Rotavirus infection is the leading cause of hospitalization for acute gastroenteritis (AGE) in Europe and, each year, is responsible for a considerable burden on healthcare systems, society, individuals, and families.1–12 A recent prospective, observational study in 7 European countries has shown that the proportion of children hospitalized with AGE who tested positive for rotavirus ranged from 53% in Spain to 69% in Italy.1 A recent estimation also suggests that rotavirus infection is responsible for about 200 deaths annually in Europe.13 Although this figure is low compared with the number of rotavirus-related deaths in the lowest income countries (approximately 520,000 deaths per year),14 it remains unacceptable given the standard of medical care in Europe.
In 2006, 2 new live attenuated rotavirus vaccines, effective against severe rotavirus disease, were licensed for use in Europe (Rotarix, GlaxoSmithKline Biologicals, Rixensart, Belgium; and RotaTeq, Sanofi Pasteur-MSD, Lyon, France). To assist policy makers when deciding on vaccination strategy, information about risk factors for severe rotavirus gastroenteritis (RVGE) is needed.
Many viral and bacterial agents have definable risk factors that predict progression to severe disease, including immunodeficiency or preexisting conditions. This review will focus on animal and human clinical investigations that examine the evidence for risk factors to predict the outcome of rotavirus infection. Two issues will be addressed: whether the severity of rotavirus disease is influenced by certain social and physical factors, and whether rotavirus infection may cause, or exacerbate, other serious conditions in children, such as intussusception, celiac disease, and diabetes mellitus.
MATERIALS AND METHODS
MEDLINE abstracts between 1996 and 2006 were searched using “rotavirus” and “malnutrition,” “celiac disease,” “gastrointestinal disease,” “extraintestinal disease,” “inflammatory bowel disease,” “diabetes mellitus,” “autoimmune disease,” “intussusception,” “malignancy,” “leukemia,” “bone marrow transplantation,” “organ transplantation,” “immunodeficiency,” “HIV,” “AIDS,” “neonate,” “prematurity,” “brain,” or “animal model.” Using these search terms, a list of 435 references was generated. The abstract for each reference was reviewed to identify those of potential relevance to this article (n = 66). Any additional sources were identified from the bibliographies of these references or from the authors’ own libraries and expertise.
Risk Factors for Severe Rotavirus Disease
This survey of the literature has revealed a number of risk factors that may predict progression of rotavirus infection to severe disease, including hospitalization and death.
Social factors contributing to the outcome of rotavirus disease have been examined in 2 case-control studies.15,16 A small association was found between hospitalization and male gender [odds ratio (OR): 1.4; 95% confidence interval (CI): 1.0–1.9], and indicators of economic disadvantage, for example Medicaid insurance (OR: 1.5; 95% CI: 1.0–2.1). Maternal age <20 years (OR: 1.1; 95% CI: 0.7–1.8) and maternal smoking (OR: 1.1; 95% CI: 0.8–1.7) were not statistically associated with rotavirus hospitalization. In another study, living in rented council housing (adjusted OR: 3.8; 95% CI: 1.2–11.9) and having contact with someone ill with infectious intestinal disease (adjusted OR: 3.6; 95% CI: 1.9–6.8) were risk factors for RVGE in children younger than 16 years in England.16 Interestingly, attending nursery/daycare was not a risk factor for developing RVGE (unadjusted OR: 0.83; 95% CI: 0.3–2.7).16 In contrast, other investigations have found that children (<5 years old) attending daycare in Europe have a higher incidence (1.21 per 1000 child-days in children younger than 4 years) of RVGE than the estimated incidence in the general population of European children of the same age (0.43 per 1000 child-days).13,17–23
An investigation of 928 children younger than 5 years hospitalized in Bangladesh found, after controlling for the effect of confounding cofactors, nonbreast-feeding was a risk factor for AGE (all cause) death (adjusted OR: 4.2; 95% CI: 1.3–13.2).24 Similar findings have been reported in other studies in developing countries.25–27 However, the case is less clear in developed regions, such as Europe. A small study in England found that bottle-feeding, with or without supplementary breast-feeding, was associated with an increased risk of RVGE (adjusted OR: 9.1; 95% CI: 1.1–76.6).16 These findings imply that exclusive breast-feeding of infants is protective against rotavirus disease.16 However, a Finnish study found that the protective effect of breast-feeding was only transient, and the effect was lost upon termination of breast-feeding.28
