Robin D Marlow

Case control study of rotavirus vaccine effectiveness in Portugal during 6 years of private market use.

Background: Although recommended by the vaccine committee of the Portuguese Paediatric Society, rotavirus vaccines have not been included in the routine immunization schedule. They have been available privately since 2006 with estimated coverage reaching approximately 30%. However, unlike other European countries using the vaccine, sentinel surveillance has detected fluctuations but no clear trends in the rate of gastrointestinal disease presentations. In this study, we set out to establish the real world effectiveness of rotavirus immunization in this low vaccine coverage setting. Methods: We carried out a test-negative case control study on a population of children attending a regional pediatric hospital, between 2006 and 2012, with symptoms of acute gastroenteritis and producing a stool sample for routine rotavirus testing. We calculated exposure odds ratio (ratio of odds of antecedent vaccination among cases compared with controls) to derive vaccine effectiveness ([1 − adjusted odds ratio]/100) against both hospital attendance and admission. Results: Vaccine effectiveness against attendance with rotavirus acute gastroenteritis was 83.7% (95% confidence interval: 73.9–89.8) and against hospital admission was 96.1% (95% confidence interval: 83.8–99.1). No significant difference between the 2 available vaccines was detected. Conclusion: Both rotavirus vaccines offer a high degree of individual protection in this population.

Assessing the impacts of the first year of rotavirus vaccination in the United Kingdom

The United Kingdom (UK) added rotavirus (RV) vaccine (Rotarix GlaxoSmithKline) to the national vaccine schedule in July 2013. During the 2012-2014 rotavirus seasons, children presenting to the Bristol Royal Hospital for Children Emergency Department with gastroenteritis symptoms had stool virology analysis (real-time PCR) and clinical outcome recorded. Nosocomial cases were identified as patients with non-gastroenteritis diagnosis testing positive for rotavirus > 48h after admission. In comparison to average pre-vaccine seasons, in the first year after vaccine introduction there were 48% fewer attendances diagnosed with gastroenteritis, 53% reduction in gastroenteritis admissions and a total saving of 330 bed-days occupancy. There was an overall reduction in number of rotavirus-positive stool samples with 94% reduction in children aged under one year and a 65% reduction in those too old to have been vaccinated. In the first year after the introduction of universal vaccination against rotavirus we observed a profound reduction in gastroenteritis presentations and admissions with a substantial possible herd effect seen in older children. Extrapolating these findings to the UK population we estimate secondary healthcare savings in the first year of ca £7.5 (€10.5) million. Ongoing surveillance will be required to determine the long-term impact of the RV immunisation programme.

Quality of life impacts from rotavirus gastroenteritis on children and their families in the UK

AIMS Rotavirus vaccines (RV) are safe and effective but demand significant investment of healthcare resource. In countries with low mortality due to rotavirus, a key component to assessing cost-effectiveness is quantifying the Health Related Quality of Life (HRQoL) lost due to rotavirus acute gastroenteritis (RVAGE). METHODS Families with children less than six years old with gastroenteritis were recruited from attendees to Bristol Childrens Hospital Emergency Department. Stools were tested for viral causes of gastroenteritis. Childrens HRQoL was assessed at presentation using Health Utilities Index 2 (HUI2) with visual analogue scale (VAS). The effect of the childs illness on the HRQoL of up to two adult carers was assessed using EQ-5D-5L. Families completed a daily symptom diary to assess time to recovery and within-family transmission. RESULTS 127 families consented to take part, 84(65%) had rotavirus as the cause of illness. At the time of attendance, mean paediatric HRQoL with RVAGE was 0.74(HUI2) and 0.42(VAS). Primary/secondary carers HRQoL was 0.68/0.80 (EQ5D) or 0.70/0.79 (VAS). The mean number of QALYs lost due to RVAGE was 3.1-3.5 per thousand children and 7.7-8.7 per thousand family units. In 52% of RVAGE families at least one other member developed a secondary case of gastroenteritis. For working parents, 69% missed work, for a mean of 2.8 days (95% CI 2.3-3.4). CONCLUSIONS We have found the HRQoL loss associated with RVAGE in children and their carers to be significantly higher than estimates used for all RV medical attendances in UK cost-effectiveness calculations.

