Incidence of respiratory syncytial virus bronchiolitis in hospitalized infants born at 33-36 weeks of gestational age compared with those born at term: a retrospective cohort study.

OBJECTIVE: The aim was to compare incidences of respiratory syncytial virus (RSV) bronchiolitis in late preterm vs. term infants (33-36 vs. >36 weeks of gestational age (WGA)). METHODS: This was a population-based retrospective study including all infants <12 months hospitalized at Soroka medical centre with bronchiolitis between 2004 and 2012. Infants with comorbidities were excluded. RSV bronchiolitis rates were calculated by extrapolating the proportion of positive tests among tested infants. Population denominator for incidence rates was calculated from hospital records. RESULTS: During the study, 374 late preterm and 2948 term infants were hospitalized with bronchiolitis. Out of 229 (61.2%) late preterm infants and 1738 (59%) term infants tested for RSV, 164 (71.6%) and 1266 (72.8%) were positive for RSV respectively. The mean yearly incidences per 1000 children of RSV bronchiolitis hospitalizations of late preterm and term infants were 35.8 ± 13.0 and 19.6 ± 4.1 respectively (p 0.009). During RSV seasons the mean incidence rate ratio between groups was 1.82 (95% CI 1.60-2.08). Duration of hospitalization was 4.8 ± 7.0 and 3.9 ± 4.9 in late preterm and term infants, respectively (p 0.003). CONCLUSIONS: Late preterm-born infants (33-36 WGA) had a higher rate of hospitalization for overall and RSV bronchiolitis during the first year of life compared to those born at term.

Impact of PCV7/PCV13 introduction on invasive pneumococcal disease (IPD) in young children: Comparison between meningitis and non-meningitis IPD.

BACKGROUND: The worldwide introduction of pneumococcal conjugate vaccines (PCV) into National Immunization Programs resulted in rapid and substantial reduction of invasive pneumococcal disease (IPD) rates in children. However, the reduction of meningitis vs. non-meningitis IPD (nm-IPD) was not yet fully elucidated. We compared 7-valent and 13-valent PCV (PCV7 and PCV13) impact on pneumococcal-meningitis vs. nm-IPD in Israeli children <5years. METHODS: We conducted an ongoing nationwide, prospective, population-based, active surveillance. PCV7 and PCV13 were implemented in Israel in July 2009 and November 2010, respectively. All pneumococcal isolates (blood and/or CSF) from IPD episodes in children <5years from July 2000 through June 2015 were included. Extrapolation for missing serotypes (34.7% of all isolates) was conducted. RESULTS: 4163 IPD cases were identified; 3739nm-IPD (89.8%) and 424 meningitis (10.2%). During the pre-PCV period (2000-2008), children <12months constituted 52.1% and 33.7% of meningitis and nm-IPD, respectively (p<0.001). The respective proportions of non-PCV13 serotypes (non-VT) were 18.2% vs. 10.1%, (p<0.001). Comparing the last study year (2014-2015) to the mean of pre-PCV period, meningitis incidence in children <5years decreased non-significantly by 27%, while nm-IPD decreased significantly by 69%. Dynamic rates of meningitis and nm-IPD caused by PCV13 serotypes were similar, with 93% and 95% overall reductions, respectively. However, non-VT increased in meningitis relatively to nm-IPD, mainly in children <24months. Serotype 12F rose sharply and significantly since 2009-2010 through 2014-2015 (28.6% of all non-VT meningitis in children <24m). CONCLUSIONS: The overall impact of PCV7/PCV13 in children <5years in Israel was less prominent in meningitis than in nm-IPD. This could be attributed to the younger age of children with meningitis and differences in causative serotypes between the two groups, as the decline of the incidence of meningitis and nm-IPD caused by vaccine-serotypes is similar. Continuous monitoring of meningitis and nm-IPD is warranted.

Dynamics of childhood invasive meningococcal disease in Israel during a 22-year period (1989-2010).

AIM: To describe the dynamics in the incidence of childhood invasive meningococcal disease (IMD) in Israel during a 22-year period (1989-2010). METHODS: A longitudinal prospective surveillance in all 27 medical centers with pediatric services in Israel. All cases of children <15 years old with positive blood/cerebrospinal fluid (CSF) culture for Neisseria meningitidis were reported. Demographic, clinical, and bacteriological data were recorded. Meningococcal vaccine was not routinely given to Israeli children during the study period. RESULTS: The mean age ± standard deviation (SD) among the 743 cases was 40.7 ± 40.2 months. The mean yearly incidence/100,000 was 2.0 ± 0.8. Age-specific incidences were 8.7 ± 2.8, 2.9 ± 1.5, and 0.8 ± 0.5 for children <1, 1-4, and >4 years old, respectively. The overall incidence decreased significantly from 3.7 in 1989 to 1.5 in 2010. Meningitis constituted 69.2 % of all cases. The most common serogroups were: B (76.9 %), C (10.9 %), Y (8.0 %), and W(135) (2.9 %). 78.6 % of all serogroup B isolates were from children <5 years old (p < 0.01). Serogroup C was found mainly in children ≥5 years old (63.4 %). The case fatality rates (CFRs) for children <1, 1-4, >4 years old, and the total study population were 9.2, 12.3, 7.7, and 9.9 %, respectively. CFRs were higher for children without meningitis (14.9 %) compared to children with meningitis (7.9 %) (p < 0.01). CONCLUSIONS: Overall, and for serogroups B and W135, childhood IMD rates decreased significantly in Israel during the study period, without routine vaccine usage. The most common serogroup in all age groups was B, which was most prevalent in children <5 years old. No change in the trend of the overall CFR was noted during the study period.

