BACKGROUND. The incidence of and mortality from invasive pneumococcal disease are significantly higher in children with sickle cell disease than in the general pediatric population. The objective of this population-based study was to assess the effect of pneumococcal conjugate vaccine on rates of invasive pneumococcal disease among children with sickle cell disease.
PATIENTS AND METHODS. Records, including the history of pneumococcal conjugate vaccine administration, of 1247 children born after 1983 residing in metropolitan Atlanta, Georgia, with confirmed hemoglobinopathies were linked to an active surveillance database for invasive pneumococcal disease for the period of January 1, 1995, through January 1, 2003. The incidence of invasive pneumococcal disease and the percentage of rate reduction were estimated before and after pneumococcal conjugate vaccine licensure. Survival analysis was used to estimate the effect of pneumococcal conjugate vaccine on invasive pneumococcal disease rates while accounting for herd immunity.
RESULTS. A significant decline in invasive pneumococcal disease in children with sickle cell disease ≤10 years of age was noted after pneumococcal conjugate vaccine licensure, from 1.7 infections per 100 person-years (1995–2000) to 0.5 infections per 100 person-years (2001–2002), which represents a 68% reduction. The effectiveness of ≥1 dose of pneumococcal conjugate vaccine was estimated by crude analysis to be 84.5% and by stratified survival analysis to be 81.4% when controlling for the presence of herd immunity in the 2 years after pneumococcal conjugate vaccine licensure. Serotype 6A invasive pneumococcal disease represented 36% of invasive pneumococcal disease before pneumococcal conjugate vaccine licensure and 0% after pneumococcal conjugate vaccine licensure, suggesting a protective effect against this pneumococcal conjugate vaccine-related serotype.
CONCLUSIONS. Invasive pneumococcal disease significantly decreased in children with sickle cell disease ≤10 years of age after pneumococcal conjugate vaccine licensure. Pneumococcal conjugate vaccine was effective even when controlling for herd immunity. Extending guideline recommendations for catch-up vaccination beyond 4 years of age should be considered.
- sickle cell anemia
- hemoglobin SC disease
- Streptococcus pneumoniae
- 7-valent PncOMPC vaccine; conjugate vaccine
- herd immunity
Children with sickle cell disease (SCD) have a significantly increased risk of invasive infection and mortality from Streptococcus pneumoniae.1–3 In surveys conducted in the late 1990s,4,5 invasive pneumococcal disease (IPD) rates were higher than those reported in the penicillin treatment arm of an earlier pivotal clinical trial of prophylaxis in children with hemoglobin SS.3 Difficulties in ensuring continuous penicillin prophylaxis administration5–9 and rising penicillin resistance5 may explain the observed differences between the trial and clinical practice. In addition, the immune response to the previously licensed and recommended10,11 23-valent pneumococcal polysaccharide vaccine (23PS) seems variable12 and declines within 3 years after administration.13
A vaccine trial in the United States14 and 2 in Africa15,16 demonstrated that the 7- and 9-valent pneumococcal conjugate vaccine (PCV), respectively, were efficacious in preventing IPD in children in the general population, including among children with HIV.15 After PCV licensure in early 2000 in the United States, a significant decline in IPD was noted in vaccinated children and unvaccinated older individuals.17–20 The reduction in IPD in unvaccinated individuals is attributed to so-called herd immunity, or decreased exposure to children who are S pneumoniae carriers, because such children received PCV vaccination.17,19–22
The objective of this population-based study was to examine the effect of PCV on IPD rates in children with SCD. Because a reduction in IPD rates may be the result of the direct protective effect of PCV or from herd immunity, PCV effectiveness was estimated while controlling for herd immunity.
