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Pediatric Invasive Pneumococcal Disease in Taiwan Following a National Catch-up Program With the 13-Valent Pneumococcal Conjugate Vaccine

Wei, Sung-Hsi MD*†; Chiang, Chuen-Sheue PhD*‡; Chiu, Cheng-Hsun MD, PhD§; Chou, Pesus DrPH; Lin, Tzou-Yien MD§¶

The Pediatric Infectious Disease Journal: March 2015 - Volume 34 - Issue 3 - p e71–e77
doi: 10.1097/INF.0000000000000565
Vaccine Reports
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Background: Seven-valent pneumococcal conjugate vaccine (PCV) has been available in Taiwan since late 2005. A national catch-up program was launched in Taiwan in 2013, providing 1 dose of 13-valent PCV to children aged 2–5 years. Here, we report the epidemiology of invasive pneumococcal disease (IPD) in children aged ≤5 years in this setting.

Methods: We collected demographic and clinical information for pediatric patients (≤5 years) with IPD between 2008 and 2013. The incidence of IPD was estimated. The logs for PCV import into Taiwan were obtained to evaluate the impact of PCV usage on IPD epidemiology.

Results: The overall incidence of IPD in children aged ≤5 years was 15.9 cases per 100,000 person-years. The IPD incidence caused by 7-valent PCV serotypes decreased significantly from 10.0 cases per 100,000 person-years in 2008 to 2.3 cases per 100,000 person-years in 2013. The incidence of IPD caused by serotype 19A increased substantially from 1.7 cases per 100,000 person-years in 2008 to 10.3 cases per 100,000 person-years in 2012, followed by a significant decrease to 5.6 cases per 100,000 person-years in 2013. The significant decrease in the incidence of serotype 19A IPD occurred primarily in children aged 2–5 years.

Conclusions: The 13-valent PCV catch-up program was associated with a significant decrease in serotype 19A IPD incidence in 2013, primarily in children eligible for the 13-valent PCV immunization. Continued surveillance is necessary to assess the further impact of the national catch-up program on pediatric IPD epidemiology in Taiwan.

From the *Centers for Disease Control; Community Medicine Research Center and Institute of Public Health, National Yang-Ming University; Center of General Education, National Taipei University of Nursing and Health Sciences, Taipei City, Taiwan (R.O.C.); §Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan (R.O.C.); and Ministry of Health and Welfare, Taipei City, Taiwan (R.O.C.).

Accepted for publication September 15, 2014.

S.-H.W. and C.-S.C. contributed equally to this work.

The authors have no funding or conflicts of interest to disclose.

Address for correspondence: Tzou-Yien Lin, MD, Ministry of Health and Welfare, No.488, Sec. 6, Zhongxiao E. Rd., Nangang Dist., Taipei City 11558, Taiwan (R.O.C.). E-mail: pidlin@adm.cgmh.org.tw; or Pesus Chou, DrPH, Community Medicine Research Center and Institute of Public Health, National Yang-Ming University, No.155, Sec. 2, Linong St., Beitou Dist., Taipei City 112, Taiwan (R.O.C.). E-mail: pschou@ym.edu.tw.

Streptococcus pneumoniae causes a variety of clinical infections, ranging from mild sinusitis to severe infections such as meningitis, pneumonia and sepsis. It is the leading cause of pediatric bacterial infections, resulting in substantial morbidity and mortality among children. It reportedly causes 14.5 million episodes of serious infection and approximately 826,000 deaths annually in children <5 years of age worldwide.1,2

The polysaccharide capsule is the virulent and antigenic factor of S. pneumoniae, of which more than 90 serotypes have been identified. The serotype profiles are diverse with respect to geographical and temporal distribution.3–5 The serotypes have been implicated in clinical virulence and drug resistance in S. pneumoniae infections.6,7

Invasive pneumococcal disease (IPD) is a disease caused by S. pneumoniae and is preventable by vaccination. In addition to the 23-valent polysaccharide vaccine that has been available since the early 1980s, the pneumococcal conjugate vaccine (PCV), which contains protein-conjugated polysaccharides that confer an enhanced immune response, has been marketed since 2000 and is now available in 7-valent, 10-valent and 13-valent forms.8,9 Of the 194 World Health Organization (WHO) member states, 86 (44%) included PCV in their national immunization program as of 2012, covering 31% of all children born in the WHO member states.10 The introduction of PCV was associated with a decrease in IPD incidence and an altered trend of serotype distribution in children eligible for immunization as well as in other age groups.11 However, the emergence of IPD caused by serotypes not included in the vaccines has become a concerning issue.5,12

