Study design
This was an observational, multicenter, cross-sectional study performed at the pediatric and microbiology departments of hospitals from provinces with different RV VCR in Spain. The VCR was estimated based on the number of RV vaccine doses distributed, provided by IQVIA (formerly IMS Health), and the number of newborns each year in the different provinces, obtained from the official census.
According to the VCR observed in the different provinces of Spain (ranging from 10 to 75%, approximately), three study groups were defined: low (≤ 30%), intermediate (31–59%), and high (≥ 60%) VCR (Fig. 1).
Hospitals that performed systematic detection of RV in all children < 5 years admitted for AGE and with electronic records in the Pediatric and Microbiology Departments were considered for inclusion. The pediatric population (≤ 14 years of age) of the catchment area of each participating hospital was collected from hospital databases.
Ethics
The study was designed, conducted and reported in accordance with the Guidelines for Good Pharmacoepidemiology Practices of the International Society for Pharmacoepidemiology [26], with the ethical principles of the Declaration of Helsinki, and with the current Spanish legislation related to observational studies (Ministerial Order SAS/3470/2009) [27]. The study was reviewed and approved by the Clinical Research Ethics Committee of the Basque Country in Txagorritxu Hospital (Vitoria, Spain).
Study population
All children < 5 years of age hospitalized (admission to hospital for at least 24 h) from June 2013 to May 2018 with a microbiologically confirmed diagnosis of RVGE were selected for the analysis.
Data collection
In each hospital, the microbiology department electronic records were examined to identify all hospitalizations with a positive laboratory test for RVGE in children < 5 years of age during the study period. The hospitals mainly used immunochromatography tests for RV detection, although the proportion of hospitals using immunochromatography versus molecular tests (PCR) increased from 1 out of 12 in 2013–2014 to 4 in 2017–2018.
The total number of all-cause emergency room (ER) visits or hospitalizations and the number of AGE of any etiology hospitalizations in children < 5 years of age were collected from the hospital administrative database. Clinical records of patients were reviewed to collect data on the type of RVGE (community-acquired or nosocomial).
All study data were reviewed and introduced in an electronic case report form by the investigators.
Statistical analysis
For the estimation of the hospitalization ratios, sample size was determined based on the results published by Orrico-Sánchez et al. in which, with a VCR that reached up to 42.13%, the proportion of RVGE cases among all hospitalizations in children < 5 years of age during the postvaccine introduction period was 1.9%. The study was performed in 20 hospitals from the Autonomous Community of Valencia over a 7-year period [15]. That represents approximately 20 RVGE hospitalizations per hospital and year. Therefore, for the present study, a convenience sample of 12 hospitals would provide a total of 1200 hospitalizations due to RVGE during the 5-year study period. This sample would allow us to estimate a proportion of 1.9% RVGE hospitalizations among all hospitalizations with a precision of 0.79% and a confidence level of 95%.
Annual hospitalization ratios were calculated according to the formula: Annual number of diagnosed RVGE hospitalizations among children < 5 years of age/Total number of all-cause hospitalizations among children < 5 years of age during the study period × 100.
The proportion of all-cause ER visits that were hospitalized due to any cause, AGE and RVGE among the study groups was also calculated. The number of ER visits was used as a proxy to estimate which proportion of children < 5 years of age attending ER are hospitalized due to any cause, AGE and RVGE.
We calculated 95% confidence intervals (95% CIs) by assuming hospitalization rates followed a normal distribution and thus used standardized tables to estimate upper and lower bounds. Hospitalization ratios and 95% CIs for community-acquired RVGE and nosocomial RVGE separately were also calculated. For this purpose, records of a randomized sample of 1000 patients were reviewed to estimate the percentage of episodes, among the total sample, that were due to nosocomial and community-acquired infection. Nosocomial RVGE was defined as any episode of AGE appearing from at least 48 h after admission to 72 h after hospital discharge with laboratory test positive for RV infection.
The proportions of all-cause hospitalizations that were due to RVGE and AGE were compared among the three study groups, using a Chi-square or Fisher exact test, and adjusted odds ratios (ORs) with respective 95% CIs were calculated. Low VCR group was used as reference group for comparisons.
All statistical analyses were performed using SAS version 9.4. A level of statistical significance of 0,0.05 was applied to all statistical tests.