Incidence of Invasive Pneumococcal Disease in Children 3 to 36 Months of Age at a Tertiary Care Pediatric Center 2 Years After Licensure of the Pneumococcal Conjugate Vaccine (2003)

A dramatic decline in the incidence of invasive disease caused by Streptococcus pneumoniae among healthy infants is anticipated to result from universal immunization with the heptavalent pneumococcal conjugate vaccine (PCV7). To assess change in the incidence of invasive pneumococcal disease among young children between the fiscal years of 1997 and 2002 at the Children’s Hospital of Pittsburgh, a retrospective review of medical records was performed. Information regarding demographics, receipt of pneumococcal vaccine, medical history, and events of the acute illness were reviewed among patients 3 to 36 months of age with a positive blood or cerebrospinal fluid culture. Penicillin susceptibility data were obtained and capsular serotyping was performed on available isolates. The incidence of invasive pneumococcal disease decreased significantly in the 2001 and 2002 fiscal years compared with previous years. This occurred predominantly in children 3 to 24 months of age. Boys were overrepresented among cases of invasive disease. The incidence of invasive disease among children of African American descent was significantly greater than expected based on local demographics. The dramatic decline in invasive pneumococcal disease in the context of increasing emergency department visits and a stable pattern of clinical practice almost certainly reflects the impact of the initial use of the PCV7. The availability and continued use of PCV7 should lead to even more impressive changes in the epidemiology of pneumococcal infection.Invasive infections caused by Streptococcus pneumoniae in infants and children result in significant morbidity and mortality worldwide. Recently, a large scale, randomized, double-blinded, placebo-controlled trial demonstrated that the heptavalent pneumococcal conjugate vaccine (PCV7), Prevnar (Wyeth-Lederle, St Davids, PA), was well-tolerated, immunogenic, and highly effective (97.4%) in preventing invasive disease in healthy children.1 This and other studies led to the licensure of the vaccine and subsequent recommendation by the Committee on Infectious Diseases of the American Academy of Pediatrics2 and the Advisory Committee on Immunization Practices3 to immunize all infants at 2, 4, 6, and 12 to 15 months of age. Universal immunization with the pneumococcal conjugate series is anticipated to decrease the incidence of invasive pneumococcal disease in infants and children.To assess the preliminary clinical impact of the PCV7 since its licensure in February 2000, a retrospective chart review was conducted to evaluate the change in incidence of invasive pneumococcal disease in children 3 to 36 months of age between the fiscal years of 1997 and 2002 at the Children’s Hospital of Pittsburgh (CHP).CHP is a 235-bed regional pediatric referral center that provides both primary and subspecialty pediatric services to ∼5.5 million residents in eastern Ohio, West Virginia, and western Pennsylvania. In the fiscal year 2001, there were 13 113 admissions to the hospital with 59 576 patient days.Eligible patients included children between 3 and 36 months of age who were evaluated at CHP and found to have a positive blood or cerebrospinal fluid culture for S pneumoniae. Data obtained from the medical record included: basic demographic information, a history of underlying medical problems, date of infection, receipt of pneumococcal vaccine(s), and events of the acute illness.The annual number (by fiscal year defined as July 1 to June 30 of the next year) of outpatient visits (ie, emergency department, primary care continuity clinic, acute ambulatory clinic, and observational 48-hour unit) and inpatient hospitalizations for children 3 to 36 months of age evaluated at CHP was determined by use of the Alliance for Decision Support database system (Health Management Systems, New York, NY). Data from July 1, 1997 to June 30, 1998 could not be reliably obtained because of insufficient computer files that predated the Alliance database system.Data collection was performed using Excel spreadsheet program (Microsoft, Redwood, WA). Between-year comparisons were done using either a binomial χ2 test or Fisher exact test for trends using Stata 6.0 statistical package (Stata Corporation, College Station, TX).Capsular serotyping of available pneumococcal isolates from each