Rotavirus vaccination as a public health strategy to reduce the burden of hospitalization: The field experience of Italy (2008−2018)

Rotavirus (RV) infection is a leading cause of severe diarrhea among children younger than 5 years old and a considerable cause of RV gastroenteritis (RVGE) hospitalization. This study aimed to evaluate the impact of vaccination in Italy in the reduction of the burden of RV‐related disease, estimating the relation between vaccination coverage and hospitalization rates. RVGE‐related hospitalizations that occurred in Italy from 2008 to 2018 among children aged 0−35 months were assessed by consulting the Hospital Discharge Record database and including records whose ICD‐9‐CM diagnosis code was 008.61 in the first or in any diagnosis position. In the 2008−2018 period, a total of 17 535 791 at‐risk person‐years were considered and 74 211 (423.2 cases × 100 000 per year) RVGE hospitalizations were observed. Higher hospitalization rates occurred in males (456.6 vs. 387.9 × 100 000 per year) and in children aged 1 year (507.8 × 100 000 per year). Poisson regression analysis showed a decrease of −1.25% in hospitalization rates (−1.19% to −1.31%, p < 0.001) per unit increase in vaccination coverage. This is the first study that correlates hospitalization rate reduction with a percentage increase in vaccination coverage. Our findings strongly support RV vaccination as an effective public health strategy for reducing RVGE‐related hospitalizations.

diarrhea mortality, especially in low-income countries with worse living standards and hygienic conditions. 9 Unfortunately, the scientific literature on the incidence of RV-related hospitalizations is scant, limiting the availability of up-to-date global health and economic impact estimates.
In 2003, Parashar et al. published for the first time a global estimate of hospitalizations attributable to RV infections, estimating that about two million hospitalizations per year occurred among children younger than 5 years old. 10 These findings were consistent with those recently reported by a number of study groups from other countries, who also accounted for the role of RV vaccination. 11,12 Medical treatments employing oral rehydration solution, sanitation, and water purification have been the only effective strategies to reduce diarrhea-associated mortality over the past two decades 13 ; such interventions, however, were not cost-effective toward RV infection and its complications; consequently, in 2007, the World Health Organization advised countries to include RV vaccination in their national immunization programs as it should be considered a the most effective and cost-effective strategy to prevent RV-related morbidity and mortality. 14,15 To date, 116 countries have incorporated RV vaccination into their national immunization programs, 16,17 and numerous European nations have embraced a universal vaccination program as part of their childhood immunization schedules.
Vaccine effectiveness against RVGE hospitalizations and outpatient visits has been demonstrated to be strong, particularly in regions with high vaccination coverage, 6,[18][19][20][21][22] although it should be noted that the RV vaccines effectiveness differs across countries. 6,9,21,22 RV vaccines are recommended for newborns beginning in the sixth week of life, and the vaccination regimen should be completed by 24 or 32 weeks of life for RV1 23 and RV5, 24 respectively. These vaccines have demonstrated high and durable efficacy against severe RV gastroenteritis in highly developed countries, but lower and less durable efficacy in sub-Saharan Africa and South Asia. 25-27 RV1, for instance, was more effective in Europe (90.4% of severe RV infections were prevented) than in Africa (61.2%). Similarly, RV5 revealed effectiveness rates ranging from 83% to 100% in high-income countries such as the United States and Finland, but rates of 30% −74% in Nicaragua, a low-income country. 6 With vaccination, the burden of RV dropped considerably, as shown by the decline in hospitalizations and emergency room visits. 28 Sicily was the first Italian region to offer universal RV vaccination

| Statistical analysis
Qualitative data were summarized as absolute frequencies and rates (cases × 100 000 at risk subjects per year). Hospitalization rates per 100 000 were calculated using the census population for children aged 0−35 months from 2008 to 2018.
Vaccination coverage was reported as relative frequency (%).
A Joinpoint regression analysis was used to evaluate the time trends of hospitalization rates and the average annual percent change through the entire considered period. This analytical approach was selected because it is a well-established methodology for modeling trends over time using connected linear segments and accurately identifying years of the trends in which rates significantly change. 35 The association between vaccination coverage and hospitalization rates, both measured on an annual and regional basis, was evaluated by a multivariable Poisson regression analysis. Regression coefficients, adjusted for year of study, was used for modeling the percentage reduction of hospitalization rates per percentage unit increase in vaccination coverage.
A p < 0.05 was considered as statistically significant.
Analyses were performed using R Software analysis (version 4.0.5; R Foundation for Statistical Computing) and, as for the Joinpoint analysis, the packages "Segmented" and "Strucchange" were used. 36

| RESULTS
During the study period, a total of 17 535 791 at-risk children aged 0−35 months were observed (9 010 282 males and 8 525 509 females), with an annual mean of 1 594 162 children.
As shown in Table 1      According to the authors, these differing findings may reflect group-and country-specific differences in access to care or healthcare behavior patterns. 12 In Italy, the average hospitalization rate in the pre-vaccine era (years 2008−2015) was 448 per 100 000 children younger than 3 years of age. Our findings are comparable to the aforementioned data.
RV vaccination has been found to be extremely effective, having a significant impact on RVGE hospitalizations, as well as emergency room and primary healthcare visits, in all European countries where a tailored immunization program has been introduced. 41 For instance, after the introduction of the RV vaccination and with a vaccination coverage ranging from 60% to 85% after the first year of universal mass immunization, the frequency of RVGE hospitalizations in European countries decreased. [18][19][20] In 2013, within 12 months of the introduction of the RV immunization program for the infants in the United Kingdom, acute gastroenteritis-related hospitalizations decreased significantly. In detail, the first year of the program was associated with a 77% reduction in laboratory-confirmed RV hospitalizations, followed by reductions of 80%−88% in succeeding years. 42 The deployment of RV universal immunization within Italian borders resulted in a significant decrease in RVGE hospitalization rates from 2016 to 2018 (−38.45%), which is a further significant finding. This reduction was smaller than the one reported in the intellectual content, and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for major aspects of the work.

CONFLICT OF INTEREST STATEMENT
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
The data set generated during and/or analyzed during the current study is available from the corresponding author on reasonable request.