Influence of age, social patterns and nasopharyngeal carriage on antibodies to three conserved pneumococcal surface proteins (PhtD, PcpA and PrtA) in healthy young children.

The acquisition of specific antibodies is paramount to protect children against pneumococcal diseases, and a better understanding of how age, ethnicity and/or Streptococcus pneumoniae (Spn) nasopharyngeal carriage influence the acquisition of antibodies to pneumococcal surface proteins (PSP) is important for the development of novel serodiagnostic and immunisation strategies. IgG antibody titres against three conserved PSP (PhtD, PcpA and PrtA) in the sera of 451 healthy children aged 1 to 24 months from Israel [Jewish (50.1 %) and Bedouin (49.9 %)] were measured by enzyme-linked immunosorbent assay (ELISA), while nasopharyngeal swabs from these children were assessed for the presence of Spn. Globally, anti-PhtD and anti-PrtA geometric mean concentrations (GMC; EU/ml) were high at <2.5 months of age [PhtD: 35.3, 95 % confidence interval (CI) 30.6-40.6; PrtA: 71.2, 95 % CI 60-84.5], was lower at 5-7 months of age (PhtD: 10, 95 % CI 8-12.4; PrtA: 17.9, 95 % CI 14.4-22.1) and only increased after 11 months of age. In contrast, an increase in anti-PcpA was observed at 5-7 months of age. Anti-PcpA and anti-PrtA, but not anti-PhtD, were significantly higher in Bedouin children (PcpA: 361.6 vs. 226.3, p = 0.02; PrtA: 67.2 vs. 29.5, p < 0.001) in whom Spn nasopharyngeal carriage was identified earlier (60 % vs. 38 % of carriers <6 months of age, p = 0.002). Spn carriage was associated with significantly higher anti-PSP concentrations in carriers than in non-carriers (p < 0.001 for each PSP). Thus, age, ethnicity and, essentially, nasopharyngeal carriage exert distinct cumulative influences on infant responses to PSP. These specific characteristics are worthwhile to include in the evaluation of pneumococcal seroresponses and the development of new PSP-based vaccines.

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.

Failure to elicit seroresponses to pneumococcal surface proteins (pneumococcal histidine triad D, pneumococcal choline-binding protein A, and serine proteinase precursor A) in children with pneumococcal bacteraemia.

Pneumococcal surface proteins (PSPs) elicit antibody responses in infants and young children exposed to Streptococcus pneumoniae. These seroresponses could contribute to the aetiological diagnosis of pneumococcal disease, e.g. during the clinical development of novel PSP-based vaccines. In this study, we assessed the kinetics of antibody responses to three highly conserved and immunogenic PSPs (pneumococcal histidine triad D (PhtD), pneumococcal choline-binding protein A (PcpA), and serine proteinase precursor A (PrtA)) in 106 children (median age, 21.3 months; males, 58.5%) admitted for pneumococcal bacteraemia. Anti-PhtD, anti-PcpA and anti-PrtA antibodies were measured by ELISA, and compared in 61 pairs of acute (≤7 days) and convalescent (>14 days of admission) serum samples. Acute serum titres were similar to those observed in healthy children, and were unaffected by the acid dissociation of circulating immune complexes. Despite proven bacteraemia, seroresponses (≥2-fold increase in anti-PSP antibody concentrations) were only identified in 31 of 61 children (50.8%), directed against PrtA (n = 23, 37.7%), PcpA (n = 19, 31.1%), and PhtD (n = 16, 26.2%), or several PSPs (two PSPs, n = 13, 21.3%; three PSPs, n = 7, 11.5%). Certain seroresponses were very strong (maximal fold-increases: PhtD, 26; PcpA, 72; PrtA, 12). However, anti-PSP antibody concentrations failed to increase in the convalescent sera of 30 of 61 (49.2%) bacteraemic children, and even declined (≥2 fold) in 13 of 61 (21.3%), mostly infants aged <6 months (8/13, 61.5%), possibly through consumption of maternal antibodies. Thus, pneumococcal bacteraemia may fail to elicit antibody responses, and may even have an antibody-depleting effect in infants. This novel observation identifies an important limitation of serology-based studies for the identification of bacteraemic children.

Pneumococcal 6-phosphogluconate-dehydrogenase, a putative adhesin, induces protective immune response in mice.

