In the present study, we determined the annual incidence of pneumococcal meningitis in adults in Japan during the period 2016−2018. The incidence of pneumococcal meningitis in patients aged 15–64 years and ≥65 years remained unchanged during this period. The incidence of pneumococcal meningitis (0.20 cases/100,000 population) in adults in 2016 was approximately four times lower than that (0.85) reported in Israel in 2014−2015, and comparable to that (0.29) in England and Wales in 2015−201614,15. We also found that the CFR of adult patients with IPD was significantly lower for those with meningitis (9.9%) than for nonmeningitis cases (17.6%), which is consistent with a report from Israel14. The lower CFR of adult patients with meningitis in our study may be partially explained by the significantly lower age of adult patients with meningitis compared with those with nonmeningitis.
Our study also demonstrated that the proportion of asplenic/hyposplenic or splenectomized adult patients with meningitis (9.5%) was significantly higher than for those with nonmeningitis (3.0%), as was the aOR of meningitis. Collectively, our data indicate that impaired splenic function may increase the risk of meningitis irrespective of the infecting serotype or the patient’s age. It is well known that asplenic or hyposplenic or splenectomized patients are at increased risk for fulminant infections with encapsulated bacteria; this is attributable to a lack of splenic filtering and decreased production of specific antibodies and memory B cells16,17. A recent study of 2,435 adult patients with IPD demonstrated that the proportion of asplenic patients with meningitis (6/37; 21.0%) was significantly higher than in patients with a spleen (112/2,398; 4.7%)18. The authors also reported that the proportions of asplenic patients requiring intensive care admission or mechanical ventilation use and suffering acute kidney injury were significantly higher than for patients with a spleen, although the difference in the CFR between the two groups was not significant. These findings confirmed that asplenic patients had more severe IPD than patients with a spleen.
We also found significantly higher odds of meningitis in patients infected with serotypes 10A or 23A, which are not included in PCV13. A recent study in England and Wales reported similar findings of significantly increased odds of meningitis with serotypes 10A, 23B, and 35B15. Another study from Israel also demonstrated that the percentage of adult patients with meningitis was significantly higher for IPD caused by serotypes 24F, 23F, 15B/C, 23B, or 23A14. These findings indicate that the serotypes that commonly cause meningitis in adults include both types contained in PPSV23 (such as 10A and 15B/C) and nonvaccine types (such as 23A, 23B, 24F), plus 23F, and support the idea of the limited impact of pediatric PCV13 on meningitis in adults. A recent study from the Pneumococcal Serotype Replacement and Distribution Estimation project assessed the serotype distribution of the remaining serotypes involved in pneumococcal meningitis worldwide19. The study demonstrated the percentage of pneumococcal meningitis occurring after infection with serotypes included in the current PCV13 and upcoming PCV products including PCV20 or PCV24, for all cases of meningitis in locations using PCV1320–23. While the percentage of PCV13 serotypes was 14.8% for patients aged < 5 years and 25.2% for those aged ≥5 years, the percentages of PCV20 or PCV24 serotypes were 56.5–57.3% and 61.4–63.4%, respectively, for patients of all ages19. The higher percentage of PCV20 or PCV24 serotypes in cases of meningitis indicates that the higher-valency PCVs have the potential to prevent more cases of pneumococcal meningitis in children and adults.
Because the rate of vaccination with PCV13 in Japanese adults is currently negligible, the significant decrease of the percentage of PCV13 serotypes in all IPD cases during the study period suggests an indirect effect of pediatric PCV13 vaccination. Although no difference was found in the percentage of PPSV23 serotypes for total cases of IPD, a slight, but significant decrease was found in the percentage of PPSV23 serotypes in nonmeningitis cases, but not in meningitis cases. This may be because the indirect effect of PCV13 is more evident in nonmeningitis than in meningitis: although the percentage of PCV13 serotypes was significantly decreased in nonmeningitis cases, no significant difference was found in meningitis cases. This finding indicates that the indirect effect of pediatric PCV13 vaccination on meningitis in adults in Japan has a limited impact, probably because of an increase in cases caused by the non-PCV13 serotypes 10A or 23A. A study from Israel also reported that nonmeningitis IPD but not meningitis decreased after PCV13 implementation14. The authors suggested that this was because of an increase in cases caused by non-PCV13 serotypes. By contrast, a study in England and Wales reported that the replacement of PCV7 by PCV13 in 2010 decreased pneumococcal meningitis cases, mainly those caused by the additional serotypes included in PCV13, without any increase in cases caused by non-PCV13 serotypes15.
In our study, 35.1% of pneumococcal isolates (n = 222) from patients with meningitis were PCG resistant. By contrast, only 0.7% and 0.4% of pneumococcal isolates (n = 1,254) from nonmeningitis cases showed intermediate resistance or resistance to PCG. The difference in the MIC values for PCG between meningitis and nonmeningitis cases was responsible for the different MIC breakpoints for PCG, because the values of MIC50 and MIC90 for each antimicrobial agent were similar for the two groups. Based on this finding of reduced β-lactam susceptibility, it may be advisable for clinicians to administer ceftriaxone or meropenem plus vancomycin for adult patients suspected of having pneumococcal meningitis until susceptibility results are reported6,24. Japanese investigators recently reported that all patients with pneumococcal meningitis were treated with two or more antibiotics25. In that study, antimicrobial treatment was frequently initiated with ceftriaxone, followed by sulbactam/ampicillin, tazobactam/piperacillin, and vancomycin.
The present study showed that the odds of meningitis were higher in the presence of the pbp1bA641C mutation (aOR 2.92, 95% CI 1.51–5.65), and lower for patients aged ≥65 years (aOR 0.55, 95% CI 0.40–0.74), although we also found a significant association between the pbp1bA641C mutation and PCG resistance. These data confirm the previously reported association of the pbp1bA641C mutation with meningitis10.
This study has several limitations. First, 33.1% of all cases (n = 2,213) reported to the NESID from 10 prefectures during the study period were not enrolled in this study. Second, the reporting of some variables was incomplete for some enrolled cases. Therefore, the results of our study may not be fully representative of the population of interest. Third, abdominal computed tomography scans were not examined for all enrolled cases to detect asplenia or hyposplenia. The clinical information about splenectomy may be inadequate. Therefore, we might have underestimated the number of IPD patients with asplenia/hyposplenia or splenectomy.
In conclusion, the incidence of pneumococcal meningitis in adults remained unchanged during 2016−2018. Patient ages and the CFR were significantly lower in meningitis cases than in nonmeningitis cases. The odds of meningitis were higher for asplenic/hyposplenic or splenectomized patients and for infection with serotypes 10A or 23A. An indirect effect of pediatric PCV13 on nonmeningitis cases in adults in Japan was evident, but its impact on meningitis cases was limited because of an increase in cases caused by non-PCV13 serotypes.