Published online September 1, 2004
PEDIATRICS Vol. 114 No. 3 September 2004, pp. 755-761 (doi:10.1542/peds.2003-0592-F)
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Population-Based Impact of Pneumococcal Conjugate Vaccine in Young Children

Katherine A. Poehling, MD, MPH*, Bonnie J. Lafleur, PhD, MPH{ddagger}, Peter G. Szilagyi, MD, MPH§, Kathryn M. Edwards, MD*, Ed Mitchel, MS||, Richard Barth, MS§, Benjamin Schwartz, MD and Marie R. Griffin, MD, MPH||,#,**

* Departments of Pediatrics
{ddagger} Biostatistics
|| Preventive Medicine
# Medicine
** Center for Education and Research on Therapeutics, Vanderbilt University Medical Center, Nashville, Tennessee
§ Department of Pediatrics and Strong Children's Research Center, University of Rochester School of Medicine and Dentistry, Rochester, New York
New Vaccine Surveillance Network, Centers for Disease Control and Prevention, Atlanta, Georgia


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Objective. To determine the population impact of pneumococcal conjugate vaccine (PCV) on pneumococcal-related diseases, including pneumonia and otitis media.

Methods. Using administrative data from Tennessee Medicaid and 3 commercial insurance plans in upstate New York, we measured annual rates of medical visits for pneumococcal-related diseases (pneumococcal and nonspecific pneumonia and invasive disease; otitis media) and pneumococcal-unrelated diseases (other acute respiratory illnesses). Disease rates before (1995–2000 in Tennessee; 1998–2000 in New York) and after (2000–2002) PCV licensure were calculated for children aged <2 years (eligible for PCV) and those 3 to 5 years (not routinely given PCV). Because annual variations should affect both age groups similarly and vaccine-related outcomes should preferentially decline in younger children, ratios (<2:3–5 years) of disease rates before and after PCV licensure were compared. Expected disease rates were calculated for children aged <2 years in each postvaccine year. The difference between observed and expected disease rates was the estimated vaccine effect.

Results. In 2001–2002, there were 67 380 and 9485 child-years of observation for Tennessee and New York children aged <2 years, respectively. We observed fewer visits for pneumonia and invasive disease per 1000 children than expected in both regions: 20 fewer emergency department or outpatient visits in Tennessee and 33 fewer outpatient visits in New York. Otitis media visits declined by 118 and 430 per 1000 children in Tennessee and New York, respectively.

Conclusions. Adding PCV to the childhood immunization schedule was associated with a 10-fold greater reduction in pneumonia and a 100-fold greater reduction in otitis media than the previously reported reduction in culture-confirmed invasive pneumococcal diseases of 1.3 episodes per 1000 children aged <2 years. Although additional studies are needed to confirm the impact of routine immunization with PCV on pneumococcal-related disease, these results suggest that its impact is substantially greater than the effects on invasive disease alone.

Key Words: pneumococcal conjugate vaccine • otitis media • pneumonia • Streptococcus pneumoniae

Abbreviations: PCV, pneumococcal conjugate vaccine • CI, confidence interval • ICD-9, International Classification of Diseases, 9th Revision • ED, emergency department

Streptococcus pneumoniae is the leading bacterial cause of meningitis, bacteremia, pneumonia, and otitis media in the United States.1–6 Children aged <2 years, adults aged ≥65 years, and people with specific high-risk medical conditions experience the highest rates of pneumococcal disease.1,5 In the Northern California efficacy trial of heptavalent pneumococcal conjugate vaccine (PCV; Prevnar, Wyeth Lederle Vaccines, Madison, NJ), children who received PCV had a 94% (95% confidence interval [CI]: 80%–99%) decline in invasive pneumococcal disease,7 an 11% (95% CI: 1%–20%) decrease in pneumonia,8 and a 7% (95% CI: 5%–9%) reduction in otitis media.9 In the Finnish PCV efficacy trial, PCV decreased overall otitis media rates by 6% (95% CI: –4% to 16%).10 Soon after PCV licensure in February 2000, the American Academy of Pediatrics and the Advisory Committee for Immunization Practices recommended routine administration of PCV to all children at 2, 4, 6, and 12 to 15 months of age.2,11 By August 2000, 81% of primary care physicians in Nashville, Tennessee, and Rochester, New York, reported offering PCV to patients aged 2 to 11 months.12 Data from the National Immunization Survey for children aged 19 to 35 months in 2002 indicated that the proportion of children who had at least 3 PCV immunizations was 40.8% for the United States, 41.8% for Tennessee, and 53.3% for New York State (excluding New York City; www.cdc.gov/nis/datafiles.htm). In a population-based analysis of the impact of PCV in the United States, Whitney et al13 reported a remarkable 69% decline (~1.3 fewer episodes per 1000 children) in culture-confirmed invasive pneumococcal disease in children aged <2 years by 2001.

