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Background. Otitis media (OM) is common in early childhood. Streptococcus pneumoniae caused approximately 30%–60% of episodes before the pneumococcal conjugate vaccine (PCV) era. The 7-valent PCV (PCV7) was introduced to the Israeli National Immunization Plan in July 2009, and was gradually replaced by the 13-valent PCV (PCV13) starting in November 2010. We aimed at assessing the impact of PCV7/PCV13 sequential introduction on pneumococcal and overall OM necessitating middle ear fluid culture in children aged <2 years in southern Israel. Methods. This was a prospective, population-based, active surveillance. Our medical center is the only one in the region, enabling incidence calculation. All pneumococcal episodes submitted for culture between July 2004 and June 2013 were included. Three subperiods were defined: pre-PCV, PCV7, and PCV13. Results. Overall, 6122 OM episodes were recorded, and 1893 were pneumococcal. Compared with the pre-PCV period, OM caused by PCV7 plus serotype 6A and the 5 additional PCV13 serotypes (5VT : 1, 3, 5, 7F, 19A) decreased by 96% and 85%, respectively (incidence rate ratios [IRRs], 0.04 [95% confidence interval {CI}, .02–.08] and 0.15 [95% CI, .07–.30], respectively) in a 2-step pattern: In the PCV7 period, only OM caused by PCV7 + 6A serotypes was decreased; in the PCV13 period, 5VT OM rates decreased, along with an additional PCV7 + 6A OM reduction. A nonsignificant increase in non-PCV13 serotype OM was observed (IRR, 1.07 [95% CI, .72–1.58]). In total, 77% and 60% reductions of all-pneumococcal and all-cause OM incidences, respectively, were observed. Conclusions. A substantial 2-step reduction of pneumococcal OM rates, with near-elimination of PCV13 disease, was observed shortly after PCV7/PCV13 introduction.

Background. Pneumococcal conjugated vaccines (PCVs) impact on complex otitis media (OM; including recurrent, nonresponsive, and chronic OM with effusion) was greater than that on simple, acute OM in previous studies. Since complex OM is often a polymicrobial disease, we speculated that reduction of complex OM by PCVs would be associated with reduction of non-pneumococcal OM. Methods. In a prospective, population-based, active surveillance, all OM episodes submitted for middle ear fluid culture in children <3 years from 2004 through 2015 were included. Three sub-periods were established: pre-PCV, PCV7, and PCV13. Incidence rate ratios (IRRs) comparing the 3 periods were calculated for pneumococcal, nontypable Haemophilus influenzae (NTHi), Moraxella catarrhalis, Streptococcus pyogenes, and culture-negative OM. Results. Overall, 7475 episodes were included. Of all-NTHi cases in the pre-PCV period, 34% were mixed with Streptococcus pneumoniae. IRRs (95% confidence interval) comparing the pre-PCV to the PCV13 period were 0.02 (0.01-0.04), 0.12 (0.08-0.20), and 0.18 (0.15-0.21) for PCV7+6A serotypes, 5 additional PCV13 serotypes, and all-pneumococcal OM, respectively; non-PCV13 serotype episodes were not significantly reduced. IRRs for single NTHi, mixed NTHi + S. pneumoniae, and all-NTHi OM were 0.30 (0.25-0.35), 0.18 (0.13-0.24), and 0.25 (0.22-0.29), respectively. Moraxella catarrhalis, S. pyogenes, and culture-negative episodes were also significantly reduced. Conclusions. Both pneumococcal and non-pneumococcal OM episodes, enriched with complex cases, declined substantially in children <3 years following sequential PCV7/PCV13 introduction. The reduction in non-pneumococcal episodes may be attributed to early OM episodes prevention, resulting in a lower rate of complex, often non-pneumococcal OM.

