Frances Justice

Changing epidemiology of intussusception in Australia

Objectives:  Oral rotavirus vaccines are expected to become available in Australia within the next 2 years. In light of evidence for an association between a rotavirus vaccine and intussusception, it is important to define the baseline epidemiology of intussusception in Australia and establish a system for intussusception surveillance in the immediate post‐licensure period. This study reports on incidence and epidemiology of intussusception in Australia.

Intussusception: Trends in clinical presentation and management

Background:  The association of a rotavirus vaccine and intussusception has renewed interest in understanding the incidence, clinical presentation and outcome of intussusception.

Influence of diet complexity on intestinal adaptation following massive small bowel resection in a preclinical model

Aims: To investigate the effect of dietary complexity on intestinal adaptation using a preclinical model.

Safety and immunogenicity of RV3-BB human neonatal rotavirus vaccine administered at birth or in infancy: a randomised, double-blind, placebo-controlled trial

BACKGROUND Despite the success of rotavirus vaccines, suboptimal vaccine efficacy in regions with a high burden of disease continues to present a challenge to worldwide implementation. A birth dose strategy with a vaccine developed from an asymptomatic neonatal rotavirus strain has the potential to address this challenge and provide protection from severe rotavirus disease from birth. METHODS This phase 2a randomised, double-blind, three-arm, placebo-controlled safety and immunogenicity trial was undertaken at a single centre in New Zealand between Jan 13, 2012, and April 17, 2014. Healthy, full-term (≥36 weeks gestation) babies, who weighed at least 2500 g, and were 0-5 days old at the time of randomisation were randomly assigned (1:1:1; computer-generated; telephone central allocation) according to a concealed block randomisation schedule to oral RV3-BB vaccine with the first dose given at 0-5 days after birth (neonatal schedule), to vaccine with the first dose given at about 8 weeks after birth (infant schedule), or to placebo. The primary endpoint was cumulative vaccine take (serum immune response or stool shedding of vaccine virus after any dose) after three doses. The immunogenicity analysis included all randomised participants with available outcome data. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611001212943. FINDINGS 95 eligible participants were randomised, of whom 89 were included in the primary analysis. A cumulative vaccine take was detected in 27 (90%) of 30 participants in the neonatal schedule group after three doses of RV3-BB vaccine compared with four (13%) of 32 participants in the placebo group (difference in proportions 0·78, 95% CI 0·55-0·88; p<0·0001). 25 (93%) of 27 participants in the infant schedule group had a cumulative vaccine take after three doses compared with eight (25%) of 32 participants in the placebo group (difference in proportions 0·68, 0·44-0·81; p<0·0001). A serum IgA response was detected in 19 (63%) of 30 participants and 20 (74%) of 27 participants, and stool shedding of RV3-BB was detected in 21 (70%) of 30 participants and 21 (78%) of 27 participants in the neonatal and infant schedule groups, respectively. The frequency of solicited and unsolicited adverse events was similar across the treatment groups. RV3-BB vaccine was not associated with an increased frequency of fever or gastrointestinal symptoms compared with placebo. INTERPRETATION RV3-BB vaccine was immunogenic and well tolerated when given as a three-dose neonatal or infant schedule. A birth dose strategy of RV3-BB vaccine has the potential to improve the effectiveness and implementation of rotavirus vaccines. FUNDING Australian National Health and Medical Research Council, the New Zealand Health Research Council, and the Murdoch Childrens Research Institute.

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.

Recurrent intussusception in infants.

Aim:  Clinical features to identify infants at increased risk of recurrence after a primary episode of intussusception (IS) are poorly defined.

Validation of clinical case definition of acute intussusception in infants in Viet Nam and Australia

OBJECTIVE To test the sensitivity and specificity of a clinical case definition of acute intussusception in infants to assist health-care workers in settings where diagnostic facilities are not available. METHODS Prospective studies were conducted at a major paediatric hospital in Viet Nam (the National Hospital of Pediatrics, Hanoi) from November 2002 to December 2003 and in Australia (the Royal Childrens Hospital, Melbourne) from March 2002 to March 2004 using a clinical case definition of intussusception. Diagnosis of intussusception was confirmed by air enema or surgery and validated in a subset of participants by an independent clinician who was blinded to the participants status. Sensitivity of the definition was evaluated in 584 infants aged<2 years with suspected intussusception (533 infants in Hanoi; 51 in Melbourne). Specificity was evaluated in 638 infants aged<2 years presenting with clinical features consistent with intussusception but for whom another diagnosis was established (234 infants in Hanoi; 404 in Melbourne). FINDINGS In both locations the definition used was sensitive (96% sensitivity in Hanoi; 98% in Melbourne) and specific (95% specificity in Hanoi; 87% in Melbourne) for intussusception among infants with sufficient data to allow classification (449/533 in Hanoi; 50/51 in Melbourne). Reanalysis of patients with missing data suggests that modifying minor criteria would increase the applicability of the definition while maintaining good sensitivity (96-97%) and specificity (83-89%). CONCLUSION The clinical case definition was sensitive and specific for the diagnosis of acute intussusception in infants in both a developing country and a developed country but minor modifications would enable it to be used more widely.