Both animal and human studies have suggested that malnutrition may contribute to the severity of rotavirus disease.24,29–31 In an animal model designed to assess factors aggravating the course of rotavirus infection in humans, 2-day-old malnourished piglets infected with rotavirus experienced intestinal inflammation and diarrhea lasting for longer than fully nourished piglets (significant difference in diarrhea score at day 16, P < 0.001).30,31 Furthermore, prolonged diarrhea in malnourished piglets was associated with a more intense and extended expression of local mediators and markers of intestinal inflammation compared with infected, nourished piglets (eg, major histocompatibility complex class I gene expression, intestinal prostaglandin E2 concentrations). Plasma insulin-like growth factor (IGF)-1 levels, villus height, and alkaline phosphatase activity (a marker for small intestine damage) remained reduced in malnourished pigs, suggesting that malnutrition hampers regeneration of intestinal villi.30 Vitamin A deficiency, common in malnourished infants, was also shown to aggravate the course of rotavirus infection in a mouse model.32 In vitamin A deficient, rotavirus-infected mice the glandular area was smaller (P < 0.05) and viral excretion lasted longer than in nondeficient controls.32 These experimental findings add to the body of evidence suggesting that malnutrition typically intensifies the duration of illness from rotavirus infection, delays intestinal recovery, and interferes with growth.
Malnutrition is a well-known risk factor for diarrheal diseases in humans,24,33,34 though reports are conflicting as to whether it contributes to increased severity of rotavirus infection. Black et al found that children who are small because of young age and/or malnutrition lost a greater proportion of their total body fluid during diarrhea and speculated that they may be expected to have a higher frequency of severe dehydration and death.35 This finding is supported by a study in Egypt, which found a longer duration of diarrhea, more diarrhea episodes, and a higher incidence of vomiting and dehydration in malnourished children compared with well-fed children; rotavirus was the causative agent in 52% of diarrheal cases.36 In contrast, a study of hospitalized children in Zambia, found that rotavirus infection was more common in children with a normal nutritional status (27.6%) than in undernourished children (19.3%).37 Similarly, an investigation of children in Bangladesh found that although severe malnutrition was a risk factor for diarrheal death (adjusted OR: 84.2; 95% CI: 9.1–775.9), rotavirus as a cause of diarrhea was not associated with a fatal outcome (OR: 0.11; 95% CI: 0.02–0.5; P < 0.004).24
Malnourished mothers have normal concentrations of neutralizing antibodies against rotavirus in their milk, but produce a daily volume of milk about 30% lower than well-nourished women, leading to a lower provision of antibodies to their children.29 In another study, rotavirus antibody titers were assessed in 200 Kenyan schoolchildren who had a high prevalence of apparent biochemical micronutrient deficiencies and stunting.38 Most children examined during the 2-year study had elevated antibody titers to rotavirus (>1:8; 86.3%), indicating that children develop a significant antibody-mediated response to rotavirus despite malnutrition. However, a study of rhesus-human reassortant tetravalent rotavirus vaccine (RotaShield, Wyeth-Lederle Vaccines, Radnor, PA) in malnourished infants in Brazil showed that the vaccine had a reduced efficacy compared with those who were well-nourished (43%, P = 0.05 for height-for-age z score >−1).39 On the basis of these studies, malnutrition may well contribute to a severe course of rotavirus infection. It is likely that this is caused by an impaired cellular immune response, as a reduced intake of protein calories is known to suppress cell-mediated immunity before antibody responses.40–42
Premature Infants and Neonates
A significant association was found in the United States (U.S.) between hospitalization for RVGE and low birth weight (1.5–2.49 kg; OR: 2.0; 95% CI: 1.2–3.5); however, a similar association was not found for very low birth weight (<1.5 kg; OR: 1.4; 95% CI: 0.3–5.8).15 Neonates and prematurely born infants are highly susceptible to nosocomial-acquired rotavirus infection.43,44 A retrospective, hospital-based study in Germany revealed that 2% of 1886 rotavirus-positive stool samples were from premature neonates with community-acquired infection, whereas 26% of rotavirus-positive samples in this age group were acquired nosocomially.43 Infants infected with rotavirus while in hospital typically have their stay extended by 1.7–5.9 days.45
