It has been demonstrated repeatedly that PCV7 has substantially reduced IPD among vaccinated children. Our data extend these observations to show significant reductions in IPD and pneumococcal pneumonia in all age groups. Our modeling results indicate that the vaccine has prevented nearly 800,000 hospitalizations for pneumococcal pneumonia in the United States during the period from 2000 to 2006. We note that 90% of the model-attributed pneumococcal pneumonia and 95% of the nonbacteremic pneumococcal pneumonia reductions were in adults ≥18 years old. These data show that indirect effects were responsible for most of the burden of pneumococcal disease prevented, although a substantial burden of both lobar and all-cause pneumonia remains.
The reductions in IPD we found in 10 states correspond closely to observations based on data from the CDC Active Bacterial Core (ABC) surveillance sites (9
). By 2006, we found reductions of 80% and 65% in all-serotype IPD among infants <2 years old and children 2 to 4 years old, respectively, while Pilishvili et al. found a reduction of 76% among all children <5 years old. Similarly, for adults ≥65 years old, we found a reduction of all-serotype IPD of 47% by 2006, while Pilishvili et al. reported a reduction of 37% by 2007. This gives us confidence that using ICD-coded data can produce results similar to those of studies using laboratory-confirmed cases only. Moreover, Pilishvili et al. also observed that the declines in IPD rates were specific to events caused by the seven serotypes of S. pneumoniae
in the vaccine; this key observation provides strong evidence that the vaccine in fact caused the reductions demonstrated here. Our analysis, however, cannot separate vaccine-type reductions from non-vaccine-type disease because ICD9 codes are not strain specific. Although the pattern of reductions in IPD incidence in our study reflects that observed in the CDC’s population-based ABC surveillance data, the baseline rates in our study (27.8 cases/100,000 in infants <2 years old and 30.6 cases/100,000 in adults ≥65 years old) are lower than those reported in the ABC study (56.8 and 60 cases/100,000, respectively) for the same time period (6
). Unlike the ABC sites, no audit is possible in our study to identify missed cases. Our estimates of hospitalized patients with IPD therefore represent an underestimate of the true burden due to this condition.
Grijalva et al. (11
) studied trends in pneumococcal and all-cause pneumonia rates before and after the year 2000. They attributed the changing trends in these outcomes before and after PCV7 introduction to the benefits of the vaccine (11
). They found that introduction of PCV7 vaccine coincided with declines in pneumococcal pneumonia rates in infants <2 years old. They also found a trend toward a reduction in pneumococcal pneumonia rates in adults ≥65 years old, although it was not statistically significant. However, while they did observe a reduction in pneumococcal pneumonia hospitalizations in infants <2 years old, among children 2 to 4 years old, this reduction was significant in 2004 (11
) but no longer so in 2006 (25
), even though this age group had achieved high PCV7 coverage by 2006. We found the lowest reduction (17%) in pneumococcal pneumonia in this age group and a nonsignificant reduction of 12% when bacteremic cases were excluded. The pneumococcal types included in PCV7 decrease in frequency after 2 years of age, and the proportion of nonvaccine types is therefore greater above that age (26
). Children who get pneumonia at 2 to 4 years of age tend to have a greater frequency of risks, such as group child care. These risks continue to make them susceptible to non-PCV7 types, so that replacement disease has a larger impact on this age group than on infants <2 years of age (27
). Nelson et al. conducted a comprehensive, population-based evaluation of trends in pneumonia and influenza (P&I) rates in a health maintenance organization population and found a nonsignificant 40% decline in the rates of hospitalization of infants for community-acquired pneumonia from 1998 to 2004, with no consistent evidence of a decline in adult rates and thus no evidence of indirect PCV7 benefits (28
). However, this study was of a smaller population (~800,000), and the severe 2003–2004 Fujian A/H3N2 influenza season likely led to increased P&I rates in the post-PCV period and an underestimation of vaccine program benefits.