The impact of routine PCV immunization on all pneumococcal-related diseases, including 1) pneumococcal and nonspecific pneumonia and invasive disease and 2) otitis media, is currently unknown. Using a similar ecologic approach to Whitney et al,13 we evaluated administrative data for large populations of children in Tennessee and upstate New York to determine the impact of PCV on pneumococcal-related disease among children aged <2 years.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Study Design
We performed an ecologic analysis in 2 geographically distinct populations to estimate the impact of PCV introduction on pneumococcal-related disease rates. Annual rates of medical visits for pneumococcal-related diseases were calculated for children aged <2 years and 3 to 5 years before and after PCV licensure. National surveillance data after PCV licensure demonstrated a striking decline in invasive pneumococcal diseases for children aged <2 years, a smaller decline for children 2 years of age, and no decline in children ≥3 years.13 Therefore, we evaluated the impact of PCV by comparing children aged <2 years, the age group with evidence of a large vaccine effect on invasive disease, with those 3 to 5 years, an age group with no evidence of a vaccine effect on invasive disease. Although disease rates for different age groups varied by study year, the ratios (<2:3–5 years) of disease rates in the prevaccine years were stable. Using these ratios, the 95% prediction intervals were computed to detect statistically significant reductions in ratios of disease rates in postvaccine years compared with 5 pre-PCV baseline years in Tennessee. In an alternative, less conservative analysis, we used 2 years of baseline data, available for both Tennessee and New York populations, to estimate expected disease rates for children aged <2 years in the postvaccine years. Expected and observed disease rates were compared to estimate the vaccine effect.

Sources of Data
TennCare is Tennessee's managed care program for Medicaid enrollees and uninsured individuals in which each enrollee selects from 1 of 10 managed care organizations. The TennCare database has been used extensively for health services research.14–19 During the study period, it included 50% of children who were born in Tennessee, with a high proportion of children from racial/ethnic minority groups and low-income families. Data from July 1995 to June 2000 were used to establish baseline rates of medical visits before PCV licensure.

The upstate New York database contains data from 3 commercial insurance managed care organizations: 1 independent practice association–model health maintenance organization and 2 physician hospital organizations. These 3 commercial insurance plans provided coverage for nearly 70% of children in the region during the study period. Two years (July 1998 to June 2000) of medical data were available to establish baseline disease rates.

Study Population
Children who were aged 0 to 5 years and enrolled in TennCare or in commercial insurance plans of upstate New York at birth or for at least 1 year were included. Tennessee children entered the first day of eligibility after June 30, 1995; New York children entered the first day of eligibility after June 30, 1998, the first year of data availability. Data on each child were analyzed for each day that the child remained enrolled until July 1, 2002, 6 years of age, loss of enrollment, or death. Institutional Review Boards of Vanderbilt University, the State of Tennessee, University of Rochester, and the Centers for Disease Control and Prevention approved this study.

