https://orcid.org/0000-0002-5336-8429
ABSTRACT
Rotavirus is a major cause of acute gastroenteritis in children under 5 years of age, with severe illness occurring in 30–40% of cases. In Italian region of Liguria, vaccination with a two-dose human attenuated vaccine was introduced in 2013. We conducted a retrospective study to assess the impact of rotavirus vaccine on hospitalizations for rotavirus-related gastroenteritis (RVGE) at the IRCCS Istituto Giannina Gaslini. Every hospitalization due to laboratory-confirmed RVGE and acute gastroenteritis of unknown origin (AGUO) in patients aged 0–14 years in the period 2008–2019 were anonymously extracted. Vaccine coverage were obtained from the regional vaccination registry. The results were divided in 2008–2012 (before RV vaccine) and 2013–2019 (after) periods. From 2008 to 2012, there was a continuous reduction of AGUO hospitalizations while RVGE increased. Since 2013, a reduction in hospitalization rate was observed for RVGE with a sharp decrease from 17.81 per 10.000 children in 2012 to 0.79 per 10,000 in 2019, parallel with the ascending values of RV vaccination coverage that increased from 36.3% in 2013 to 63.9% in 2019. A significant negative correlation was found between the proportions of vaccinated newborns and RVGE rates (p = .012). Intussusception-related hospitalization did not show substantial modifications. We confirm vaccination as a safe practice that has a significant impact in pediatric hospitalization rates.
Introduction
Rotavirus (RV) is a major cause of acute gastroenteritis in children under 5 years of age, with severe illness and hospitalization occurring in 40–50% of affected subjects.Citation1–3 In an Italian national hospital admission study, the majority of rotavirus gastroenteritis (RVGE) hospitalizations (33.7%) were reported among children aged ≤2 years.Citation4 A first-generation vaccine was withdrawn from use since 1999 because of intussusception reports,Citation1 while new generation RV vaccines show 85–100% safety and efficacy.Citation2,Citation5
In Italy, Sicily was the first region to offer universal RV vaccination in 2013, showing a decrease in hospitalizations due to RV gastroenteritis from 394 per 100,000 hospitalizations (period 2009–2012) to 220 per 100,000 (period 2013–2016).Citation6 In Liguria, RV vaccination with a two-dose human attenuated vaccine was introduced in 2013, first offered in co-payment regimen, and from 2017 offered free of charge to all newborns, as part of the Italian National Immunization Program.
According to WHO, in order to monitor trends in gastroenteritis and rotavirus disease burden and interpret the data in conjunction with vaccination coverage rates is a proper method to document the impact of the immunization campaign.Citation2,Citation7 The advantage of monitoring disease trends is that it can be reached by using routine data. Because the efficacy of RV vaccines is higher against severe disease, the impact of vaccination is expected to be of great on severe outcomes such as hospitalization.Citation2,Citation7
Therefore, we conducted a retrospective study to assess the impact of RV vaccine on hospitalizations for RVGE at the IRCCS Istituto Giannina Gaslini (IGG), Genoa-Italy.
Methods
The IRCCS Istituto Giannina Gaslini (IGG), Genoa-Italy, is a tertiary care pediatric hospital of northern Italy, representing a referral hospital at the regional/national levels. IGG is the only pediatric hospital in the whole Genoa metropolitan area and the only hospital with a pediatric emergency ward. Every child hospitalization is therefore carried on at IGG. International Classification of Diseases, Nineth Revision – Clinical Modification (ICD9-CM) codes were adopted to extract anonymously all cases of hospital admission due to laboratory-confirmed RVGE (code # 00861), acute gastroenteritis of unknown origin (AGUO) (code #0091) or intussusception (IS) (code # 560.0) diagnosed in patients aged 0–14 years in the period 2008–2019.
Every patient hospitalized for acute gastroenteritis collected stool specimens who were analyzed by means of rapid immunochromatographic assay (Combi-Strip, Coris BioConcept, Belgium) to detect RV (specificity 100%, sensibility 99.1%).
Data were expressed as rates of events for 10.000 children from Genoa metropolitan area of the same age group (yearly inhabitant numbers were retrieved from Italian National Statistics Institute – ISTAT; www.istat.it). Analysis was performed both on overall case series (0–14 years) and in patients aging <5 years (pre-scholar age) at the time of admission. Vaccine coverages were obtained from the regional vaccination registry and expressed as the proportion of vaccinated newborn per year. The results were then divided into two periods: 2008–2012 (before introduction of RV vaccine) and 2013–2019 (after introduction).
Data were expressed as proportions (percentages or rates) for categorical variables and median with 95% Confidence Interval (95%CI) for continuous variables. Normal distribution of events during the study period was evaluated by means of Kolmogorov-Smirnov test. The possible presence of a correlation between rates of events and year of observation was analyzed by means of the Pearson r-test, and the strength of the association between the two variables was considered on the basis of absolute values of r: 0–0.19 (very weak), 0.2–0.39 (weak), 0.40–0.59 (moderate), 0.6–0.79 strong, 0.8–1 (very strong).
A p value ≤ 0.05 was considered as statistically significant.
