Shalom Ben-Shimol

Near-Elimination of Otitis Media Caused by 13- Valent Pneumococcal Conjugate Vaccine (PCV) Serotypes in Southern Israel Shortly After Sequential Introduction of 7-Valent/13-Valent PCV

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.

Early impact of sequential introduction of 7-valent and 13-valent pneumococcal conjugate vaccine on IPD in Israeli children <5 years: An active prospective nationwide surveillance

BACKGROUND The 7-valent pneumococcal conjugated vaccine (PCV7) was introduced to the Israeli national immunization plan (NIP) in July 2009 (administered at age 2, 4 and 12 months), with a fast reduction of invasive pneumococcal disease (IPD) caused by PCV7 serotypes. Starting in November 2010, PCV13 gradually replaced PCV7. AIM To report the impact of PCV7/PCV13 sequential introduction on IPD in Israeli children <5 years. METHODS An ongoing nationwide, prospective, population-based, active surveillance. All IPD episodes (Streptococcus pneumoniae isolated from blood and/or cerebrospinal fluid) from July 2004 through June 2013 were included. RESULTS Overall, 2670 IPD episodes were recorded. Incidence of IPD caused by PCV7+6A serotypes during the PCV13 period vs. pre-PCV period decreased by 95% (Incidence Rate Ratio [IRR]=0.05; 95% CI=0.03-0.09). This reduction was observed in a two-step manner: 90% in the PCV7-period and further 5% in the PCV13-period. The rates of IPD caused by the 5 additional PCV13-serotypes (1, 3, 5, 7F, 19A; 5VT) increased initially by 47%, but subsequently decreased by 79%, resulting in an overall 70% reduction during the entire study period (IRR=0.30; 0.21-0.44). A two-fold increase in non-PCV13 serotypes IPD was observed (IRR=2.43; 1.73-3.66). In total, a 63% reduction of all-serotype IPD episodes was observed in children <5 years (69% and 48% in children <2 and 2-4 years old, respectively). CONCLUSIONS After initiation of PCV NIP, a rapid and substantial 2-step IPD reduction was observed in children <5 years. The serotype-specific rate reduction reflected the sequential introduction of PCV7/PCV13.

Rapid reduction in invasive pneumococcal disease after introduction of PCV7 into the National Immunization Plan in Israel.

BACKGROUND The 7-valent conjugated vaccine (PCV7) was introduced into the Israeli National Immunization Program (NIP) in July 2009 (2, 4, 12 months schedule; 2 dose catch-up in second year of life). Nationwide active prospective surveillance on invasive pneumococcal disease (IPD) has been conducted in children since 1989. In the current study, IPD epidemiology in children <5 years during the 20 years before and 18 months after PCV7 NIP initiation, is reported. METHODS All 27 centers performing blood/cerebrospinal fluid (CSF) cultures in children reported monthly IPD cases. Capture-recapture approach was used for completeness. RESULTS During 1989-2010, 6022 IPD cases were reported in children <5 years; PCV7 serotypes (7VST) caused ∼50% of all episodes. In 2009 and 2010, 7VST IPD incidences <5 years of age (per 100,000) were 15.9 and 5.4, respectively (a 43% and 81% decrease, respectively) compared to 2003-2007 (mean incidence 27.8). Serotype 6A dynamics resembled those of 7VST. The respective overall IPD incidence decreases were 23% and 42%. The incidence dynamics of serotypes 1, 3, 5, 7F and 19A IPD were characterized by considerable fluctuations over the study period without any upwards or downwards trend in any of the age groups. The overall incidence of serotypes not included in the 13-valent pneumococcal conjugate vaccine (PCV13) did not vary significantly during the study period. By the end of 2010, 72% of the remaining IPD was caused by pneumococcal serotypes included in PCV13. CONCLUSIONS An active prospective long-term surveillance, showed a rapid and sharp decline in IPD in children <5 years following initiation of NIP with PCV7. No serotype replacement has been observed so far. The transition from PCV7 to PCV13 initiated in October 2010 may lead to a further substantial decrease in IPD. Follow-up is needed to better determine the long-term PCV effects.

Impact of PCV7/PCV13 introduction on community-acquired alveolar pneumonia in children <5 years