Definitions of Study Time Periods and Age Groups
Study years antedating routine administration of PCV (baseline) were July 1995 to June 2000 in Tennessee and July 1998 to June 2000 in New York. During the transition year (July 2000 to June 2001), providers began using PCV12 and culture-confirmed invasive pneumococcal disease in children aged <2 years fell 12% in Tennessee (4 urban counties participating in national surveillance for invasive pneumococcal disease) and 66% in New York (Monroe and surrounding counties participating in national surveillance) compared with 1998–2000 rates. During the post-PCV year (July 2001 to June 2002), invasive pneumococcal disease in children aged <2 years fell 72% in Tennessee and 93% in New York as compared with 1998–2000. Invasive pneumococcal disease among children aged 3 to 5 years remained relatively stable throughout the study period, similar to the data from Whitney et al.13

Study Outcomes
All medical events were categorized by International Classification of Diseases, 9th Revision (ICD-9) codes as 1 of 3 mutually exclusive disease groups in the following hierarchical order: 1) pneumonia or invasive disease specified as pneumococcal or in which there was no specified organism, subsequently referred to as "pneumonia and invasive disease"; 2) otitis media; and 3) other acute respiratory illnesses, as previously defined.20 Pneumonia and invasive disease composed all medical visits with an ICD-9 code for meningitis, septicemia, peritonitis, pneumonia, or unspecified site with S pneumoniae or no specified organism. Otitis media composed all medical visits with an ICD-9 code for acute otitis media. Only the first 2 disease groups—1) pneumonia and invasive disease and 2) otitis media—were considered pneumococcal-related diseases because S pneumoniae causes a large portion of these diagnoses.3,6,21,22 Other acute respiratory illnesses encompassed all medical visits with an ICD-9 code for pneumonia with an organism other than S pneumoniae, as well as influenza, bronchitis, bronchiolitis, pharyngitis, sinusitis, upper respiratory tract infection, and asthma. Although S pneumoniae may cause a few other acute respiratory illnesses, other organisms cause the large majority of these illnesses.

Each medical encounter was categorized in the following hierarchical order: hospitalization, emergency department (ED) visit, or outpatient visit by the Physicians' Current Procedural Terminology, 4th Edition codes, as previously described.20 When multiple medical encounters occurred on the same day, the highest medical encounter in this hierarchy was used for data analysis.

Statistical Analysis
Disease rates equaled the total number of medical visits divided by the age-specific child-years for each study year; these rates were expressed per 1000 child-years. On the basis of previous PCV efficacy studies, we assumed that full implementation of PCV should prevent 10% to 40% of pneumonia and invasive disease and 6% to 7% of otitis media episodes while having little or no effect on other acute respiratory illnesses for children aged <2 years.7,9,10

In an earlier study, using the same population but confined to pre-PCV years, we found substantial yearly variability in medical visits for pneumococcal-related diseases.20 The Active Bacterial Core Surveillance network data also indicate annual variability, with lower rates of culture-confirmed invasive pneumococcal disease among children aged <5 years in 1997 than in 1998 and 1999.23–25 Because pneumococcal-related disease rates varied annually, whereas the relationship between rates in younger and older children remained relatively stable, we analyzed the ratio of rates. The ratio for each disease group equaled the disease rate for children aged <2 years divided by that for children aged 3 to 5 years. Prediction intervals (for a new observation) were calculated using all individual disease ratios from July 1995 to June 2000 for Tennessee to establish the expected limits at baseline. Ratios outside the 95% prediction intervals in post-PCV years were considered significant. With only 2 years of baseline data, we could not calculate valid prediction intervals for New York.

We used an alternative, less conservative analytic approach that was applied to both Tennessee and New York study populations and calculated a baseline average ratio for each disease group using data from July 1998 to June 2000. CIs around these average ratios were calculated using the method discussed by Gart and Nam26 using the first-order variance estimates of the log limits.27,28 Expected rates for children aged <2 years equaled the average ratio antedating PCV use multiplied by the observed rates for children aged 3 to 5 years after PCV use. The difference in expected and observed disease rates for children aged <2 years equaled the estimated reduction in pneumococcal-related diseases per 1000 child-years attributable to PCV.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
The TennCare population included 442 281 child-years for those aged <2 years and 586 027 child-years for the comparison group of children aged 3 to 5 years. The New York commercial insurance population included 44 233 and 77 540 child-years aged <2 and 3 to 5 years (Table 1). The proportion of children with high-risk conditions, defined according to the Advisory Committee on Immunization Practices,2 was stable in both populations. However, the proportion of children who were aged <2 years and had high-risk conditions was 2-fold higher in Tennessee than in New York. The proportion of children with asthma was stable in Tennessee but increased by one third in New York and approached the proportion seen in Tennessee in the 3- to 5-year age group.


