Background
Streptococcus pneumoniae frequently colonizes the nasopharyngeal tract of children and causes noninvasive infections, such as otitis media and nonbacteremic pneumonia. Furthermore, it can cause meningitis, bacteremic pneumonia, bacteremia/septicemia, and other invasive pneumococcal diseases (IPDs) [
1,
2].
The introduction of a heptavalent pneumococcal conjugate vaccine (PCV7) has dramatically reduced the incidence of invasive pneumococcal disease (IPD) among vaccinated young children [
3‐
6] and, as a result of herd immunity, has decreased IPD among the elderly. However, non-PCV7-type IPD has increased 35 years after PCV7 introduction among adults. This increase may have occurred because of serotype replacement, a phenomenon in which the prevalence of nonvaccine serotypes rises while that of vaccine serotypes falls [
7].
PCV7 was approved for voluntary vaccination for children in February 2010 in Japan. From November 2010, PCV7 vaccination was further encouraged for children aged <5 years by an official program, the Provisional Special Fund for the Urgent Promotion of Vaccination by the Japanese government. PCV7 was included in the routine schedule in April 2013, and replaced with a 13-valent pneumococcal conjugate vaccine (PCV13) in November 2013. Consequently, a high vaccination rate (94.2%) was observed in children at 24 months of age in 2015 [Sakiyama H, Oishi K, unpublished data]. For adults, a 23-valent pneumococcal polysaccharide vaccine (PPSV23) was approved in 1988 and included in routine immunization in October 2014 for individuals aged 65 years or older, and PCV13 was approved for adults aged 65 years or older in June 2014, on a voluntary basis. After the introduction of PCV7, a decrease of 98% in the incidence of IPD caused by the PCV7 serotypes was reported in Japan [
8]. This resulted in the 57% decline in overall IPD, although an increase of IPD incidence caused by PCV13 minus PCV7 serotypes and non-PCV13 serotypes among children younger than 5 years of age was observed [
8]. However, the epidemiology of IPD in Japan, including its serotype distribution among adults, after the introduction of PCV for children remains unknown.
In this paper, we describe the disease characteristics and serotype distribution of pneumococcal isolates in IPD among adults in Japan in the period of April 2013-March 2015.
Discussion
This study reports the characteristics and serotype distribution of causative isolates among adult patients with IPD. The majority of patients had underlying diseases, including immunocompromised conditions.
The proportion of patients in our study whose IPD was preceded by influenza (6%) was in agreement with a previous study reported in the US [
11]. As the current proportion of vaccination with PPSV23 among the elderly (older than 65 years of age) in Japan is estimated to be approximately 33% (estimated by the reported number of shipped doses of PPSV23 from MSD K.K. Japan between Jan 1st 2009 and March. 31th 2015/Japanese population older than 65 year-old (Oct. 1st 2012 national statistics [
12], the proportion of vaccination with PPSV23 (9%; 13/150) in adult IPD patients ≥ 65 years of age found in this study was very low. This low vaccination proportion is likely explained by the reason why we calculated the vaccination proportion based on IPD case series; however, these results indicate that it is critical to encourage the unvaccinated elderly to receive a PPSV23 vaccination via the routine immunization program.
The results of our study suggest that the introduction of PCV7 followed by PCV13 in children may have reduced the coverage proportions of PCV13 and PPSV23 from 61% and 85% to 46% and 66%, respectively, compared with the proportions observed in 2006–2007 [
13]. Although the surveillance sites and the method of sample collection differed between the two studies, the factors that affect serotype distribution, such as age and comorbidities, were found to be equivalent. From November 2010, PCV7 was promoted by the Japanese government for children aged < 5 years by the Provisional Special Fund for the Urgent Promotion of Vaccination. Thereby, all children aged < 5 years were subsidized for the vaccination of PCV7. Since then, vaccination coverage of PCV7 has increased among children in Japan. Subsequently, serotype replacement in children after PCV7 introduction was reported from the prospective population based on surveillance from 2008 to 2013 among 10 selected prefectures in Japan [
8], of which seven prefectures were included in our study sites. Furthermore, a recent publication reported that the coverage proportions of PCV13 and PPSV23 had decreased for isolates from adult cases of IPD between 2010 and 2013, as assessed by hospital-based surveillance performed in Japan [
14]. Our study of adult IPD, which was performed between April 2013 and March 2015, demonstrated that the coverage proportions of PCV13 (46%) and PPSV23 (66%) for isolates from all IPD cases (
n = 291) were >10% lower than those detected for all IPD cases between April 2010 and March 2013. Collectively, these findings suggest the effects of immunization with PCV7 among children may have had indirect effects on adult IPD cases.
