In 1978, we began longitudinal studies of Streptococcus pneumoniae invasive disease in children and adults residing in the Huntington, WV, metropolitan community; and during the 26 years from 1978 to 2003, we tracked the occurrence of capsular serotypes/serogroups (SGTs) and the emergence of penicillin- and multidrug-resistant SGTs; since 2000 we assessed the impact of conjugate pneumococcal vaccine (PCV7) vaccination on the occurrence of S. pneumoniae invasive disease in infants and children. 1–4 Our investigation of S. pneumoniae invasive disease represents the longest continuing longitudinal study that spans both the prevaccine and postvaccine periods in a single metropolitan area.
MATERIALS AND METHODS
The study population comprised 161 consecutive infants and children 14 years and younger with community-acquired S. pneumoniae invasive disease, including sepsis, pneumonia and meningitis, admitted for treatment in the only 2 community hospitals, St. Mary’s Hospital and Cabell Huntington Hospital, both affiliated with the Marshall University School of Medicine, in Huntington, WV, during epidemiologic years between 1978 and 2003 (an epidemiologic year encompasses July 1 through June 30). 3,4 Huntington and environs, located in the southwest part of the state along the Ohio River across from Ohio and Kentucky, includes a market area of ~250,000 persons. This research project was approved by the Institutional Review Board of Marshall University School of Medicine, including approval by St. Mary’s Hospital and Cabell Huntington Hospital.
The diagnosis of sepsis was based on symptoms and signs of infection without localizing signs and the absence of an infiltrate consistent with pneumonia on a chest roentgenogram; the diagnosis of pneumonia was based on clinical evidence of pneumonia as judged by the treating physicians or radiologic evidence of pneumonia on chest roentgenogram or both; the diagnosis of meningitis was based on clinical signs and symptoms of meningitis.
Community-acquired S. pneumoniae invasive disease was identified by isolation of the pneumococcus from blood, cerebrospinal fluid or other sterile site specimens submitted to the microbiology departments of each hospital; both used National Committee for Clinical Laboratory Standards-approved procedures for isolation and identification of S. pneumoniae. 3,4 For most of the study period, the microbiology departments used a manual procedure, namely thiol broth and tryptic soy broth, but in 1996 they replaced it with the BacTec system (BD Biosciences, Franklin Lakes, NJ) and Microstrep plates (Dade Diagnostic, Miami Lakes, FL). We obtained nearly all S. pneumoniae strains recovered at both hospitals; a few strains isolated before 1991 that inadvertently were not sent to us were included in these analyses, and the SGT of these strains was categorized as not available.
All S. pneumoniae strains were transported on trypticase soy agar supplemented with 5% sheep blood to our research laboratory for capsular identification using quellung procedures with antipneumococcal sera obtained from the Statens Seruminstitutet, Copenhagen, Denmark as previously described. 3,4 All serotyping was done on fresh strains. Capsular types are designated according to the European nomenclature system; subtyping was not done, given that factor serums were unavailable to us. All strains were stored in glycerol–brain–heart infusion freezing media at −70°C for subsequent tests.
Penicillin susceptibility was measured by determining the minimum inhibitory concentration (MIC) of each strain with the use of the E–test (AB Biodisk, Solna, Sweden). All strains that exhibited a borderline penicillin result, whether susceptible (≤0.06 μg/ml), intermediately resistant (IR) (0.1–1.0 μg/ml) or highly resistant (HR) (≥2.0 μg/ml), were tested 3 times to ensure accuracy. Susceptibility testing to 10 other antibiotics was done via the Kirby–Bauer disk diffusion method according to the guidelines of the National Committee for Clinical Laboratory Standards, as previously described. 3,4
Clinical Information and Statistical Analysis.
Clinical and demographic data and vaccination status with PCV7 were abstracted from each patient’s hospital and outpatient charts. Dichotomous data were compared by χ2 with Yates correction. Incidence rates were calculated using the 1990 U.S. Census data which represented the midpoint of the study.
