Rotavirus (RV) infection is a major cause of infectious diarrhea in children worldwide. In developing countries, RV infections contribute considerably to morbidity and mortality among young children; 93% of the estimated 140 million annual RV episodes occur in children younger than 5 years of age, and 98% of the estimated 440,000 annual deaths from RV disease occur in developing countries.1
Although mortality from RV disease is very low in developed countries, community-acquired RV infections (CARV) are responsible for a significant morbidity, with a major impact on the total medical costs. There is also the risk of nosocomial RV (NRV) infections, which are a major component of hospital-acquired infections in children. However, medical costs associated with both CARV and NRV are still insufficiently documented, and they vary in different countries and organizations of the health care system.
This review article attempts to assemble existing information on the epidemiology, severity and costs associated with NRV disease in the 6 largest European countries (France, Germany, Italy, Poland, Spain and the United Kingdom) and highlights the importance of this viral pathogen for the overall burden of diarrheal infections.
MATERIALS AND METHODS
The burden of NRV infections is studied according to 5 main parameters: (1) the frequency of RV in nosocomial infections; (2) the epidemiology and clinical characteristics of NRV infections (describing clinical manifestations and transmission patterns, risk factors and seasonality, as well as incidence of the infections); (3) the severity of NRV infections (estimating morbidity, mortality and duration of hospitalization, as well as assessing the potential coinfections and complications); (4) the economic burden of NRV infections; and (5) the existing policies against hospital cross-infections (looking at existing surveillance systems and prevention procedures for nosocomial infections in Europe) and their potential effects.
Frequency of RV in Nosocomial Infections
The major burden of nosocomial infections occurs in the adult population, with nonviral infections representing the large majority of all nosocomial infections (85–95% of the total). Urinary tract (80% associated with the presence of a catheter), respiratory tract and surgical site are the predominant sites of infections, whereas gastrointestinal infections are less common.2–4 The most frequent agents are Gram-positive (eg, Staphylococcus spp., Streptococcus spp.) and Gram-negative (Escherichia coli, Klebsiella spp.) bacteria. Fungi (Candida spp. and Aspergillus spp.) also play a significant role in some settings.5
Very few studies have looked at the nosocomial infection rate in the pediatric population. Gastrointestinal and respiratory tract (upper and lower) infections are the 2 most common pediatric nosocomial infection locations, accounting for up to 65–90% of all pediatric hospital-acquired infections (with gastrointestinal infections occurring more frequently than respiratory tract infections).2,6–8 Viral nosocomial infections are predominant in children, with a rate ranging from 23 to 34%.6,9,10 Viruses account for 91–94% of all causes of pediatric nosocomial diarrhea, RVs being the single major etiologic agent (31–87% of cases).6,11–25 However, the role of other viruses (eg, noroviruses, astroviruses and adenoviruses) has been underestimated until recently because of limitations with diagnostic techniques, mainly lack of sensitivity and difficulty in handling.20,26–29 Specifically noroviruses have been shown to account for 17–46% of causes of nosocomial diarrhea among pediatric population in studies where they have been sought.9,16
Epidemiology and Clinical Characteristics of the Nosocomial Infections
Clinical Manifestations of NRV Infections.
NRV is generally introduced to pediatric wards after hospitalization of children with CARV and disease, and/or following a stay in the emergency room before hospitalization. NRV infections usually become apparent between the 2nd and the 6th day of hospitalization.6 Typical symptoms are fever (60–100% of cases), together with acute vomiting and diarrhea.6,30 RV excretion can begin shortly before the start of clinical symptoms and might be prolonged well after resolution of diarrhea (up to 57 days), although the period of transmissibility is limited to 2 weeks;31 excretion is longer in immunosuppressed patients.
Asymptomatic infection is frequent in neonates and young infants (younger than 3 months), ranging from 18 to 39% of all NRV cases.13,17,32–36 Several explanations have been brought forward to explain the limited expression of clinical symptoms in this population, such as specific strains of RV (“nursery strains”) or the presence of transitory maternally acquired immunity.