Since October 2007, IPD has been a reportable disease in Taiwan. IPD patients who have S. pneumoniae isolated from their sterile sites are eligible for reporting, while those diagnosed positive by S. pneumoniae PCR or urine antigen test do not fulfill the reporting criteria. Despite years of surveillance, reports regarding population-based pediatric IPD epidemiology in Taiwan remain limited.13,14

The 7-valent PCV was first available in late 2005, and now all 3 forms of PCV have been licensed in Taiwan. The Taiwan Advisory Committee on Immunization Practice has recommended PCV administration using the 3+1 schedule (3 primary doses administered between 2 and 6 months of age with a minimum interval of 8 weeks between doses and 1 booster dose after 12 months of age). The recommended schedules for immunizing children with different PCV formulas or for those who receive the first dose after 6 months of age were consistent with that in the United States.15 PCV immunization was performed primarily at the recipient expense until 2013. According to information provided by the manufacturer, the cumulative coverage rates of 7-valent PCV among children aged <5 years increased each year from 2005 to 2008 (0.7%, 8.6%, 15.9% and 25.2%, respectively).16 These results are supported by a study that reviewed medical records for infants and children aged 2 months to <5 years, with increasing rates of at least 1 dose of 7-valent PCV immunization each year from 2005 to 2010 (0.2%, 5.7%, 17.1%, 26.9%, 37.5% and 45.5%, respectively).17 A national catch-up immunization program was launched in March 2013, providing 1 dose of 13-valent PCV for children 2–5 years old. Because this type of national catch-up program has not been implemented in other countries, we report here the population-based IPD epidemiology in this unique situation in children aged ≤5 years.

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MATERIALS AND METHODS

Study Population

Physicians in Taiwan were required to report patients with IPD to the Taiwan Centers for Disease Control (TCDC) and recorded their demographic and essential clinical characteristics in a web-based database. The S. pneumoniae strains isolated from IPD patients were transferred to TCDC for species and serotype identification. We collected the S. pneumoniae serotype information and demographic and clinical information from the TCDC database separately for patients aged <2 years and 2–5 years who were diagnosed between January 1, 2008, and December 31, 2013, to evaluate the pediatric IPD epidemiology.

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Definitions

IPD was defined as isolation of S. pneumoniae from a normally sterile site. Underlying health conditions included use of steroids or other medication with an immunosuppressive or immune modification effect, congenital diseases for which impaired immunity is one of the presentations or complications, malignancies and neurological diseases with an increased risk of respiratory complications.

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Incidence of IPD

To calculate the incidence of IPD, age- and gender-specific population statistics were obtained from the website maintained by the Department of Household, Ministry of the Interior.2 The IPD incidence was expressed as the number of cases per 100,000 person-years. Age- and serotype-specific incidences were also calculated.

We calculated the IPD incidence separately for those <2 years of age and those aged 2–5 years because only the latter group was eligible for the catch-up 13-valent PCV in 2013. The trends were evaluated for the time periods 2008–2010, 2011–2012, when the 13-valent PCV was introduced to Taiwan, and 2013, when the national 13-valent PCV catch-up program was launched.

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Impact of Immunization on IPD Incidence

We assumed that the amount of PCV imported was equivalent to the amount of PCV used in Taiwan. The import logs of 7-valent, 10-valent and 13-valent PCVs were obtained from the Taiwan Food and Drug Agency to evaluate the impact of PCV immunization on IPD epidemiology. The amount of imported PCV was also expressed as a proportion of the infants immunized with the 3+1 schedule in the respective periods.

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Ethics Statement

The ethics review board of the TCDC approved the study protocol. The ethic review board waived the need for informed consent, and we did not obtain the informed consent from the parents.

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Statistics

The change in incidence between the 2 time periods is expressed as the incidence rate ratio and 95% confidence interval. The age-specific trends of IPD incidences are examined using the Cochran–Armitage trend test using SAS, version 9.3 (SAS Institute Inc., Cary, NC). Categorical comparisons were performed using χ2 or Fisher exact tests. Statistical analyses other than the Cochran–Armitage trend test were performed using Stata, version 11 (Stata Corp., College Station, TX). A 2-sided P < 0.05 was considered statistically significant.