There is evidence that nosocomially-acquired rotavirus infection in neonates may be milder and provide protection from severe gastroenteritis, thus providing a kind of natural vaccination against severe rotavirus disease later in infancy.46 However, for premature infants and neonates being cared for in neonatal intensive care facilities, there is evidence that rotavirus infection may take a more severe course. A prospective, longitudinal study in a neonatal intensive care unit in the U.S., found that neonates testing positive for rotavirus (49%) experienced more frequent passage of watery stools (P = 0.023) and a higher percentage of bloody mucoid stools (P = 0.003) than neonates without rotavirus infection.47 Premature infants had an increased frequency of bloody mucoid stools (P = 0.001), abdominal distension (P = 0.03), and intestinal dilatation (P = 0.016), compared with full-term infants. A study from a German neonatal care unit compared cardiac and respiratory profiles among neonates with and without rotavirus infection.44 Neonates with rotavirus infection were more likely to have bradycardia (33% versus 8%; P < 0.001), apnea (7% versus 0%; P < 0.05), and cyanosis after bradycardia (11% versus 0%; P < 0.05), and were more likely to have a subsequent intervention (31% versus 14%; P < 0.05) than neonates with rotavirus-negative stools. The authors interpret this finding as possible central nervous system (CNS) involvement in rotavirus infection.44 However, an alternative explanation might be that a condition leading to bradycardia or apnea episodes might also predispose to symptomatic rotavirus infection.
Children who are immunosuppressed after transplantation may be at risk for rotavirus infection with increased severity. A study in the United Kingdom described 21 patients (aged 7 months to 32 years) with rotavirus infection who had undergone allogeneic stem cell transplantation.48 These patients had a longer median duration of illness (15 days; range, 4 days to 4 months) than nonimmunocompromised hosts (∼7 days) and 18 of them (86%) required hospitalization. In another study, disease course was examined in 4 patients (6 months to 71 years) with rotavirus diarrhea after solid organ transplantation.49 Infections were self-limiting; however, all 4 patients developed other relevant infectious complications, which significantly increased their duration of hospital stay. In contrast, a prospective study in South India observed that rotavirus infection within 4 weeks of allogeneic bone marrow transplantation was not associated with an increased rate of mortality, unlike bacterial gastrointestinal infections.50 Based on these findings, patients with primary, acquired, or iatrogenic immunodeficiency occasionally show signs of severe disease because of rotavirus infection.
Human Immunodeficiency Virus (HIV) Infection.
A study in Venezuela compared infection with enteric viruses in stool samples from 27 HIV-seropositive children with 38 HIV-seronegative children.51 Rotavirus was detected less frequently in HIV-positive children than HIV-negative children although this difference did not reach significance (5% versus 8%; P = NS). Similar findings were reported in a Malawian study.52 At follow-up, children with HIV infection more frequently shed rotavirus in their stools, but this was not associated with diarrhea.52 Of 125 stool samples from HIV-infected adults in Venezuela examined for enteric viruses associated with gastroenteritis, none were positive for rotavirus.53 These data suggest that an association between incidence or severity of rotavirus infection in patients with HIV is unlikely. In contrast, a study in Peru found rotavirus to be significantly associated with persistent diarrhea (≥7 days’ duration) in HIV-positive patients compared with HIV-negative controls (12 versus 0 cases, respectively).54 In another study, rotavirus infection was identified in stool samples from 9 of 377 HIV-positive patients and was associated more often with acute, as opposed to, chronic, diarrhea (67% versus 33%, respectively); unlike some other viruses, including adenovirus.55 Nevertheless, on the basis of all the evidence, asymptomatic and mildly symptomatic HIV infection does not seem to influence the outcome of rotavirus infection. On the other hand, in developing countries, HIV infection in children is often associated with severe malnutrition and chronic diarrhea. Although specific data are not available, it is possible that rotavirus infection in an already severely immunocompromised child can exacerbate the disease course.
