Acute disseminated encephalomyelitis and routine childhood vaccinations - a self-controlled case series.

Acute disseminated encephalomyelitis (ADEM) is an autoimmune, central nervous system demyelinating disorder that follows antecedent immunologic challenges, such as infection or vaccination. This study aimed to investigate the potential association between routine childhood vaccinations and ADEM. Children under 7 years of age admitted to the two tertiary level pediatric hospitals in Victoria, Australia with ADEM from 2000-2015 had their clinical information linked to vaccination records from the Australian Childhood Immunization Register. Chart review was undertaken utilizing the Brighton Collaboration ADEM criteria. The self-controlled case-series (SCCS) methodology was employed to determine the relative incidences of ADEM post-vaccination in two risk intervals: 5-28 days and 2-42 days. Forty-six cases were eligible for SCCS analysis with a median age of 3.2 years. Of the forty-six cases, three were vaccine proximate cases and received vaccinations 23, 25 and 28 days before ADEM onset. Two vaccine proximate cases received their 4-year-old scheduled vaccinations (MMR and DTPa-IPV) and one vaccine proximate case the 1-year old scheduled vaccinations (MMR and Hib-MenC). The relative incidence of ADEM during the narrow and broad risk intervals were 1.041 (95% CI 0.323-3.356, p = 0.946) and 0.585 (95% CI 0.182-1.886, p = 0.370) respectively. Sensitivity analyses did not yield any substantial deviations. These results do not provide evidence of an association between vaccinations routinely provided to children aged under 7 years in Australia and the incidence of ADEM. However, these results should be interpreted with caution as the number of ADEM cases identified was limited and further research is warranted.

Phase I trial of RV3-BB rotavirus vaccine: a human neonatal rotavirus vaccine.

INTRODUCTION: RV3 is a human neonatal rotavirus strain (G3P[6]) that has been associated with asymptomatic neonatal infection and replicates well in the infant gut. RV3-BB rotavirus vaccine has been developed as a rotavirus vaccine candidate for administration at birth. METHODS: A single-centre, double-blind, randomised placebo-controlled Phase I study evaluated the safety and tolerability of a single oral dose of the second generation RV3-BB rotavirus vaccine (8.3×10(6)FFU/mL) in 20 adults, 20 children and 20 infants (10 vaccine and 10 placebo per age cohort). Vaccine take was defined as seroconversion (a 3-fold increase in serum anti-rotavirus IgA or serum neutralising antibody (SNA) from baseline at day 28 post-dose) or evidence of RV3-BB viral replication in the faeces by RT-PCR analysis 3-6 days post-vaccination. RV3-BB presence was confirmed by sequence analysis. RESULTS: The RV3-BB vaccine was well tolerated in all participants, with no pattern of adverse events shown to be associated with the study vaccine. In the infant cohort, vaccine take was demonstrated in 8/9 infants following a single dose of vaccine compared with 2/7 placebo recipients. In the infant vaccine group, 5/9 infants exhibited either IgA or SNA seroconversion and 7/9 infants had evidence of RV3-BB replication on days 3-6, compared with 2/7 infants who seroconverted and 0/10 infants with evidence of replication in the placebo group. Two infants in the placebo group had serological evidence of a rotavirus infection within the 28-day study period: one demonstrated an IgA and the other an SNA response, with wild-type virus replication detected in another infant. CONCLUSION: A single dose of RV3-BB rotavirus vaccine was well tolerated in adults, children and infants. Most infants (8/9) who received RV3-BB demonstrated vaccine take following a single dose. These data support progression of RV3-BB to Phase II immunogenicity and efficacy trials.

Australian immunisation registers: established foundations and opportunities for improvement.

The National Immunisation Program Schedule in Australia is formulated and funded nationally under the population-wide Medicare system. The policy is implemented by the eight state and territory jurisdictions. The national immunisation registers consist of the Australian Childhood Immunisation Register (ACIR), and, more recently, the National Human Papillomavirus (HPV) Vaccination Program Register. Moreover, a variety of jurisdiction-based registers and primary care practice software systems exist, which interact with the national registers. General practitioners can obtain reports listing patients under seven years attending their practice and recorded as 'not fully immunised', and immunisation coverage rates for their practice linked to government incentives through Medicare. A 2011 report documents national coverage of 91.8% fully immunised at 12 months, and 92.6% at 24 months. The HPV register provides information on vaccination coverage with the potential to link with a register of cervical cancer screening results. Limitations of current national register include inability to easily access immunisation histories beyond seven years of age, and issues of underreporting and timeliness, which impact significantly the immunisation coverage estimates. The linkage of these registers with healthcare outcome data will further enhance public health outcomes by enabling rapid, population-level vaccine safety and effectiveness investigations in a nation with a track record as an 'early adopter' of new childhood vaccines.