The main transmission mode of NRV is by contact, through a direct or indirect fecal-oral route.35,37 The infective dose is very small, and RV is excreted in very high amounts in stools of infected children, both elements contributing to the highly contagious nature of RVs.9,38 Vomiting can be another route of transmission, although rarely documented.39 Airborne transmission (through respiratory droplets) has been suggested but remains controversial,40,41 although it could explain, in some instances, the failure to document fecal-oral transmission during outbreaks of RV diarrhea.42
The main vectors of transmission are contaminated (mostly uninfected) health care workers; RVs are found on the hands of 76–78% of health care workers taking care of the children with CARV, and also on 20% of health care workers not taking care of children.11,35,37,43–45 The environment is a key reservoir of RV, with the virus able to survive for a few days on hands and from 1 to 10 days on dry and nonporous surfaces (eg, toys, medical tools) in a low humidity environment (<50%).43,46,47 The large share of asymptomatic carriage contributes to the spread of RV, given that no precautions are taken in the absence of (typical) symptoms.36,48
Risk Factors for NRV Infections.
A set of risk factors in otherwise healthy children has been associated with an increased risk of acquiring NRV infection. The first is the duration of hospitalization because the rate of NRV infection can rise to 70% if patients stay hospitalized for >6 days.30,35,49 Others risk factors are: young age,16,49 because of age-specific susceptibility to RV infection and the importance of nursing care and diapering;16 insufficient organization of pediatric services because of insufficient staff; limited respect of hygiene procedures; limited availability of disposable equipment;9,50,51 and the presence of a nonmedical population (including parents and relatives) on the wards (playing the role of either RV carrier or primary case in nosocomial transmission). Further underlying risk factors for NRV have also been identified: prematurity and low birth weight;9,52 severe immunodeficiencies; malnutrition; and other diseases (eg, bronchiolitis) associated with a prolonged duration of hospital stay.49,53–56
Seasonality of the RV Infections.
In Europe, RV infection has been described as highly seasonal, with most CARV and NRV outbreaks occurring during late autumn, winter and early spring (Fig. 1).6,19,21,30,50,53,57–64 In the United States, the RV epidemic follows a unique progressive wave from South West States towards North East States from winter to spring, with no clear explanation.65 An unexplained shift of the peak of RV epidemic activity from winter to early spring has been reported in Japan during the last 2 decades.66 This phenomenon was not observed with respiratory viruses [ie, respiratory syncytial virus (RSV) and influenza] or norovirus infections and has not been reported in other countries.
A difference in seasonality from South West (in autumn-early winter) to North and East (late winter-early spring) has been observed in Europe.67 Data on the seasonality of NRV from France and Poland showed an early nosocomial peak (in December and January, respectively).19,30 This could be explained by the acquisition of RV infection after hospitalization for RSV or influenza virus infections, both having a coincidental epidemic pattern with RV infection. In a Moscow pediatric infectious disease hospital, seasonality of nosocomial RV cases closely followed that of admissions of the RV infections.68
In very young children (younger than 4 months of age), the winter seasonality seems to be less pronounced, with cases of NRV occurring all year round (see pattern for Germany in children younger than 4 months of age in Fig. 1).58
Incidence of NRV Infections.
Five indicators have been analyzed to measure the incidence of NRV: (1) the number of NRV cases/number of hospitalizations for children; (2) the number of NRV cases/100,000 children; (3) the number of NRV cases/number of community-acquired RV infections followed by hospitalization; (4) the incidence of NRV per 1000 days of hospitalization; and (5) the total number of NRV cases (extrapolated from the incidence per 100,000 children or from the incidence per 1,000 days of hospitalization).