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RESULTS

Study Population

During the study period, 1143 patients with IPD were identified (515 girls, 45.1%; 628 boys, 54.9%; Table 1). The mean (±SD) age of the 1143 patients was 2.7 (±1.5) years. Of these, 268 (23.4%) and 875 (76.6%) occurred in children of <2 years and 2–5 years, respectively. Fifty (4.4%) children had underlying health conditions, and 30 (2.6%) died. The mortality rate was significantly different between IPD patients with underlying health conditions and those without (P = 0.01), but there were no significant differences based on gender or age.

TABLE 1

TABLE 1

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Incidence of IPD

The overall incidence during the study period was 15.9 cases per 100,000 person-years. The incidence of IPD was higher in boys, but the difference was not statistically significant (16.8 vs. 15.0 cases per 100,000 person-years for boys and girls, respectively; P = 0.06). The highest incidence was 19.8 cases per 100,000 person-years in 2011, and the lowest was 11.3 cases per 100,000 person-years in 2013 (Fig. 1). Generally speaking, children aged 2–4 years had a higher incidence than children of other ages (Fig. 2). The IPD incidence for children aged ≥2 years increased between 2008 and 2011 or 2012 and decreased thereafter. However, no obvious trend for IPD incidence was observed for infants or toddlers 1 year of age.

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

During the study period, no pediatric IPD cases were caused by serotype 4, which was in the 7-valent PCV, or serotypes 1, 5 and 7F, which were in both the 10- and 13-valent PCVs. The serotype-specific IPD incidence is shown in Table 2.

TABLE 2

TABLE 2

For children <2 years of age, the overall IPD incidence decreased slightly from 12.9 cases per 100,000 person-years in 2008–2010 to 10.2 cases per 100,000 person-years in 2013. The IPD incidence caused by 7-valent PCV serotypes decreased significantly from 7.7 cases per 100,000 person-years in 2008–2010 to 3.1 cases per 100,000 person-years in 2013. In contrast, the IPD incidence caused by the extra serotypes contained in 13-valent PCV increased significantly from 3.1 cases per 100,000 person-years in 2008–2010 to 5.5 cases per 100,000 person-years in 2011–2012 and remained high in 2013 (5.2 cases per 100,000 person-years). This increase in IPD incidence was mainly attributed to the increasing incidence caused by serotype 19A during the study period. The incidence of IPD caused by serotypes of non 13-valent PCV moderately increased from 1.4 cases per 100,000 person-years in 2008–2010 to 1.7 cases per 100,000 person-years in 2013. The leading serotypes of IPD caused by non 13-valent PCV included serogroup 15 (18/35, 51.4%) and serotype 23A (8/35, 22.9%).

For children 2–5 years of age, who were eligible for the 13-valent PCV immunization in 2013, the overall IPD incidence changed drastically. It increased from 16.8 cases per 100,000 person-years in 2008–2010 to 22.8 cases per 100,000 person-years in 2011–2012 and then decreased significantly to 11.9 cases per 100,000 person-years in 2013. The IPD incidence caused by 7-valent PCV serotypes decreased significantly from 9.6 cases per 100,000 person-years in 2008–2010 to 5.7 cases per 100,000 person-years in 2011–2012 and further decreased to 1.8 cases per 100,000 person-years in 2013. For each serotype included in 7-valent PCV, except serotype 19F, the serotype-specific IPD incidence demonstrated a sustained decreasing trend throughout the study period. The IPD incidence caused by the extra serotypes included in 13-valent PCV increased significantly from 6.0 cases per 100,000 person-years in 2008–2010 to 14.1 cases per 100,000 person-years in 2011–2012 and then decreased significantly to 6.7 cases per 100,000 person-years in 2013. This change in incidence was largely attributed to the incidence caused by serotype 19A, which increased significantly from 4.3 cases per 100,000 person-years in 2008–2010 to 12.9 cases per 100,000 person-years in 2011–2012 and decreased significantly to 6.0 cases per 100,000 person-years in 2013. The IPD incidence caused by serotypes 3 and 6A showed a consistent decreasing trend during the study period. The incidence of IPD caused by serotypes of non 13-valent PCV increased significantly from 1.0 cases per 100,000 person-years in 2008–2010 to 2.4 cases per 100,000 person-years in 2013. The leading serotypes of IPD caused by non 13-valent PCV included serogroup 15 (44/76, 57.9%) and serotype 23A (22/76, 28.9%). Serogroup 15 IPD showed a consistent increasing trend from 0.4 cases per 100,000 person-years in 2008–2010 to 2.0 cases per 100,000 person-years in 2013

