Increasing rates of pediatric parapneumonic empyema (PPE) have been reported in both the United States and Europe.1,2 The heptavalent pneumococcal conjugate vaccine (PCV7), licensed in 2000 in the United States and shortly afterward in much of Europe, has been implicated as a possible contributor to the increase in PPE.3 The 7 pneumococcal serotypes targeted by the vaccine have declined along with rates of invasive pneumococcal disease in general,4 but nonvaccine serotypes, presumably because of reduced competition from the 7 vaccine serotypes, have become increasingly common.5 Some of these nonvaccine serotypes are often associated with PPE.1–3,6–8
In the fall of 2005, we noted that admissions to our hospital for PPE seemed to be increasing. However, no data had been collected to verify that an upward trend was occurring, or to discern why. We undertook a retrospective review of medical records to: (1) quantify whether, and by how much, pediatric empyemas were increasing; (2) identify what organism(s) were responsible; (3) compare the trend in empyema to trends in other types of invasive pneumococcal disease (meningitis, bacteremia, and pneumonia without PPE), and (4) determine whether pneumococcal serotype replacement was occurring at our hospital. Our hypothesis was that widespread use of PCV7 had led to nonvaccine serotypes becoming more prevalent and causing more empyemas.
MATERIALS AND METHODS
We obtained Institutional Review Board approval to review the charts of all patients at our hospital (a children's hospital within a large, urban, academic medical center) who met the following criteria:
- Aged 0–18 years on day of admission.
- Admitted between January 1, 1996 and December 31, 2006.
- Discharge diagnoses included at least one of the following:
- Parapneumonic empyema caused by any organism, (ICD-9 code 510.9);
- Pneumococcal meningitis (ICD-9 codes 320.1 or 320.2 with subcode 041.2);
- Pneumococcal bacteremia (ICD-9 code 790.7 with subcode 041.2);
- Pneumococcal pneumonia (ICD-9 code 481 with subcode 041.2).
Exclusion criteria included: incorrect coding (ie, the patient did not have one of the diagnoses above); empyema after penetrating chest trauma; and pneumonias that were hospital acquired. Each patient was counted only once. If a patient had been coded with 2 or more eligible diagnoses, the diagnosis that had required the highest-level care, or which had predominated in their presentation and treatment, was counted.
Three hundred sixteen patients who met our selection criteria were initially identified by our medical records department. After the application of exclusion criteria, the number was reduced to 190 patients. Of these, 97 patients had empyema, 43 had pneumococcal pneumonia without empyema, 26 had pneumococcal meningitis, and 24 had pneumococcal bacteremia, usually without a locus of infection.
Data collected from each chart included patient demographics and treatment histories, bacterial cultures and antibiotic susceptibilities, and results of imaging studies.
Our hospital's microbiology laboratory routinely keeps isolates from culture-positive blood and cerebrospinal fluid (and occasionally other tissues) frozen at −70°C for 5 years. To determine whether pneumococcal serotype replacement was occurring at our hospital, we attempted to locate frozen bacterial isolates from all study patients with positive Streptococcus pneumoniae cultures. We identified 51 pediatric patients who had positive S. pneumoniae cultures in the post-PCV7 period (2001–2006). Of these, 23 isolates from 20 patients (39% of total post-PCV7 patients) were found preserved in our laboratory. The isolates from these 20 patients were sent to Focus Diagnostics for serotyping using the slide coagglutination method. The 20 patients included 2 children with empyema, 5 with meningitis, 6 with bacteremia, and 7 with pneumonia.
As shown in Figure 1, the number of PPE cases at our hospital increased steadily after PCV7 was introduced in 2000, resulting in a 10-year climb from 2 cases in 1996 to 19 cases in 2006. A comparison of the number of cases in the 5-year pre-vaccine (1996–2000) and post-vaccine (2001–2005) periods revealed a 5-fold increase in PPE, from 13 to 65 cases (X2 = 19.5; P ≤ 0.0001).