For most bacteria, adherence to human cells is achieved by bacterial lectins binding to mammalian surface glyconjugates. 6-Phosphogluconate dehydrogenase (6PGD) was identified by us as one of Streptococcus pneumoniae cell wall lectin proteins, which elicits an age-dependent immune response in humans. This study assesses the role of 6PGD in S. pneumoniae pathogenesis as an adhesin and its ability to elicit a protective immune response in mice. Recombinant 6PGD (r6PGD) was cloned from S. pneumoniae serotype 3 (strain WU2). r6PGD interference in adhesion of three genetically unrelated unencapsulated pneumococcal strains (3.8, 14.8 and R6) and two genetically unrelated encapsulated pneumococcal strains (WU2 and D39) to A549 type II lung carcinoma cell was tested. BALB/c mice were immunized with r6PGD and boosted after 3 weeks. Immunized mice were challenged intranasally with a lethal dose of S. pneumoniae. r6PGD inhibited 90% and 80% of pneumococcal adhesion to the A549 cells of three unencapsulated S. pneumoniae strains and two encapsulated S. pneumoniae strains, respectively, in a concentration-dependent manner (P < 0.05). Antibodies to r6PGD produced in mice significantly inhibited bacterial adhesion to A549 cell (P < 0.05). Immunization of mice with r6PGD protected 60% (P < 0.001) of mice for 5 days and 40% (P < 0.05) of the mice for 21 days following intranasal lethal challenge. We have identified 6PGD as a surface-located immunogenic lectin protein capable of acting as an adhesin. 6PGD importance to bacterial pathogenesis was demonstrated by the ability of r6PGD to elicit a protective immune response in mice.

Effect of a conjugate pneumococcal vaccine on the occurrence of respiratory infections and antibiotic use in day-care center attendees.

BACKGROUND: Incidence and severity of respiratory infections are increased in day-care center attendees. Streptococcus pneumoniae is an important contributor to these infections. OBJECTIVE: To examine whether the use of a pneumococcal conjugate vaccine could reduce the occurrence of respiratory infections and the ensuing antibiotic drug use in the day care. METHOD: In this double blind, randomized, controlled study performed in 8 day-care centers located in Beer-Sheva, Israel, 264 toddlers ages 12 to 35 months at enrollment were randomized to receive either a 9-valent conjugate pneumococcal vaccine (conjugated to CRM197) or a control vaccine [conjugate meningococcus C vaccine (conjugated to CRM197)] and were followed for an average of 22 months. The main outcome measures were respiratory morbidity and antibiotic use. RESULTS: An overall reduction of 7% in child months with > or = 1 reported illness episodes was observed among vaccinees (P = 0.008), and 85% of all episodes were related to the respiratory tract. Reductions of 15, 16 and 17% were observed in upper respiratory infections, lower respiratory problems and otitis media, respectively. An overall reduction of 17% in antibiotic days was observed [10% for upper respiratory infections, 20% for otitis and 47% for lower respiratory problems (P < or = 0.005 for each entity)]. The reduction in episodes and antibiotic use was greater for those <36 months of age than for the older children. CONCLUSION: The reduction of respiratory problems, including those not traditionally considered of pneumococcal origin and the ensuing lowered antibiotic use in day-care center attendees by pneumococcal conjugate vaccination suggest a broader benefit from the vaccine than preventing invasive disease only.

A decade (1989-1998) of pediatric invasive pneumococcal disease in 2 populations residing in 1 geographic location: implications for vaccine choice.

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.

Acute otitis media caused by antibiotic-resistant Streptococcus pneumoniae in southern Israel: implication for immunizing with conjugate vaccines.

The potential coverage of antibiotic-resistant pneumococci causing acute otitis media (AOM) by 7-, 9-, and 11-valent conjugate pneumococcal vaccines was studied in southern Israel. A total of 876 cases of pneumococcal AOM were studied in the context of various clinical conditions. Of the isolates, 68% were resistant to >/=1 drug, 61% were resistant to penicillin, and 13% were resistant to >/=3 antibiotic classes. Antibiotic resistance and coverage by the various candidates were age and population dependent and were higher among those with a complicated clinical course, as indicated by recent antibiotic use and recurrence of AOM. The results suggest that, if efficacious, the conjugate pneumococcal vaccines can substantially reduce the occurrence of pneumococcal AOM in general and complicated pneumococcal AOM in particular.

Marked differences in pneumococcal carriage and resistance patterns between day care centers located within a small area.

Carriage rates of Streptococcus pneumoniae and their antibiotic resistance, capsular types, and genetic patterns were studied among 264 children aged 12-35 months attending 8 day care centers located within a 2.5-mile radius in the same city. Nasopharyngeal cultures were obtained within a 2-month interval from all 264 children. Significant differences in each of the studied characteristics were found between day care centers, and each day care center had a unique pattern of the carried pneumococci. Our findings show that day care centers are independent microenvironments and emphasize their role in the transmission and augmentation of antibiotic-resistant S. pneumoniae in the community.