Our study extends these findings using a longer time series, 100% state inpatient data, and all identified (not just primary diagnosis) cases. It also introduces a novel modeling approach to overcome the nonspecificity of the all-cause pneumonia endpoint, with the result that we find significant reductions in pneumococcal pneumonia in all age groups after the PCV7 launch in the United States. A primary goal of our investigation was to tease out the specific effects of PCV7 vaccination on pneumococcal pneumonia rates. In particular, we wanted to look at the age-specific effect of the vaccine on the total pneumococcal pneumonia burden, including both the “tip of the iceberg” that is indicated by the ICD9 481 code and the much larger “under-the-waterline” portion that, although caused by S. pneumoniae infection, is not diagnosed as such. We believe that model-attributed pneumococcal pneumonia, being more specific to S. pneumoniae infection, is a more telling outcome than all-cause pneumonia, which is affected by many viral and bacterial infections that PCV7 cannot prevent.
To attribute the pneumococcal pneumonia portion of all-cause pneumonia, we adapted statistical methods that influenza epidemiologists have long used to attribute a portion of the winter rise in pneumonia hospitalizations and deaths to influenza (29
). Specifically, we modified the approach of Thompson et al. (16
), which relied on the time pattern of laboratory-confirmed illness due to RSV and influenza virus to estimate the portion of hospitalizations related to influenza (16
). We, however, used ICD-coded hospitalizations specific to respiratory pathogens and included hospitalizations due not only to influenza virus and RSV infections but also to pneumococcal pneumonia. In this regard, we followed Pitman et al. (22
) in that we included time patterns for multiple pathogens to attribute a portion of the observed all-cause pneumonia pattern to each pathogen. Doing so allowed us to estimate the proportion of all-cause pneumonia attributable to S. pneumoniae
infection while controlling for pneumonia associated with the other two pathogens.
Regarding our modeling of the reductions in burden, with the exception of all-cause pneumonia, we found significant reductions in hospitalizations for each age group and for each outcome (IPD and observed and model-attributed pneumococcal pneumonia) across all age groups, with patterns very much like those estimated from ABC data derived from laboratory-confirmed IPD cases. For all-cause pneumonia, however, we found a significant burden reduction only among infants <2 years old and a nonsignificant reduction of 200,000 hospitalizations across all age groups (). We attribute this result to the fact that all-cause pneumonia is the least specific outcome analyzed and particularly susceptible to variability in influenza severity between seasons. For example, across all age groups at the baseline (1996–1997 through 1998–1999), our model attributes ~30% of what is coded as all-cause pneumonia to pneumococcal infection and 7% to influenza across all age groups.
Another goal of our investigation was to assess the effect of PCV7 on influenza-related pneumonia. The variability of influenza season severity confounded our time series modeling efforts. We therefore studied state differences in influenza-attributed pneumonia within single seasons, taking advantage of between-state differences in PCV7 coverage up through the 2003–2004 season, when the recommendation for influenza immunization was extended to children and <10% of young children were fully immunized against influenza (32
). We used a Poisson regression technique to evaluate whether, for each age group and season, states with higher coverage had significantly greater reductions than those with lower coverage. Because we included the baseline of each state and age group as a covariate, each acted as its own control for bias resulting from interstate differences in socioeconomic status and other potential confounders.
In these single-season analyses, we found that reductions in model-attributed influenza-related pneumonia hospitalization were significantly associated with higher PCV7 coverage for the first four seasons after vaccine use began; although the trend was toward reduction among seniors, the results were not significant (). The window of time within which there was significant variance between states in PCV coverage and before there was widespread herd immunity to the PCV7 types in the United States was limited to these seasons. During this time, we see an association of 10% PCV7 coverage variance with significant 39 to 50% reductions in influenza-associated pneumonia in infants <2 years old. This is similar in magnitude to the observation of a 45% reduction in influenza-associated pneumonia hospitalization among African infants <2 years old who received PCV9 vaccination in an environment in which the PCV9 types accounted for only half of the types causing disease in that age group (21
). These data suggest that the majority of influenza-associated pneumonia hospitalizations in this age group may be due to pneumococcal coinfection.
Although the associated reductions with influenza are encouraging, we also note that the model failed to detect significant reductions for IPD in seniors (column 2, ) although ABC data have shown it and we have already demonstrated it in and . This was likely the result of instability of the model as only few datapoints were available for single-year analysis. Although the estimates for rate reductions in IPD produced by our single-year analysis have wide confidence intervals (CIs), the estimates agree reasonably well with those produced by our multiyear model, namely, 0.81 and 0.93 for the youngest and oldest age groups, respectively, per 10 percentage point increase in PCV7 coverage. This helps to increase our confidence in our model-attributed influenza-related pneumonia results.