BACKGROUND Alveolar community-acquired pneumonia (A-CAP) is mostly considered a bacterial disease, mainly pneumococcal. This study was conducted to document the impact of sequential 7-valent and the 13-valent pneumococcal conjugate vaccines (PCV7; PCV13) on emergency room and hospitalization for A-CAP among children <5 years of age. METHODS This is an ongoing prospective population-based study in southern Israel. The current analysis spans over the period July 2002 through June 2013. A-CAP was defined using the World Health Organization (WHO)s criteria for radiologically-confirmed pneumonia. PCV7 was introduced in Israel in July 2009 and gradually replaced by PCV13 in November 2010. Pneumococcal conjugate vaccine (PCV) impact was calculated by comparing incidences during 3 pre-defined periods: pre-PCV (2002-2008), PCV7 (2010-2011) and PCV13 (2012-2013). RESULTS Overall, 10,142 A-CAP episodes occurred. The annual incidences (per 1,000 inhabitants) in children <5 years old declined from a mean (±standard deviation) of 13.8 ± 0.9 in the pre-PCV period to 11.2 ± 2.7 in the PCV7 period and 7.4 in the PCV13 period, representing a reduction of 13% and 47%, respectively. The overall decrease was significantly faster among outpatients than among hospitalized children (42% and -8%, respectively in the PCV7 period; 68% vs. 32% in hospitalized children in the PCV13 period). While in children 12-23 months a significant decline was observed during the PCV7 and PCV13 periods, significant declines in A-CAP rates were observed only during the PCV13 period in the <12 months and 24-59 months age groups (44% and 46%, respectively). CONCLUSIONS A moderate decline in hospital A-CAP visits in children <5 years old was observed after PCV7 introduction. In contrast, after PCV13 introduction a substantial reduction in all visits was evident.

Short-course Antibiotic Treatment for Community-acquired Alveolar Pneumonia in Ambulatory Children A Double-blind, Randomized, Placebo-controlled Trial

Background: Studies on short-course treatment of childhood pneumonia in the developed world are lacking. We compared clinical and laboratory outcomes of a 3-day or a 5-day to a 10-day treatment in young children with community-acquired alveolar pneumonia. Methods: A double-blind, randomized, placebo-controlled trial was conducted in 2 stages: (1) 3 days versus 10 days and (2) 5 days versus 10 days. Amoxicillin (80 mg/kg/d; divided into 3 daily doses) was used for all arms. Case definition was: age 6–59 months; radiologically confirmed community-acquired alveolar pneumonia; temperature ≥38.5°C; peripheral white blood cell count ≥15,000/mm3; status permitting outpatient treatment. Scheduled visits were on days 4–5 and 10–14 with daily telephone interviews for 30 days. Treatment failure was defined by the need for a rescue treatment or hospitalization. Secondary outcomes were: duration of fever and symptoms and white blood cell and C-reactive protein responses. Results: During Stage 1, 4/10 (40%) and 0/12 (0%) evaluable patients failed in the 3-day and 10-day arms, respectively (P = 0.16). Therefore, the 3-day arm was replaced by a 5-day arm (Stage 2). No failures occurred in the 5-day (n = 56) and 10-day (n = 59) arms. Overall, 4/10 (0%), 0/56 and 0/42 (0%) children failed in the 3-day, 5-day and 10-day arms, respectively (P < 0.001, 3-day versus 5-day or 10-day). Secondary outcomes were similar in the 5-day and 10-day arms. Conclusion: In 6- to 59-month-old outpatients with community-acquired alveolar pneumonia, a 5-day course with high-dose oral amoxicillin was not inferior to a 10-day course. The 3-day regimen may be associated with an unacceptable failure rate.

Impact of Widespread Introduction of Pneumococcal Conjugate Vaccines on Pneumococcal and Nonpneumococcal Otitis Media

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.

Pneumococcal nasopharyngeal carriage in children <5 years of age visiting the pediatric emergency room in relation to PCV7 and PCV13 introduction in southern Israel

ABSTRACT The 7-valent and the 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13, respectively) were introduced to the Israeli National Immunization plan in July 2009 and November 2010, respectively. Our aim was to assess pneumococcal conjugate vaccines (PCVs) uptake and dynamics in serotype-specific pneumococcal nasopharyngeal (NP) carriage in children <5 years old in southern Israel, during the immediate 5 y following PCV introduction. This was an ongoing, prospective, population-based, active surveillance, from July 2009 through December 2014. PCVs uptake and NP cultures were obtained daily from children seen at the Pediatric Emergency Room for any reason. Overall, 10,702 vaccine status and 7,610 NP swabs were obtained. Both PCV7 and PCV13 uptake were high, reaching ˜90% by July 2012 and December 2013, respectively. All-pneumococcal carriage rates significantly declined by 10%, from 54.3% in the early-PCV7 period, to 49.1% in the PCV13 impact period. The respective declines for PCV7, 6A and additional PCV13 serotypes carriage rates were 76%, 90% and 66%. In contrast, non-PCV13 serotypes carriage rates increased significantly throughout the study by 71%. All-pneumococcal carriage rates in children <12 months old decreased significantly by 15%, with similar trends observed in other age groups. Initially, all-pneumococcal carriage rates were 45.7%, and 61.9% in Jewish and Bedouin children, respectively (P < 0.001), with a significant 17% reduction throughout the study observed only in Bedouins. While early carriage rates were higher in unvaccinated children compared to vaccinated children, PCV impact on carriage were similar in both groups. In conclusion, a relatively moderate decline in pneumococcal carriage rates, facilitated by a substantial decrease of vaccine-serotypes and increase of non-vaccine serotypes was observed in the immediate period following PCVs introduction in southern Israel.