Intussusception following rotavirus vaccine administration: post-marketing surveillance in the National Immunization Program in Australia.

INTRODUCTION: In Australia, post-marketing surveillance for intussusception following vaccination commenced with funding of RotaTeq(®) and Rotarix(®) vaccines under the National Immunization Program (NIP) in July 2007. METHODS: Two active surveillance mechanisms (hospital-based case ascertainment and monthly reports from paediatricians) identified intussusception cases between 1st July 2007 and 31st December 2008 in four states. Linkage to vaccination records identified cases occurring within 1-7 and 1-21 days of rotavirus vaccination. Expected cases within the post-vaccination windows were calculated by applying rates of intussusception from national hospitalisation data over 6 years (mid-2000 to mid-2006), by age and state, to numbers vaccinated (by dose) according to the Australian Childhood Immunization Register. RESULTS: Combining exposure windows associated with all doses of rotavirus vaccine from 1 to 9 months of age, there was no evidence of an increased risk of intussusception following vaccination for either vaccine. However, in infants 1 to <3 months of age, there was suggestive evidence of excess intussusception cases 1-7 and 1-21 days following dose 1 (1-7 days: RotaTeq(®) relative risk (RR)=5.3, 95% confidence interval [CI] 1.1,15.4; Rotarix(®) RR 3.5, 95% CI 0.7,10.1; 1-21 days: RotaTeq(®) RR 3.5, 95% CI 1.3, 7.6; Rotarix(®)RR 1.5, 95% CI 0.4, 3.9). There was no evidence that clinical outcome of intussusception occurring within 21 days of rotavirus vaccination differed from that in cases occurring later post-vaccination. CONCLUSION: Although we found no overall increase in intussusception following receipt of rotavirus vaccine, there was some evidence of an elevated risk following the first dose of both vaccines. Larger population-based studies using linked databases are required to provide more definitive evidence.

Maternal antibodies to rotavirus: could they interfere with live rotavirus vaccines in developing countries?

INTRODUCTION: Past experience with live oral vaccines including licensed rotavirus vaccines demonstrates a trend towards reduced vaccine efficacy in developing countries compared with developed countries. The reasons behind this disparity are not well understood. Transplacental transfer of maternal antibodies and breast milk ingestion may attenuate vaccine responses in infants in developing countries where rotavirus infections are endemic, and maternal antibody levels are high. We examined the prevalence and level of rotavirus antibody in maternal and cord serum, colostrum and breast milk in a developing country setting. METHODS: 100 mother-infant pairs were prospectively recruited from December 2008 to February 2009 at Dr. Sardjito Hospital, Yogyakarta, Indonesia. Maternal and cord sera were collected during delivery. Colostrum and transitional breast milk were collected between day 0-3 and day 7-10 postpartum respectively. Rotavirus-specific IgA and IgG were estimated for all specimens and virus neutralization assays were conducted on a subset of milk specimens. RESULTS: All maternal and cord serum samples were positive for rotavirus-specific IgG antibodies with a strong correlation between levels of rotavirus-specific IgG in mothers and levels transferred to infants in cord blood (r=0.86; p=0.001). 78% of colostrum and 67% of transitional breast milk specimens were positive for rotavirus-specific IgA. There was a median 4-fold decrease in rotavirus-specific IgA from colostrum to transitional breast milk. Neutralizing antibodies were present in 56% of colostrum specimens assayed (19/34) and in 41% of transitional milk specimens assayed (14/34). CONCLUSIONS: Maternal serum and breast milk antibodies to rotavirus are highly prevalent in a developing country setting. Evaluation of the impact of maternal anti-rotavirus serum and breast milk antibody upon vaccine immunogenicity would help to inform rotavirus vaccination strategies, especially in developing settings.

Influenza in the neonatal intensive care unit.