Two studies were identified that related malignancy to rotavirus disease.56,57 Of 18 children (aged 1–69 months) with juvenile myelomonocytic leukemia who were screened for viral infection, 1 patient was infected with rotavirus, although infection did not affect his clinical status.56 A retrospective, case-control study of pediatric cancer patients with and without rotavirus antigens observed that the patients with rotavirus infection spent a prolonged period in hospital (median, 8 versus 4 days; P = 0.008), and more rotavirus-positive patients required parenteral nutrition and tube feeding (P < 0.001).57
Rotavirus infection has been associated with CNS complications, including convulsions and encephalopathy.58–65 Many of these cases occurred in infants who were previously healthy.58–64 A review of hospital databases in the U.S. showed that <4% of rotavirus hospitalizations were associated with serious CNS symptoms,61 though a causal relationship between rotavirus infection and encephalopathy has not been established. A retrospective review of all in-patient records of children admitted into a pediatric hospital in Hong Kong, revealed no other risk factors for the development of AGE-related encephalopathy other than a positive stool culture, whether bacterial or viral (especially rotavirus).58
A possible association between cardiac disease and rotavirus infection was examined by viral analysis of myocardial tissues in patients who suffered sudden, unexpected death. This study revealed that rotavirus antigens were present in 4 of the 13 patients (aged 2–67 years) who were studied.66 Two of the rotavirus-positive cases were adults who had preexisting cardiac disease. No other studies were identified that could confirm any association with cardiac disease and a severe course of rotavirus infection.
Viral illness has been associated with gastroparesis, a clinical entity characterized by symptoms related to a delayed gastric emptying into the duodenum in the absence of mechanical obstruction. In a study by Sigurdsson et al, 8 (aged 5–30 months) out of 11 children suffering persistent gastroparesis after acute viral illness tested positive for rotavirus in their stools.67 All children were previously healthy and recovered within 6–24 months. No other gastrointestinal diseases were found to be risk factors for developing rotavirus disease, or experiencing a severe disease course.
Rotavirus Infection as a Contributing Factor to Other Conditions
Rotavirus infection has been proposed to act as a contributing factor to the development of certain conditions, such as intussusception, autoimmunity, gastrointestinal disease, and immune deficiency. This section will discuss the evidence published around these claims.
Withdrawal of the rhesus-human reassortant tetravalent rotavirus vaccine (RRV-TV), RotaShield, because of a suggested link with intussusception,68,69 raised the question of whether wild-type rotavirus was associated with the development of this condition in infants. Several detailed animal and clinical studies have been carried out to investigate this possibility.70–78
A large study of more than 500 infants in Australasia found a higher incidence of intussusception in Vietnam (302 per 100,000 infants <1 year of age) than Australia (71 per 100,000 infants <1 year of age).70 Although there was a strong association between intussusception and adenovirus infection at both study sites, no association between intussusception and rotavirus infection was found. A further study in Singapore found that, unlike rotavirus infections, there was no seasonal variation in the incidence of intussusception, suggesting a lack of association between the 2 events.71 Similar results were obtained from New Zealand,72 Southern California,73 Australia,74 Hong Kong,75 Chile,76 Venezuela,77 Mexico,78 and England.79 However, other studies have found conflicting results. A single study in France observed a significant seasonal peak of intussusception in spring, comprising 37% of all cases of intussusception.69 Nakagomi found that G3 rotaviruses are associated with intussusception in some susceptible infants, suggesting that the incidence of intussusception may be higher in years with a relative frequency of G3 strains.80 Furthermore, during the period that RotaShield vaccine was used in the U.S. (1998–1999), Simonsen et al found a net decrease in rates of hospital admission for intussusception among children younger than 365 days in 10 states with a high use of rotavirus vaccine (mean, 28% coverage among birth cohort), compared with the previous year and the preceding 5-year period.81,82 A subanalysis also found that hospital admissions for rotavirus fell by 3% in 14 high-use states (17% coverage) relative to the previous year.83 In contrast, there was a modest overall increase in intussusception hospital admissions in 6 low-use states (4% coverage), relative to the previous year.
Although no strong epidemiological association between rotavirus infection and intussusception has been found, an ultrasound study found an increased distal ileum wall thickness and lymphadenopathy during rotavirus infection in infants, suggesting a plausible pathogenic mechanism.84 In a mouse model, 2 murine wild-type homologous rotavirus strains and 2 simian heterologous rotavirus strains enhanced the rate of intussusception in the presence of lipopolysaccharide; this was dependent on the replication of rotavirus and required doses greater than 50% of infectious dose.85 The intussusception-inducing effect was mediated via inflammatory markers including tumor necrosis factor-α and interferon-γ, sensitizing the gut to lipopolysaccharide. Rotavirus-induced intussusception cases had no observable lymphoid lead points. Furthermore, rotavirus infection had no effect on gastrointestinal transit time. In another animal model, reassortant rotavirus of neither simian nor bovine origin had the capacity to cause lymphoid hypertrophy or hyperplasia of Peyer's patches, which is often associated with intussusception.86 Nevertheless, infectious virus was detected in Peyer's patches and mesenteric lymph nodes after oral inoculation with simian reassortant rotaviruses, though this was not the case for bovine reassortant rotaviruses.
