Rotavirus Infections: A 2-Year Comprehensive Review in Admitted Pediastric Patients Amid Conflicting National Policies

Abstract

Highlighting rotavirus (RV) as a significant food and waterborne pathogen, particularly affecting infants and children, causing serious gastrointestinal infections and dehydration, is important. It should be noted that there are significant debates regarding the effectiveness and outcomes of RV vaccination. In contrast to Turkey’s nonmandatory vaccination policy, many developed countries implement mandatory vaccination policies, raising questions about their impact on disease prevalence and healthcare expenditures. Our study aims to comprehensively understand RV infections in Turkey and compare them with countries that have mandatory vaccination policies. We found similar, and even better, hospitalization rates, length of hospital stays, and laboratory parameters demonstrating the effectiveness of Turkey’s independent vaccination approach. These findings contribute valuable insights to global vaccination strategies and disease control.

Introduction

Rotavirus (RV) is one of 31 identified foodborne and waterborne pathogens (Srivastava and Prasad, 2023) impacting global economic growth (Ferri and Vergara, 2021). Studies show that among foodborne pathogens, only seven account for >90% of hospitalizations and deaths, with RV constituting part of the remaining 10% (Dhaliwal et al., 2021). In Turkey, RV accounts for 46.3% of pediatric diarrheal cases (Arslan et al., 2019).

In contrast to Turkey’s approach of making the RV vaccine accessible but nonmandatory through its National Immunization Schedule (Karaayvaz, 2021), numerous developed countries in Europe and America have enforced compulsory vaccination policies (Hallowell et al., 2020). This distinction in vaccination strategies raises critical questions about the impact of mandatory vaccination on disease prevalence, severity, and healthcare expenditure. Debates persist on mortality reduction, with some studies supporting (Burnett et al., 2020) and others refuting (Parker et al., 2018) the vaccine’s efficacy. A 2022 study in Ireland found no delay in RV season postvaccination and no reduction in infection peak (Barsoum, 2022). An English study suggests that an RV vaccination program could potentially save just £11 million annually (Clark et al. 2014).

The main objective of this study is to comprehensively delineate the course of RV infections in Turkey, where independent policies are implemented, to enable a better understanding of the outcomes of conflicting policies. By comparing hospitalization rates, length of hospital stays, infection severity, and laboratory parameters in Turkey, where the vaccine is not mandatory, against the compulsory vaccination environments of Europe and America, we aim to contribute valuable insights to global public health. Such insights can potentially inform future policy decisions and guide nations.

Materials and Methods

Study design

Our 2-year retrospective cohort study was conducted at Karabuk University Faculty of Medicine Training and Research Hospital from January 01, 2022, to November 24, 2023, in Turkey. We designed the study with three groups. The first group consisted of patients aged 0–5 years with severe rotavirus gastroenteritis (RVGE) (n 250), the second group included patients aged 6–18 years with severe RVGE (n 160), and the third group comprised healthy children (n 503). Patients’ records were retrospectively retrieved from the hospital automation system through scanning. Then, these records were meticulously reviewed. The vaccinated incidence, infection severity, laboratory parameters, hospitalization rates, and length of hospital stays were systematically detected.

Definitions and data collection

Patients were diagnosed with the following conditions using International Classification of Diseases (ICD) diagnosis codes: •

Acute hastroenteritis (AGE): The definition of AGE includes admissions coded as AGE (ICD-10 A00-A09) or as noninfectious gastroenteritis (K52.9) (Heinsbroek et al., 2019). A total of 6361 AGE cases were found.

•

RVGE: Patients diagnosed with A08.0 (Rotavirus enteritis) according to the ICD coding system. Laboratory confirmation for RVGE was defined as patients with service code 907980 according to the ICD coding system and positive results for the “RV antigen” laboratory test (Heinsbroek et al., 2019).

•

Requiring intervention cases (infection severity) (main cohort): Our study included patients requiring intravenous (IV) hydration therapy due to RV both in the pediatric ward and in the emergency department (ED). This approach aimed to determine the proportion of severe RV cases (Parez et al., 2014; Patel et al., 2009). A total of 410 cases were found and defined as our main cohort.

•

Population of children: The population data for children aged 0–18 in Karabük province, used to calculate the annual hospitalization rate per capita, were obtained from the 2022 data of the Turkish Statistical Institute. The number of children aged 0–18 in Karabük province was determined to be 47,385 and can access the relevant information through the following link: https://data.tuik.gov.tr/Bulten/Index?p=Istatistiklerle-Cocuk-2022-49674.