Retrospective hospital based surveillance of intussusception in children in a sentinel paediatric hospital: benefits and pitfalls for use in post-marketing surveillance of rotavirus vaccines.

UNLABELLED Evaluation of the safety of rotavirus vaccines, particularly with respect to the risk of intussusception, is recommended for countries planning to introduce rotavirus vaccines into the National Immunisation Program. However, as prospective studies are costly, require time to conduct and may be difficult to perform in some settings, retrospective hospital based surveillance at sentinel sites has been suggested as an option for surveillance for intussusception following introduction of rotavirus vaccines. OBJECTIVE To assess the value of retrospective hospital based surveillance to describe clinical and epidemiological features of intussusception in children aged <24 months and to investigate any temporal association between receipt of a rotavirus vaccine and intussusception. METHODS A retrospective chart review of all patients diagnosed with intussusception at Royal Childrens Hospital, Melbourne, Australia over an 8-year period including before and after rotavirus vaccine introduction into the National Immunisation Program, was conducted using patients identified by a medical record database (ICD-10-CM 56.1). Patient profile, clinical presentation, treatment and outcome were analysed along with records of immunisation status obtained using the Australian Childhood Immunisation Register. RESULTS A 9% misclassification rate of discharge diagnosis of intussusception was identified on critical chart review. The incidence rate of intussusception at the Royal Childrens Hospital over the study period was 1.91 per 10,000 infants <24 months (95% CI 1.65-2.20). Intestinal resection was required in 6.5% of infants (95% CI 3.6%, 11.0%). Intussusception occurred within 30 days after vaccination in 2 of 27 patients who had received at least 1 dose of a rotavirus vaccine. CONCLUSIONS Valuable data on the incidence, clinical presentation and treatment outcomes of intussusception can be obtained from data retrieved from hospital medical records in a sentinel paediatric hospital using standardised methodology. However, there are methodological limitations and the quality of the data is highly dependent on the accuracy and completeness of the patient information recorded, the system of coding and record retrieval.

Validación de la definición clínica de caso de invaginación intestinal aguda en lactantes en Viet Nam y Australia

Introduction The withdrawal of the first rotavirus vaccine to be licensed in the United States (RotaShield, Wyeth-Lederle Vaccines, Philadelphia, PA, United States), due to an unexpected association with intussusception, resulted in a major setback in the effort to reduce the global burden of rotavirus gastroenteritis. (1-3) Although the risk of intussusception following immunization with RotaShield is low, it has posed a major challenge to the future development of a safe and effective vaccine. (2) Large-scale clinical trials are now required to detect a risk of intussusception of Intussusception is the invagination of the bowel by a more proximal segment. The intussusception can be propelled distally by peristalsis, resulting in intestinal obstruction and vascular compromise of the intestine. Prompt identification and reduction by air enema or hydrostatic enema or by surgery is vital to minimize the morbidity and mortality that may be associated with this condition. To assist in the early recognition of infants with intussusception a clinical case definition for the diagnosis of acute intussusception in infants and young children was developed by WHO and the Brighton Collaboration. (7) The aim of the clinical case definition is to provide practical clinical criteria that will identify the majority of children with intussusception presenting at a variety of health-care settings. The clinical case definition that was developed showed promise (sensitivity = 97%; specificity = 87-91%) in a retrospective study in a tertiary care hospital in Australia. (8) The aim of this study was to validate the clinical case definition for intussusception by assessing the performance of the criteria prospectively in parallel studies in a developed country and in a developing country where there is a high incidence of intussusception. Each component of the definition was analysed to assess the reliability of individual symptoms and signs as well as groups of symptoms and signs to assess the sensitivity and specificity of the definition. Methods Prospective studies were performed at the National Hospital of Pediatrics in Hanoi, Viet Nam, during a 14-month period (1 November 2002-31 December 2003) and the Royal Childrens Hospital in Melbourne, Australia, over a 24-month period (19 March 2002-18 March 2004). The study was approved by the Ethics Committee of the Ministry of Health, Viet Nam, and the Ethics in Human Research Committee of the Royal Childrens Hospital, Melbourne. Free and informed consent was obtained from each childs legal guardian. The sensitivity of the clinical case definition was evaluated in infants aged The specificity of the definition was assessed in patients with symptoms and signs that may occur in intussusception but for whom an alternative diagnosis was established (non-intussusception control group). The non-intussusception control group included infants aged