This study examined IPD occurrence before and immediately after PCV licensure in children with SCD residing within the Georgia Emerging Infections Program (EIP) surveillance area (www.cdc.gov/abcs).23 The Georgia EIP has conducted active, population-based surveillance for IPD (defined as isolation of S pneumoniae from normally sterile body sites) in the Atlanta metropolitan area since 1994. Initially, 8 metro Atlanta counties were included in the Georgia EIP surveillance catchment area. In 1997, surveillance was extended to 20 counties (total population in 2000 census: 4.1 million). To identify subjects with SCD, a registry of all of the patients with a possible diagnosis of SCD regardless of age from any of 3 referral health centers was created (Fig 1). This registry included all of the patients receiving care in a combined adult and pediatric public hospital SCD service and in 2 regional referral pediatric hospitals. For the former, patients were identified from the SCD clinic scheduling database. For the latter, patients were identified from billing databases with an International Classification of Diseases, Clinical Modification, diagnostic code corresponding with SCD. Both source electronic databases had clinical information starting in 1984. Data on individuals receiving care in >1 hospital or with 2 of the same and 1 divergent identifier were reconciled to avoid counting the same individuals more than once. IPD events in these patients were identified by matching this registry with patients with IPD identified by Georgia EIP surveillance.
The current analysis was limited to children ≤10 years of age, with a confirmed diagnosis of hemoglobin SS, hemoglobin S β-thalassemia 0 (SB0), or hemoglobin SC, who resided in the EIP surveillance area and received care between January 1, 1995, and January 1, 2003 (study observation period). Hemoglobin diagnosis was confirmed by reviewing laboratory computer records, the public hospital's SCD clinic database, which includes transcribed newborn screening results,24 and patients' medical charts. Children with hemoglobin SB0 were considered to have a hemoglobinopathy equivalent to children with hemoglobin SS.25 All 3 of the sickle cell clinics followed recommended IPD prophylaxis and vaccinations.10,11,26,27
S pneumoniae isolate penicillin susceptibility and serotyping were performed at the Centers for Disease Control and Prevention. A minimum inhibitory concentration of penicillin between ≥0.12 and <2.00 μg/mL was considered “intermediate resistant,” and a minimum inhibitory concentration ≥2.0 μg/mL was deemed “resistant.”28 The term “penicillin nonsusceptible” includes both intermediate and resistant strains.
Pneumococcal vaccination information of children with SCD was obtained from hospital medical charts, vaccination logs, and Georgia's mandatory immunization registry (http://health.state.ga.us/programs/immunization/grits) after the end of the observation period. One health center (center 2), where patients with SCD receive both primary and specialized care in a single clinic, obtained vaccines through the Vaccines for Children program, whereas the other centers did not. For comparison, vaccine coverage in children 19 to 35 months of age from the general population of Fulton and DeKalb counties, the largest of the surveillance counties, was obtained from the National Immunization Survey (NIS; www.cdc.gov/nis). The NIS continuously collects vaccination history as reported by providers on randomly sampled children from birth through the date of household interview. NIS coverage estimates represent weighted averages for each calendar year. The corresponding estimate in children with SCD was calculated by averaging daily vaccine coverage rates for children 19 to 35 months of age for each calendar year. Coverage rates of children ≤10 years of age were also obtained, and an algorithm was created to determine the percentage of children who were up to date with PCV immunization according to guidelines.27
Rate of IPD
To calculate person-time patient-years, dates of first or last recorded visits were obtained from billing and appointment records regardless of diagnostic code (ie, reason for visit). Patient-years were counted from the start of the study period (January 1, 1995) or the date of the first visit if the first visit occurred after the start of the study. The last observation point was the last recorded visit date or the end of the study period (January 1, 2003), whichever came first. If IPD occurred as the first or last recorded visit, this date was counted as the first or last instance of observation. Repeat IPD diagnoses in a single patient were counted as separate events. Patients were said to have received hematologic care if ≥1 visit occurred in 1 of the 3 referral centers' hematology clinics or if billing records indicated that services were provided by a hematologist. The location of the last hematology clinic visit or the last hospital visit, if the patient did not receive hematologic care, determined the patient's location of care. General population IPD rates from the same surveillance area were also based on data obtained from the Georgia EIP database and were calculated by year, age, and ethnicity, including black (non-Hispanic black) children, a group at increased risk for SCD.29
PCV Herd Immunity
The presence of herd immunity was assessed by examining rates of IPD in children with SCD who did not have documented PCV vaccination. If IPD rates in these unvaccinated groups of children were the same or higher than before PCV licensure (before 2000), then the herd immunity effect was said not be measurable. IPD included PCV vaccine serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F) and isolates with unknown serotypes (isolate missing or nonviable for typing). Overall IPD rates in children from the corresponding general population of children aged 6 to 10 years, just above the recommended age of PCV of vaccination, were also examined.