Serotypes 3, 19A, and 22F were the most common isolates among adult patients with IPD in our study. According to previous data, serotype 19A was frequently isolated from pediatric IPD cases in Japan, whereas serotypes 3 and 22F were rarely isolated from these cases between 2011 and 2013 [
8]. After the introduction of PCV13 for children, serotype 19A (included in PCV13) appeared to decrease among adult patients with IPD overseas [
15], and therefore we need to observe carefully any changes in serotype 19A isolation among adult IPD cases caused by the indirect effect of PCV13 among children by continuing the surveillance. Furthermore, we wonder whether the incidence of IPD caused by serotype 3 decreases after the introduction of PCV13 among children. Although a 44% reduction of IPD incidence caused by serotype 3 was reported in the UK among individuals who were aged 65 years or older after the introduction of PCV13 for children, a herd immunity effect against serotype 3 is unclear worldwide [
15,
16]. In addition, the immunogenicity of PCV13 against serotype 3 remains controversial in children and was reported to be lower than that of PCV13 serotypes other than serotype 3 in the elderly [
17‐
20].
The proportion of vaccine types was lower in immunocompromised patients than those in each age group of nonimmunocompromised patients in our study. This finding is consistent with those reported by Luján et al. [
21]. Those authors reported that serotypes not included in PCV13/PPSV23 were isolated more frequently in patients with cardiac and respiratory comorbidities and in certain subgroups of immunocompromised patients, such as HIV-infected individuals and those with hematologic cancer. This finding suggests that monitoring the emergence of non-vaccine serotypes is crucial, especially in patients with specific underlying conditions.
This study had several limitations. The proportion of cases available for both case-report data and isolate data was 51% (291/567) among cases reported to national surveillance sites from the ten selected prefectures in this study, and reporting of some variables was incomplete, such as preceding influenza was not available for 34% of IPD patients; therefore, it may not represent the population of interest. The number of registered cases in the enhanced surveillance data increased annually (101 cases from April 2013 to March 2014 vs 202 cases from April 2014 to March 2015). Laboratory method or the procedure of specimen collection was unchanged during this period. The annual increase of registered cases might be explained by the improved flow of collecting isolates and case reporting forms from hospitals to NIID through local public health institutes during the study period, and heightened awareness of the IPD surveillance. This explanation is supported by the finding that the number of reported cases from the 10 selected prefectures to NESID increased during the study period (224 cases from April 2013 to March 2014 vs 343 cases from April 2014 to March 2015). The patients whose culture results were positive for S. pneumoniae in the normally sterile sites other than blood or CSF were not included because of the notification criteria of IPD in NESID; thus our results may be an underestimation.
Acknowledgments
We sincerely thank the staff of local public health centers who collected bacterial isolates and the case-reporting form from the hospitals, and the staff of public health institutes/laboratories who conducted the serotyping PCR for the Adult IPD Study Group (
http://www.nih.go.jp/niid/ja/ibi.html).
In addition to MF, BC, YT, TM, K Oshima, TMaruyama, HW, KKuronuma, KKasahara, HT, JN, JF, TK, TS, TMatsui, and KOishi, the members of the Adult IPD Study Group are; Michiharu Nakano (Hokkaido Institute of Public Health), anonymous (Sendai City Public Health Center), Tasuya Ikeda (Yamagata Prefectural Bureau of Public Health and Welfare), Yu Suzuki, Junji Seto, Kazue Yahagi (Yamagata Prefectural Institute of Public Health), Kurumi Kazama (Welfare and Public Health Bureau of Niigata Prefecture), Satoru Yamazaki and Emiko Kumakura (Health and Sanitation Department of Niigata City), Minoru Hiraoka (Department of Health and Welfare, Mie Prefecture), Yuhki Nagai, Sagako Naraya (Mie Prefecture Health and Environment Research Institute), Eri Tsujimoto (Department of Medical Policy, Nara Prefecture), Michiaki Matsumoto (The Public Health Institute of Kochi Prefecture), Hiroaki Shigemura, Fuyuki Okamoto, Nobuyuki Sera (Fukuoka Institute of Health and Environmental Science), Mutsuyo Gokuden (Center for Environment and Health, Kagoshima Prefecture), Toru Itokazu (Welfare and Public Health Bureau of Okinawa Prefecture), Akihito Yokoyama (Kochi Medical School, Kochi University), Hiroki Takahashi (Sapporo Medical University School of Medicine), Tetsuji Aoyagi (Tohoku University Graduate School of Medicine), and Takuri Takahashi (NIID).