patient was performed using rabbit type-specific antiserum by quellung reaction assay. (Statens Serum Institut, Copenhagen, Denmark; DAKO, Inc, Carpinteria, CA). Minimal inhibitory concentrations (MIC) for each isolate were determined by standard broth microdilution procedures using guidelines set forth by the National Committee for Clinical Laboratory Standards.4 Isolates with a MIC ≤.06 μg/mL were defined as penicillin-susceptible; isolates with a MIC ≥.1 μ/mL were defined as penicillin-nonsusceptible.This study was done with approval from the Human Research Committee at CHP.Table 1 shows the incidence of invasive disease attributable to S pneumoniae for the fiscal years of 1998–2002. Overall, there was a statistically significant decrease in the incidence of invasive pneumococcal disease in fiscal years 2001 (P ≤ .003) and 2002 (P < .0001) compared with previous years. Between fiscal years 2001 and 2002, a further reduction in the incidence of invasive disease occurred (P = .018). Table 2 shows the cases of invasive disease by age. When categorized by age group, a significant decrease of invasive disease was observed among children 3 to 12 months of age in 2001 (P < .01) and 2002 (P < .01) compared with fiscal year 1998. Likewise, a decrease in incidence was observed among children 13 to 24 months of age in 2000 and 2001 compared with both fiscal years 1998 (P = .001 and P < .001, respectively) and 1999 (P = .0001 and P < .0001, respectively). Four patients with invasive pneumococcal infection died: 2 deaths occurred in 1997, 1 in 1999, and 1 in 2002. Two of the deaths were attributed to invasive pneumococcal disease. The first death occurred before licensure of the PCV7 in a previously healthy 12-month-old child with pneumococcal bacteremia, meningitis, and mastoiditis. This illness was caused by a nonvaccine-associated serotype. In the 2002 fiscal year, death occurred in a previously healthy, unvaccinated 6-month-old child with (vaccine-associated serotype) pneumococcal bacteremia. The deaths of the other 2 children could not be directly attributed to pneumococcal disease.Demographic information by age group is provided in Table 3. Nearly 61% of children with invasive disease were boys. Children of African American descent accounted for 45% (81 of 182 cases) of the cases of invasive disease, but comprised only 27% of population in the city of Pittsburgh and 12% of the population of Allegheny County in 2000.Pneumococcal isolates were available for 95%, 92%, 78%, 64%, and 100% of cases of invasive pneumococcal disease from fiscal years 1998–2002. Vaccine-associated serotypes accounted for 90%, 82%, and 94% of the invasive disease isolates from fiscal years 1998–2000. Serotypes 6, 14, and 18 were the most common (57%–64%) vaccine-associated serotypes isolated from children with invasive disease. Twenty-two children had invasive pneumococcal disease in fiscal year 2001. Only 14 of the 22 isolates were available for capsular typing. Ten of 14 (71%) were vaccine serotypes. Three of the 22 children received at least 1 dose of the PCV7. None of the 3 children who received PCV7 had completed the series. The remaining 19 children did not receive PCV7. Two of the 3 isolates from vaccinated patients were available for capsular typing. Only 1 isolate was a vaccine-associated serotype. All 9 cases of invasive disease in fiscal year 2002 had isolates available for capsular typing. Six of the 9 children were immunized. Three of the 9 isolates were vaccine-associated serotypes. Only 1 of these 3 patients received PCV7 (ie, 3 doses) vaccine. Five of the 6 patients with invasive disease caused by nonvaccine serotypes received PCV7 (all received 3 doses of PCV7). There was no significant difference in the incidence of penicillin-susceptible and penicillin-nonsusceptible isolates of S pneumoniae by year (P > .05). Day care attendance did not influence the penicillin-susceptibility status among isolates (P > .05; data not shown).A significant decrease (P < .001) in the incidence of invasive pneumococcal disease among children 3 to 36 months of age cared for at CHP occurred in the 2001 and 2002 fiscal years. The greatest impact of the vaccine was observed in children 3 to 24 months of age. Three of the 22 children who developed invasive disease in fiscal year 2001, received at least 1 dose of PCV7; none completed the series. In fiscal year 2002, 6 of the 9 children with invasive disease received at least 2 doses of PCV. Only 1 of these 6 children had