•

Hospitalization (rate and lengths of stay [LOS]): RVGE hospitalizations were identified based on diagnosis codes. The reasons for hospitalization varied among patients and were not limited to dehydration alone. Such as electrolyte imbalances, persistent vomiting, or other medical concerns necessitating close monitoring and supportive care. All reasons for hospitalization among patients were included for analysis. A total of 102 patients were found (in 2 years). As per the study design, hospital LOSwere calculated using the formula: the difference in days between the discharge date and the admission date, plus 1 day (Rinder et al., 2014).

•

Vaccinated rate: The vaccination rate of the 410 patients identified with severe RV infection (main cohort) was retrospectively obtained from hospital automation systems by scanning patient records. In addition, we calculated the vaccination rate among hospitalized patients. Patients with missing data were contacted via phone to confirm their vaccination status.

•

Control group: Comprised healthy children aged 0–18 years who had received a diagnosis under the ICD code Z00.1 (routine child health examination). A total of 503 healthy children were scanned. Subsequently, the e-Nabız patient information system of the Ministry of Health (https://enabiz.gov.tr/) was accessed to identify and exclude patients with acute and chronic illnesses.

•

Laboratory findings: The following laboratory values were recorded from blood and urine samples of these patients: hemoglobin (HB), mean corpuscular volume (MCV), red blood cell (RBC), white blood cell (WBC), platelet (PLT), urea (UREA), creatinine (CREATIN), aspartate aminotransferase (AST), alanine aminotransferase (ALT), sodium (SODIUM), C-reactive protein (CRP), urine density, urine leukocyte.

Evaluation of dehydration

Various scales combining different signs and symptoms have been developed, including the clinical dehydration scale (CDS), the World Health Organization (WHO) scale, and the Vesikari scale. However, evidence regarding the superiority of any of these scales in the literature is conflicting (Rinder et al., 2014). Therefore, different practices regarding the use of these scales among pediatric physicians in our hospital are observed. The most accurate method for assessing dehydration is to calculate the percentage of weight loss (Rinder et al., 2014). Adhering to these criteria in prospective studies is easy, but retrospective studies encounter significant challenges such as missing records and data. In our study, it was found that most infants and children presenting to the pediatric department and ED did not have records of their recent weights. As clinical records for dehydration were not accessible from our hospital automation system, a table related to these scales could not be constructed. This limitation constitutes one of the constraints of our study.

Inclusion and Exclusion Criteria 1.

Inclusion criteria (RVGE): •

We included all inpatients aged 0–18 years admitted from January 01, 2022, to November 24, 2023, who attended at pediatric ward owing to RV.

•

Patients who were admitted and discharged from the ED, those who required IV hydration therapy owing to RV, without attending another ward.

Exclusion criteria (RVGE):

Over 18 years old at time of admission.

Patients who followed up as outpatients from the pediatric polyclinics.

Patients who were admitted and discharged from the ED without requiring any IV therapy or only undergoing observation.

(NOTE: The patients with RV were divided into two groups based on age: 0–5 years and 6–18 years.)

Inclusion criteria of the healthy children group: •

Similar age-gender-number groups were admitted to the pediatric outpatient clinics and had no acute no chronic and no genetic diseases [Diagnosed with Z00.1 (Routine child health examination) according to the ICD coding system].

Exclusion criteria of the healthy children group: •

Over 18 years old

•

Any acute or chronic disease [Subsequently, the e-Nabız patient information system of the Ministry of Health (https://enabiz.gov.tr/) was accessed to identify and exclude patients with acute and chronic illnesses.]

Source of comparative data (studies presenting data from countries compared with our study)

For literature review, we used the Google Scholar and PubMed databases. The RV vaccine has been integrated into the national vaccination schedules of many countries in the region of the Americas (AMRO) since 2006. Among studies on RV conducted after 2006, we searched for those simultaneously containing information on both LOS and hospitalization rate. However, we observed a limited number of studies addressing both variables in countries within AMRO (Table 1). Furthermore, we found no study that simultaneously presented these three search criteria: “vaccination rate, hospitalization rate, and length of hospital stay.” Therefore, our study stands as a rare instance presenting all three of these data points concurrently with laboratory parameters.