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Impact of PCV Immunization on IPD

Between 2006 and 2010, a total of 1,210,937 doses of 7-valent PCV were imported, which would provide complete immunization for 33.2% of infants born between 2006 and 2010 using the 3+1 schedule. A total of 286,720 and 2,027,160 doses of 10-valent and 13-valent PCV were imported in 2010–2013 and 2011–2013, respectively, which would provide complete immunization for 10.5% and 85.9% of infants born during the respective periods using the 3+1 schedule. With the increasing amount of imported 7-valent PCV doses, incidence of 7-valent PCV covered IPD continuously decreased from 10.0 cases per 100,000 person-years in 2008 to 2.3 cases per 100,000 person-years in 2013 (P < 0.001; Fig. 3). Incidence of IPD caused by additional serotypes in 13-valent PCV, that is, serotype 3, 6A and 19A, continuously increased from 3.0 cases per 100,000 in 2008 to 11.5 cases per 100,000 person-years in 2012 (P < 0.001). After launch of 13-valent PCV catch-up program, it decreased to 6.2 cases per 100,000 person-years in 2013. The trend of IPD caused by additional serotypes in 13-valent PCV was mainly associated with that caused by serotype 19A, which increased continuously from 1.7 cases per 100,000 person-years in 2008 to 10.3 cases per 100,000 person-years in 2012 (P < 0.001); then, it decreased to 5.6 cases per 100,000 person-years in 2013.

FIGURE 3

FIGURE 3

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DISCUSSION

PCV is one of the key intervention measures for IPD control.18 Previous studies have shown that the introduction of PCV results in a significant decrease in IPD disease burden caused by vaccine serotypes.19–22 The coverage rate of 7-valent PCV reportedly increased from 0.2% in 2005 to 45.5% in 2010.17 Similarly, the 7-valent PCV imported between 2006 and 2010 in the present study would have provided immunization for 33.2% of infants using the 3+1 schedule. With the increasing coverage of 7-valent PCV, the incidence of pediatric IPD caused by the vaccine serotypes decreased significantly during the study period. Although some children did not receive the 7-valent PCV because it was only provided in the private market, those who did not receive the vaccine might have benefited from herd immunity.23

Although the IPD incidence caused by 7-valent PCV serotypes decreased, the overall disease burden of pediatric IPD remained high in 2008–2011. The IPD disease burden caused by serotypes not contained in 7-valent PCV, especially serotype 19A, offset the benefit of the 7-valent PCV. IPD caused by serotype 19A accounted for 53.6% of IPD cases in 2011–2012, despite the introduction of 13-valent PCV in the private market. However, with the launch of the 13-valent PCV catch-up program in March 2013, the coverage rate of 13-valent PCV in children 2–5 years of age increased rapidly. According to the information from the National Immunization Information System, the proportion of children aged 2–5 years immunized with the recommended schedules of 13-valent PCV increased from 31.9% in February 2013 to 64.2% in December 2013 (unpublished data). The increasing coverage of 13-valent PCV corresponded with a significant decrease in IPD in this age group, especially that caused by 19A.

In the present study, we report that providing 1 dose of 13-valent PCV to children aged 2–5 years is effective in reducing the IPD incidence. Previous studies have shown that PCV administration is associated with decreased pneumococcal carriage rates.24,25 Although the pneumococcal carriage rate is significantly higher in infants without PCV immunization than those with PCV immunization using the 3+1 schedule, the rates became closer after the former received catch-up PCV immunization.26 The catch-up PCV in the present study is also presumed to contribute to decreased pneumococcal carriage, thus results in decreased incidence of IPD in children ≥2 years.

