Dan Miron

Urinary tract infection: is there a need for routine renal ultrasonography?

Aims: To assess the yield of routine renal ultrasound (RUS) in the management of young children hospitalised with first uncomplicated febrile urinary tract infection (UTI). Methods: All children aged 0–5 years who had been hospitalised over a two year period with first uncomplicated febrile UTI in a medium size institutional regional medical centre were included. Children with known urinary abnormalities and/or who had been treated with antibacterial agents within seven days before admission were excluded. All included children underwent renal ultrasonography during hospitalisation and voiding cystouretrography (VCUG) within 2–6 months. The yield of RUS was measured by its ability to detect renal abnormalities, its sensitivity, specificity, and positive and negative predictive values for detecting vesicoureteral reflux (VUR), and by its impact on UTI management. Results: Of 255 children that were included in the study, 33 children had mild to moderate renal pelvis dilatation on RUS suggesting VUR, of whom only nine had VUR on VCUG. On the other hand, in 36 children with VUR on VCUG the RUS was normal. The sensitivity, specificity, positive predictive value, and negative predictive value of abnormal RUS for detecting VUR were 17.7%, 87.6%, 23.5%, and 83.2% respectively. In none of the patients with abnormal RUS was a change in the management at or following hospitalisation needed. Conclusion: Results show that the yield of RUS to the management of children with first uncomplicated UTI is questionable.

Safety and Immunogenicity of Improved Shigella O-Specific Polysaccharide-Protein Conjugate Vaccines in Adults in Israel

ABSTRACT Data suggest that the O-specific polysaccharide (O-SP) domain of the lipopolysaccharide (LPS) of Shigella species is both an essential virulence factor and a protective antigen and that a critical level of serum immunoglobulin G (IgG) to this antigen will confer immunity to shigellosis. Because covalent attachment of polysaccharides to proteins increases their immunogenicity, especially in infants and in young children, the O-SP of Shigella species were bound to medically useful proteins, and the safety and immunogenicity of the resultant conjugates were confirmed in adults and 4- to 7-year-old children. Succinylation of the carrier protein improved the immunogenicity of Shigella conjugates in mice and increased their yield. Based on these results, a clinical trial of O-SP conjugates of Shigella sonnei and Shigella flexneri 2a bound to succinylated mutant Pseudomonas aeruginosa exotoxin A (rEPAsucc) or native or succinylated Corynebacterium diphtheriae toxin mutant (CRM9 or CRM9succ) was conducted in healthy adults. The conjugates were safe and immunogenic. S. sonnei-CRM9,S. sonnei-CRM9succ, and S. sonnei-rEPAsucc elicited significant rises of geometric mean (GM) IgG anti-LPS within 1 week of injection (P < 0.001). At 26 weeks, the GM anti-LPS levels elicited by these three conjugates were similar and higher than their prevaccination levels (P < 0.0001). GM IgG anti-LPS levels elicited by S. flexneri2a-rEPAsucc were significantly higher than those elicited by S. flexneri 2a-rCRM9succ at all intervals after injection. At 26 weeks, the levels of IgG anti-LPS in vaccinees were higher than their prevaccination levels (P < 0.0001). The serum antibody responses were specific, as there was no significant rise of anti-LPS to the heterologous O-SP in any vaccinee. Both conjugates elicited statistically significant rises of serum antibodies to the injected carrier protein. At 6 months, these five Shigellaconjugates elicited higher fold rises than similar conjugates (D. N. Taylor et al., Infect. Immun. 61:3678–3687, 1993). Based on these data, we chose S. sonnei-CRM9 and S. flexneri2a-rEPAsucc for evaluation in children.

Safety and immunogenicity of Shigella sonnei-CRM9 and Shigella flexneri type 2a-rEPAsucc conjugate vaccines in one- to four-year-old children.