Influenza has historically been an uncommon illness in the newborn period, although epidemic outbreaks in neonatal intensive care units have been described. There is currently significant concern about the possibility of a new pandemic of influenza in the near future. During a pandemic neonates are likely to be exposed, with significant illness more likely in pre-term newborns due to reduced levels of passively transferred protective maternal antibodies. While newer therapies have been shown to be effective in reducing the severity of illness in adults and children, such therapies are untried in neonates. Supportive care and measures to contain and prevent spread of infection may well be the most important measures in the event of a neonate acquiring influenza, including the avian variety.

Performance of a whole blood interferon gamma assay for detecting latent infection with Mycobacterium tuberculosis in children.

BACKGROUND: The diagnosis of latent Mycobacterium tuberculosis (MTB) infection with a tuberculin skin test (TST) in children is complicated by the potential influence of prior exposure to Bacille Calmette Geurin (BCG) vaccination or environmental mycobacteria. A whole blood assay has recently been developed to quantitatively measure interferon gamma (IFN-gamma) production by lymphocytes specific to the MTB antigens ESAT-6 and CFP-10, but its use and assessment in children has been limited. A study was undertaken to compare the performance of the whole blood IFN-gamma assay with the TST in diagnosing latent tuberculosis (TB) infection or TB disease in children in routine clinical practice. METHODS: One hundred and six children with a high risk of latent TB infection or TB disease were enrolled in the study. High risk was defined as contact with TB disease, clinical suspicion of TB disease, or recent arrival from an area of high TB prevalence. The whole blood IFN-gamma assay was undertaken in 101 children. RESULTS: Seventeen (17%) of the 101 assays yielded inconclusive results due to failure of positive or negative control assays. There was poor correlation between the whole blood IFN-gamma assay and the TST (kappa statistic 0.3) with 26 (70%) of the 37 children defined as latent TB infection by TST having a negative whole blood IFN-gamma assay. There were no instances of a positive whole blood IFN-gamma assay with a negative TST. Mitogen (positive) control IFN-gamma responses were significantly correlated with age (Spearman's coefficient = 0.53, p<0.001) and, in children with latent TB infection identified by TST, those with a positive IFN-gamma assay were older (median 12.9 v 6.92 years, respectively, p = 0.007). The whole blood IFN-gamma assay was positive in all nine children with TB disease. CONCLUSION: There was poor agreement between the whole blood IFN-gamma assay and TST for the diagnosis of latent TB. The whole blood IFN-gamma assay may have lower sensitivity than the TST in diagnosing TB infection in children. A significant proportion of whole blood IFN-gamma assays fail when used as a screening assay in routine practice.

Determining the rate of varicella vaccine rash in children with moderate-severe eczema.

OBJECTIVES: To determine the rate and severity of vesicular reactions following varicella vaccine in children with moderate-severe eczema. Secondary endpoints included the rates and severity of local reactions and eczema severity change within 42 days of vaccination. METHODS: Prospective open intervention pilot study of varicella vaccine in children aged 12 months to 13 years with moderate-severe eczema. Children were given varicella vaccine alone and followed for 42 days after vaccination. RESULTS: Fifty children, aged 12 months to 10.5 years were recruited, with complete follow-up for 48. A vesicular rash with a single lesion occurred in one child (2.1% (95% CI: 0, 11.1%)), 10 days following vaccination. Local reactions, including erythema, swelling and tenderness, were reported in eight children (16.7%). A flare-up of moderate-severe generalized eczema was reported in one child (2.1%) during the first week following varicella vaccine. CONCLUSIONS: Vesicular rash and local reactions following varicella vaccination were no more common or severe in children with moderate-severe eczema than that reported in the published literature in children without eczema. Eczema in the 42 days following vaccination did not appear to increase in severity.

Blood cultures in newborns and children: optimising an everyday test.

Effective use of blood cultures is a key component of the management of septic newborns and children. The technical and practical aspects of paediatric practice and the heightened susceptibility of children to infection because of immunological immaturity make automatic extrapolation of adult data difficult and potentially unfounded.

Randomized, controlled trial comparing once daily and three times daily gentamicin in children with urinary tract infections.