BackgroundIntroduction of the 7-valent pneumococcal conjugate vaccine (PCV7) in the United States in 2000 was temporally associated with an increase in the incidence of disease caused by Streptococcus pneumoniae serotype 19A (Sp19A) and with increasing drug resistance within this serotype. A causative role of PCV7 was speculated. We prospectively studied the dynamics of acute otitis media (AOM) caused by Sp19A in southern Israel before the introduction of PCV7 MethodsAOM in children <5 years old undergoing tympanocentesis during 1999–2006 was studied. Antibiotic prescriptions for ∼20% of children <5 years old were recorded. Sp19A isolates were studied for antibiotic-resistance and pulsed-field gel electrophoresis patterns; multilocus sequence typing of representative isolates was compared with that of international clones ResultsSp19A caused 438 (9.8%) of 4449 pneumococcal AOM episodes, increasing by 63.1% from 1999–2001 (mean ± SD, 8.4% ± 0.8%) to 2004–2006 (mean ± SD, 13.7% ± 0.9%) among Bedouin children, who were characterized by overcrowding and high antibiotic use. Penicillin, erythromycin, and multidrug resistance increased from <10% to 78.6%, 50.0%, and 50.0%, respectively (P<.001), and was associated with the introduction and proliferation of 2 multidrug-resistant clones that were not previously associated with multidrug resistance. This was temporally associated with the introduction of and rapid increase in azithromycin use and the frequent use of oral cephalosporins ConclusionsThe introduction and proliferation of multidrug-resistant Sp19A occurred before the introduction of PCV7. The increasing proportion of antibiotic-resistant Sp19A suggests that antibiotic use plays an important role in the community

Background. The 13-valent pneumococcal conjugate vaccine (PCV13) was licensed to replace the 7-valent pneumococcal conjugate vaccine (PCV7) based on serological noninferiority criteria. To date no randomized PCV13 pediatric trial has included clinical endpoints. Methods. This randomized double-blind trial compared the impact of PCV13 versus PCV7 on nasopharyngeal (NP) colonization and immunogenicity. Healthy infants were randomized (1:1) to receive PCV7 or PCV13 at ages 2, 4, 6, and 12 months; NP swabs were collected at 2, 4, 6, 7, 12, 13, 18, and 24 months, and blood was drawn at 7 and 13 months. Rates of NP acquisition and prevalence, and serotype-specific immunoglobulin G (IgG) concentrations were assessed. Results. The per protocol analysis population included 881 PCV13 and 873 PCV7 recipients. PCV13 significantly reduced NP acquisition of the additional PCV13 serotypes 1, 6A, 7F, and 19A; the cross-reacting serotype 6C; and the common PCV7 serotype 19F. For serotype 3, and the other PCV7 serotypes, there were no significant differences between the vaccine groups. There were too few serotype 5 events to draw inference. The impact on prevalence at predefined time points was similar to that observed with NP acquisition. PCV13 elicited significantly higher IgG responses for PCV13 additional serotypes and serotype 19F, and similar or lower responses for 6/7 PCV7 serotypes. Conclusions. PCV13 resulted in lower acquisition and prevalence of NP colonization than PCV7 did for 4 additional PCV13 serotypes, and serotypes 6C and 19F. It was comparable with PCV7 for all other common serotypes. These findings predict vaccine effectiveness through both direct and indirect protection. Clinical Trials Registration. NCT00508742.

After worldwide implementation of 10-valent and 13-valent pneumococcal conjugate vaccines (PCV10/PCV13), a 20-valent PCV (PCV20) was developed. We assessed dynamics of non-PCV13 additional PCV20 serotypes (VT20-13), compared with all other non-VT20 serotypes, in children <2 years of age in late PCV13 (2015-2017) and early PCV (2009-2011) periods. Our prospective population-based multifaceted surveillance included isolates from carriage in healthy children, children requiring chest radiography for lower respiratory tract infections (LRTIs), and children with non-LRTI illness, as well as isolates from acute conjunctivitis, otitis media (OM), and invasive pneumococcal disease (IPD). After PCV13 implementation, VT20-13 increased disproportionally in OM, IPD, and carriage in LRTI. VT20-13/non-VT20 prevalence ratio range was 0.26-1.40. VT20-13 serotypes were more frequently antimicrobial-nonsusceptible than non-VT20 serotypes. The disproportionate increase of VT20-13 in respiratory infections and IPD points to their higher disease potential compared with all other non-VT20 as a group.