Background and objective. Shigella conjugate vaccines have been shown to be safe, immunogenic and efficacious in adult volunteers. We have now investigated the safety and immunogenicity of investigational Shigella sonnei and Shigella flexneri 2a conjugate vaccines in 1- to 4-year-old children, the age group at greatest risk for shigellosis. Methods. The O-specific polysaccharides of S. sonnei and S. flexneri 2a, the two most common shigellae from patients in Israel, were bound to medically useful carrier proteins to form conjugates. Eighty healthy 1- to 4-year-olds were randomized to receive two 0.5-ml im injections 6 weeks apart of either S. sonnei-CRM9 or S. flexneri 2a-r EPAsucc. Blood was taken before, 6 weeks after the first injection, 4 weeks after the second injections and 2 years after immunization for assay of IgG anti-lipopolysaccharide, diphtheria toxin and Pseudomonas aeruginosa exotoxin A antibodies by enzyme-linked immunosorbent assay. Results. During an 8-day surveillance period after each immunization, low fever (37.8–39.0°C) lasting only 24 to 48 h occurred in 2 of 40 recipients after the first injection and 4 of 40 recipients after the second injection of S. flexneri 2a-r EPAsucc and in 2 of 38 of S. sonnei-CRM9 after the second injection; no fever was detected after the first injection. Liver function tests were normal in all vaccinees. S. sonnei-CRM9 elicited a >4-fold rise in IgG anti-LPS in 92.1% and S. flexneri 2a-r EPAsucc in 85% (P < 0.0001) after the second injection; both conjugates elicited type-specific booster responses. At 2 years the geometric mean concentrations of both IgG anti-lipopolysaccharides were significantly higher than preimmunization levels. A >4-fold rise of IgG anti-diphtheria (65.8%) and IgG anti-ETA (77.5%) was observed. Conclusion. These experimental Shigella conjugate vaccines were safe and immunogenic in 1- to 4-year-old children.

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.

CALVES AS A SOURCE OF AN OUTBREAK OF CRYPTOSPORIDIOSIS AMONG YOUNG CHILDREN IN AN AGRICULTURAL CLOSED COMMUNITY

Transmission of Cryptosporidium from animals to humans, originating mainly in calves, had been suggested previously but has remained unproved. An outbreak of cryptosporidiosis that started among calves was transmitted to multiple pediatric groups living in close contact through one family who had close contact with the calves. Eleven of 19 (58%) infants and young children ages 10 to 15 months had Cryptosporidium compared with 3 of 27 (11%) of those ages 36 to 60 months and none of those ages 16 to 35 months. None of the asymptomatic children was positive for Cryptosporidium. These data emphasize that an extensive human to human transmission does not rule out the zoonotic nature of cryptosporidiosis.

Safety and Immunogenicity of Shigella sonnei and Shigella flexneri 2a O-Specific Polysaccharide Conjugates in Children

O-specific polysaccharide conjugates of shigellae were safe and immunogenic in young adults, and a Shigella sonnei conjugate conferred protection [1-3]. Shigellosis is primarily a disease of children; therefore, the safety and immunogenicity of S. sonnei and Shigella flexneri 2a conjugates were studied in 4- to 7-year-old children. Local and systemic reactions were minimal. The first injection of both conjugates elicited significant rises in geometric mean levels of serum IgG only to the homologous lipopolysaccharide (LPS) (S. sonnei, 0.32-8.25 ELISA units [EU]; S. flexneri 2a, 1.15-20.5 EU; P<.0001). Revaccination at 6 weeks induced a booster response to S. flexneri 2a LPS (20.5-30.5 EU, P=.003). Six months later, the geometric mean levels of IgG anti-LPS for both groups were higher than the prevaccination levels (P<.0001). Similar, but lesser, rises were observed for IgM and IgA anti-LPS. The investigational Shigella conjugates were safe and immunogenic in children and merit evaluation of their efficacy.

Sole pathogen in acute bronchiolitis: is there a role for other organisms apart from respiratory syncytial virus?

Background: Acute bronchiolitis (AB) is a common disease of young children with peak incidence during the winter season. Respiratory syncytial virus (RSV) is a major causative organism, yet recent relatively small sized studies have suggested an increased role of other organisms as sole or codetected organisms. The aim of this study was to assess the prevalence of sole- and mixed-organisms infections in hospitalized children with AB, using combined antigen-based and polymerase chain reaction assays (PCR). Methods: Sputum or nasal wash specimens obtained from 490 previously healthy children ≤2 years of age hospitalized with AB between December 1, 2005 and March 31, 2006 were tested: (1) For RSV, by rapid antigen detection test; (2) For RSV, influenza A, B, Parainfluenza 1 to 3, and adenovirus antigens by direct fluorescent assay; (3) For influenza A and B, RSV, Parainfluenza 1 to 3 viruses RNA by reverse transcription (RT) PCR assay; (4) For human metapneumovirus and rhinovirus RNA by RT real-time PCR assay; (5) For adenovirus, and Bordetella pertussis DNA by conventional PCR assays; (6) For human bocavirus DNA by real-tine PCR assays. Results: At least 1 organism was detected in 465 (91%) children. In 283 (61%), 117 (25%), and 23 (5%) children, 1, 2, and 3/4 organisms were detected, respectively. The most commonly detected organism was RSV, detected in 76%, and as a sole organism in 49%. Rhinovirus, human metapneumovirus, influenza virus A, bocavirus, Bordetella pertussis, and adenovirus were detected as a sole organism in 7%, 2.1%, 1%, 0.6%, 0.6%, and 0.2% of the children, respectively. Conclusions: Respiratory organisms were detected in the majority of the children, of whom about one third suffered from mixed organism infection. RSV was the most prevalent sole detected organism. The relevance of all other organisms may be much less than previously suggested.