During the 26 years of this study, we identified 161 community-acquired invasive infections in infants and children younger than 14 years of age, including 89 children with septicemia, 53 with pneumonia and 19 with meningitis. Sixty-five (69.9%) of 93 infections in children younger than 2 years of age were caused by vaccine SGTs, compared with 34 (50.0%) of 68 infections in children 2 years of age and older (χ2 = 5.75, df = 1, P = 0.016). The overall case fatality rate was low, at 3 (1.9%) of 161 children; 2 (10.5%) with meningitis and 1 (1.9%) with pneumonia died, but this child had sustained a skull fracture that accounted for her death. The incidence rates in infants and children younger than 1 year of age, in children 1 and 2, 3 and 4 and 5 and 6 years of age were 73.7, 50.2, 12.0 and 7.4 cases/100,000/year. The other age groups showed incidence rates < 4.0 cases/100,000/year.
S. pneumoniae invasive disease was detected in all months of the year except August. The temporal pattern of invasive disease was cyclical with peaks about 6 or 7 years starting after 1984. By month for all years combined, invasive disease occurred mainly between September and May and appeared bimodal with one peak in November–December and one in March–May.
The 161 invasive infections were distributed among 20 SGTs. The most common SGTs, in rank order, 14, 18, 6, 1, 19, 4 and 23 (at least 7 strains each), accounted for 112 (69.6%) of 161 strains. Only SGT 1 is not included in PCV7. SGT 14 occurred in 13 years and SGTs 6 and 18 occurred in 12 and SGT 1 in 10 years of this study. The other SGTs occurred in fewer years.
Vaccine SGTs accounted for 99 (61.5%) of 161 invasive infections, including 32 (82.1%) of 39 infections during the last 6 years. SGTs 6, 9, 14, 19 and 23, the types likely to develop penicillin resistance, accounted for 70 (43.5%) of 161 strains, including 26 (66.7%) of 39 strains recovered during the last 6 years. The proportion of SGTs 6, 9, 14, 19 and 23 increased during the 4 successive 5-year periods and the last 6-year period starting with 1978–1982 and ending with 1998–2003, namely 23.8, 31.2, 30.2, 50.0 and 66.7%, respectively. During 1998–2003, the high proportion of SGTs 6, 9, 14, 19 and 23 was offset by fewer SGTs 1 and 8 and the absence of SGT 5 compared with 1993–1997.
During the 26 years of the study, 27 (38.6%) of 70 strains of SGTs 6, 9, 14, 19 and 23 exhibited penicillin resistance, distributed as 14 IR and 13 HR strains. No HR strain exceeded a penicillin MIC of 3.0 μg/ml. In the last 6-year time period, 18 (69.2%) of 26 strains of SGTs 6, 9, 14, 19 and 23 showed penicillin resistance including 12 of 13 HR strains (8 serotype 14, 3 SGT 23 and 1 SGT 9). No child with an IR or HR strain died.
During the last 4 years of the study, after licensure of the PCV7 and its immediate use in the community, including the second half of 2000 and 2001, 2002 and 2003, we determined the vaccine status of children with S. pneumoniae invasive disease. Fifteen (45.5%) of 33 children with invasive pneumococcal disease were considered eligible for PCV7 during these 4 years because they were born after June 30, 1998 and were at least 2 months of age when they developed infection (Table). Of 4 children (36.4%) who had received 1 or more doses of PCV7, none of whom had immune disorders, 1 was infected with serotype 6 in 2001 and 2 with SGT 19 in 2002, and 1 who had received 4 doses of PCV7 was infected with type 3 in 2002. During 2003, the last epidemiologic year of this study, S. pneumoniae invasive disease was not detected in any child younger than 2 years of age. Eighteen children with S. pneumoniae invasive disease were considered ineligible for PCV7 and did not receive it; 14 of them had infections with vaccine SGTs (Table 1).