Crude effectiveness of PCV was examined by comparing rates of IPD in vaccinated and unvaccinated children. Vaccine effectiveness was defined as 100 × [(IDu − IDv)/IDu], where IDu was the incidence density (rate) of IPD in the unvaccinated population and IDv was the rate of IPD in the vaccinated population. A stratified Cox proportional hazard model examined the occurrence of IPD in patients during the introduction of PCV in the general population using person-time data. Person-time was divided into 3 equal periods corresponding with each calendar year after PCV licensure (2000, 2001, and 2002). Models controlled for the possible effect of herd immunity by including a term for the initial period when herd immunity was absent and the subsequent period when herd immunity was present. Models also controlled for possible differences in rates of IPD among health care centers and were stratified by hemoglobin type and by age (midpoint of observation age at 1-year intervals). Only IPD with PCV vaccine serotypes and isolates with unknown serotypes were included in this analysis. Uninfected patients without a record of PCV administration and with <3 documented diphtheria-tetanus-pertussis doses (a proxy for incomplete vaccination information) were excluded from the primary analysis.
Differences in proportions were assessed using the 2-tailed Fisher's exact method. Differences in the rates of IPD were calculated by a person-time denominator cohort method.30 Univariate differences between survival data subsets were assessed by the log-rank test. Survival analysis hazard ratios were calculated by the counting process31 and included robust sandwich covariance matrix estimates.32 Cox models were considered valid only if variable parameter estimates were greater than the corresponding SEs and if the proportional hazards assumption was met. An association was defined significant at an α level of <.05. Data software included Microsoft Access and Excel 2000 (Microsoft Corporation, Redmond, WA), Epi-Info 6.04d (Centers for Disease Control and Prevention, Atlanta, GA), and SAS 9.1 (SAS Institute, Inc, Cary, NC). Institutional review board approval for the study was obtained from Morehouse School of Medicine, Emory University, Children's Health Care of Atlanta, and the Grady Heath Care System.
A total of 1247 children ≤10 years of age with hemoglobin SS, hemoglobin SB0, or hemoglobin SC were included in the analysis (Fig 1). Eighty percent of children (993 of 1247) were followed in the same health center at the beginning and end of the observation period. Ninety-seven percent (1211 of 1247) received specialized hematologic care at least once, and 79% (982 of 1247) were seen ≥5 times. Although children with hemoglobin S β thalassemia + (SB+) were excluded from the analysis, no IPD was noted in these children during the entire period (hemoglobin SB+: 0 of 92 vs hemoglobin SS/SB0 or SC: 50 of 1247; P = .045).
One or more IPD events occurred in 4% (50 of 1247) of children with hemoglobin SS, hemoglobin SB0, or hemoglobin SC during the period of observation. Eight repeat IPD events were noted a median 455 days from a previous event (range: 20–1434 days). Infected children were 52% girls (26 of 50); most were black; 1 was Hispanic (2%). Infected children with hemoglobin SS or hemoglobin SB0 were a median 2.9 years old (range: 0.4–9.7 years), and infected children with hemoglobin SC were a median 1.9 years old (range: 0.3–9.8 years) at IPD. Overall, 24% (14 of 58) of IPD occurred in children aged 5 to 10 years. Serotype and penicillin sensitivity data were available in 91% of isolates (53 of 58). Serotype 6A represented 36% (11 of 30) of IPD before PCV licensure and 0% (0 of 12) after PCV licensure (P = .052). One child with hemoglobin SC developed 3 IPD events with different serotypes (6B, 6A, and 12F). Twenty-one percent (3 of 14) of children infected after 1999 were aged ≥8 years (hemoglobin SC: n = 1; hemoglobin SS: n = 2).