Incidence and Clinical Manifestations of Breast Milk-Acquired Cytomegalovirus Infection in Low Birth Weight Infants

OBJECTIVES:To determine the incidence and clinical manifestations of human breast milk (HMB)-associated acquired cytomegalovirus (CMV) infection in small premature infants.STUDY DESIGN:A prospective study of premature infants born at or prior to 32 weeks gestation, and or infants weighing 1500 g or less at birth. The babies were divided into two groups: Group 1 included babies of CMV seropositive mothers who received HBM throughout the study period. Group 2 included babies of seronegative mothers or babies that did not receive HBM at all. Urine sample were obtained once weekly from birth until the age of 8 weeks or until discharge and were tested for the presence of CMV-DNA by PCR.RESULTS:Four of 70 infants from group 1 (5.7%, 95% CI, 0 to 11%) acquired CMV infection between the ages of 3 and 7 weeks as compared to none of 26 babies in group 2. Only one infected baby had severe CMV disease with complete recovery.CONCLUSION:The relative incidence of HBM-associated CMV infection and the severity of HBM-associated CMV disease in premature infants are low.

Effectiveness of a nationwide infant immunization program against Haemophilus influenzae b

An ongoing nationwide prospective surveillance program for invasive H. influenzae b (Hib) disease in Israel enabled us to study the effectiveness of a national infant Hib immunization program, which included all infants born since January 1994. The vaccine used was Hib polysaccharide conjugated to outer membrane protein complex of Neisseria meningitidis b (PRP-OMPC). For the cohort born during the 3 years since January 1994, the vaccine effectiveness was 94.9% for all invasive Hib diseases and 96.6% for meningitis. The efficacy in fully immunized subjects was 98.7 and 99.5%, respectively. A herd immunity effect could be observed, since a reduction in cases also occurred among infants too young to be immunized. No increase in invasive cases caused by S. pneumoniae and N. meningitidis was observed during the study period. This is the first report outside North America and Western Europe that demonstrates a nationwide extensive reduction of invasive Hib disease within a short time of the introduction of Hib conjugate vaccines to the infant immunization program.

A Double-Blind, Placebo-Controlled, Randomized Trial of Montelukast for Acute Bronchiolitis

BACKGROUND. Cysteinyl leukotrienes are implicated in the inflammation of bronchiolitis. Recently, a specific cysteinyl leukotriene receptor antagonist, montelukast (Singulair [MSD, Haarlem, Netherlands]), has been approved for infants in granule sachets. OBJECTIVE. Our goal was to evaluate the effect of montelukast on clinical progress and on cytokines in acute bronchiolitis. METHODS. This was a randomized, placebo-controlled, double-blind, parallel-group study in 2 medical centers. Fifty-three infants (mean age: 3.8 ± 3.5 months) with a first episode of acute bronchiolitis were randomly assigned to receive either 4-mg montelukast sachets or placebo, every day, from hospital admission until discharge. The primary outcome was length of stay, and secondary outcomes included clinical severity score (maximum of 12) and changes in type 1 and 2 cytokine levels (including interleukin4/IFN-γ ratio as a surrogate for the T-helper 2/T-helper 1 ratio) in nasal lavage. RESULTS. Both groups were comparable at baseline, and cytokine levels correlated positively with disease severity. There were neither differences in length of stay (4.63 ± 1.88 [placebo group] vs 4.65 ± 1.97 days [montelukast group]) nor in clinical severity score and cytokine levels between the 2 groups. No differences in interleukin 4/IFN-γ ratio between the 2 groups were seen. There was a slight tendency for infants in the montelukast group to recover more slowly than those in the placebo group (clinical severity score at discharge: 6.1 ± 2.4 vs 4.8 ± 2.2, respectively). CONCLUSIONS. Montelukast did not improve the clinical course in acute bronchiolitis. No significant effect of montelukast on the T-helper 2/T-helper 1 cytokine ratio when given in the early acute phase could be demonstrated.