Graeme L. Barnes

Clinical immunity after neonatal rotavirus infection: a prospective longitudinal study in young children.

To determine whether rotavirus infection in newborn babies conferred immunity to postneonatal rotavirus infection, we studied 81 babies at birth and kept them under clinical and serologic study for three years. During the first 14 days of life, 44 of the infants excreted rotavirus, and 37 did not. Fifty-five per cent of those with neonatal infection and 54 per cent of those without it had rotavirus infection during the next three years. Symptoms associated with postneonatal rotavirus infection were significantly less frequent and less severe in the infants who had had neonatal infection (P = 0.003) than in those who had not. Thirty-eight per cent of the former group (9 of 24 infants) had symptoms of mild (3 infants) or moderate (6) severity during the first postneonatal infection. In contrast, 85 per cent of the latter group (17 of 20 infants) had mild (3), moderate (6), or severe (8) symptoms. We conclude that neonatal rotavirus infection does not confer immunity against reinfection but does protect against the development of clinically severe disease during reinfection.

Clinical signs of dehydration in children.

102 children with acute gastroenteritis were thought by the admitting junior doctors to be 5% or more dehydrated. As judged by subsequent weight recovery in hospital, the main indicators of mild to moderate dehydration were decreased peripheral perfusion, deep breathing, decreased skin turgor, high urea, low pH, and a large base deficit; a history of increased thirst was just short of statistical significance. Dehydration was not indicated by a history of oliguria, by the presence of restlessness or lethargy, sunken eyes, dry mouth, or a sunken fontanelle or by the absence of tears. Clinical signs of dehydration became apparent at 3-4% rather than 5% dehydration. The degree of dehydration was overestimated by a mean of 3.2%; this caused unnecessary hospital admissions and overtreatment with intravenous fluid.

Structural and functional abnormalities of the small intestine in infants and young children with rotavirus enteritis.

Abstract. Structural and functional alterations in duodenal mucosa from 17 children with rotavirus enteritis were assessed. Structural changes were found in specimens from all patients. Patients with the most severe mucosal damage were more likely to require intravenous therapy to correct dehydration. Depression of one or more mucosal disaccharidases was found in 14 of 16 patients. Repeat duodenal biopsy three to eight weeks later in six patients showed marked improvement. The study clearly shows that rotavirus can cause a marked structural and functional lesion in the upper small intestine which is rapidly reversible.

Extended excretion of rotavirus after severe diarrhoea in young children

BACKGROUND Rotaviruses are the major cause of severe childhood diarrhoea. Knowledge of the natural history of infection, including duration of intestinal virus shedding, is important in the understanding of transmission, sources of infection, and immune responses. METHODS We carried out a study of rotavirus excretion in 37 children admitted to hospital with severe rotavirus diarrhoea. Sequential faecal specimens were collected from each child during 100 days of surveillance, and screened for rotavirus by EIA and by amplification of genome double-stranded RNA by reverse-transcription PCR. IgA coproantibody was estimated by EIA. FINDINGS Duration of rotavirus excretion ranged from 4 to 57 days after onset of diarrhoea. Excretion ceased within 10 days in 16 (43%) children, and within 20 days in 26 (70%) children. Extended excretion was detected for 25-57 days in the remaining 11 (30%) children owing mainly to continued excretion of the primary infecting strain. Extended excretion was significantly associated with antirotavirus IgA coproantibody boosts during 100 days of surveillance (p=0.001, log-rank test), and with recurrence of mild diarrhoea symptoms during convalescence (p=0.006, Fishers exact test). INTERPRETATION Severe rotavirus disease in young children may be followed by extended excretion of rotavirus. The risk of transmission to others may be greater than previously believed. Extended excretion could also explain some cases of the postgastroenteritis syndrome.

Distribution of rotavirus genotypes after introduction of rotavirus vaccines, Rotarix® and RotaTeq®, into the National Immunization Program of Australia.

Background: Rotavirus vaccines, RotaTeq and Rotarix, were introduced into the Australian National Immunization Program on July 1, 2007. The simultaneous introduction in different Australian states and territories provides a unique opportunity to compare the affect of each vaccine on the types of circulating rotavirus strains. This report describes the rotavirus genotypes responsible for the hospitalization of children during the first 2-year period after vaccine introduction. Methods: A total of 764 rotavirus-associated diarrheal cases were collected from children presenting to hospital in 10 Australian centers. Rotavirus genotype was determined using reverse transcription polymerase chain reaction assays. Results: G1P[8] was the dominant genotype nationally (52%), followed by G2P[4] (19.8%), G9P[8] (12.2%), and G3P[8] (11%). Differences in the prevalence rates of G2P[4] and G3P[8] were seen in the various states. G2P[4] strains were more prevalent in states using Rotarix, whereas G3P[8] strains were more prevalent in states using RotaTeq. Conclusions: Differences in rotavirus genotypes were observed across Australia, which suggest that different immune pressures are exerted by the different vaccines, but do not necessarily imply lack of protection by either vaccine. These differences may simply be related to the variation that can occur because of natural annual fluctuation in rotavirus strain prevalence.

Early phase II trial of human rotavirus vaccine candidate RV3

A naturally attenuated, human neonatal strain, rotavirus vaccine candidate RV3, was tested in a limited phase II randomized double-blind controlled trial. Doses of 1 ml, containing placebo or 6.5 x 10(5) fluorescent cell forming units (fcfu) of virus in AGMK cells, were given at 3, 5 and 7 months of age. Limited replication in the small intestine is implied by the lack of virus excretion, and by the occurrence of an immune response in only 46% of the infants. However, those who developed an immune response were partially protected against rotavirus disease during the subsequent winter epidemic (protective efficacy 54%), supporting observations of protection induced by natural infection by this strain. Protection appeared to be heterotypic. Further trials are warranted, employing strategies to increase immunogenicity of this human rotavirus candidate vaccine.

