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Pneumococcal Meningitis in Adults After Introduction of PCV7 And Pneumococcal Meningitis in Adults after Introduction of PCV7 and PCV13, Israel, July 2009–June 20151 Gili Regev-Yochay, Klaris Reisenberg, Michal Katzir, Yonit Wiener-Well, Galia Rahav, Jacob Strahilevitz, Valery Istomin, Evgenia Tsyba, Avi Peretz, Shirley Khakshoor, Ron Dagan, on behalf of the Israeli Adult Invasive Pneumococcal Disease Group2 The indirect effect of pneumococcal conjugate vaccine on of invasive pneumococcal disease (IPD). Untreated pneu- adult pneumococcal meningitis has not been thoroughly mococcal meningitis usually leads to death, and even with investigated. We present data from active surveillance on optimal treatment, mortality rates are high and disease is pneumococcal meningitis in adults in Israel occurring dur- severe with frequent long-term sequelae (1,2). ing July 2009–June 2015. Pneumococcal meningitis was Since the introduction of pneumococcal conjugate diagnosed for 221 patients, 9.4% of all invasive pneumo- vaccines (PCVs) into the national immunization plans coccal disease (IPD) cases. Although overall IPD incidence decreased during the study period, meningitis increased (NIPs) for children in different countries, IPD incidence nonsignificantly from 0.66 to 0.85 cases/100,000 popula- has declined, not only among children but also among un- tion. Incidence of vaccine type (VT) pneumococcal meningi- vaccinated adult populations through herd (indirect) pro- tis (VT13) decreased by 70%, but non-VT13 pneumococcal tection (3–6). Despite non-VT strains nearly completely meningitis increased from 0.32 to 0.75 cases/100,000 pop- replacing VT strains as the causative agents of invasive ulation (incident rate ratio 2.35, 95% CI 1.27–4.35). Pneu- nasopharynx disease, this replacement by non-VT strains mococcal meningitis patients were younger and healthier was only partial in both the pediatric and adult populations, than nonmeningitis IPD patients, and 20.2% had a history of presumably because of the lower invasive potential of most previous head surgery or cerebrospinal fluid leak compared non-VT strains (7). However, a higher magnitude replace- with <2.0% of nonmeningitis patients (p<0.0001). Non-VT13 ment of the serotypes associated with invasive disease was types that rarely cause IPD (15B/C, 6C, 23A, 23B, 24F) observed among immunocompromised and elderly popula- seem to be emerging as common causes of meningitis. tions than among the rest of the general population (4,8). Although several studies have assessed the effect of PCV treptococcus pneumoniae is the leading cause of bacte- on meningitis in children (9–11), data on the indirect ef- Srial meningitis for persons of all ages (1). Pneumococ- fects on adult pneumococcal meningitis are scarce. The cal meningitis is a relatively rare but the most severe form available data mostly address the effect of the 7-valent PCV (PCV7) (12,13) or PCV10 on pneumococcal menin- Author affiliations: Sheba Medical Center, Ramat Gan, Israel gitis in adults (14), and only 2 studies addressed the effect (G. Regev-Yochay, G. Rahav, S. Khakshoor); Tel Aviv University, of PCV13 (15,16). Tel Aviv, Israel (G. Regev-Yochay, M. Katzir, G. Rahav); Soroka In Israel, pneumococcal polysaccharide vaccine 23 Medical Center, Beersheba, Israel (K. Reisenberg); Bar-Ilan (PPSV23) has been part of the NIP for adults for many University, Safed, Israel (K. Reisenberg, A. Peretz); Meir years; the constant coverage rate is >70% for adults >65 Medical Center, Kfar Saba, Israel (M. Katzir); Shaare Zedek years of age. Administration of PCV7 at 2, 4, and 12 Medical Center, Jerusalem, Israel (Y. Wiener-Well); Hadassah- months of age and a catch-up plan was introduced to the Hebrew University, Jerusalem (J. Strahilevitz); Hillel Yaffe Medical NIP for children in July 2009, resulting in >70% vaccine Center, Hadera, Israel (V. Istomin); Barzilai Medical Center, 1 Ashkelon, Israel (E. Tsyba); Baruch Padeh Medical Center, Some results from this study were presented at the 10th International Symposium on Pneumococci and Pneumococcal Tiberias, Israel (A. Peretz); Ben-Gurion University of the Negev, Diseases, June 26–30, 2016, Glasgow, Scotland. Beersheba (R. Dagan) 2Additional members of the Israeli Adult Invasive Pneumococcal DOI: https://doi.org/10.3201/eid2407.170721 Disease Group are listed at the end of this article. Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 24, No. 7, July 2018 1275 RESEARCH coverage (>2 doses) for children <2 years of age within the IAIPD representative at each of the 27 laboratories 1 year of implementation (17). Starting in October 2010, performing blood and cerebrospinal fluid (CSF) cultures administration of PCV13 began to replace that of PCV7, reported all invasive S. pneumoniae isolates on a weekly and immunization coverage rapidly reached ≈95% for 2 basis and transported them to study headquarters (Pediatric doses and ≈90% for 3 doses (18). We previously described Infectious Disease Laboratory, Soroka University Medical the indirect effect of PCV on the adult population in Israel Center), as described previously (18). and reported an ≈20% decrease of overall IPD incidence IAIPD investigators retrospectively collected data for 4 years after the introduction of PCV7 and 2.5 years after every laboratory-identified case from the medical files. the introduction of PCV13; we also reported that the pro- Data were available from 24 of the 27 centers, constituting portion of pneumococcal meningitis cases among all IPD 90.9% of all IPD cases that were identified. Data collected cases increased and that incidence did not decrease as did included sociodemographic data (sex, age, place of birth, other IPDs (4). In this article, we assess meningitis IPD and city of residence); medical history, including concurrent nonmeningitis IPD incidence and the change in associated medical conditions and IPD-predisposing medical condi- serotypes in adults 6 years after PCV7 introduction. tions; substance abuse; smoking history; influenza in the days preceding hospitalization; and vaccination history for Materials and Methods influenza and pneumococcal pneumonia. The Centers for Disease Control and Prevention definition for IPD-predis- Ethics Statement posing medical conditions, on which vaccination recom- This study was conducted after protocols were approved mendations are based (https://www.cdc.gov/vaccines/vpd/ by the Sheba Medical Center Institutional Review Board pneumo/downloads/pneumo-vaccine-timing.pdf), was (Ramat Gan, Israel) and the Soroka University Medical used to divide adults into 3 categories: 1) high-risk patients, Center Institutional Review Board (Beersheba, Israel). Be- defined as patients having chronic renal failure, HIV, medi- cause this study was a retrospective observational study, cally induced or innate immunodeficiencies, asplenia, he- the institutional review boards waived the need for written matologic or metastatic malignancies, CSF leak, or prior informed consent, so informed consent was not obtained neurosurgery; 2) at-risk patients, defined as patients with from participants. Therefore, all patient records and infor- diabetes mellitus, congestive heart failure, chronic lung mation were deidentified before analysis. disease, cirrhosis, or an addiction to alcohol; and 3) not at- risk patients, defined as those who were not recognized as Study Period and Population having a predisposing medical condition. According to the The period evaluated was July 1, 2009–June 30, 2015, a NIP for adults in Israel, it is recommended that high-risk 6-year period starting when PCV7 was introduced into the patients be vaccinated with PCV13 and PPSV23 and at- NIP for children. We included all culture-confirmed IPD risk patients with PPSV23. We also collected data on in- patients of the adult (>18 years of age) population in Israel hospital complications: septic shock, need for ventilation, (n = 5,029,600 in 2009; n = 5,504,900 in 2015; http://www. disability as determined by transition to a long-term care cbs.gov.il). facility, and concurrent medical conditions. Surveillance System and Study Design Case Definition To ensure both a high rate of reporting and data collec- We defined IPD cases on the basis of positive pneumococcal tion from the medical records, a large research network cultures and did not include PCR testing or antigen detec- named the Israeli Adult Invasive Pneumococcal Disease tion, as described previously (4). We defined pneumococcal (IAIPD) group was established. This group includes 2 re- meningitis patients as those with an S. pneumoniae–posi- searchers from each of the 27 acute care hospitals of Is- tive CSF culture or those with an S. pneumoniae–positive rael: a researcher from the microbiology laboratory and blood culture who were also given a clinical diagnosis of an infectious disease physician devoted to following the meningitis by the treating physician (i.e., given a discharge IPD patients and collecting the required data, as described diagnosis code of meningitis). previously (4). In Israel, all invasive S. pneumoniae isolates are re- Vaccination Policy and Vaccine Uptake quired by law to be reported and sent to the Ministry of PCV7 was licensed in Israel in 2007 and was introduced Health reference laboratory (Jerusalem, Israel), and several into the NIP for children in July 2009 with a 2-, 4-, and different methods were used by clinical staff members to 12-month schedule and a 2-dose catch-up plan for all chil- collect these bacterial isolates before submission. In addi- dren <2 years of age at the time of introduction. The meth- tion
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