invasive disease caused by a vaccine-associated serotype.Although the vaccine was licensed in February 2000, there was no insurance coverage for Prevnar in our community until July 2000. In addition, it is likely that many community practitioners may not have been aware of the new recommendations or had the vaccine promptly available. By October 2000, most local insurers had approved the use of Prevnar for infants and children through 2 years of age. Thus, the reduction in the incidence of invasive pneumococcal disease (>50%) in 2001 reflects only partial utilization of the PCV7 series. The dramatic decrease in the incidence of invasive disease seen in fiscal year 2002 reflects the impact of widespread use of the PCV7 series among children 3 to 36 months of age.Several demographic characteristics of interest were noted: there were significantly more African American children with invasive disease compared with the population prevalence of both the county and city (P < .01). This is consistent with previously published data in which the risk of invasive pneumococcal disease was greater among African Americans compared with whites.5–7 Boys were overrepresented among our cases, although male gender has not been an identified risk factor in previous studies. Previous investigations indicate that children who attend out-of-home day care are at increased risk for invasive disease.8 In the absence of a control group, attendance at day care could not be assessed as a risk factor for invasive pneumococcal disease.There are several limitations to our study. The direct impact of vaccine is best assessed by prospective, randomized, double-blinded clinical trials or cohort study by assessment of disease occurrence per 100 000 children at risk. Previous studies have demonstrated this on a much greater scale.9 Although such studies demonstrate vaccine efficacy, data provided in this study demonstrate the “effectiveness” of this vaccine series in the community setting. Because CHP services the community as well as referral areas, cases of invasive disease may be overrepresented. Evaluation of incidence of disease through review of hospital records may be influenced by numerous factors other than new preventive strategies. However, the decrease in incidence of invasive pneumococcal infections documented in this report occurs in the context of an increase in emergency department visits, a major portal of entry for community-acquired infections. The prevalence of children with complicated medical issues who are likely to be at greater risk for disease has remained stable over the study years. Furthermore, clinical practice tendencies have not resulted in a decrease in the number of blood cultures obtained from patients cared for at CHP. Too few isolates were available in 2001 and 2002 to detect general trends that may predict changes in the epidemiology of invasive disease caused by S pneumoniae. Of note, however, the majority of invasive disease isolates in 2002 were nonvaccine-related serotypes. Thus, these cases could not be prevented by use of the PCV7 series.The dramatic decline in the incidence of invasive pneumococcal disease among children 3 to 36 months of age in our institution reflects the early impact of PCV7 use in infants and children. Children immunized with the PCV7 series have been noted to have a significant decrease in the nasopharyngeal carriage rates of vaccine-associated pneumococcal serotypes (ie, 4, 6B, 9V, 14, 18C, 19F, 23F).10–12 Diminution in the nasopharyngeal colonization rates for S pneumoniae should lead to a decrease in its horizontal transmission. Furthermore, vaccine-associated serotypes account for 85% of the most prevalent penicillin-resistant pneumococcal serotypes.13 Thus, continued use of the vaccine should lead to a greater decline in both the overall incidence of invasive pneumococcal infections and the incidence of antibiotic-resistant pneumococcal infections. Current shortages of PCV7 pose a threat to progress in this area. In addition, some studies have noted a substantial increase in nasopharyngeal colonization with nonvaccine-related (“replacement”) serotypes among vaccinated children.12,14,15 This raises the question of whether the dramatic decline in incidence of invasive pneumococcal disease will be followed by a resurgence of disease caused by nonvaccine-related serotypes. Continued surveillance will yield important information.We thank David Kazimir and Adrianne Farley for their efforts in data collection.