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Comparison of Incidence of Invasive Streptococcus pneumoniae Disease Among Children Before and After Introduction of Conjugated Pneumococcal Vaccine

Haddy, Richard I. MD*; Perry, Kelvin MD*; Chacko, Chris E. BS*; Helton, William B. BS*; Bowling, Mark G. MD*; Looney, Stephen W. PhD; Buck, George E. PhD

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The Pediatric Infectious Disease Journal: April 2005 - Volume 24 - Issue 4 - p 320-323
doi: 10.1097/01.inf.0000157090.40719.9b
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Abstract

The heptavalent Streptococcus pneumoniae protein conjugate vaccine (Prevnar) was introduced into the Louisville, KY, area in the winter of 1999–2000. At that time, a large campaign, aimed at all physicians treating children and led by the Jefferson County Public Health Department and the Division of Pediatric Infectious Diseases of the University of Louisville School of Medicine, was introduced into the Louisville area, with the goal of immunizing all infants at the recommended times with this new vaccine. The primary aim of our study was to gather evidence regarding whether the incidence of invasive S. pneumoniae disease among children in the Louisville area has been reduced significantly since the introduction of the vaccine. Data regarding demographic features and other factors related to invasive pneumococcal disease were also gathered.

METHODS

All hospitals that care for children in Louisville, KY, were used for this study. These hospitals were Kosair Children's Hospital, Norton Audubon Hospital, Norton Suburban Hospital, Norton Southwest Hospital, Caritas Hospital and Baptist Hospital East. We first approached the microbiology laboratories of Norton Hospital and other hospitals and asked for hospital numbers of all patients in the younger than 18-year-old age range with positive cultures for S. pneumoniae from blood, cerebrospinal fluid (CSF) or pleural fluid, beginning in July 1999. Eighteen randomly selected cases from the July 1997 through June 1999 time period were also studied to round out the demographic data only. We then approached the medical records departments of the hospitals and reviewed the respective charts for demographic data, presence of fever at admission, leukocyte counts, underlying disorders, final diagnoses, death and antibiotic sensitivities of the organisms. Fever was defined as a temperature of ≥100.5°F within 24 hours before the positive culture. Leukocyte counts were defined as high, normal or low on the basis of The Harriet Lane Handbook.1 Underlying disorders were defined as disorders that patients might have had that would predispose them to serious infections; examples would include advanced malignancy, corticosteroid treatment and congenital immunodeficiency syndromes. Patients were said to have died as a result of their infections if they died within 7 days after the positive blood culture, with no other intervening events that might explain their deaths. Bacteremia without focus was defined as bacteremia (diagnosed on the basis of fever and positive blood culture) without a discernible focus of infection, from which the patient rapidly recovered without antibiotic therapy.

In the autumn of 1999, in anticipation of the release of the conjugated S. pneumoniae vaccine, a large media campaign was initiated by the Jefferson County Public Health Department and the Division of Pediatric Infectious Diseases of the University of Louisville School of Medicine, to urge physicians to use this vaccine immediately, at recommended ages, for infants in the Louisville area. For this study a child was defined as a younger than 18-year-old patient. Also, it was assumed that the hospitals treating children in Louisville served Jefferson, Oldham and Bullitt Counties. The numbers of cases of invasive S. pneumoniae disease were obtained from these hospitals for the time periods of July 1 through June 30 of 1999–2000, 2000–2001 and 2001–2002. The total number of children in these counties (on the basis of the 2000 Census, obtained from the Kentucky Data Center) was 197,555. In addition, these children were stratified according to age, ie, younger than 2, 2–5 and 5–18 years of age. The total numbers of children living in the 3 counties in each of these 3 age groups (according to the 2000 Census) were 21,692, 32,383 and 143,480, respectively.

Methods based on binomial distribution were used to construct exact 95% confidence intervals for the true rates of invasive pneumococcal disease for each year for each age group and for all ages combined. Fisher's exact test was used to compare the rate for each year with that for the following year. The Cochran-Armitage method was used to test for a significant trend in rates across the 3 time periods. The Mann-Whitney-Wilcoxon test was used to determine whether significantly more S. pneumonia isolates from CSF were penicillin-resistant, compared with isolates from blood or pleural fluid.