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  		TABLE 1. Population Characteristics During the Three Study Periods in Tennessee and New York

 
Baseline Disease Rates
Rates of all medical visits for pneumonia and invasive disease among children aged <2 years were higher in Tennessee (110–135 per 1000 child-years) than in New York (87 per 1000 child-years), whereas rates for children aged 3 to 5 years overlapped at 44 to 53 per 1000 child-years. Rates of otitis media visits were higher in New York (2125–2247 and 795–903 per 1000 child-years aged <2 years and 3–5 years) than in Tennessee (1775–2019 and 471–562 per 1000 child-years aged <2 years and 3–5 years). Rates of other acute respiratory illnesses were similar in both populations and age groups (~1550 and 930 per 1000 child-years aged <2 and 3–5 years, respectively).

Ratio of Total Disease Rates
To control for annual variability in disease rates, we calculated the ratios (<2:3–5 years) of disease rates for each study year and population. For both populations, the computed ratios of pneumonia and invasive disease rates varied little in the baseline years before declining in 2001–2002 in Tennessee and in both post-PCV years in New York (Fig 1A). After PCV licensure, ratios of otitis media rates progressively declined in both populations (Fig 1B). In the post-PCV years, ratios of other acute respiratory illnesses fluctuated modestly in Tennessee and declined in both years in New York (Fig 1C).


Figure 1
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  		Fig 1. Ratios of rates for pneumonia and invasive disease (A), otitis media (B), and other acute respiratory illnesses (C) for children aged <2 years:3–5 years in Tennessee ({diamondsuit}) and New York ({diamond}) with 95% prediction intervals shown for Tennessee only.

 
Five years of baseline data in Tennessee allowed for calculation of "prediction intervals" (Fig 1). None of the total post-PCV ratios was outside these prediction intervals. However, the ratio for total visits for pneumonia and invasive disease in 2001–2002 was at the lower bound of the prediction interval. In addition, when specific sites for pneumonia and invasive disease visits were examined, there was a 16% decline in hospitalizations and a 17% decline in outpatient visits, which were below the prediction intervals. No other site-specific outcomes were outside their prediction intervals.

In the less conservative, alternative analysis applied to both populations, the average ratio of disease rates and 95% CI in the 2 baseline years were compared with the ratios in the transition and post-PCV years (Table 2). By 2001–2002, there were significant declines in ED (18%) and outpatient visits (17%) for pneumonia and invasive disease among Tennessee children. In New York, declines in outpatient visits for pneumonia and invasive disease in the transition (31%) and postvaccine years (34%) also represented significant changes from baseline. Ratios of otitis media visits in the ED and outpatient settings declined significantly by 2001–2002 compared with baseline, with larger respective declines in New York (41% and 19%) than in Tennessee (16% and 4%). After PCV licensure, ratios of outpatient visits for other acute respiratory illnesses in Tennessee fluctuated; in New York, these outpatient visits decreased 10% and 11% in the transition and postvaccine years, respectively.


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  		TABLE 2. Average Ratio (Pre–PCV) and Observed Ratios (Children Aged <2 Years:3–5 Years) of Pneumococcal–Related Diseases and Percentage Change in 2000–2001 (Transition Year) and 2001–2002 (Post–PCV)

 
Estimated Vaccine Effects
We computed the difference between observed rates of disease for children aged <2 years in each postvaccine year and rates expected on the basis of the product of 1) the average ratios in the 2 prevaccine years and 2) observed rates in children aged 3 to 5 years (see Methods). Significant declines in pneumonia and invasive disease in 2001–2002 represented 8 and 12 fewer ED and outpatient visits, respectively, per 1000 Tennessee children and 33 fewer outpatient visits per 1000 New York children (Table 3). Significant declines in ED and outpatient visits for otitis media were noted in both regions. For Tennessee, there were 56 and 62 fewer ED and outpatient visits, respectively, per 1000 children. For New York, there were 34 and 396 fewer ED and outpatient visits, respectively, per 1000 children.