Table 1.

Comparing European and American Countries in Terms of RVGE

WHO region	Country	Authors	Age (Year)	Number of patients hospitalized owing to rotavirus İnfection	Total AGE Cases	Rotavirus hospitalization rates among all-cause gastroenteritis hospitalizations	LOS (Day)
EURO	Netherlands	Bruijning-Verhagen et al., 2012	0–18	58	936	6.2%	4.2
EURO	Sweden	Rinder et al., 2014	0–5	604	1549	38.9%	6.9
EURO	Italy	Dona et al., 2016	0–5	3	460	16.3%	0.67
EURO	Germany	Pietsch and Liebert, 2019	0–5	847	9557	8.8%
EURO	Spain	García-Magán et al., 2014	0–5	27	51	53%	6.7
EURO	France	Parez et al., 2014	0–5	186	755	64.4%	3.8
EURO	UK	Heinsbroek et al., 2019	0–15	16	272		5.0
EURO	Turkey	Our study	0–18	102	6361	26.1%	3.6–4.3
AMRO	Canada	Morton et al., 2015	0–5	8976 (total of 5 years)	400313 (total of 5 year)	2.2%	2
AMRO	United States	Desai et al., 2012	0–5	212077 (total of 10 years)	1153300 (total of 10 year)	18.3%	2.2–2.6
AMRO	El Salvador	de Palma et al., 2010	0–2 year	251	863	29%	2
AMRO	Nicaragua	Patel et al., 2009	0–2	285	1615		3
AMRO	Brazil	Gurgel et al., 2009	0–10	59	534	5%

The patient numbers in the study by Heinsbroek et al. were referenced based on postnational vaccination data; prevaccination data was not included.

LOS, lengths of stay; RVGE, rotavirus gastroenteritis.

Statistical analysis

The data obtained within the scope of the research were analyzed using SPSS for Windows (Version 20.0, Statistical Package for Social Sciences) software. Computer-assisted data analysis programs were used for basic analyses of research data (correlation, frequency). The distribution of the data was examined using the Kolmogorov–Smirnov test to check for normality. The results indicated that the data did not follow a normal distribution. The comparison between the blood values of the two groups (RV and control group) was analyzed using the Kruskal–Wallis H-test for continuous variables and Spearman correlation for correlation analysis. The relationship between categorical variables was examined using the chi-square test. The study analyses were conducted at a 95% confidence interval, and significance level was set at p < 0.05.

Results

Over a 2-year period, a total of 6361 AGE admissions to our hospital among individuals aged 0–18 years were identified based on diagnostic codes. The majority of these cases were managed with outpatient treatment services. However, it was found that hospitalized AGE cases in the pediatric ward of our hospital totaled 390. Of these cases, 102 hospitalizations were recorded for RVGE. The annual average hospitalization rate for AGE and RVGE, calculated per 10,000 people, was 41.1 and 10.76, respectively. No cases of mortality related to RVGE were identified during the study period. Out of a total of 6361 admissions for AGE, 410 were identified as severe cases of RVGE as defined in the Methods section. Thus, the annual incidence of severe RVGE among total AGE cases requiring intervention was calculated to be 6.45%.

In our cohort, out of a total of 410 patients, 56 individuals have been vaccinated against RV. Therefore, the vaccinated incidence rate can be approximated as 13.66%. It was determined that out of the 102 hospitalized patients, only 18 (17.6%) were vaccinated. The mean length of hospital stay for vaccinated patients was 4.3 days, whereas for unvaccinated patients, it was also 3.6 days. The Mann–Whitney U-test yielded a test statistic of −0.87 with a corresponding p value of 0.37. These findings suggest that there is no substantial difference in the length of hospital stay between vaccinated and unvaccinated patients (Table 2).

Table 2.

Relationship Between Length of Hospital Stay and Vaccination Status (Day)

	Vaccinated (n = 18)	Unvaccinated (n = 84)
Feature	Median (Min–Max)	Median (Min–Max)	Test^a	p
Length of hospital stay (Day)	3.5 (1–11)	3 (1–10)	−0.87	0.37
	Mean ± SD	Mean ± SD
	4.3 ± 2.61	3.65 ± 1.94

Mann–Whitney U-test.

