes), and calculated annual rates of disease attributed to each of these two subgroups.

We conducted two comparative analyses for all cases identified from 10/05–9/08. First, we compared patient characteristics between cases of pneumococcal bacteremia due to vaccine serotypes vs. non-vaccine serotypes. Second, we examined potential population risk factors for bacteremic pneumococcal disease including all pneumococcal serotypes. For the first set of analyses, we used simple logistic regression for comparisons, fitting one variable models for each tested characteristic. We planned to fit multivariable models only if multiple factors were significant on initial bivariable analysis. For the second set of analyses, we calculated demographic and clinical subgroup specific annual rates of disease, with 95 % confidence limits, using weighted population estimates from the SPHHS survey. The SPHHS uses probabilistic geographic sampling across the five counties. The inverse of the sampling probabilities provided sample weights for creating population projections and accounted for the complex sample design in the SPHS. Multivariable Poisson regression using the projection weights was then used to estimate adjusted relative rates and their respective 95% CIs, where population appears as an offset in the model. In order to address the issue of missing data in the model, we completed a second multivariable regression using multiple imputation. We used ICE (imputation by chained equations) in Stata,16, 17 to impute missing values of the covariates in the regression models. ICE is a multivariate approach that uses the conditional distribution of each covariate given other predictor variables, to cycle between filling the missing values for each covariate. We implemented the default approach, which repeats the imputation process 5 times, to create 5 data sets with complete data. We then conducted Poisson regression on each imputed data set and combined the results using Proc MI in SAS. As a separate analysis, we reran the multivariable model excluding patients with documented HIV in order to assess the degree to which HIV infection might confound the relationship between children in the home and disease risk.

All analyses were completed with Stata 10 and SAS 9.1, with two sided tests of hypothesis and a p-value <0.05 as the criterion for statistical significance.

RESULTS

Secular trends in pneumococcal disease

From October 1, 2002 through September 30, 2008, we identified a total of 2418 adult cases of pneumococcal bacteremia from the acute care hospital network within the 5-county Philadelphia region. The figure plots the annual rate of adult cases for the study period, starting at 12.8 cases per 100,000 in 2002–2003 and ending at 15.4 cases per 100,000 in 2007–2008. The annual rate of disease demonstrated a significant positive linear trend (p=.007) with an estimated relative increase of 7% per year. In 2002–2003, annual rates of disease were 5.8, 12.9, 30.0, 63.2 cases per 100,000 for adults age 18–49, 50–64, 65–79 and ≥ 80 years, respectively. In 2007–2008, annual rates of disease were 7.9, 18.9, 26.8, and 53.6 cases per 100,000 for adults age 18–49, 50–64, 65–79, and ≥ 80 years, respectively.

figure nihms159659f1
Annual rate of adult bacteremic pneumococcal disease

Overall, 13% of adult cases were due to one of the seven serotypes contained within the conjugate vaccine. The figure plots the annual rate of disease due to vaccine and non-vaccine serotypes over the study period. The rate of disease due to vaccine serotypes significantly declined over the observation period (RR = 0.71 per year, 95% CI 0.67, 0.75). In contrast, we observed a significant linear increase in non vaccine serotypes (RR=1.13 per year, 95% CI 1.08, 1.19). Among specific non-vaccine serotypes, the greatest relative increase was seen in 19A from 0.8 cases per 100,000 in 2002–2003 to 3.4 cases per 100,000 in 2007–2008.

Comparison of patients with pneumococcal bacteremia due to vaccine vs. non-vaccine serotypes

Detailed clinical and demographic information were collected on all cases from October 1, 2005-September 30, 2008. (Table 1) Forty-three percent of cases were age 65 years or older. Fifty percent of cases were males, 63% were white, non-Hispanic and 48% lived in the city of Philadelphia. Current smoking was documented for 67% of cases, HIV infection for 13%, and asthma for 15%.

Table 1
Characteristics of patients with bacteremic pneumococcal disease 10/05–09/08

During this three-year period, 6% of cases were due to one of the seven serotypes contained in the conjugate vaccine. We compared vaccine cases with all other non-vaccine cases. Vaccine cases were younger, but otherwise did not differ demographically or clinically (Table 2).

Table 2
Comparison of adults with bacteremic disease due to vaccine serotypes vs. non vaccine serotypes.*

Risk factors for bacteremic disease due to any pneumococcal serotype

Table 3 summarizes subgroup specific annual rates of bacteremic pneumococcal disease. Adults 18–49 experienced 8.3 cases per 100,000 compared to 59.4 cases per 100,000 among adults 80 years and older. Annual rate of disease was higher in urban Philadelphia county (19.1 cases per 100,000) compared to outlying suburban and rural counties (13 cases per 100,000). Annual rate of disease was higher in African Americans (26.4 cases per 100,000) compared to whites (13.7 cases per 100,000) Rate of disease also declined with increasing number of children in the home. Adults living in homes with no children < 7 years experienced 21.5 cases per 100,000 compared to 3.3 cases per 100,000 among adults living with 2 or more children in the home. Rates of disease were higher in smokers and patients with diabetes mellitus.