Most of the increase in PPE was associated with culture-negative empyema, which accounted for 61% of all post-2000 cases; the next largest portion, 19%, was associated with culture-positive pneumococcal empyema. S. aureus accounted for 12% of cases. Of all study patients with culture-negative empyema, 84% (46/55) had received antibiotics (usually amoxicillin with or without clavulanate) before admission. Of those with culture-positive S. pneumoniae empyema, 96% (21/22) had either not been treated with antibiotics before cultures were drawn, or were infected with resistant or intermediate-resistant strains of the organism.
Meningitis, Bacteremia, and Pneumonia Trends.
During the same period, the combined incidence of pediatric pneumococcal meningitis and bacteremia fell after introduction of PCV7. We had a peak of 9 cases of pneumocococcal meningitis and bacteremia in 2000, which dropped to 1 case in 2005 (X2 = 1, P = 0.32). In contrast, pediatric hospitalizations for pneumococcal pneumonia remained stable, with no discernable trend.
Of the 20 patients from the post-PCV7 period whose frozen pneumococcal isolates were sent for serotyping, 18 (90%) were infected with non-PCV7 serotypes. The 2 empyema cases sent for serotyping were both nonvaccine serotype 19A, the most prevalent replacement serotype found at our hospital.
Although our data do show a significant 5-fold increase in PPE since 2000, our ability to attribute this increase to PCV7 is limited by the fact that 61% of PPE cases since 2000 were culture-negative. Six reports since 2002 have evaluated the use of the polymerase chain reaction to identify the etiology of culture-negative parapneumonic empyema.6,9–13 All found pneumococcus as the predominant organism, with an overall 65% detection rate of this bacteria in culture-negative cases. Two of those studies determined serotypes, and identified non-PCV7 serotypes, especially serotype 1 (but also 3 and 19A) as the most common pathogens in culture-negative cases.6,10 Eltringham et al used genetic analysis to determine the antibiotic susceptibility of these strains, and found that culture-negative childhood empyema was most often caused by penicillin-susceptible serotype 1.10
The hypothesis that antibiotic-susceptible, non-PCV7 serotypes are more likely to cause culture-negative PPE is supported by our finding that at least 84% of the patients with culture-negative PPE at our hospital had prior treatment with antibiotics. It is possible that the organism responsible for the patients’ initial pneumonia was susceptible to standard dosages of outpatient antibiotics, usually amoxicillin (with or without clavulanate). This argument is further supported by the finding that 96% of the patients with culture-positive pneumococcal PPE either had not had prior antibiotic treatment or were infected with resistant or intermediate-resistance strains.
The National Centers for Disease Control reports that serotype replacement is occurring on a national level, but that the effect on invasive disease rates in children has so far been minor.14 Our data raise the possibility, however, that parapneumonic empyema may be emerging as a major category of invasive pneumococcal disease, and that this trend would be largely missed by Centers for Disease Control surveillance (which tracks positive pneumococcal cultures) because empyema is often culture-negative.
Our study was limited in a number of ways that affect the strength of our conclusions. First, we are inferring from numerous other studies on PPE that our culture-negative cases were likely caused by pneumococcus, particularly non-PCV7 serotypes, but we have no direct evidence. Second, only 2 of the pneumococcal isolates that were sent for serotyping came from empyema patients; both of the tested empyema cases were caused by non-PCV7 serotype 19A. Third, we lacked prevaccine serotype data from our institution to compare our postvaccine data. We are assuming that the frequency of non-PCV7 serotypes at our hospital before 2000 mirrored that reported in other regions (including the Centers for Disease Control's Northern California surveillance site15), and that, therefore, our current serotype frequencies represent a change. Fourth, the difference in the pre- and post-PCV7 incidence of PPE could be a result of factors other than the vaccine, such as a change in community hospital referral patterns to our institution (although we have no evidence that such a change in referral patterns has occurred). Also, recent data indicate that serotype 19A, an important replacement serotype, was increasing before introduction of PCV7 in some parts of the world,16 suggesting that natural population trends could have led to some rise in PPE even without the vaccine. In the United States, however, increases of serotype 19A invasive disease have occurred coincident with PCV7 introduction,17 mirroring the increase in PPE that occurred at our hospital in this time period.
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