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  		TABLE 3. Expected and Observed Rates of Pneumococcal–Related Diseases per 1000 Children Aged Younger Than 2 Years and the Rate Difference (Observed–Expected) in 2000–2001 and 2001–2002

 
Changes in rates of other acute respiratory illnesses varied. In Tennessee, there was a significant decline and then rise in outpatient visits. The 10% and 11% declines in outpatient visits for other respiratory illness in New York represented 169 and 180 fewer visits, respectively, per 1000 children.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
We provide the first data that demonstrate a decline in all pneumococcal-related diseases, not just invasive disease, in children aged <2 years since the introduction of PCV in the United States. An ecologic analysis was chosen for 2 reasons: 1) it is particularly useful for interventions with a high population uptake over a short period of time, and 2) it evaluates changes over time in the entire population and hence avoids the selection bias associated with comparing vaccinated and unvaccinated children. After the introduction of PCV, culture-confirmed invasive pneumococcal disease decreased for children aged <2 years but not for those aged 3 to 5 years.13 Assuming that all children are subject to similar annual variations and secular trends in disease rates,20,23–25 we controlled for these factors by using ratios (<2:3–5 years) of disease rates to evaluate changes after PCV introduction. If PCV were selectively effective in children aged <2 years, then the ratio (<2:3–5 years) of pneumococcal-related disease rates should decrease.

Pneumonia and otitis media, most of which are not culture confirmed, are diagnosed much more frequently than invasive disease. Overall, diagnoses for pneumococcal or nonspecific pneumonia and invasive disease decreased by 18% in Tennessee and 31% in New York. In comparison, culture-confirmed invasive pneumococcal disease decreased by 69% in a post-PCV licensure ecologic analysis and by 94% in the Northern California trial.7,13 Despite a smaller percentage decrease in all pneumonias and invasive disease, the absolute declines in medical visits for these events were 20 to 30 per 1000 children, >10-fold greater than the decline reported for invasive disease alone.

In terms of otitis media rates, the 1 to 2 cases of otitis media per child-year in the pre-PCV years are consistent with data from Colorado Medicaid and from control groups of 2 PCV trials.7,10,29 In Tennessee, overall rates of otitis media decreased by 6%, which is remarkably similar to the 7% and the 6% decrease reported in the Northern California and Finnish trials, respectively.9,10 Overall rates of otitis media decreased by 20% in upstate New York. Although this was greater than expected, a 17% decrease in otitis media was reported in a 9-valent PCV trial of Israeli children who were aged 1 to 2 years and enrolled in child care. The 9-valent PCV provided coverage for the same proportion of S pneumoniae serotypes that cause otitis media in Israel as the 7-valent PCV provided in the United States and Finland.30 Overall declines in otitis media were >100-fold greater than declines in invasive disease in children aged <2 years.

In Tennessee, overall pneumococcal-related disease rates decreased, whereas rates of other acute respiratory illnesses fluctuated. The 3% increase in Tennessee in 2001–2002 may reflect a shift in the diagnosis of respiratory illnesses away from pneumococcal-related diseases. In contrast, there was no evidence for a shift of diagnoses to other categories in New York, where rates of other acute respiratory illnesses decreased in both postvaccine years. This decline was unexpected, because this category was selected specifically to represent disease unrelated to pneumococcal organisms. However, the Israeli clinical trial referred to above also reported that children who received PCV had 15% and 16% fewer upper and lower respiratory tract infections, respectively. Another possible explanation is that population changes in New York, which included an increasing proportion of older children with asthma (Table 1) and increasing disease rates among children aged 3 to 5 years in the postvaccine years, resulted in exaggerated declines in the ratios in New York children aged <2 years for all disease categories. Although the explanation for the greater-than-expected declines in New York remains uncertain, that the greatest declines in New York were in the 2 pneumococcal-related disease categories is reassuring.