WHO has advised that PCV be included in the infant vaccine program for all countries18 However, integrating 3 to 4 PCV doses into the existing vaccine program is costly and may raise significant administrative and logistic burden to the public health system. In addition to vaccination recommendations for children using the 3+1 schedule of PCV, Taiwan government provides catch-up PCV immunization to children ≥2 years of age as the initial strategy of integrating PCV to national immunization program. Our experience demonstrates that this method of integrating PCV into the national immunization program is effective, flexible and cost-effective. With the assumption that children <2 years old could also benefit from vaccination, the 13-valent PCV catch-up immunization program in Taiwan was expanded to include children aged 1–2 years at the beginning of 2014. The effectiveness of immunization in this age group will be monitored closely.

The role of 7-valent PCV on the serotype 19A-related incidence of IPD remains controversial.5,27 Choi et al7 reported an increase of a multidrug resistant 19A strain before the use of 7-valent PCV in Korea. A study of pediatric pneumococcal nasopharyngeal carriage and IPD in Taiwan showed a low rate of serotype 19A carriage and a high proportion of IPD caused by serotype 19A, implicating that the virulence of serotype 19A, in addition to replacement carriage of serotype 19A, played a significant role in the prevalence of IPD caused by serotype 19A.13 Further studies are warranted to determine the cause of increased serotype 19A IPD in the setting of 7-valent PCV usage.

Pediatric IPD caused by serotypes 1, 5 and 7F were not identified in the present study. Previous studies have also demonstrated that serotypes 1, 5 and 7F are uncommon serotypes for invasive infection as well as for nasopharyngeal colonization in Taiwan.17,28 These reports suggest that 7-valent and 10-valent PCVs might play similar roles in IPD prevention in Taiwan. Poolman et al.29 reported that the polysaccharide–protein conjugate 19F in 10-valent PCV induced a considerable level of cross-opsonophagocytic antibodies against serotype 19A. However, clinical trials on the protective effect of the 10-valent PCV on serotype 19A infection remain inconclusive.30,31 Further study is necessary to explore the effectiveness of 10-valent PCV to prevent serotype 19A-caused IPD.

This study has certain limitations. Although physicians are subject to penalties for neglecting to report IPD cases, it is unknown if all cases were reported to the TCDC; therefore, the pediatric IPD incidence may be underestimated. The prescription of antimicrobials for ambulatory patients with upper respiratory tract infection has not been reimbursed by the National Health Insurance in Taiwan since 2001.32 However, antimicrobials are still frequently prescribed for patients with respiratory tract infection without microbiological evidence; this may also results in underestimated IPD incidence.33,34 The validity of the IPD epidemiology during the period of the catch-up program since 2013 is limited by the short surveillance period. The natural fluctuation of the overall IPD incidence may have resulted in an under- or overinflated IPD incidence in 2013. However, the consistent trends in the incidence of IPD caused by the serotypes beyond 13-valent PCV in children aged ≤5 years old and serotypes contained in the 13-valent PCV in children <2 years old provide support for the conclusion of a decreasing IPD incidence in children eligible for immunization in 2013. Finally, the amount of imported PCV, instead of a direct measurement of pediatric PCV coverage, was used to evaluate the impact of PCV on IPD epidemiology. Because of the diverse dosing schedules in PCV immunization, the amount of imported PCV might not be an accurate indicator of PCV coverage.

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CONCLUSION

The overall incidence of IPD among children aged ≤5 years or younger was 15.9 cases per 100,000 person-years, and children aged 2–4 years experienced a higher IPD incidence than children of other ages. Following the introduction of the 7-valent PCV, the incidence of pediatric IPD caused by serotypes contained in the vaccine decreased. However, the overall incidence of IPD did not decrease because of an increase in IPD caused by serotype 19A. The 13-valent PCV catch-up program was associated with a decrease in IPD incidence primarily in children aged 2–5 years old, who were eligible for the immunization in 2013. Therefore, a systematic catch-up program with 13-valent PCV in the pediatric population is suggested. The information in the present study supports the evaluation of vaccine effectiveness and policy making in Taiwan as well as the Western Pacific region.

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ACKNOWLEDGMENTS

This work was supported by grants DOH99-DC-2008, DOH101-DC-2202, MOHW103-CDC-C-315-000103, MOHW103-CDC-C-315-000501 and DOH102-DC-2106 from the Centers for Disease Control, Taiwan.

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Keywords:

pneumococcal conjugate vaccine; invasive pneumococcal disease; catch-up

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