RESULTS

A total of 115 children with invasive pneumococcal disease in hospitals in the Louisville area, beginning in 1997, were used in the study. There were 48 cases of invasive disease in 1999–2000, 37 in 2000–2001 and 12 in 2001–2002. Table 1 shows the rate per 100,000 children for each year, for all ages combined and for each of the 3 age strata. Figure 1 shows the decreasing trend for rates of invasive S. pneumoniae disease during the study period. There was a statistically significant downward trend for every group except for children 5–18 years of age. The reduction from 1999–2000 to 2000–2001 was not statistically significant for any of the 3 age subgroups or for all ages combined (P > 0.294 for all 4 comparisons). However, the reduction from 2000–2001 to 2001–2002 was statistically significant for all 3 age subgroups and for all ages combined (P < 0.039 for all 4 comparisons). (These results are based on the 1999–2002 data; the rest of the results in this article are based on the entire 1997–2002 data set.)

TABLE 1
TABLE 1:
Rates of Invasive Streptococcus pneumoniae Disease in the Louisville, KY, Area
FIGURE 1.
FIGURE 1.:
Rates and 95% confidence intervals for invasive S. pneumoniae disease for children in the Louisville, KY, area in 1999–2002. A, Rates and 95% confidence intervals for invasive S. pneumoniae disease for all children younger than 18 years of age. The downward trend was significant (P < 0.001). B, Rates and 95% confidence intervals for invasive S. pneumoniae disease for all children younger than 2 years of age. The downward trend for 3 years was significant (P = 0.002). C, Rates and 95% confidence levels for invasive S. pneumoniae disease for all children ≥2 years and younger than 5 years of age. The downward trend for 3 years was significant (P = 0.002). D, Rates and 95% confidence intervals for invasive S. pneumoniae disease for all children ≥5 and younger than 18 years of age. The downward trend for 3 years was not significant (P = 0.118).

The sources of the organisms causing invasive S. pneumoniae disease were as follows: 101 (86.3%) from blood, 7 (6.0%) from CSF, 4 (3.4%) from both blood and CSF, 4 (3.4%) from pleural fluid and 1 (0.9%) from blood and pleural fluid. The mean age for the patients was 2.22 years. Seventy-four (64.3%) patients with pneumococcal disease were male and 41 (35.7%) were female (ratio, 1.8:1). Leukocyte counts were high for 71 (61.7%) of the patients with invasive S. pneumoniae, normal for 33 (28.7%), low for 5 (4.4%) and not measured for 6 (5.2%).

Eighty-one percent of the patients had no underlying disorder for invasive S. pneumoniae disease. The most common underlying disorders (in decreasing order) were none detected, otitis media, renal failure and advanced malignancy. Table 2 lists the final diagnoses for the patients with invasive S. pneumoniae disease. Thirty-nine percent of the organisms were resistant to penicillin, and 8% were resistant to cefotaxime. Three percent of the organisms were resistant to clindamycin, and 46% were resistant to erythromycin. Thirty-three percent of the organisms were resistant to tetracycline. No organisms were resistant to vancomycin. All 11 organisms that caused meningitis were resistant to penicillin. There was a significantly higher rate of resistance to penicillin among S. pneumoniae strains that caused CSF infections than among strains that caused non-CSF infections (P < 0.001). A total of 110 (97.7%) patients with invasive S. pneumoniae disease survived, 3 (2.6%) died and this information was unavailable for 2 (1.7%).