Table 3
Annual population rates of bacteremic pneumococcal disease among adults

In multivariable models adjusting for all of the factors examined in Table 3, increasing numbers of children in the home remained a protective factor (Table 4). For example, compared to having no children < 7 years in the home, adults with two or more children in the home had a 76% relative reduction in the risk of bacteremic pneumococcal disease, even after adjusting for age (RR = .24, 95% CI 0.18, 0.33). African American race, current smoking, and diabetes mellitus remained significant risk factors for adults in the adjusted models.

Table 4
Adjusted risk factors for bacteremic pneumococcal disease.*

We conducted additional analyses to explore the relationship between the number of children in the home and risk of bacteremic pneumococcal disease. To better adjust for age in the analyses, we conducted stratified analyses using 10 year age increments (e.g., 20–29, 30–39, etc.) In these stratified analyses, the presence of two or more children in the home was associated with a significant reduced risk of disease for adults age 30–39, 40–49, 50–59, and 80 years and older (RR = 0.2, 0.1, 0.5, and 0.2, respectively, all p < .05). For the age groups 60–69 and 70–79, the association between children in the home and risk of disease was not significant. Using these finer age increments, compared to adults without children in the home, the adjusted risk of disease were 44% lower for adults with one child in the home (RR = 0.56, 95% CI 0.45, 0.71) and 78% lower for adults with two or more children in the home (RR = 0.22, 95% CI 0.17, 0.30). In order to address the role of missing data in the multivariable analysis, we completed multiple imputation to generate multiple data sets without missing data. In the combined multivariable adjusted result with all imputed datasets, compared to adults with no children in the home, adults with two or more children had a 78% reduced risk of bacteremic pneumococcal disease (RR = .22, 95% CI 0.17, 0.30). Finally, in order to exclude confounding effects of HIV infection, we also examined the association between children in the home and risk of disease in the subgroup of cases without documented HIV infection. In this analysis, compared to adults without children in the home, the adjusted incidence rates of disease were 47% lower for adults with one child in the home (RR =.53, 95% CI 0.40, 0.71) and 70% lower for adults with two or more children in the home (RR =0.3, 95% CI 0.21, 0.41).

DISCUSSION

Active surveillance for bacteremic pneumococcal disease in adults since 2002 in the greater Philadelphia region demonstrated a small but significant increase in the annual rate of disease. This increase was due to increased rates of disease due to non-vaccine serotypes while disease due to vaccine serotypes continued to decline over this time period. Patients with bacteremic pneumococcal disease due to vaccine serotypes were demographically and clinically similar to patients with disease due to non-vaccine serotypes, except that patients with non-vaccine serotypes were older. In terms of overall risk of bacteremic pneumococcal disease, certain well established risk factors remained important including African American race, advanced age, smoking, and diabetes mellitus. However, one striking new finding is that the presence of additional children in the home was associated with decreased risk of disease, even after adjusting for other demographic and clinical factors.

Risk factors for pneumococcal disease have been recognized for some time and used to inform vaccine policy. These factors include extremes of age, African American race, and several comorbidities including chronic heart and lung diseases, HIV infection, diabetes mellitus, and smoking history.1820 Recent studies have demonstrated that the increased risk of disease among African Americans compared to whites has narrowed since the introduction of conjugate vaccine,21 but our study demonstrates that the risk remains elevated. Our study was unable to explore the continuing role of other established risk factors (e.g., HIV) because data on the population distribution of these factors was not available in the household survey we used to measure the distribution of these factors in the source population. .

Prior studies from the pre-conjugate vaccine era demonstrated that the presence of children in the home, particularly children in day care, was associated with increasing risk of pneumococal disease.19 Children are well known to be a major reservoir for pneumococcal bacteria and thought to be a primary source for bacterial spread in the community. However, with the introduction of the conjugate vaccine, patterns of pneumococcal carriage in children have shifted dramatically. As a result, it is possible that children are no longer a primary source of infection for adults and the absence of children in the home may be a marker of other factors that lead adults to have increased exposure to alternative sources of pneumococci. Adults without children in the household may have increased exposure to other populations that transmit pneumococcal disease. For example, they may spend more time outside the home in settings that are higher risk for transmission now that transmission from children has been reduced by the vaccine. Alternatively, adults with children in the home may have reduced prevalence of other comorbidities that are associated with disease risk, including chronic heart and lung diseases or other immunosuppressive disorders.