When comparing group blood values, variations in AST, ALT, and CRP were observed, showing higher levels in both the RVGE group (p < 0.001). Our study found significantly elevated urea levels in RV patients compared with healthy controls in both age groups (p < 0.001). In addition, low sodium levels were associated with RV patients compared with healthy controls in both age groups (p < 0.001) (Table 3). When comparing group urine values, urine density was significantly higher in children over 5 years old (p < 0.001). Conversely, no significant difference was observed in urinary leukocyte values between the groups (p > 0.05) (Table 3).

Table 3.

Comparison of Blood Values Among Groups

	Rotavirus (0–5 Years)	Rotavirus (6–18 Years)	Healthy-control group
Feature	Median (Min–Max)	Median (Min–Max)	Median (Min–Max)	Test^a	p
HB	11.95 (7–15.3)^a	13.1 (10.8–16.3)^b	13.33 (4.51–17.9)^b	36.23	0.00
MCV	77.05 (56.3–87.7)^a	81.6 (60.6–89.9)^a	84.55 (56.3–96.6)^b	79.13	0.00
RBC	4.76 (3.63–5.85)^ab	4.9 (4.25–6.1)^a	4.79 (2–8.9)^b	6.35	0.04
WBC	8300 (2900–17400)^a	8400 (3600–24000)^a	295 (0–1346)^b	215.59	0.00
Trombosit/1000	306 (154–662)	307 (133–469)	276 (35–560)	5.40	0.07
URE	29 (6–68)^a	29 (13–48)^a	22 (6–55)^b	41.09	0.00
CRE	0.3 (0.1–0.6)^a	0.5 (0.3–0.9)^b	0.6 (0.1–1.13)^c	121.35	0.00
AST	41 (7–143)^a	32 (14–55)^a	19 (7–75)^b	141.12	0.00
ALT	21.5 (0.4–109)^a	21 (9–62)^a	14 (3–74)^b	43.24	0.00
SODIUM	137 (123–143)^a	138 (123–142)^a	140 (124–166)^b	61.87	0.00
CRP	7 (0.1–173.8)^a	8.5 (0.1–268.3)^a	3.39 (0–145.8)^b	40.92	0.00
Density (Urine)	1021.5 (1000–1047)^ab	1029 (1004–1040)^a	1020 (1000–1053)^b	20.38	0.00
Leukocyte (Urine)	0 (0–130)	0 (0–255)	0 (0–903)	2.88	0.24

Kruskal–Wallis H-test.

a–c

There is no significant difference between groups with the same letter.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; HB, hemoglobin; CRE, creatinine; MCV, mean corpuscular volume; PLT, platelet; RBC, red blood cell; SODIUM, sodium; URE, urea; WBC, white blood cell.

Discussion

Our study examined urinary density and urinary leukocyte parameters. It was found that urinary density was higher in the RV (6–18 years) group (p < 0.01). We could not find a study conducted after 2000 that investigated this relationship in pediatric patients. However, a study conducted in Poland reported that urinary tract infection could develop in 34% of RVGE patients (Nitsch-Osuch et al., 2013).

In our study, normal levels of WBC were observed in patients with RV. A study conducted in Macedonia confirmed that an increase in WBC is not expected in uncomplicated cases (Stojkovska et al., 2013). However, a recent study in the Western Pacific Region reported high levels of WBC and CRP values (Indrawan et al., 2023). These findings, although consistent with the high CRP levels in our study’s RVGE patients, do not align with our normal WBC levels.

The transaminase levels we found, although higher compared with the healthy control group, were at the upper limit of the reference values. A recent study conducted in Turkey also yielded similar results (Kılıcaslan et al., 2022). In addition, we examined urea and creatinine values in our study. We found that, in RVGE patients, there was no significant difference in creatinine levels compared with the healthy normal group, but there was a significant increase in urea levels (p < 0.01). A study conducted in Germany found elevated urea levels, whereas elevated creatinine levels were detected in approximately 1% of patients (Kaiser et al., 2012). Moreover, a recent study in Israel observed a decrease in urea and creatinine values in the postvaccination patients (Zaitoon et al., 2022). The connection between liver enzymes and kidney metabolites hints at RV’s potential systemic impact, extending beyond the gastrointestinal system. The association between liver enzymes and kidney metabolites suggests that RV may affect various systems in the body beyond its impact on the digestive system. These multisystemic effects lead to numerous ED visits and hospitalizations every year.