•PCV7/13 impact on meningitis, bacteremic-pneumonia (BP) and other-IPD differed.•In all 3 entities, disease caused by PCV13 serotypes (VT13) declined by ∼90%.•Diseases caused by non-VT13 increased by 256%, 302% and 116%, respectively.•Meningitis patients were younger; BP had higher proportion of non-PCV7 serotypes.•This suggests different pathogenesis and host susceptibility between the 3 entities. Widespread introduction of pneumococcal conjugated vaccines (PCVs) impacted on invasive pneumococcal disease (IPD). However, IPD reduction may not be similar in all outcomes within IPD. We assessed PCV7/PCV13 impact on pneumococcal meningitis, bacteremic pneumonia (BP) and other (non-meningitis, non-pneumonia) IPD episodes in children <5years in Israel. A prospective, population-based, active nationwide surveillance. All pneumococcal invasive episodes with positive blood/CSF cultures, July 2000 through June 2016, were included. Three sub-periods were defined: pre-PCV (2000–2008), PCV7 (2009–2011) and PCV13 (2014–2016). Incidence rate ratios (IRRs) were calculated. Overall, 4321 episodes were recorded; 456 (10.6%) meningitis, 1478 (34.2%) pneumonia and 2387 (55.2%) other-IPD. In the pre-PCV period, proportion of serotypes in PCV13, but not in PCV7 (mainly serotypes 1, 5 and 19A) was higher in BP (43.3%) compared with other-IPD episodes (32.8%, p<0.001) and similar to that of meningitis (37.6%, p=0.1). The proportion of episodes in children <12months was higher in meningitis (52.1%) compared with pneumonia (23.2%) and other-IPD episodes (39.5%; p<0.001 for both). The declines of the 3 entities were not similar; Meningitis rate non-significantly declined by 24% (IRR=0.76; 95% CI 0.57–1.01), while BP and other-IPD rates significantly declined by 57% and 70%, respectively. In contrast to other entities, BP did not decline significantly after PCV7 introduction but started to decline only after PCV13 introduction. Rates of meningitis, pneumonia and other-IPD caused by PCV13-serotypes (VT13) substantially declined by 88%, 95% and 97%, respectively, comparing PCV13 and the pre-PCV periods. However, diseases caused by non-VT13 increased by 256%, 302% in meningitis and pneumonia, respectively, but only 116% in other-IPD. Following PCV7/PCV13 introduction, rates of episodes caused by VT13 were substantially reduced in all 3 groups. However, differences in age distribution, serotype replacement and specific serotype decrease suggest different pathogenesis and host susceptibility between the 3 entities.

Background The COVID-19 pandemic led to improved hygiene and reduced social encounters. Near elimination of the activity of respiratory syncytial virus and influenza viruses were observed, worldwide. Therefore, we assessed the rates of pediatric outpatient clinic visits and medications prescribed at those visits during the coronavirus disease 2019 (COVID-19) pandemic and pre-COVID-19 period (2016–2019). Methods Monthly and annual incidence rates for respiratory and non-respiratory diagnoses and dispensed prescription rates were calculated. Acute gastroenteritis (AGE) visits were analyzed separately since the mode of transmission is influenced by hygiene and social distancing. Results Overall, 5,588,702 visits were recorded. Respiratory and AGE visits declined by 49.9% and 47.3% comparing the COVID-19 and pre-COVID-19 periods. The respective rate reductions for urinary tract infections, trauma, and skin and soft tissue infections were 18.2%, 19.9%, and 21.8%. Epilepsy visits increased by 8.2%. Overall visits rates declined by 21.6%. Dispensed prescription rates of antibiotics and non-antibiotics respiratory medications declined by 49.3% and 44.4%, respectively. The respective declines for non-respiratory antibiotics and non-antibiotics were 15.1% and 0.2%. Clinic visits and prescription rates reductions were highest in April–May, following the first lockdown in Israel. Conclusions COVID-19 pandemic resulted in a substantial reduction in respiratory outpatient clinic visits and dispensed respiratory drugs, with only a mild reduction seen for non-respiratory visits. These trends were probably driven by COVID-19 mitigation measures and by the profound disruption to non-SARS COV-2 respiratory virus activity.