Enteric colonization in sporadic neonatal necrotizing enterocolitis.

Summary Microflora of the gut was studied close to the onset of sporadic necrotizing enterocolitis (NEC) in neonates. Enteric flora in 25 babies with NEC differed from that in 23 matched controls. Bacteroides spp and lactobacilli were less common in babies with NEC compared with controls: 32 versus 61% (p = 0.03) and 12 versus 48% (p = 0.006), respectively. Clostridium perfringens was isolated from 40% of babies with NEC compared with 13% of controls (p = 0.03). It was present in 33% of babies with NEC aged less than 14 days but was not detected in control babies of the same age. The incidences of C. butyr icum and C. difficile were similar in patients and controls. Colonization with C. perfringens in the absence of a protective barrier flora may be crucial in the pathogenesis of severe sudden onset NEC. Two potentially valuable marker factors to predict onset of this form of sporadic NEC are the use of fecal smears and estimation of fecal tryptic activity.

Epidemiological Patterns of Rotaviruses Causing Severe Gastroenteritis in Young Children throughout Australia from 1993 to 1996

ABSTRACT Rotavirus strains that caused severe diarrhea in 4,634 (2,533 male) children aged less than 5 years and admitted to major hospitals in eight centers throughout Australia from 1993 to 1996 were subject to antigenic and genetic analyses. The G serotypes of rotaviruses were identified in 81.9% (3,793 of 4,634) children. They included 67.8% (from 3,143 children) serotype G1 isolates (containing 46 electropherotypes), 11.5% (from 531 children) serotype G2 isolates (27 electropherotypes), 0.8% (from 39 children) serotype G3 isolates (8 electropherotypes), and 1.6% (from 76 children) serotype G4 isolates (9 electropherotypes). G6 (two strains) and G8 (two strains) isolates were identified during the same period. G1 serotypes were predominant in all centers, with intermittent epidemics of G2 serotypes and sporadic detection of G3 and G4 strains. With the exception of two strains (typed as G1P2A[6] and G2P2A[6]) all serotype G1, G3, and G4 strains were P1A[8] and all serotype G2 strains were P1B[4]. Two contrasting epidemiological patterns were identified. In all temperate climates rotavirus incidence peaked during the colder months. The genetic complexity of strains (as judged by electropherotype) was greatest in centers with large populations. Identical electropherotypes appeared each winter in more than one center, apparently indicating the spread of some strains both from west to east and from east to west. Centers caring for children in small aboriginal communities showed unpredictable rotavirus peaks unrelated to climate, with widespread dissemination of a few rotavirus strains over distances of more than 1,000 km. Data from continued comprehensive etiological studies of genetic and antigenic variations in rotaviruses that cause severe disease in young children will serve as baseline data for the study of the effect of vaccination on the incidence of severe rotavirus disease and on the emergence of new strains.

Genetic and Antigenic Characterization of Rotavirus Serotype G9 Strains Isolated in Australia between 1997 and 2001

ABSTRACT Rotavirus serotype G9 is recognized as the most widespread of the emerging serotypes, emerging since 1996 as a frequent cause of severe acute gastroenteritis in children from many countries covering all continents of the world. This study characterized serotype G9 strains collected in three widely separated Australian centers from 1997 to 2001. All G9 strains possessed the VP4 P[8] and VP6 subgroup II genes. The overall prevalence of the G9 strains increased in Australia, from 0.6% of the strains found in 1997 to 29% of the strains found in 2001. The prevalence of G9 relative to all other serotypes varied from year to year and with geographic location. In Melbourne (representing east coast urban centers), G9 made up 11 to 26% of all of the strains found from 1999 to 2001. In Perth (representing west coast urban centers), G9 made up less than 2% of the strains found in 1997 to 2000 but increased to 18.6% of the strains found in 2001. In Alice Springs (representing widely dispersed settlements in northern arid regions), G9 made up 0 to 5% of the strains found from 1997 to 2000 and was the dominant strain in 2001, making up 68.9% of all of the strains found. Three distinct antigenic groups based on reaction with neutralizing monoclonal antibodies (N-MAbs) were identified, including a dominant group (63%) that cross-reacted with the serotype G4 N-MAb. Phylogenetic analysis of the VP7-encoding gene from Australian strains, compared with a worldwide collection of G9 strains, showed that the Australian G9 strains made up a genetic group distinct from other serotype G9 strains identified in the United States and Africa. Future epidemiological studies of the occurrence of G9 strains should combine reverse transcription-PCR and typing with G1 to G4 and G9 N-MAbs to determine the extent of G9 and G4 cross-reactions among rotavirus strains, in order to assess the need to incorporate G9 strains into new candidate vaccines.

Cost effectiveness of rotavirus vaccination in Australia.

OBJECTIVE Rotavirus gastroenteritis causes substantial morbidity, including hospital admission, in young children. In the context of recent vaccine developments, this study aimed to estimate the cost-effectiveness of a rotavirus vaccination program in Australia. METHOD Standard methods of health economic evaluation were used to assess the total cost of rotavirus immunisation (as the difference between estimated vaccination program costs and the cost of disease that would be avoided by immunisation) and relate this to the number of cases of disease that would be prevented. Estimates were made from both societal and health care systems perspectives. RESULTS Based on Australian data on disease incidence and cost of hospitalisation, the current annual cost of rotavirus disease is about