With the available epidemiological data revoking a link between rotavirus infections and intussusception, and there being no evidence for an association with intussusception from large-scale clinical studies87,88 or field use of new human and bovine human rotavirus vaccines in infants,89 the implications of these findings from animal models are unclear. Continued surveillance for this potentially serious condition is warranted.
Rotavirus infection has been linked with the development of certain autoimmune diseases in humans. In a study from Peru it was found that intestinal permeability was increased for up to 20 days after rotavirus infection in children younger than 36 months.90 This finding raised the possibility that rotavirus could contribute to the pathogenesis of certain gastrointestinal conditions, such as celiac disease. Zanoni et al identified a peptide which was recognized by patients with active celiac disease, but not by patients on a gluten-free diet.91 In patients with active celiac disease, a subset of antitransglutaminase IgA antibodies recognize rotavirus viral protein 7 (VP7), suggesting a possible involvement of rotavirus in the pathogenesis of celiac disease through molecular mimicry. Moreover, such antibodies also recognize the self-antigens, tissue transglutaminase, heat shock protein 60, desmoglein 1, and Toll-like receptor 4, which are functionally active and are able to increase intestinal permeability and induce monocyte activation.91 In another prospective study of 1931 children carrying celiac disease human leukocyte antigen risk alleles, 54 children (2.8%) developed celiac disease autoimmunity, defined as positivity at 2 or more subsequent clinic visits for tissue transglutaminase autoantibodies.92 Two or more infections with rotavirus carried an increased risk of developing celiac disease autoantibodies, though the association was not statistically significant (adjusted rate ratio of 3.24, 95% CI: 0.39–27.3). The suggested link between rotavirus infection and the development of celiac disease needs to be further evaluated in cohort studies and, eventually, the possible protective role of rotavirus vaccine.
Another chronic disease which may be associated with rotavirus infection is type 1 diabetes; however, conflicting data regarding this association have been published.93–97 In a T-cell proliferation study, the dominant epitope of tyrosine phosphatase, IA-2, (a molecular target of pancreatic islet autoimmunity in type 1 diabetes), was found to show homology with a sequence of the rotavirus VP7.93 The authors suggested that T-cell activation by rotaviruses could therefore trigger or exacerbate β-cell autoimmunity through molecular mimicry with IA-2. In another study from the same group, there was a highly significant association between seroconversion for rotavirus and increases in islet antibody levels, most strongly with IA-2, then insulin and glutamic acid decarboxylase antibody, further supporting this hypothesis.94 In vitro rotavirus can infect pancreatic islet cells of mice.98 Furthermore, other members of the reovirus family can infect β cells causing cytolysis.99 Thus, possible mechanisms whereby rotavirus infection contributes to induction of diabetes in predisposed hosts might be destruction of pancreatic β cells, release of β-cell antigens inducing autoimmunity, or presentation of rotavirus antigens in conjunction with autoantigens on infected β cells.100
In contrast, a prospective study with newborns carrying human leukocyte antigen-DQB1 alleles, which are associated with increased risk of type 1 diabetes, found no association between rotavirus infection and development of autoantibodies.95 Of 27 infants who developed 2 or more of the 4 diabetes-associated autoantibodies at 24 months of age, 19% had rotavirus infection, compared with 28% of infants without diabetes-associated autoantibodies. Furthermore, in a study by Makela et al, T-cell responses to rotavirus were not significantly different in children with newly diagnosed type 1 diabetes and controls.96 A follow-up to this study showed that the concentration of insulin-binding autoantibodies was greater in children after rotavirus infection, compared with children who had not been infected.97 It was suggested that rotavirus infection enhances the immune response to insulin, which is induced primarily by bovine insulin in cow's milk.