Our longitudinal study provides a unique viewpoint of S. pneumoniae invasive disease infections in infants and children because it encompasses a single metropolitan area, includes 22 years before and 4 years after the introduction of the PCV7 and spans many years before and after the emergence of penicillin-resistant strains. SGTs included in the PCV7 accounted for two-thirds of all strains recovered, similar to the findings of investigators in the United States and in other countries. 1 In the last 6 years, vaccine SGTs accounted for four-fifths of all strains recovered from infants and children, which compared with the previous 10 years (1988–1997) represented a 1.4-fold increase. This shift to the predominance of vaccine SGTs began before licensure of the PCV7 and appeared unaffected by extensive use of the vaccine during epidemiologic years 2000 and 2001. By contrast, during epidemiologic years 2002 and 2003, the number and proportion of invasive disease caused by vaccine SGTs declined by more than one-half and in 2003 no invasive infections were identified in children younger than 4 years of age, suggesting a vaccine effect. A reduction in invasive disease after widespread use of PCV7 has been reported in several other studies. 5–8
The temporal pattern of invasive disease in children seemed to follow a cycle of peaks and troughs with peaks ~6 or 7 years starting after 1984. Cyclical variation in the occurrence of invasive disease should be considered in evaluating the impact of immunization with PCV7. Annually, invasive disease occurred predominantly between September and May with a nadir in the summer, as also noted by Dowell et al. 9
Seventeen strains of SGT 1 occurred throughout this study, placing it fourth in frequency after SGTs 14, 20 and 6 and confirming its continuing importance as a pathogen of invasive disease in children. 1 A group of investigators from South Africa reported that an experimental 9-valent (that included SGTs 1 and 5) conjugate PPV proved efficacious in a large clinical trial. 10 This 9-valent vaccine would cover three-fourths of the invasive infections in Huntington.
S. pneumoniae invasive disease remains a major community-acquired disease, especially among children younger than 2 years of age providing sufficient reason for immunizing all children in this age group with PCV7, because the vaccine covers the major portion of invasive strains. As demonstrated here and by others, use of the PCV7 reduces S. pneumoniae invasive disease in children. 5–8
Our sincerest appreciation to D. Porter, MD and R. Gaskins and staff of the Pathology Department, Cabell Huntington Hospital; and A. C. Harris, MD and L. Lucas and staff of the Pathology Department, St. Mary’s Hospital in Huntington, WV, whose cooperation facilitated this research. We also thank S. Wells, RN and Joseph Werthammer, MD, Department of Pediatrics, and his staff for their assistance in collecting clinical information.
1. Hausdorff WP, Bryant J, Paradiso PR, Siber GR. Which pneumococcal serogroups cause the most invasive disease: implications for conjugate vaccine formulation and use: part I. Clin Infect Dis
2. McIntosh K. Community-acquired pneumonia in children. N Engl J Med
3. Mufson MA, Stanek RJ. Bacteremic pneumococcal pneumonia in one American City: a 20-year longitudinal study, 1978–1997. Am J Med
4. Sahloul RT, Stanek RJ, Mufson MA. Surveillance of penicillin-resistant Streptococcus pneumoniae
in one American metropolitan area, 1989–1998. Eur J Clin Microbiol Infect Dis
5. Black SB, Shinefield HR, Hansen J, Elvin L, Laufer D, Malinoski F. Postlicensure evaluation of the effectiveness of seven valent pneumococcal conjugate vaccine. Pediatr Infect Dis J
6. Black SB, Shinefield HR, Ling S, et al. Effectiveness of heptavalent pneumococcal conjugate vaccine in children younger than five years of age. Pediatr Infect Dis J
7. Lin PL, Michaels MG, Janosky J, Ortenzo M, Wald ER, Mason EO Jr. 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. Pediatrics
. 2003;111(4 pt 1):896–899.
8. Whitney CG, Farley MM, Hadler J, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med
9. Dowell SF, Whitney CG, Rose CE Jr, Schuchat A. Seasonal patterns of invasive pneumococcal disease. Emerg Infect Dis
10. Klugman KP, Madhi SA, Huebner RE, Kohberger R, Mbelle N, Pierce N. A trial of a 9-valent pneumococcal conjugate vaccine in children with and those without HIV infection. N Engl J Med