Invasive pneumococcal disease (IPD) remains a major cause of morbidity and mortality in children worldwide and a leading cause of community-acquired pneumonia, bacteremia, and meningitis.1,2
Widespread use of 7-valent pneumococcal conjugate vaccine (PCV7; Wyeth Lederle Vaccine) in the United States since 2000 has significantly changed the epidemiology of IPD.3 The Centers for Disease Control and Prevention Active Bacterial Core surveillance sites report a decrease of >70% in the incidence of IPD in children <5 years from 95 cases/100,000 in 1999 to 23 cases/100,000 in 2004.4 Some centers in the United States reported a less dramatic decrease in IPD and the early emergence of IPD due to non-PCV7 serotypes.4 – 6 A 13-valent pneumococcal conjugate vaccine (PCV13; Wyeth Pharmaceuticals Inc.) was licensed in 2010, which includes PCV7 serotypes and emerging serotypes 1, 3, 5, 6A, 7F, and 19A.
This study describes the epidemiology of pneumococcal disease (PD) from 1996 through 2009 using International Classification of Diseases, ninth revision (ICD-9) coded hospital discharge data in Utah from the prevaccine period through the eve of the introduction of PCV13.
Human Subjects Protection.
The institutional review boards of the University of Utah and Intermountain Healthcare (Intermountain) approved this study. Informed consent was waived.
Setting and Study Population.
The study spanned 1996–2009. We defined 3 time periods for analysis based on levels of PCV7 coverage. We defined the prevaccine period as the 60-month period from 1996 to 2000, which preceded PCV7 licensure in the United States. We defined the early postvaccine period as the 48 months from 2001 to 2004, when PCV7 uptake (≥3 doses) was increasing but coverage was <80% for children <36 months. The late postvaccine period included the 60 months from 2005 to 2009, when PCV7 coverage was >80% for children in Utah. Vaccine coverage rates for PCV7 in Utah were determined using the Centers for Disease Control and Prevention's National Immunization Survey and were similar to national rates.3
Intermountain is a large healthcare system, which operates 20 hospitals in Utah. During the study, 71% to 87% of all pediatric emergency admissions and hospital admissions in Utah occurred at an Intermountain facility (S. Lloyd, Intermountain, personal communication). The proportion of pediatric admissions at an Intermountain facility remained stable during this period.
Identification of ICD-9 Coded PD.
We defined a case of PD as a medically attended event occurring among children <18 years of age residing in Utah during the study period with an ICD-9 discharge diagnosis code specific for diseases caused by S. pneumoniae, who received care at an Intermountain facility. We defined PD as previously described by Grijalva et al.7 Briefly, patients were considered to have PD if they had a code-specifying pneumococcal pneumonia, pneumococcal meningitis, pneumococcal septicemia, or codes for a specific syndrome plus another code specifying pneumococcal infection.
The age-specific incidence of PD among Utah children was calculated using Utah population estimates, which were adjusted for the proportion of children who received care at an IH facility (0.71–0.87) based on annual market share data.8 Mann-Whitney U tests were used for pairwise comparisons of age groups, and Poisson regression was used to compare PD rates during the time periods.
Incidence of PD in Utah.
Between 1996 and 2009, 1463 children <18 years were treated at an Intermountain facility for an illness with an ICD-9 discharge code associated with PD. A total of 534 children were identified during 1996–2000, 354 during 2001–2004, and 575 during 2005–2009. Overall, the incidence of PD in Utah children <18 years of age decreased from 19.9/100,000 (1996–2000) to 14.4/100,000 during 2001–2004 (−28%; 95% confidence interval [CI]: −36%, −8%, P < 0.001), and it was 16.1/100,000 during 2005–2009 (−19%; 95% CI: −28, −10, P < 0.001). The increased incidence of PD from 2001 to 2009 did not reach statistical significance.
During the years 2001–2004, the incidence of PD among children <5 years, the PCV7 vaccine target group, decreased by 36% (P < 0.001) compared with 1996–2000. During 2005–2009, the incidence of PD remained stable, but below 1996–2000 (−34%; P < 0.001) (Table 1).
There were sustained decreases in the incidence of PD during the 2001–2004 and 2005–2009 periods when compared with the prevaccine period among children <12 months (−52%; 95% CI: −62, −39; P < 0.0001 for 2001–2004 compared with the prevaccine period and −41%; 95% CI: −52, −38; P < 0.0001 for 2005–2009 compared with the prevaccine period), 12 to 23 months (−27%; 95% CI: −45, −4; P = 0.03 and −35%; 95% CI: −50, −15; P < 0.001), and 2 to <5 years (−17%; 95% CI: −35, 5; P = NS and −22%, 95% CI: −37, −3; P = 0.03). However, there was no change in the incidence of IPD among Utah children 5 to 17 years (Table 1).