The resulting figures reveal a significant burden of NRV infections in the 6 European countries studied (Table 1), although wide variations were observed.13,14,19,36,50,51,58,69–77 NRV infections represent 0.3–27.7% of all hospital admissions, have an incidence ranging from 160 to 630 cases/100,000 children younger than 5 years of age, represent 1.6–15.8 per 1000 hospitalization days and account for a yearly estimate of 3000–20,000 RV infection cases in children younger than 5 years of age. However, the reported studies reveal a significant heterogeneity in methodology, which makes the extrapolation of the results from a single study to the entire country difficult, as well as the comparison between countries. Main variations in study parameters are: the size of samples; the nature of selected samples (eg, inclusion of all children admitted, or only children admitted during the day and/or the night) and type of ward (eg, general pediatric, surgical, reanimation); the target age groups (eg, all children younger than 5 years of age or younger than 2 years; or between 3 months and 2 years); the type of study (prospective versus retrospective); the delay before considering a diarrhea/gastroenteritis episode as hospital-acquired (varying from 24 to 72 hours after hospitalization); the recall of families after discharge from hospital to identify additional infections acquired at hospitals but declared at home; the duration of the studies (implemented only during RV epidemics or covering the entire year or several years); the focus on symptomatic cases only or consideration of both symptomatic and asymptomatic infections (or cases with no typical symptoms); the date/age of the study; and the type of hospital contributing to the study (eg, general hospital, pediatric hospital, general hospital with pediatric unit).
In addition, many limitations related to study parameters impact on the significance and comparability of the results and question their robustness (accuracy of reporting and relevance for today’s reality). Typical limitations are: small sample size; retrospective studies (instead of prospective) that rely on officially reported figures, and therefore underestimate largely the true rate of nosocomial infections in the absence of systematic detection of RV in cases of diarrhea/gastroenteritis, as well as the absence of a mandatory reporting system in any of the countries studies; the absence of recall of families after discharge from hospital, which leaves aside an additional 10–60% of NRV cases;13,17,18,28 and the time of publication of studies, older studies being less relevant than more recent ones, given the progress achieved in detection methods and in preventing nosocomial infections. Moreover countries are undergoing major changes in their health care systems, which will probably significantly impact on the incidence of NRV infection and disease. For instance, France and Germany are reviewing their hospital reimbursing mode, adopting the Diagnostic Related Groups classification system in Germany and the Tarification à l’Activité in France. Under these systems, hospitals will get paid a fixed amount of money to treat a particular disease based on an estimated duration of stay (including the development of potential complications), instead of a payment by day of hospitalization. If hospitalization lasts longer than the estimated duration, the hospital will carry most of the additional costs. It is unclear currently whether NRV infection will be considered as a normal complication/comorbidity (and potentially justifying additional funding for hospitals in cases of NRV disease), but hospitals will have financial incentives to reduce the duration of stay (including the extra length of stay because of hospital-acquired infections).
The management of children with diarrhea has also changed over time and in different countries. Less severe cases are seen more often as outpatients, and hospital admissions have shifted toward more severe cases. As a result, there are less RV disease cases introduced in the wards, thus in theory, reducing the risk of nosocomial spread, although NRV cases might be more severe because patients being infected are more severely ill.
Studies on the incidence of RV infection by age showed that younger age groups are more affected by NRV than CARV infections, with a peak incidence in the 0- to 11-month age group for NRV versus 6–23 months for CARV (Fig. 2).18,19,36,50,58,60,70,74,77,78 A Spanish study showed that asymptomatic infections were more frequent in infants younger than 6 months and even younger than 3 months of age.36 In addition to hospital-acquired infections, a significant number of RV infections are transmitted between siblings at home, or within child-care centers.79 These events should not be underestimated and require more detailed evaluation.
Severity of NRV Infections
RV Morbidity and Mortality.
Mortality associated with RV is very low in developed countries,1,21,81 and no figures are available estimating deaths caused by NRV infections.1,20,80 As a consequence, considerations relating to the NRV morbidity burden in Europe are focused much more on aspects such as the temporary reduction of the quality of children’s lives and the increased direct and indirect costs (eg, increased consumption of medical resources, time loss from work for parents) rather than mortality.