The promise of immunisation against rotavirus

Infectious diarrhoea is a common disease of childhood. It is estimated to be responsible for over 1.3 million deaths per year, predominantly in resource-poor countries. In wealthy nations, it causes significant morbidity, healthcare burden and associated cost. In both scenarios, the most common cause is rotavirus. This article reviews the experience of primary prevention of rotavirus disease through immunisation and considers the case for extending vaccine use further in Europe and globally.

The evolving epidemiology of rotavirus gastroenteritis in central Portugal with modest vaccine coverage

BACKGROUND Rotavirus (RV) vaccines have been available on the private market in Portugal since 2006, with an estimated coverage rising from 16 to 42% between 2007 and 2010. OBJECTIVES To assess trends, surveillance of children presenting with acute gastroenteritis (AG) to a large paediatric emergency service (ES) in the central region of Portugal was conducted yearly during the winter-spring seasons. STUDY DESIGN Stool samples, collected throughout five epidemic seasons (January-June, 2006 to 2010) from children ≤ 36 months of age attending the ES with AG, were tested for RV by immunochromatographic rapid test and positive samples were genotyped. RESULTS A total of 6145 AG cases were identified: 1956 (32%) provided a stool sample (range: 28% in 2008-37% in 2009). The proportion of AG subjects who tested positive for RV fluctuated over the five surveillance seasons (49%, 39%, 25%, 26% and 39%, respectively) as did the distribution of co-circulating RV genotypes. There were no consistent changes in seasonality or age distribution and the proportion of admitted AG subjects who tested RV-positive did not show progressive trends over time. CONCLUSIONS Our results demonstrate fluctuations in RVAG incidence with no clear progressive trends or seasonal RV shifts among our surveillance subjects over five years, in the context of limited rotavirus vaccine coverage. Significant annual changes in genotype distributions were detected. Higher vaccine coverage may be necessary than at present for consistent impact on disease.

Accurate paediatric weight estimation by age: mission impossible?

Background According to the Advanced Paediatric Life Support (APLS) guidelines, the weight of children between the ages of 1 and 10 years can be safely estimated using the formula: weight=2 × (age +4). Although several alternative methods have been proposed to be more accurate, they are not widely used. In this study we compare the accuracy of the standard APLS guideline to alternative age based methods of weight estimation. Methods Data was obtained retrospectively from the recorded weights of 140 314 children aged between 0 and 16 years attending a large UK Paediatric Emergency Department. The accuracy of the APLS guideline and alternative formulae were audited by comparing predictions with measured weight. For each method the percentage of study population predicted to measured weight +/−10% was derived along with mean, absolute, root mean squared and percentage error of weight estimation. Results Between the ages of 1 and 10 years, the APLS method correctly predicted 35% of patients within +/−10% of measured weight. The Best Guess (BG) method formula (2×age +10) estimated 44% of weights to +/−10%. Under 1 year the BG infant formula ((age in months+9)/2) correctly predicted 45% of patients +/−10% (table 1). Abstract P3 Table 1 Summary of results Method APLS Argall Luscombe Best Guess 2xage + 10 Formula 2xage+8 2(age+4) 3xage+6 3(age+2) 3xage+7 1–5)2xage+10 6–10)4xage 2xage+10 2(age+5) Percentage accuracy +/− 10% 35.1 39.0 43.1 43.7 44.7 Mean error / % bodywt (95% CI) 13.1 (−22.1–48.4) 5.0 (−37.3–47.4) −0.9 (−43.8–42.1) −5.6 (−49.3–38.0) 1.4 (−40.5–43.3) Root mean square % bodywt error 22.3 22.2 21.9 23.0 21.4 Mean error /kg (95% CI) 3.8 (−8.3–16.0) 1.4 (−9.4–12.2) 0.4 (−10.4–11.2) −0.4 (−11.1–10.4) 1.8 (−10.3–14.0) Percent>10% overestimated 6.1 19.3 28.3 37.5 25.2 Percent>10% underestimated 58.8 41.7 28.6 18.8 30.1 Conclusion Although all age based methods of weight estimation are inaccurate, this study suggests the most widely used, APLS, is the least accurate. For optimal resuscitation of children, clearly, the most accurate formula is desirable. The results of our study support findings of previous studies suggesting a change in current practice is required. We suggest adoption of a modified form of the Australian BG method using the formula: weight=2 × age+10 between the ages of 1 to 10 years.