OBJECTIVE: To undertake population pharmacokinetic modeling and to determine the safety and efficacy of once daily (OD) gentamicin dosing in children with severe urinary tract infections (UTI). METHODS: An open, randomized, controlled trial comparing OD with three times daily (TD) gentamicin dosing in hospitalized children ages 1 month to 12 years with UTI. Daily doses (milligrams per kg per day) of gentamicin in both groups were 7.5 (<5 years old), 6.0 (5 to 10 years old) and 4.5 (>10 years old). RESULTS: There were 179 children enrolled (90 OD, 89 TD). Baseline clinical characteristics and pathogens were similar, except that circulatory compromise and renal cortical scintigraphic defects were more common in the OD group. Median gentamicin treatment durations were 3.0 (OD) and 2.7 (TD) days. Mean peak gentamicin concentrations were 17.3 (OD) vs. 6.4 (TD) mg/l; 99% of peak concentrations were >7 mg/l in the OD group whereas 16% of peak concentrations were <5 mg/l in the TD group. Mean trough concentrations were 0.35 (OD) vs. 0.55 (TD) mg/l. In the OD group 4% of trough concentrations were > or = 2 mg/l, whereas in the TD group only 0.7% were > or = 2 mg/l. Age or prior elevated peak concentrations did not predict high trough concentrations. Population pharmacokinetic modeling of the data fitted a one-compartment model with first order elimination. There were no clinical or bacteriologic failures. The two disease-related complications were confined to the OD group. No nephro- or ototoxicity was identified. CONCLUSIONS: With age-appropriate dosing and measurement of serum trough concentrations before the second dose, OD gentamicin is safe and effective for the treatment of UTI requiring parenteral treatment in children aged 1 month to 12 years.

Designing meningitis vaccines.

Conjugate polysaccharide vaccines are a recent intervention to combat the relative inability of young children to mount an effective immune response against encapsulated bacteria, especially Haemophilus influenzae (Hib), Neisseria meningitidis (Nm) and Streptococcus pneumoniae (Sp). These organisms cause the majority of community acquired septicaemia and meningitis in UK children. Their capsular polysaccharides, important virulence factors in evading phagocytosis, are poorly immunogenic in young children compared to adults. Conjugation, by covalent linking, of the polysaccharide to an immunogenic protein, has been demonstrated for each of these organisms to produce good antibody response to the polysaccharide. Conjugate Hib vaccines have proven effective in reducing Hib meningitis and invasive disease in the countries that have introduced them. Pneumococcal conjugate vaccines have proven effective in preventing invasive disease caused by serotypes contained in the vaccines. Efficacy studies are awaited for meningococcal conjugate vaccines.

Multiresistant Pseudomonas aeruginosa outbreak in a pediatric oncology ward related to bath toys.

BACKGROUND: Nosocomial outbreaks of Pseudomonas aeruginosa in pediatric hospitals frequently involve neonates and immunosuppressed patients and can cause significant morbidity and mortality. OBJECTIVE: To describe the investigation of a multidrug-resistant P. aeruginosa outbreak in a pediatric oncology ward at the Royal Children's Hospital, Melbourne, Australia. DESIGN AND METHODS: Specimens were collected from infected patients and the ward environment. Bacterial isolates were characterized by antibiotic susceptibility patterns and bacterial DNA fingerprinting performed by pulsed-field gel electrophoresis (PFGE). A case-control study was carried out to assess possible risk factors for infection. RESULTS: Eight patients had clinical illnesses including bacteremia (n = 5) and infections of skin (n = 2), central venous catheter site (n = 1) and urinary tract (n = 1). The environmental ward survey yielded isolates of multiresistant P. aeruginosa from a toy box containing water-retaining bath toys, as well as from three of these toys. Pulsed-field gel electrophoresis of bacterial DNA demonstrated identical band patterns of the isolates from patients, toys and toy box water. A case-control study involving the 8 cases and 24 disease-matched controls demonstrated a significant association between P. aeruginosa infection and use of bath toys (P = 0.004), use of bubble bath (P = 0.014), duration of stay (P = 0.007) and previous antibiotic exposure (P = 0.026). Cultures from the bubble bath liquid were negative. CONCLUSION: This is the first description of a nosocomial outbreak associated with toys. We caution against the use of water-retaining bath toys in wards treating immunocompromised children.

Pediatric bacteremia due to Staphylococcus warneri: microbiological, epidemiological, and clinical features.

Between 1991 and 1995, an apparent high rate of Staphylococcus warneri bacteremias at the Royal Children's Hospital, Melbourne, Victoria, Australia, raised the possibility of a virulent nosocomial strain. In a retrospective review of 30 S. warneri bacteremias in children, organisms were viable and verified in 22 episodes, 12 representing significant bacteremias. Of these 12 episodes, 2 pairs shared chromosomal DNA pulsed-field gel electrophoresis patterns in unconnected patients, dispelling concerns about a single virulent strain.