Our results suggest that replacement disease is disproportionately affecting older adults. A recent report from the CDC’s Active Bacterial Core Surveillance Network also noted that since introduction of the conjugate vaccine, adults with comorbidities represent an increasing proportion of cases with invasive pneumococcal disease.22 Earlier reports indicated that invasive disease was declining in older adults as a result of pediatric vaccination campaigns, a form of herd immunity. However, serotype replacement may ultimately reverse these gains and also increase the prevalence of disease in higher risk adults.

Our observations are consistent with other surveillance studies that have highlighted the rise in invasive disease due to non-vaccine serotypes. Over a 5 year period, we observed a significant increase in the rates of disease due to non-vaccine serotypes, including a > four-fold rise in the rate of disease due to 19A. During this time period, vaccine related disease declined by 80%. Notably, our surveillance began two years after introduction of the conjugate vaccine, so it is highly likely that the full impact of the vaccine on disease due to vaccine serotypes has been even greater and the rate of disease in adults in 2008 is likely still lower than in the pre-conjugate vaccine era. For example, results from the Centers for Disease Control and Prevention’s Active Bacterial Core Surveillance program reported the incidence of invasive pneumococcal disease in 1998 as 23, 46.4, and 98.5 cases per 100,000 for adults age 50–64, 65–79, and ≥80 years,18 which are all higher than the age-group specific rates we observed in 2007–2008. Regardless, the total rate of disease in adults has risen during the period 2002–2008. In addition, the observation that disease due to vaccine serotypes declined while disease due to non-vaccine serotypes increased suggests that these patterns are not due to changes in testing of adults with suspected bacteremic disease.

From a health policy perspective, it is unclear whether the observed increases in invasive and non-invasive disease due to non-vaccine serotypes, especially 19A, are the result of the introduction of conjugate vaccine. In the U.S., multiple reports have emphasized that serotype replacement is temporally related to the introduction of conjugate vaccine in 2000.9, 20, 22, 23 However, in other countries, serotype replacement was observed prior to the introduction of conjugate vaccine,24 suggesting that other secular forces (e.g., antimicrobial drug use patterns, socioeconomic conditions) may underline trends in pneumococcal serotype epidemiology.25 The emergence of these serotypes emphasizes the importance of newer conjugate vaccine formulations, including a conjugate vaccine with 13 serotypes that includes 19A, which is currently under review.

Our study has some limitations, most notably that we were unable to compare the full range of potential risk factors for bacteremic pneumococcal disease due to limited data on the source population. Also, some clinical and demographic data were missing on many of the subjects who were unable to complete telephone interviews and therefore had medical record abstractions. In addition, our measures of population rates of disease relied on hospital-based clinical testing, which would be sensitive to changes in testing practices and would fail to detect non-hospitalized cases of the disease.

In conclusion, over the last 6 years, there has been a significant increase in the rate of disease due to pneumococcal serotypes not included in the conjugate vaccine. At the moment, the reduction in disease due to vaccine serotypes still exceeds the level of increase due to non-vaccine serotypes. The changing epidemiology of pneumococcal disease may be leading to important shifts in risk factors for the disease. Continued surveillance will allow us to monitor ongoing patterns of disease in order to develop and target newer strategies for the prevention of pneumococcal disease.

ACKNOWLEDGMENTS

Funding sources: This project was supported by grants R01-AI46645 and K24-AI073957 (JPM) from the National Institute of Allergy and Infectious Diseases, National Institutes of Health. The funding agency had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or preparation, review or approval of the manuscript.

The authors acknowledge the valuable contributions of Linda Crossette, MPH, for coordinating the activities of this study, and the staff at the Clinical Microbiology Laboratory of the Hospital of the University of Pennsylvania for the microbiology testing.

Footnotes

Author Contributions:

Conception and design (JPM, EL, PHE)

Acquisition of data (JPM, PHE)

Analysis and interpretation of data (JPM, EL, YL, JS, PHE)

Drafting of the manuscript (JPM, YL, JS)

Critical revision of the manuscript (JPM, EL, YL, JS, PHE)

Statistical analysis (JPM, YL, JS)

Obtaining funding (JPM, EL, PHE)

Administrative, technical or material support (JPM, EL, JS, PHE)

Supervision (JPM, PHE)

Dr. Metlay had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflicts of Interest: Dr. Lautenbach has received research funding from Merck, Ortho-McNeil, Astra-Zeneca, and Cubist pharmaceuticals. None of the other authors have any conflicts of interest or financial disclosures.

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