In our study, we found the hospitalization rate for RVGE to be 26.1% of total AGE hospitalization. In European countries, these rates have been found to range from low to high as follows: in the Netherlands, 6.2%; in Germany, 8.8%; in Italy, 16.3%; in Sweden, 38.9%; in Spain, 53%; and in France, 64.4%, as reported in previous studies (Bruijning-Verhagen et al., 2012; Dona et al., 2016; García-Magán et al., 2014; Pietsch and Liebert, 2019; Parez et al., 2014; Rinder et al., 2014). Although the lowest rate was observed in the Netherlands in Europe, there was a particular situation hindering the accurate estimation of disease burden in the country. During the period of the study, many hospitals in the Netherlands did not apply ICD coding. This raises questions about the accuracy and validity of disease burden estimates in the Netherlands (Bruijning-Verhagen et al., 2012). When we look at AMRO, hospitalization rates range from low to high as follows: in Canada, 2.2%; in Brazil, 5%; in the USA, 18.3%; and in El Salvador, 29% (Desai et al., 2012; de Palma et al., 2010; Gurgel et al., 2009; Morton et al., 2015). In addition, in these studies, except for Italy, longer hospitalization durations were observed in the EURO region compared with the AMRO region.

The rate of 26.1% for hospitalization rate found in our study is quite reasonable compared with the rates ranging from 6.2% to 64.4% in EURO region and 2.2% to 29% in AMRO region. It is important to examine the rates of RV vaccination to understand how countries achieve these values. It is important to examine the extent to which RV vaccination rates contribute to these values. According to the World Health Organization, Germany has a vaccination rate of 68%, Italy 74%, Sweden 82%, Canada 87%, USA 77%, Brazil 77%, El Salvador 76%, and Nicaragua 92% for RV. However, vaccination rates for France, Spain, and the Netherlands are not provided (Available at: https://apps.who.int/gho/data/node.main.ROTACn). In contrast, in our study, we found that the vaccination rate among the main cohort was 17.6%.

In addition, Spain, unlike other European countries, did not reintroduce the RV vaccine into the national vaccination program after removing it. In a more recent study conducted in Spain, a more reasonable rate (15–20%) was reported. However, it is crucial to emphasize the following to avoid misconceptions about the RV vaccine: The same study reported an increase in RVGE and AGE hospitalizations in Spain in the years following the cancellation of the RV vaccine (Díez-Domingo et al., 2019). Turkey and Spain, where vaccination is not mandatory, have quite reasonable hospitalization rates compared with other EURO and AMRO countries where vaccination is mandatory. We suggest that maintaining the national vaccination rate above a certain level can lead to reasonable hospitalization rates. In particular, determining the minimum vaccination rate to trigger herd immunity will be a significant factor in the RV vaccination programs of low-income countries.

Our study found that although 17.6% of the 102 hospitalized patients were vaccinated, 13.66% of the 410 patients receiving IV hydration therapy were vaccinated. It was observed that as the vaccination rate decreased, the number of emergency admissions requiring intervention cases could increase. A study conducted in Brazil found that as the vaccination rate increased, the rate of stool samples containing RV and the number of patients presenting to the ED decreased (Gurgel et al., 2009). Similar results have been observed in studies conducted in El Salvador, France, and Nicaragua (de Palma et al., 2010; Parez et al., 2014; Patel et al., 2009). Therefore, it is important to accurately determine the minimum national vaccination rate that we believe can trigger herd immunity (Seybolt and Bégué, 2012). More prospective studies are needed to achieve this goal.

Conclusion

The findings of this study shed light on the hospitalization rates, length of hospital stays, infection severity, and laboratory parameters of RV infections in pediatric patients, particularly in the context of Turkey’s nonmandatory vaccination policy compared with the mandatory vaccination policies in Europe and America. By comparing RV infections in settings with differing vaccination policies, our findings contribute to the global discourse on vaccination strategies and disease control.

Footnotes

Authors’ Contributions

Y.D.: Data curation, project administration, resources, and writing—original draft. B.D.: Data curation and investigation. I.K.E.: Supervision and validation. S.E.: Data curation and writing—review & editing. E.S.: Methodology and data curation. E.D.: Data curation and formal analysis.

Ethical Considerations

The study strictly adhered to the ethical principles outlined in the Declaration of Helsinki. Approval for the study was granted by the Karabük University Local Ethics Committee (Decision No: 2023/1563).

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Supplemenatry Material

Supplementary Table S1

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