This study demonstrates the dramatic increase in pediatric empyema cases in Utah in the years following the licensure of PCV-7. By 2007, more than one-third of pediatric hospitalizations for pneumonia were complicated by empyema. In Utah, PPE is now the most common form of IPD in children. The majority of PPE is due to serotypes 1, 3, 7F, and 19A, and many cases occur in children older than the current recommended age for immunization (4
). The molecular analysis of empyema isolates demonstrated that PPE in the postvaccine period in Utah was the result of replacement disease by nonvaccine serotypes.
We have documented high rates of empyema in the Utah pediatric population since 1993 (13
). Serotype 1 has consistently been associated with empyema and complicated pneumonia worldwide (24
). Serotype 1 was an important cause of IPD in Utah children prior to the introduction of PCV-7. While we continued to see a significant proportion of IPD caused by serotype 1, we also noted increases in serotypes 3, 7F, and 19A in the post-PCV-7 years. Serotypes 7F and 3 have been reported to cause complicated pneumonia and empyema in Spain (37
). Furthermore, serotype 7F has been associated with severe or fatal pneumococcal infection in children (43
). Serotype 19A has emerged as the most important cause of IPD in the United States in the postvaccine years (40
). Infection with 19A has been associated with meningitis (35
) in 20 U.S. hospitals, mastoiditis (38
) in Houston, TX, and pneumonia and empyema in the Alaskan native population (45
Our serotype and MLST analysis revealed that replacement ST were responsible for increases in empyema in the postvaccine period. For the serotypes 3, 7F, and 19A, MLST analysis revealed that the dominant ST for each of these three serotypes was the same as that commonly isolated in the United States prior to the introduction of PCV-7 (5
). Molecular analysis of serotype 1 isolates demonstrated a decrease in the predominance of ST 227 and expansion of ST 304 and 306, members of the same lineage.
Prior to the introduction of PCV-7, all of serotype 1 isolates obtained from children in Utah were ST 227 (13
). Following licensure of the PCV-7 vaccine in the United States, we noted a persistence of serotype 1 as a cause of empyema; however, by 2003, multiple ST, including 304, 306, 2126, and SLV of these, were demonstrated. Brueggemann and Spratt demonstrated in 2003 that ST 227, 304, and 306 are all related and members of a major lineage with a geographic distribution that includes Europe and North America (9
). ST 2126 is also closely related to ST 227, differing at only the spi
locus. Clonal expansion of specific ST of serotype 1 have been reported previously, including an epidemic of meningitis in Ghana and Burkina Faso associated with ST 217 (29
) and the carriage of ST 306 in healthy children following immunization with PCV-7 (36
The analysis of serotypes 3, 7F, and 19A revealed a limited number of ST. All serotype 3 isolates were ST 180, and both serotype 7F isolates were either ST 191 or an SLV of 191. In the United States, ST 180 and ST 191 represent the most common ST seen in serotypes 3 and 7F, respectively, both before and after the introduction of PCV-7 (5
). Similarly, 12/13 (92%) of 19A isolates were ST 199 or SLVs of 199, the most common 19A ST in the United States, especially among children (5
). We were not able to demonstrate serotype switching in the 19A isolates from Utah children that resulted in empyema. Our findings were similar to those seen in Alaska, where the most common ST seen was ST 199 and serotype replacement that occurred following immunization with PCV-7 involved ST that existed in control communities (31
The pneumococcal strain distributions associated with pediatric empyema in Utah in the PCV-7 period is reflective of the complex ecology and epidemiology of pneumococci. In our analysis of pediatric empyema, we note an overall increase in empyema cases and a similar disease phenotype for infections that resulted from multiple ST of serotype 1 and from serotypes 3, 7F, and 19A. Serotype 1 ST 227 was a predominant cause of IPD, along with vaccine serotypes, prior to the introduction of PCV-7. With the selective pressure of the vaccine, PCV-7 serotypes have decreased dramatically in the United States (47
) and, in Utah, account for <5% of IPD in 2008 and 2009 (C. L. Byington, unpublished data). The decrease in vaccine serotypes likely created ecological niches that allowed for replacement by other pneumococcal serotypes.
The reasons for the increased rate of empyema in our population are unknown. S. pneumoniae
strains differ in their abilities to invade different tissue sites, certain pneumococcal serotypes have a propensity to cause invasive disease and others are more often associated with colonization (6
). It is also possible that the pneumococcal isolates in our study population contain virulence genes that confer an increased ability to invade the pleural space. Recent studies have demonstrated that strains of identical serotypes and ST can differ in the presence of important virulence determining loci (42
). Ehrlich and others have observed that S. pneumoniae
possesses a supragenome, comprised of all genes available for a species (20
). Individual pneumococcal isolates contain core genes present in all members of the species, distributed genes shared in subsets of strains, and unique genes found only in a single strain (25
). Genetic material available in the supragenome may include unknown genes that confer the ability to invade the pleural space and thus have resulted in the significant increase in pediatric empyema that we have observed. We are currently testing this hypothesis through comparative genomic analysis of empyema isolates of multiple serotypes and ST.
Our study has limitations. First, not all empyema isolates were viable. It is possible that some serotypes or ST may be less viable and are underrepresented. In addition, all of our pneumococcal isolates come from children in Utah, a single geographic location. Thus, our findings may not be representative, especially if pneumococcal diversity is related to geographic location. However, studies by Hiller et al. failed to demonstrate a correlation between genetic diversity and geographic distance (25
). Our own findings related to empyema caused by serotype 1 and the emergence of serotypes 3, 7F, and 19A are similar to reports from other parts of North America and Europe (28
In spite of the limitations, we believe our findings have several important implications. First, serotype replacement occurred rapidly following the introduction of the PCV-7 vaccine and is continuing to occur. The introduction of broader pneumococcal vaccines, such as PCV-13, may provide protection for the dominant serotypes present at the time of vaccine licensure, but new pathogenic strains may continue to emerge. The ecology of the organism changes under vaccine selective pressure, and we must be alert to changes in IPD clinical presentations and susceptible populations. Finally, in the monitoring of emerging pathogens, it will become increasingly important to identify genes from the supragenome that facilitate survival in different environments and develop surveillance mechanisms for these (20