Before PCV licensure, 63% (17 of 27) of IPDs with PCV serotype isolates were penicillin nonsusceptible: 18% (n = 5) were intermediate resistant and 44% (n = 12) were resistant. After PCV licensure, 80% (8 of 10) were penicillin nonsusceptible: 20% (n = 2) were intermediate resistant and 60% (n = 8) were resistant. Seventy-two percent of 6A isolates were penicillin nonsusceptible: 55% (n = 6) were intermediate resistant and 18% (n = 2) were resistant. All 5 of the isolates that had serotypes not related to PCV were penicillin susceptible (10A, 12F, 15C, and 33F).
Meningitis was diagnosed in 15% (7 of 46) of IPD in children with hemoglobin SS (serotypes: 6A, 14, 18C, 19F, and 23F [n = 3]). IPD resulted in death in 11% (5 of 46) of children with hemoglobin SS (serotypes: 6A, 15C, 19F [n = 2], and 23F). Both 19F isolates were penicillin nonscuceptible, whereas the remainder of isolates were penicillin sensitive. Four patients were reportedly not taking penicillin prophylaxis at the time of IPD, and 2 were older than 4 years. Children with hemoglobin SS identified in the database as not having received specialized hematologic care were at greater risk of death from IPD than those who had been seen at least once for hematologic/SCD care (3 of 28 vs 2 of 817; odds ratio: 49; 95% confidence interval [CI]: 9–303; P < .001). Among children with hemoglobin SC, 1 developed meningitis (1 of 11 [9%]; serotype: 23F [n = 3]). No patient with hemoglobin SC died.
Of the children with SCD ≤10 years of age, 62% (619 of 994) received a first dose of PCV between 2000 and the end of 2002. Of these, 34% (209 of 619) received a first dose of PCV before 2 years of age, 26% (160 of 619) at 2 to 4 years of age, and 40% (250 of 619) between 5 and 11 years of age. Sixty-one percent (609 of 994) received ≥1 dose of 23PS; in 50% (310 of 619), 23PS was administered before a first dose of PCV. During the 3-year period after PCV licensure, on average, 45% of children received ≥1 PCV dose. Twenty-one percent received 2 doses, 8% received 3, and 3% received 4 doses. On average, PCV administration was “up-to-date”27 in 40% of children, when those vaccinated for the first time after 59 months of age were included. PCV coverage rates were lowest for center 3 compared with the other 2 centers (42% vs 55%; log rank test: P < .001). Coverage in 19- to 35-month-old children with SCD compared with the general population is presented in Fig 2. Children who did not have documentation of PCV and ≥3 doses of DTP were excluded from the PCV vaccine estimate (160 of 994 [16%]).
IPD rates in children with SCD declined significantly after PCV licensure (Fig 3⇓; Table 1) and, although ∼10 times higher, followed a similar decline as children in the general population. This corresponds with a 68.3% (95% CI: 25.6 to 86.5) reduction of IPD in children with SCD between 1995–2000 and 2001–2002 and a 76.7% (95% CI: 4.5 to 94.3) between 1995–1999 and 2002. Children with SCD represented 4.5% (44 of 986) of all IPD in black children 0 to 5 years of age between 1995 and 2000 and 3.5% (4 of 115) of all IPD between 2001 and 2002. Among those ages 6 to 10 years old, children with SCD represented 20% (8 of 41) of all IPD between 1995 and 2000 and 8% (1 of 13) of all IPD between 2001 and 2002. Overall, SCD accounted for 10% of the IPD rate discrepancy between black and nonblack children under 6 years of age and 32% in children 6 to 10 years old (data not shown). The IPD rate in children with hemoglobin SC was 47.2% lower (95% CI: −1.7 to 72.6; P = .063; Fig 1) than in children with hemoglobin SS/SB0. The IPD rate before 2000 for health centers 1 and 2 was 1.0 per 100 patient years and was 1.5 per 100 patient years (P > .05) for center 3. After PCV licensure, IPD rates were, respectively, 0.3 and 1.4 per 100 patient years (P = .014).