We recognize at least three potential limitations of our study. First, we relied on ICD9 codes for the status of the inpatients we studied. The cases were not ascertained by medical chart review, and thus, our approach assumes that physicians assigned ICD9-coded diagnoses correctly. Specifically, since ICD9 code 481 is indicated for cases of S. pneumoniae or lobar pneumonia, we cannot know whether the doctor reached that conclusion from laboratory testing, X-ray results, or clinical judgment; however, because the temporal trend resembles that of IPD in our study, we can argue that the 481 code is capturing the “ground truth” reduction in pneumococcal disease. Moreover, because only a small subset (10 to 20%) of all records with ICD9 code 481 also have IPD codes, we can assume that in most cases ICD9 code 481 represents clinical lobar pneumonia rather than microbiologically defined pneumococcal pneumonia.
Second, the method we used to attribute a portion of all-cause pneumonia to S. pneumoniae infection (Poisson regression modeling) assumes that the trends and patterns in the ICD-coded explanatory variables changed over time only as a result of vaccine effectiveness. If, for example, the PCV7 program had caused physicians to become less likely to diagnose S. pneumoniae infection and use ICD9 code 481—because they submitted samples for testing less frequently after the vaccine was introduced, for example—then the model would tend to overestimate the benefits of the PCV7 program. Although this phenomenon may have occurred in outpatient settings, we think it less likely for the diagnosis of inpatients, because hospital physicians may be more responsive to medical and economic imperatives to order laboratory testing to determine the etiology of their patients’ illnesses.
Third, we did not take into account aging within the senior age group; an increasing percentage of seniors are over 80 years of age, and the risk of pneumonia hospitalization increases with age. This may explain, in part, the finding that the all-cause pneumonia hospitalization rate did not decrease over time in the oldest age group (). Thus, by not controlling tightly for age in persons over 65, we may have underestimated the true benefits of the vaccine program for seniors in terms of all-cause pneumonia reduction. For the more specific outcomes like IPD and S. pneumoniae pneumonia (ICD9 code 481), this is less of a problem in that the estimated reduction is profound.
In early 2010, a new 13-valent version of the vaccine (PCV13) was introduced in the United States with the promise of further reducing the residual burden of pneumococcal disease. According to our study, in the 2005–2006 season, there was a residual hospitalization burden of 5.5 IPD cases, 12.4 noninvasive ICD9 481 cases, and 115 model-attributed pneumococcal pneumonia cases per 100,000 among children less than 2 years of age, with considerably higher residual burdens among adults. We plan to continue to follow these rates in years to come, in order to assess the magnitude and sustainability of the disease burden reduction following PCV13 introduction.
The ability of PCV7 to induce herd immunity invites a discussion of how best to protect seniors, a group that does not respond as well to vaccination because of immune senescence or underlying illness. Although PCV7-vaccinated children accounted for only ~5% of the U.S. population by 2006, our study suggests that this was sufficient to reduce the burden of pneumococcal disease substantially in all age groups. Our results further suggest that more than 90% of the prevention of hospitalizations and deaths due to pneumonia attributable to the vaccine occurred among patients ≥18 years old, and most of this occurred among those ≥65 years old. There is evidence that this group has not been well protected by direct immunization with either the 23-valent pneumococcal vaccine (33
) or influenza vaccine (34
). It is possible that indirect protection (herd immunity) through vaccination of children will more effectively protect seniors against pneumococcal disease.
Immunization with PCV7 in the United States has led to profound reductions in the disease burden among adults in the first 7 years of the program. Whether this continues to be the case in the future should be monitored carefully due to the possibility of strain replacement. Whether the U.S. experience can be extrapolated to other countries remains to be seen. The different patterns of social mixing, overcrowding, and residual carriage of vaccine types among HIV-infected infants (38
) all demand caution in extrapolating these observations to developing countries, where studies on herd immunity induced by PCV introduction will be an essential part of vaccination impact measurement.