Functional distinctions in cytosolic calcium regulation between cells of the glomerular filtration barrier

The importance of intracellular calcium ([Ca2+]i) regulation in the glomerular filtration barrier (GFB) has recently been highlighted by mutations in the cation channel TRPC6, resulting in a renal-specific phenotype. We examined the effects of FFA, a tool that can activate TRPC6, on [Ca2+]i in human conditionally immortalised glomerular endothelial cells (ciGEnC) and human podocytes (ciPod) that form the GFB. Changes in [Ca2+]i stimulated by FFA were measured in Fura 2-AM loaded cells. In GEnC, cell activation by FFA was dependent on external Ca2+, yet in ciPod it was not. Depletion of internal Ca2+ stores with thapsigargin did not affect cell activation by FFA in ciGEnC, but inhibited it in ciPod in a nephrin-dependent manner, demonstrated using nephrin deficient (ND) ciPod in conjunction with nephrin rescue experiments. FFA induced [Ca2+]i store release in ciPod, but not in ciGEnC or ND ciPod. In parallel, there were differences in the localisation of overexpressed TRPC6 between ciGEnC and ciPod. Furthermore, co-transfection of nephrin with TRPC6 in HEK293 cells reduced the FFA-induced increase in [Ca2+]i and nephrin clustering altered TRPC6 distribution. In conclusion, cell activation by FFA in podocytes stimulates the opening of a Ca2+ channel, probably TRPC6, in a nephrin-dependent manner with a different activation profile to GEnC.

G241(P) Comparing Usability of Paediatric Weight Estimation Methods

Aims In acutely ill children, weights are often estimated to calculate drug and fluid dosage. Many methods exist, attempting to balance complexity and accuracy. The most accurate are based on physical measurements, but those commonly used in the UK are based on age alone. In 2011 the Advanced Paediatric Life Support (APLS) recommendations changed from using a single formula to three. Meanwhile the UK Resuscitation Council maintains that complexity increases risks of error and still advocates the single formula. To date no studies have assessed the crucial human factors affecting ease of use or rates of error. This project aimed to pilot a technique for testing accuracy, speed and user preference (usability) of different methods. Methods We developed a website (www.pemresearch.org) where participants applied four common weight estimation methods (table 1) to a range of ages. Orders of methods and ages were randomised between each entry. To reflect a real resuscitation scenario, participants were instructed to complete the test as quickly and accurately as possible. Psychological pressure was generated by a visible running timer combined with a leaderboard competition. Subject inter-method variability of speed and accuracy were analysed using one way ANOVA and pairwise t-tests with adjusted p-values. Results 34 acute paediatric staff completed the test. 74% routinely used the single formula APLS method. Post-test 77% reported the reference table method easiest to use. Both single formula APLS and reference table were significantly quicker to use than other methods (p < 0.001 and <0.001). There was no significant difference detected in accuracy between methods. (table 2) Conclusions This is a feasible technique of assessing usability. Although in our pilot there was no significant difference in accuracy detected, the time taken to apply each method and preference to use appear related to complexity. This novel method of assessing usability has potential advantages over other such as in-situ real-time simulation, including rapid turnaround and distribution via the internet. We plan to expand this study to a larger sample size and validate against in-situ simulation. After refining the technique we will extend its application to other everyday tools such as clinical decision rules. Abstract G241(P) Table 1 Method Age range Formula Single formula APLS 1–10 years weight = (age + 4) x 2 Three formulae APLS <12 months1–5 years6–12 years weight = (0.5 x age in months) + 4 weight = (2 x age) + 8 weight = (3 x age) +7 Modified Best Guess Method <12 months 1–9 years 10–14 years weight = (age in months +9)/2weight = (2 x age) +10weight = (4 x age) Reference tableDerived from UK growth data 0–16 years weight = 50th centile for age and sex Abstract G241(P) Table 2 Old APLS New APLS BGM Table Mean time taken (seconds) 49.55 57.76 55.17 33.68 Accuracy of answers (%) 90.5 94.4 95.8 95.5 Pre quiz normal method n (%) 25 (73.5) 7 (20.6) 1 (2.9) 1 (2.9) Post quiz preferred method n (%) 4 (11.8) 2 (5.9) 2 (5.9) 26 (76.5)