Background. The antibody response to pneumococcal conjugate vaccines (PCVs) in infants is variable. Factors responsible for this variability have not been fully elucidated. The objective of this study was to investigate whether pneumococcal carriage around the time of the first dose of 7-valent PCV (PCV7) affects serotype-specific immunologic response. Methods. Healthy 2-month old infants were randomized to receive 2 (at the ages of 4 and 6 months) or 3 (at the ages of 2, 4, and 6 months) PCV7 doses and a booster dose (at the age of 12 months). Nasopharyngeal or oropharyngeal specimens were obtained for culture shortly before the first PCV7 dose. Serotype-specific immunoglobulin (Ig) G levels were measured at ages 2, 7, and 13 months. Results. Of 545 children studied, 332 received a booster dose. The most common serotypes carried around the time of the first PCV7 dose were 6B (n = 37), 19F (n = 22), and 23F (n = 14). In carriers before the first dose, the IgG response to the carried serotype after 2 or 3 doses was significantly lower than in noncarriers. In contrast, response to the noncarried serotypes was not affected. Although all children responded to the booster dose, the response to the originally carried serotype was generally lower. Conclusions. Serotype-specific hyporesponsiveness to PCV7 after pneumococcal carriage in infants is demonstrated for the first time. This phenomenon was common, lasted for at least several months, and was only partially overcome by the 12-month booster. Trial registration. isrctn.org identifier: ISRCTN28445844.

During 1 decade (1989-1998), data on invasive pneumococcal disease were collected prospectively to assess the burden of disease among Jewish and Bedouin children in southern Israel and the potential reduction in illness that can be achieved by using conjugate vaccines. Data on 513 children <15 years old with bacteriologically proven invasive pneumococcal disease were obtained. Among Jewish and Bedouin children <5 years old, incidence rates were 45 and 139 cases per 100,000 child-years of observation, respectively. Jewish and Bedouin children differed in clinical manifestations, seasonal patterns of disease, serotype distribution, and antibiotic susceptibility rates. The potential coverage by 7-, 9-, and 11-valent conjugate vaccines is 41%, 67%, and 71%, respectively, for Jewish children and 22%, 63%, and 65%, respectively, for Bedouin children. The 9- and 11-valent pneumococcal conjugate vaccines have the potential to substantially decrease invasive pneumococcal disease in southern Israel.

Background.This study describes the epidemiologic, microbiologic, and otologic features and selected signs and symptoms of acute otitis media (AOM) caused by Moraxella catarrhalis and compares them with AOM caused by other bacterial pathogens. Methods.Patients aged <5 years with culture-positive AOM from whom a middle ear fluid specimen was obtained and cultured during 1999–2006 were enrolled in the study. Results.Of a total of 12,799 AOM episodes, 8198 (64%) were culture positive, with isolation of 10,382 pathogens: Haemophilus influenzae, 4982 (48.0%); Streptococcus pneumoniae, 4450 (42.9%); M. catarrhalis, 501 (4.8%); and group A streptococci, 449 (4.3%). The distribution of single versus mixed M. catarrhalis infection was significantly different compared with the 3 other pathogens (165 cases [32.9%] as a single pathogen of all M. catarrhalis AOM episodes vs 3108 [62.4%] in AOM caused by H. influenzae, 2592 [58.2%] in AOM caused by S. pneumoniae, and 304 [67.7%] in AOM caused by group A streptococci; P<.001for all comparisons). In multivariate analysis, M. catarrhalis AOM was more frequent in patients experiencing their first AOM episode versus recurrent AOM and mixed infections. M. catarrhalis AOM was associated with lower proportions of spontaneous perforation of tympanic membrane compared with all other pathogens. None of the AOM episodes caused by M. catarrhalis was associated with mastoiditis. Conclusions.Compared with AOM caused by other pathogens, AOM caused by M. catarrhalis is characterized by a higher proportion of mixed infections, younger age at diagnosis, a lower proportion of spontaneous perforation of the tympanic membrane, and no mastoiditis.