Clinical Syndromes of PD.
Of 1463 children with PD, 692 (47%) had uncomplicated pneumonia, 288 (20%) had bacteremia without focus, 257 (18%) had complicated pneumonia/empyema, 125 (9%) had meningitis, and 101 (7%) had other sterile site infection. Compared with the prevaccine period, there were sustained decreases in the incidence of uncomplicated pneumonia and bacteremia without focus among children <5 years. In contrast, the incidence of complicated pneumonia/empyema increased significantly during the study period (Fig. 1). Among children 5 to 17 years, there were significant increases in complicated pneumonia/empyema (2%, P = 0.95 for 2001–2004 compared with the prevaccine period and 70%, P = 0.02 for 2005–2009 compared with the prevaccine period) and bacteremia (92% and 102%).
In this study, we used hospital discharge data to study the incidence of PD in Utah for 14 years, including 9 years of widespread use of PCV7. We observed a sustained modest decrease in the incidence of PD in children <18 years. The change was primarily because of decreasing PD in children <5 years. The introduction of PCV7 had a different impact on individual disease syndromes, with decreasing rates of uncomplicated pneumonia, bacteremia, and meningitis. In contrast, we observed a significant increase in the incidence of complicated pneumonia/empyema.
The widespread use of PCV7 has decreased PD in the United States.9,10 The decrease in IPD because of PCV7 serotypes has been partially offset by increases in infection with non-PCV7 serotypes.10,11 PCV13 targets several common non-PCV7 serotypes that have emerged in the United States and is expected to further decrease PD burden, but changes in the epidemiology and serotype distribution seem likely.12
Shortly after the introduction of PCV7, several studies in the United States reported decreases of 65% to 70% in cases of IPD in children <5 years.4,6,13 In comparison, our study found a modest 36% decrease in PD among children <5 years. Similarly, decreases in PD were observed among children <12 months and 12 to 23 months but lower than those reported at Active Bacterial Core sites.10 Differences in methodology between active laboratory surveillance and hospital discharge-based surveillance may account for some of the difference. However, the differences could be partially due to differences in serotype distribution. PCV7 serotypes accounted for ∼69% of IPD in Utah before the introduction of the vaccine, substantially lower than the 80% to 98% reported by other US centers, but similar to the rate among Alaskan Native children. This difference in serotype distribution may have played a role in the overall impact of PCV7.6
Our findings of decreases in uncomplicated pneumonia, bacteremia, and meningitis are similar to other US reports.4,6,10 In contrast, complicated pneumonia/empyema increased during the early and late postvaccine periods (59% and 83%, respectively). The largest increase in complicated pneumonia/empyema was among children <5 years. The increase in complicated pneumonia/empyema in Utah is similar to the findings reported by other investigators.5 – 7 The causes of increasing rates of empyema are unclear, but are likely related to the shift in circulating pneumococcal clones and possibly tissue-specific virulence factors.14
Other epidemiologic or host factors might explain the differences in epidemiology. In a case-control study of IPD in Utah, risk factors associated with IPD were similar to those reported from other geographic regions, although children ≥2 years were 2.2 times (95% CI: 1.3–3.7) more likely than younger children to have IPD caused by non-PCV7 serotypes.15 Utah has the largest family sizes, the highest rates of household crowding, and the greatest number of households with children in the United States.16 The high prevalence of invasive non-PCV7 serotypes in Utah before PCV7 introduction likely favored early serotype replacement.
This study has limitations. ICD-9 coding may be subject to misclassification, both potentially missing cases and incorrectly ascribing disease to S. pneumoniae. These problems are likely to be stable over time, allowing analysis of trends. Surveillance based on discharge diagnosis cannot be directly compared with active laboratory-based surveillance. However, our PD incidence rates are close to those derived from active laboratory-based surveillance.10,11 Our study is based in a single geographic area, and pneumococcal epidemiology is known to display substantial regional variation.
In summary, we demonstrated a sustained modest decrease in PD of 34% among children <5 years and 27% among all children <18 years following the licensure of PVC7 in Utah. Pneumococcal bacteremia, uncomplicated pneumonia, and meningitis decreased substantially. Conversely, complicated pneumonia/empyema has increased among children <18 years. To optimize prevention strategies, continued surveillance with attention to regional variation and clinical syndromes will be essential to identify further evolution of the epidemiology and serotype distribution of invasive S. pneumoniae disease.
The authors thank Intermountain Healthcare, Salt Lake City, Utah.
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