Hospitalization and Rehospitalization.
Several studies report increased duration of hospitalization caused by NRV infections from 1.7 to 5.9 days.13,18,19,36,49,50,69,70,77,81 Despite this general trend, conclusions are hard to draw because most studies gathered samples from different hospitals, in different settings (age group, recall of the families after discharge), and often not matching the characteristics of cases with controls (Table 2).
Only 2 studies were found on rehospitalization in France, which estimate the proportion of nosocomial diarrhea requiring rehospitalization to be between 2 and 13%.50,75
There are no specific coinfections reported in association with RV in developed countries. However, additional enteric pathogens coexist in 20–30% of community-acquired gastroenteritis cases where RV is found (norovirus, astrovirus, adenovirus, Campylobacter jejuni).77 Furthermore a strong association between hospitalization for RSV bronchiolitis and NRV infections has been reported in France and Spain.30,49 However, in these cases, we should speak about concomitant or overlapping infections.
Complications of NRV Infections.
Dehydration is the “standard” complication of RV illness,20 and there are no known complications specifically caused by NRV. Other complications can be split between acute (such as consequences of dehydration, poor tolerance to fever or febrile convulsions, bacterial superinfection) and chronic complications (secondary intolerance to lactose, failure to thrive). There is evidence suggesting that RV infection can lead to convulsions, possibly through the induction of nitric oxide, although this remains to be proved.82 On the other hand, the increased severity of RV disease that was observed in vitamin A-deficient mice might help to explain the high mortality of RV infections in developing countries.83
Economic Burden of NRV Infections
The evaluation of the economic burden of NRV infections must consider the different types of costs as well as the cost drivers involved in nosocomial infection and the valuation of those factors. Costs are defined as quantitative/qualitative, and/or direct/indirect and/or fixed/variable, and different combinations are used by authors depending on the information available.84–87 The definition of the different types of costs depends also on the perspective, ie, hospital, community or payers’ perspective (eg, a community perspective would define missing working days for parents as direct costs, whereas a hospital perspective would consider these costs as indirect).88,89 The cost drivers considered can be the duration of hospital stay, the additional drug treatments, the ward closures/opening measures and contamination of staff members and the loss of working days for parents and staff (Table 3). The valuation of the cost drivers is achieved using concurrent or comparative methodology. Most studies used comparative methodology, comparing the length of stay and costs of infected patients with those of uninfected patients.84,85,90,91
Only a few publications estimated the cost of NRV infections in selected countries. Among them, the cost per NRV case is reported to be as high as 2500 euros per infection (Table 4).19,50,69,77,92 These figures cover only direct quantitative costs (taking the hospital perspective) and usually using the additional length of stay as the unique cost driver. Even though those costs represent a large share of the total costs,84,93–96 the studies significantly underestimate the true cost associated with NRV.97 Moreover only 2 studies matched cases and controls to ensure relevance of results.69,77
Comparison of the figures between countries is difficult for several reasons, including differences in health systems3,19,50,69,84,86,92 and the age and characteristics (such as the severity of the disease requiring hospitalization) of the studied population (eg, nosocomial infections are more frequent in neonatal intensive care units than in general pediatric wards). Thus studies allowing for the calculation of the total cost of NRV at country level are of limited reliability in any of the countries studied.
Existing Policies Against Hospital Cross-infections
Nosocomial Infections Surveillance Systems.
Thus far, most studies have been conducted in countries more or less advanced for the reporting of severe nosocomial infections (blood-borne pathogens, antibiotic-resistant bacteria such as methicillin-resistant Staphylococcus aureus). However, none of them has structures and procedures in place to monitor and report NRV cases (no mandatory reporting of cases, absence of dedicated International Classification of Disease code). As a result, incidence figures based on national/hospital databases severely underestimate the burden of NRV infections, and little is known in countries where prospective studies are scarce (eg, Italy, Poland, Spain).