TABLE 2
TABLE 2:
Final Diagnoses for Children With Invasive Pneumococcal Disease, 1997–2002

DISCUSSION

We think that this study shows efficacy of the heptavalent S. pneumoniae protein conjugate vaccine within our community. A study was performed within the Kaiser Permanente system in which 36,868 young children randomly received either the S. pneumoniae heptavalent conjugate vaccine or Neisseria meningitis group C CRM197 conjugate vaccine at 2, 4 and 6 months of age. There were 39 cases of S. pneumoniae vaccine-serotype invasive disease among fully vaccinated children and 7 cases among partially vaccinated children in the control group, whereas there was only 1 case in the experimental group, which indicated the efficacy of S. pneumoniae heptavalent conjugate vaccine to be 97.4% (95% confidence interval, 82.7–99.9%; P < 0.001).2,3 In 2004, that study group published follow-up data for the population of children they are monitoring.4 In the last year of observation, no cases of vaccine-serotype invasive pneumococcal disease were seen among children younger than 1 year of age, compared with incidences between 51.5 and 98.2 cases per 100,000 person-years in the years before vaccine introduction.4 In a similar study from a tertiary care pediatric hospital in Pittsburgh, Pennsylvania, a significant decrease in the incidence of invasive pneumococcal disease among children 3 to 36 months of age was found during fiscal years 2001 and 2002.5

The mean age of 2.22 years for patients in our study is consistent with 2.71 years found in another study.6 Our increased ratio of male to female children with invasive pneumococcal disease (1.8:1) was also reported elsewhere.5–9 These data remind physicians that children with invasive bacterial illness, like adults, may present with or without fever and with high, normal or even low leukocyte counts.10

Our data indicate that most patients with invasive S. pneumoniae disease do not have an underlying disorder predisposing them to this condition. This finding provides evidence against policies in other countries that, because of vaccine shortages, recommend this vaccine only for children with identifiable risk factors. A study by Bennett et al11 on S. pneumoniae bacteremia among all ages revealed that 39.4% of patients had no underlying disorders. The most common underlying disorders in a study from Santiago, Chile (chronic pulmonary disorders, nephritic syndrome, cardiac conditions, portal hypertension and leukemia),12 contrast with the underlying disorders in our study. At the time of this writing, heptavalent pneumococcal vaccine is not yet being used in Chile. The most common underlying disorders in the study by Bennett et al11 were congestive heart failure, chronic obstructive pulmonary disease and diabetes mellitus.

The mortality rate for our study (2.6%) is similar to those of other studies, ie, 1.3%,6 2.0%,7 2.2%,9 6.6%8 and 11.8%.12 This contrasts with a mortality rate of 15% in the study by Bennett et al,11 although only 2% of their patients were younger than 5 years of age, and patients >65 years of age have higher rates of death resulting from this disease.

One problem with this study was that limited data exist regarding the percentages of infants who received heptavalent S. pneumoniae conjugate vaccine during the study years. Information from the Kentucky State Department of Public Health indicated the percentages of Kentucky infants who were given ≥3 doses of vaccine to be 25.4 ± 5.3% for the period from July 2001 to June 2002 and 47.7 ± 7.0% for the year 2002. Although no statistics were available for the time before 2001, these data indicate that, overall, rates of immunization are increasing. The retrospective nature of this study made it impossible to perform serotype testing of the S. pneumoniae isolates. In summary, we present evidence of a significant decrease in rates of invasive S. pneumoniae disease among children in a U.S. community since the introduction of heptavalent S. pneumoniae protein conjugate vaccine.

REFERENCES

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2.Black S, Shinefeld H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J. 2000;19:187–195.
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9.Dagan R, Englehard D, Piccard E. Epidemiology of invasive childhood pneumococcal infections in Israel. JAMA. 1992;268:3328–3332.
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11.Bennett NM, Buffington J, LaForce FM. Pneumococcal bacteremia in Monroe County, New York. Am J Public Health. 1992;82:1513–1516.
12.Levine MM, Lagos R, Levine OS, et al. Epidemiology of invasive pneumococcal infections in infants and young children in metropolitan Santiago, Chile, a newly industrializing country. Pediatr Infect Dis J. 1998;17:287–293.
Keywords:

pneumococcus; invasive; vaccine; pediatrics

© 2005 Lippincott Williams & Wilkins, Inc.