Rotavirus infection has been associated with worsening of chronic inflammatory bowel disease such as Crohn's disease and ulcerative colitis. In a study of 87 patients with gastrointestinal disease, exacerbations of their condition were reported in 54 patients; 3 of these cases were related to rotavirus infection.101 Nevertheless, the authors concluded that common types of viral gastroenteritis do not represent a significant risk factor for the development of inflammatory bowel disease because of low infection rates in these patients. In a review article assessing the contribution of gastrointestinal pathogens to the development of chronic inflammatory bowel disease, no association with rotavirus infection was found.102
The effect of rotavirus infection on the outcome of conditions associated with immunodeficiency is unclear. In Malawian children, rotavirus infection did not affect blood HIV load or CD4+ cell counts.103 Findings from a study in Senegal with a large group of HIV-positive adults (n = 318) showed that, independent of HIV serostatus, patients with diarrhea (all causes) had lower CD4+ cell counts.104 Rotavirus was the causative agent in 8.2% of diarrhea cases in immunocompromised individuals.
Pneumatosis intestinalis is a severe complication commonly observed after solid organ transplantation. In a retrospective study of 116 thoracic organ transplant recipients, pneumatosis intestinalis was observed in 8 patients, representing an annual risk of 0.86%.105 Three of these patients also had rotavirus antigen isolated in their stools. Risk factors for pneumatosis intestinalis were high daily doses of steroids and tacrolimus. However, the risk factors in patients with rotavirus infection did not differ from those without.
Damage to the gut mucosa occurring during RVGE may allow rotavirus and enteric bacteria to leave the small intestine and enter the bloodstream.106 Bacteraemia secondary to RVGE has been described in previously healthy infants and neonates.106Enterobactercloacae and Klebsiella pneumoniae, members of the Enterobacteriaceae family that form part of the normal flora of the human intestine, were identified in blood culture in 3 infants and 1 neonate, respectively. Clinical symptoms were characterized by fever, either recrudescence of fever or new-onset fever in previously afebrile infants.106
This hypothesis is further supported by studies in neonatal rat and mice models in which rotavirus antigen and infectious virus were detected in multiple organs, though not in the brain.107,108 Data in children indicate that rotavirus routinely extends beyond the intestine into the blood. In a study of children (≤3 years of age) with rotavirus diarrhea, antigenemia was detected in 66 of 102 (64%) patients.109 However, no association was found between clinical symptoms/disease severity and the level of RNA in serum (r = 0.022; P = 0.911).109
Oliguria has been reported in association with rotavirus infection.110 After 7 days of RVGE and severe dehydration, a 13-month-old boy developed oliguria, which was caused by uric acid stones. This boy was previously healthy and did not display conventional risk factors for this condition including tumor, lymphoproliferation, and hypoxanthine-guanine phosphoribosyl transferase deficiency. It was also not caused by hypovolaemia. No further studies were identified that could confirm this possible link between rotavirus infection and oliguria.
Several social risk factors have been associated with rotavirus disease, but in most cases they are too widespread among European populations to focus prevention measures on particular risk groups. There is evidence to suggest that certain factors may increase the risk of a child developing severe rotavirus disease, including being born prematurely, requirement for neonatal intensive care facilities, low birth weight (1.5–2.49 kg), malnutrition, or immunosuppression (Table 1). 15,36,47–49,67 Currently, rotavirus vaccines cannot be targeted to these special populations of infants as the safety, immunogenicity, and efficacy have not been established. However, studies in neonates and HIV-positive children are underway.
A number of publications have suggested an association between rotavirus infection and the progression, or outcome, of other diseases, such as celiac disease, acquired immunodeficiency, and renal complications; however, many of these reports remain unconfirmed. Although rotavirus vaccination cannot be targeted specifically for such patients, the possibility that rotavirus infection may exacerbate other conditions strengthens the case for widespread childhood rotavirus vaccination to prevent rotavirus disease and possibly infection. The most appropriate strategy is to vaccinate all infants without discrimination, with a universal mass vaccination program beginning at the age of 6 weeks. This approach is particularly suitable for rotavirus vaccines given the short window in which the first dose can be given (between 6 and 12 weeks of age) and the unfeasibility of catch-up vaccination for those older than 12 months.
The authors thank Pediatric Rotavirus European Committee (PROTECT) members, Ulrich Desselberger, Elisabetta Franco, Emmanuel Grimprel, Zsófia Meszner, Jacek Mrucowicz, Carlos Rodrigo, and Vladimir Tatochenko, for their input. The contribution of Timo Vesikari was particularly valuable. We would also like to thank Alison Lovibond for medical writing assistance in the preparation of this manuscript.
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