Prevention and Treatment of NRV Infections and Their Efficiency.
Theoretically prevention of nosocomial infections should be achieved through the implementation of physical and/or biologic measures. Broad guidelines for physical prevention exist in most countries, but in the absence of formal detailed procedures, it is up to each hospital to decide which measure to implement. These guidelines apply to infection acquired by contact (mostly stools, sometimes vomit), thereby usually excluding airborne transmission, a potential infection route of RV infection. Illustrative guidelines from the Comité Technique National des Infections Nosocomiales in France are: hand washing and/or disinfection after discharge of disposable gloves between patients and activities, with detailed instruction leaflets for each case; glove discharge (changed between patients), eye protection, mask, over clothing; isolation of children with diarrhea (isolation or cohorting, single use medical instruments, etc.); child care given in the patient room, with no interruptions; limitation of “traffic” around patients (short visits, patient transport); handling and disposal of spoiled material and biologic samples.
Appropriate hand washing is the most important and effective measure.98–104 Specifically the use of alcohol-based hand sanitizers (60–70% ethanol or isopropanol), instead of soap and water, is very effective in reducing the number of viable pathogens on the hands.98,101–105 A recent study conducted in a U.S. pediatric hospital showed that a vigorous hand washing hygiene program lowered the rate of nosocomial RV infection from 5.9 to 2.2 episodes per 1000 hospitalizations.106 However, compliance with hand washing protocols continues to be low (20–50%).99,107–109 Prevention measures are perceived as partially efficient (given the very highly contagious nature of RV) but face numerous barriers to implementation such as lack of staff, high staff turnover, limited respect of hygiene procedures, inadequate hospital infrastructures which prevent patient isolation (lack of single rooms, absence of cohorting) and overcrowding of pediatric wards (patients and parents circulating on the wards). In addition, because fever can be the only symptom of RV infection for 1 or 2 days (before the start of gastrointestinal symptoms), patients can be erroneously categorized as having a serious bacterial infection and placed in general wards without precautions that otherwise would be taken.
Biologic prevention of RV infection can be achieved through breast-feeding, although there are conflicting data concerning its protective role.110–118 Probiotics (eg, Lactobacillus GG) can also have a positive impact on acquisition of infection, although several studies have been published with conflicting results.119
No specific drug treatment is available for RV infection. However, several strategies are used for the management of children with RV disease, including oral rehydration solutions which have been shown to be highly effective and at low cost.78,120,121 Other potential treatments might include drugs like smectite, which seems to reduce the duration of diarrhea (although unpublished data has shown a limited reduction in the duration of diarrhea of 16 hours), but not of vomiting and fever,122 or racecadotril, proposed as a treatment against all secretory diarrheas;123 however, the actual usefulness of both drugs is very doubtful. The use of oral immunoglobulin has been proposed for premature infants; however, randomized controlled trial data do not support their routine use.124 Probiotics are also useful for the treatment of RV-associated diarrhea.125–127
NRV infections represent a significant epidemiologic and economic problem in most European countries. However, studies are limited and focus on specific populations and cannot be simply extrapolated to reflect the total European situation. Additional large scale, multicentric prospective studies are required to provide a fair and reliable view of the situation at a national level.
Numerous prevention measures exist that have shown variable efficiency in different settings. However, these measures have to be combined and rigorously applied by everyone in hospital wards (health care workers, patients, visitors) to be efficacious. Many barriers to implementation of such prevention policies exist and might explain their global relative usefulness.
The availability of an effective vaccine against RV infection may have a major impact in reducing both community-acquired infections and, as a consequence, NRV infections. At present, no study has been performed to demonstrate the potential efficacy of individual vaccination in preventing acquisition and transmission of NRV infection in hospitalized infants.
Finally, because multiple pathogens are involved in acute and severe diarrhea in infants and children, vaccination should be considered as a major constituent, but not the only one, of the entire prevention measures battery needed against NRV infections.
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