Rapid impact of rotavirus vaccine introduction to the National Immunization Plan in Southern Israel: Comparison between 2 distinct populations

BACKGROUND Rotavirus vaccines were licensed in Israel in 2007, and in 2011 the pentavalent-vaccine (RV5) was introduced into the Israeli National Immunization plan. AIM To determine the effect of rotavirus-vaccines on the incidence of hospital visits due to rotavirus gastroenteritis (RVGE) and all-cause diarrhea in Jewish and Bedouin children <5 year residing in southern Israel. METHODS We conducted a population-based, prospective, observational study. Data from 2006 through 2013 were analyzed. Our hospital is the only medical center in the region, enabling age-specific incidences calculation. RESULTS In the pre-vaccine period, the overall RVGE hospital visits rates per 1000 in children <12, 12-23 and 24-59 m were 16.1, 18.6 and 1.4 in Jewish children, respectively. The respective rates in Bedouin children were 26.4, 12.5 and 0.7 (P<0.001 for <12 m). Hospitalization rates were higher among Bedouin than among Jewish children (60.0% vs. 39.7%, P<0.001). Vaccine uptake was faster in the Jewish vs. the Bedouin population. In the year following RV5 introduction, RVGE hospital visits rates declined by 82%, 70% (P<0.001 both) and 36% (P=0.092) in Jewish children <12, 12-23 and 24-59 m, respectively. In Bedouin children, the respective RVGE rates declined by 70% (P<0.001), 21% (P=ns) and 14% (P=ns). Throughout the study, RVGE rates declined significantly in children <12, and 12-23 m by 80% and 88% in Jewish children, respectively, and by 62 and 75% in Bedouin children, respectively (P<0.001 for all declines). In children 24-59 m, RVGE rates declined by 46% (P=0.025) in Jewish children, but no reduction was observed in Bedouin children. The dynamics of all-cause diarrhea rates were similar to that of RVGE. CONCLUSIONS Significant reductions of RVGE rates were observed, following Rota-vaccine introduction in southern Israel in both Jewish and Bedouin children. However, the impact was faster and more profound in Jewish children, probably related to higher vaccine uptake and possibly to lifestyle differences.

Differential impact of pneumococcal conjugate vaccines on bacteremic pneumonia versus other invasive pneumococcal disease.

Background: Bacteremic pneumonia (BP) accounts for ~35% of invasive pneumococcal disease (IPD) in young children. Our aims were to compare age, seasonal and serotype distribution of BP versus non-BP IPD and to determine whether the impact of the sequential 7/13-valent pneumococcal conjugate vaccine (PCV7/PCV13) introduction on disease incidence differed between BP and non-BP IPD in children <5 years of age. Methods: A nationwide, prospective, population-based, active surveillance (July 2004–June 2013) was conducted. All IPD episodes were included. PCV7 was introduced to the Israeli National Immunization Plan in July 2009 and has been replaced by PCV13 since November 2010. Results: In all, 983 (36.8%) BP and 1687 (63.2%) non-BP IPD episodes were recorded. A higher proportion of BP than that of non-BP IPD episodes (42.0% vs. 20.7%; P < 0.001) occurred in children >24 months old. Seasonality differed between BP and non-BP IPD, with yearly earlier peaks of non-BP IPD. The proportion of the 5 additional PCV13 serotypes (1, 3, 5, 7F and 19A) was higher in children with BP versus non-BP IPD (39.6% vs. 23.6%; P < 0.01). Shortly after PCV7 introduction, non-BP IPD rate was significantly reduced but that of BP was not. However, PCV13 introduction resulted in rapid reduction of BP rate, with a further reduction of non-BP IPD. Conclusion: The differences in age distribution, seasonality and serotype distribution between BP and non-BP IPD suggest that the pathogenesis of these 2 entities is not identical and resulted in different impact rate dynamics after PCV7 and PCV13 introduction.

Seasonality of Both Bacteremic and Nonbacteremic Pneumonia Coincides With Viral Lower Respiratory Tract Infections in Early Childhood, in Contrast to Nonpneumonia Invasive Pneumococcal Disease, in the Pre-Pneumococcal Conjugate Vaccine Era

We assessed the seasonality of viral lower respiratory tract infections (V-LRI), bacteremic pneumonia, nonbacteremic pneumonia and nonpneumonia invasive pneumococcal diseases (IPD) in the pre-PCV era. Both bacteremic and nonbacteremic pneumonia seasonality peaked in winter, coinciding with V-LRI seasonality, whereas non-pneumonia IPD peaked in autumn before V-LRI increase, suggesting different pathogenesis.