Differences in the 2 populations may account for some discrepancies in rates of disease, ratios, and percentage changes after PCV implementation. Differences in insurance plans in Tennessee (Medicaid) and New York (commercial) may reflect differential access to medical care, access to primary and preventive care, socioeconomic status, parental education, and child care attendance. Medical visits for these conditions may also vary by geographic region.20 Previous studies have noted lower hospitalization rates for asthma in Rochester, New York, compared with other communities.31,32 Other differences in the 2 study populations included the sample size and number of years of data. Using the more robust 95% prediction intervals in Tennessee, hospitalizations and outpatient visits for pneumonia and invasive disease significantly declined. Total visits for pneumonia and invasive disease and otitis media approached the lower bounds of the prediction interval. With larger numbers in Tennessee, the 95% CIs of the average ratio from 1998 to 2000 were narrower in Tennessee than in New York. Given differences in sample sizes, relatively small changes in outpatient visits for other acute respiratory illnesses were statistically different from the baseline ratios, whereas the increases in hospitalizations were not statistically significant.

These results need to be interpreted in light of several limitations. The PCV status of children in the postvaccine years is not known. However, the greater decrease in culture-confirmed pneumococcal disease in New York (92%) than in Tennessee (69%) suggests that New York had a higher uptake of PCV. Study results were limited to the people who qualified for TennCare and New York commercial insurance. Because eligibility criteria for Medicaid varies from state to state, results from Tennessee may not be representative of all Medicaid populations. Administrative databases may contain errors or inconsistency in diagnostic codes; multiple visits for a single episode of illness may be indistinguishable; and only visits that are billed are included. Lack of confirmation of pneumococcal disease as the causative agent for our study outcomes is a limitation, but even careful clinical investigation of outcomes such as pneumonia and otitis media face this limitation. Because PCV shortages in 2001–2002 may have decreased the vaccination rate, declines in pneumococcal-related diseases may be higher in future years. Studies are needed to confirm these results in other populations and in study years without PCV shortages. As diagnostic and therapeutic practices change and as invasive pneumococcal disease becomes less common, it will be important to monitor other pneumococcal- and non–pneumococcal-related outcomes.


   CONCLUSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
Coinciding with PCV use, overall rates of pneumonia and invasive disease decreased 19 to 33 per 1000 children per year. Similarly, overall rates of otitis media decreased by 125 to 430 per 1000 children per year. Because of the high prevalence of pneumonia and otitis media, the impact of PCV on pneumonia and otitis media in our study was 10-fold and 100-fold greater than the reported decrease of 1.3 culture-confirmed invasive pneumococcal diseases per 1000 children in 2001 as reported by the Centers for Disease Control and Prevention.13 Using data from the Kaiser Permanente PCV clinical trial, Black et al33 estimated that for every episode of invasive disease prevented, PCV would prevent 4.4 pneumonias and 83 otitis media episodes. In fact, in a cost-effectiveness analysis, these latter events accounted for a large portion of the estimated costs averted with vaccination and rendered PCV similar to varicella and hepatitis B vaccines in cost effectiveness.33 Our data suggest that in our study populations, PCV is meeting these expectations for reduction of pneumonia and otitis media.


   ACKNOWLEDGMENTS
 
This work was supported in part by cooperative agreements U38/CCU417958 from the Centers for Disease Control and Prevention and U50/CCU30086, TS-0825 from American Teachers of Preventive Medicine/Centers for Disease Control and Prevention. Dr Poehling is supported by the Robert Wood Johnson Foundation’s Generalist Physician Faculty Scholar program.

We thank William O. Cooper, MD, MPH, for critique of this manuscript.


   FOOTNOTES
 
Accepted Dec 22, 2003.

Reprint requests to (M.R.G.) Department of Preventive Medicine, Vanderbilt University Medical Center, A-1110 Medical Center North, Nashville, TN 37232-2637. E-mail: marie.griffin{at}vanderbilt.edu


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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PEDIATRICS (ISSN 1098-4275). ©2004 by the American Academy of Pediatrics



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