G13 Trends in admission and death rates due to Paediatric Head injury in England and Wales 2000–2012

Over the last ten years there has been a steady rise in short paediatric admissions. This is likely to be multi-factorial but is in part attributed to the introduction of the four hour Emergency Department (ED) target and changes in primary care provision. Head injury is the most common paediatric injury presentation. The National Institute for Health and Care Excellence (NICE) published guidance for head injury management in 2003 and 2007. Both prioritised early definitive diagnosis by early brain imaging although paediatric practice often includes a period of observation. We aimed to establish whether introduction of national guidance resulted in significant change of death or admission rates. Methods A retrospective observational study of admissions and deaths due to paediatric head injury between 2000 and 2012 was performed using Hospital Episode Statistics and Office for National Statistics publications. Results See Figures 1-3. Correcting for changes in population size, per 100,00 children aged 0–14 years there is a downward trend in mortality (Figure 1) (R2 = 0.7 p < 0.001) but an upward trend in admission rates (Figure 2) (R2 = 0.3 p = 0.05). Admission rates for paediatric head injury as a percentage of all admissions decreased (Figure 3) (R2 = 0.65 p < 0.001). Abstract G13 Figure 1 Annual number of head injury admissions per 100 000 paediatric population 2000–2012. Abstract G13 Figure 2 Percentage of paediatric admissions due to head injury (HI) 2000–2012. Abstract G13 Figure 3 Annual number of head injury deaths per 100 000 paediatric population 2000–2012. Conclusion We have found statistically significant changes in rates of death and admission due to paediatric head injury over this time period. However even accounting for implementation delays, the trends that we have demonstrated do not directly correlate with the timings of national guidance, ED targets or changes to primary care provision. For a more complete understanding of the impact of the guidelines this analysis should now be expanded to incorporate ED attendance rates and length of stay. However these existing data provide a useful benchmark against which to compare the effect of the 2014 update to NICE guidance.

Lack of impact of rotavirus vaccination on childhood seizure hospitalizations in England – An interrupted time series analysis

Observational studies have linked a reduction in childhood seizures (CS) to the introduction of rotavirus vaccination (RV). England is opportunely placed to explore this due to well-defined introduction, high uptake of RV and centralised Hospital Episodes Statistics recording all admissions. We investigated the association between seizures and vaccine use through interrupted time-series analysis of all CS admissions in children <3 years old (ICD-10 codes; G40∗-G41∗, R56.0∗) during 2007-2017. We did not detect a statistically significant association between the introduction of RV and admission with febrile (p = 0.84), afebrile (p = 0.83) or all CS (p = 0.93), even when limited to peak rotavirus seasonality (March). This is the first ecological study in a country that exclusively uses the monovalent vaccine. Although a negative finding, we would argue that if an effect cannot be detected at this population level then it is unlikely to be clinically or economically significant but generates hypotheses of potential non-specific effects.