Herd immunity was not measurable in patients with SCD in 2000, because IPD rates in unvaccinated children were higher compared with previous years; a modest decline was measurable in 2001 (Table 1). IPD rates among children 6 to 10 years old in the total population (IPD per 100 000 population) were 5.4 in 1995–1999, 5.7 in 2000, 4.7 in 2001, and 2.2 in 2002. IPD rates among black children of the same age were 9.0 in 1995–1999, 5.3 in 2000, 9.5 in 2001, and 1.7 in 2002. When compared with rates before licensure, IPD rate declines in children 6 to 10 years old from the general population were significant by 2002 (P = .019).
In the first 3 years after licensure, the crude effect of PCV (percentage of IPD reduction) was 84.5% (95% CI: 29.4 to 96.6; Table 1). In the first 2 years after licensure, when herd immunity seemed limited, the crude effect was 88.5% (95% CI: 10.2 to 98.5). PCV effect was also examined in multivariate survival models that controlled for herd immunity, health care centers, hemoglobinopathy, and age (Table 2). In these models, PCV effect (expressed as 1 − hazard ratio × 100), was estimated between 81.4% (95% CI: 19.3 to 95.7) and 84.5% (95% CI: 15.8 to 96.2), depending on whether herd immunity was assumed to be negligible in 2000 or negligible in 2000 and 2001. When patients with hemoglobin SS/SB0 were examined separately, PCV effect was, respectively, 79.0% (95% CI: 3.3 to 95.4) and 81.9% (95% CI: 11.8 to 96.3). In a sensitivity analysis that considered all of the patients without PCV documentation as unvaccinated, measured PCV effect remained similar (data not shown). Neither the effect of herd immunity nor the effect of health care center reached significance in these models.
The incidence of invasive S pneumoniae disease in children with SCD residing in a large metropolitan area was examined for a 5-year period before and a 3-year period after PCV licensure. A highly significant, greater than two thirds decline in IPD rates was noted in children with hemoglobin SS/SB0 or hemoglobin SC after PCV licensure. Using the same approach as in the current study, significant reductions in IPD were reported recently in patients with SCD identified using a Tennessee Medicaid registry.33
Penicillin prophylaxis administration was unlikely to account for the observed decline in IPD after PCV licensure, because no policy change occurred regarding prophylaxis during this period. Also, 80% of PCV serotype isolates were nonsusceptible to penicillin. In a previous study, penicillin prophylaxis had limited-to-no effect in preventing penicillin-nonsusceptible IPD.5
PCV vaccination and IPD serotype data were available on most patients, allowing the examination of the direct protective effect of PCV in children with SCD by comparing IPD rates in vaccinated and unvaccinated children. Isolates that were not serotyped were considered PCV serotypes, a conservative assumption that favored decreased vaccine effectiveness. During the 2-year period after PCV licensure, when herd immunity effect was either absent or, at best, modest, a crude estimate of the PCV effect was significant. The direct protective effect of PCV was further examined in multivariate survival models that controlled for herd immunity and health care center. Analyses were stratified by hemoglobin type to account for possible differences in IPD presentation5 and by age. Separate models considered herd immunity as present the 2 years after PCV licensure or only the third year after licensure. The estimated protective effect of PCV remained significant in both models and was similar to those observed in 2 other studies that examined partially immunized children in the general population.34,35 It is expected that the effectiveness of PCV in children with SCD who are fully immunized according to the recommended schedule10,11 will be greater than that observed in this study. Serotype 6A IPD, a leading cause of infection in patients with SCD before PCV licensure, was not documented after PCV licensure, suggesting a possible cross-protective effect with vaccine type 6B in children with SCD similar to that observed in the general population.35 Earlier PCV vaccination of children with SCD compared with the general population may have contributed to the ability to observe the effect of PCV, before herd immunity became prevalent. PCV introduction seems to have averted prophylaxis failures from rising penicillin-nonsusceptible IPD.5,36,37
The median age at IPD was close to 2 years in children with hemoglobin SC and 3 years in children with hemoglobin SS, supporting current guidelines10 to vaccinate at-risk children at ages 24 to 59 months if not previously vaccinated. However, children with SCD >4 years of age remain at risk for IPD and IPD-related death.5,33 IPD in children with SCD explained a third of the IPD rate discrepancy observed between black and nonblack 6- to 10-year-old children.18 Therefore, clear catch-up recommendations for unvaccinated children with SCD beyond the age of 4 years should be considered,10 because 40% of patients received a first dose of PCV after that age in the current study.