Statistical analyses were performed by means of the free web platform Social Science Statistics (www.socscistatistics.com) and Jamovi, an open-source R-based platform.
IRB approval was waived considering the retrospective fashion of the study and the anonymous data extraction.
Results
During the study period, a total of 1744 hospitalizations were recorded. RVGE was diagnosed in 749 cases, 457 (61%) in pre vaccinal era (2008–2012) and 292 (39%) in post vaccinal. 798 AGUO were counted, 429 (53,8%) in pre vaccinal era and 369 (46,2%) in post-vaccinal while a total of 197 IS were observed, 109 (55,3%) between 2008–2012 and 88 (44,7%) from 2012 to 2019. In children aged <5 years resulted to be 674/749 (89.9%) for RVGE, 597/798 (74.8%) for AGUO and 166/197 (84.3%) for IS.
reports hospitalization rates for each disease in each year during the study period.
Table 1. Events and rates (events/10.000 inhabitants from Genoa metropolitan area of the same age) of hospitalization for acute gastroenteritis and rotavirus vaccine in pediatric patients in the city of Genoa from 2008 to 2019
From 2008 to 2010, there was an increase in AGUO rates in all age groups. The increase in RVGE rate, on the other hand, continued until 2012. Starting from the end of 2010, a steep decline in AGUO rate was observed (with a continuously rising RVGE rate). A sharp reduction in RVGE rates only occurred at the end of 2012 (from 17.81 * 10, 000 children to 6.77 in 2013), when the vaccination coverage rate was 36.3% ()). The RVGE therefore showed a constant reduction, reaching the lowest rate of the last 11 years in 2019 (0.79 * 10, 000). In the same year, the highest vaccination coverage was also recorded (63.9%). A statistically significant strong negative correlation between vaccination coverage rate and RVGE was found (−0.694; strong, p = .012). In the whole study period, hospitalization rates for IS showed minimal modifications, and moreover, we found a statistically significant negative correlation between vaccination coverage and IS rate (−0.734, strong, p = .007). In children aging 0–2 years, epidemiological changes were very similar ()) to that observed in the overall population. A very strong positive correlation was found between IS rates and RVGE (r 0.881, p < .001) but not with AGUO. Similar to 0–14 population, in <5 years a negative correlation between vaccinal coverage and RVGE was found r − 0.666, p = .018).
Figure 1. Impact of rotavirus vaccination in reducing rates of hospitalization *10.000 children of Genoa metropolitan area from 2008 to 2019.
Discussion
Since the implementation of RV-vaccination in Liguria in 2013, in the town of Genoa hospital admission for RVGE showed a continuously decreasing trend both overall and in children aging 0–2 years, confirming the remarkable impact of a RV vaccination program on hospitalizations, especially in the first 2 years of life.Citation4 These data are similar to that observed in Sicily, after the implementation of routine RV vaccination in 2013. By the end of 2013 (first year of universal RV vaccination in Sicily), the number of children aged 0–59 months who had been admitted with RVGE was reduced by 39.3%, with 48.3% reduction in children aged 0–11 months.Citation8 Further follow-up in Sicily revealed an overall decrease of 47% of RVGE hospitalization when the RV vaccination coverage reached 45%.Citation6 A deeper impact analysis confirmed the consistent connection between the reduction of the hospital discharge rates and vaccination coverage, which was the highest (56.5%) where the coverage peaked 58.6% and lowest (15.7%) where the coverage was down to 19.1%.Citation9 Vaccination coverage in Genoa evolved from 36.3% in 2013 to 63.9% in 2019, with a turning point in 2017, when the vaccine was offered free to all newborns: RVGE hospitalization rate in children <5 years dropped down from 25.85 in 2017 to 2.71 in 2019. These data are consistent with a 5-year survey in UK that showed a significant reduction in hospitalizations for acute gastroenteritis in all age groups after the introduction of RV vaccination.Citation10
IS was the most feared complication of RV vaccination. In our study, IS hospitalization rate remained substantially constant and comparable before and after RV vaccine introduction. These results are in line with the official report released from the Italian National Drug Agency (AIFA) in 2019, where the IS rate was 0.4/100.000 administered doses, calculated at the national level after RV vaccination.Citation11 This is further consistent with international experiences like those in England and Germany resulting in no overall increase in IS hospital admission rate neither in disease severity after RV universal mass vaccination introduction.Citation12,Citation13
In our case-series, IS rate showed a peak of 4.30 cases *10,000 children 0–14 in 2011, the year with highest RVGE rate. We also found a very strong correlation between RVGE and IS together with a negative correlation between IS and rotavirus vaccine coverage. A recent analysis of the literature has shown that there is no univocal consensus in rotavirus natural infection as a risk factor for ISCitation14 although some authorsCitation15 demonstrated that it is biologically plausible. The interpretation we can provide on our data is that the role of rotavirus in severe gastroenteritis requiring hospitalization is paramount, so it is not impossible that RVGE could lead to an increase in IS rate.
We would like to underline is that, in our study, IS rate is even inversely correlated with rotavirus vaccination coverage rate, further demonstrating the safety of this practice.
Disclosure statement
No potential conflict of interest was reported by the author(s).
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