Universal PCV vaccination is expected to have a significant impact on preventing IPD-related deaths in children with SCD. However, 1 of the 5 deaths in this study was caused by a non-PCV isolate (15C, before PCV licensure). Patients who did not receive specialized care seemed at greater risk for fatal IPD,5 suggesting that such care is beneficial. Better integrated primary and specialized care,38,39 with the use of electronic registries, including vaccination records, as well as education of patient's families and health care providers, may help ensure that all children with SCD are fully immunized and receive uniform high-quality care. Until a vaccine that covers most or all serotypes is developed, continued use of penicillin prophylaxis according to current guidelines26 seems prudent. IPD with isolates not covered by PCV are likely to continue to occur and be penicillin susceptible, at least for now. However, penicillin prophylaxis may not be needed for certain SCD subgroups, such as patients with hemoglobin SB+, because no children with this diagnosis were infected before or after PCV licensure. All children with SCD should receive PCV, up to and perhaps including adolescents, even when the vaccine is in short supply or not universally available.
This work was supported in part by National Institutes of Health grant 1 K23 HL 04251 01A1, Centers for Disease Control and Prevention grant UR6/CCU417667-02, Emory Medical Care Foundation grant 96001 (to Dr Adamkiewicz), and the Centers for Disease Control and Prevention–funded Georgia EIP (to Dr Farley).
For support and encouragement, we thank the National Heart, Lung, and Blood Institute Division of Blood Diseases and Resources, especially Ellen Werner, PhD; David Satcher, MD, PhD, Kamille Brown, MS, and Iris Buchanan, MD (Morehouse School of Medicine); JoAnn Beasley, RN, and Sheila Palmer, PA, MBA (staff at the Georgia Comprehensive Sickle Cell Center); staff of Children's Healthcare of Atlanta; James A. Singleton, MS, and Qian Li (Centers for Disease Control and Prevention National Immunization Survey) for providing general population immunization data; and Mitch Klein, PhD, for statistical advice, Allan Platt, PA, Harry Keyserling, MD, James Eckman, MD, Peter Lane, MD and Allan Platt, PA (all of Emory University). We especially thank the record review team: Tracy Brown, MPH, Louis Harrigan, Sandra McCoy, MPH, Darryl Ramoutar, and Megan Tehan, MPH; and Nadine Odo for assistance in article preparation.
- Accepted September 6, 2007.
- Address correspondence to Thomas V. Adamkiewicz, MD, MsCR, FRCP(C), MSM T90/R90 Training Program in Genomics and Hemoglobinopathies, Department of Family Medicine, Morehouse School of Medicine, 1513 E Cleveland Ave, Building 100, Suite 300-A, East Point, GA 30344. E-mail:
The authors have indicated they have no financial relationships relevant to this article to disclose.
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- ↵Halasa NB, Shanka SM, Talbot TR, et al. Incidence of invasive pneumococcal disease among individuals with sickle cell disease before and after the introduction of the pneumococcal conjugate vaccine. Clin Infect Dis.2007;44 (11):1428– 1433
- Copyright © 2008 by the American Academy of Pediatrics