Rotavirus (RV) infection is the leading cause of severe dehydrating diarrhoea in young children worldwide (1). According to 2008 estimates, diarrhoea attributable to RV infection causes approximately half a million deaths globally each year in children younger than 5 years (1,2). More than 85% (∼500,000) of these deaths occur in developing countries, mostly in Africa and Asia (3). Although the overall childhood diarrhoea–related mortality has declined during recent years, the proportion of severe RV gastroenteritis (RVGE) has increased (1). Bacteria and parasites, mainly transmitted through contaminated food and water, have been significantly reduced, owing to the improvements in sanitation and hygiene. These advances, however, have had less effect on RVGE, which is transmitted primarily by the faecal-oral route, directly from person to person or indirectly via contaminated fomites (1,4). The resistance of RV to environmental factors such as pH, temperature, and moisture along with their resistance to disinfectants or wastewater treatments contributes significantly to their persistence on contaminated surfaces long enough to be transmitted to susceptible children.
In Europe, RV is the leading cause of acute gastroenteritis, requiring hospitalisation in infants and children younger than 2 years (3,5), in whom the disease is more severe (3,5,6). The duration of hospital stay because of RVGE ranges from 2 to 9.5 days (median 4.8 days) (7). Acute gastroenteritis is more severe and associated with greater dehydration in patients who are RV positive compared with other causes (7). Across Europe, acute RVGE accounts for 56% of hospitalisations and 32% of emergency department visits among children younger than 5 years (5). Furthermore, RV infection is also one of the leading causes of nosocomially transmitted infections in children (6,8), and it has been estimated that one-fifth of hospitalised children become infected with RV during their stay (7). Nosocomial or hospital-acquired acute RVGE can increase the duration of hospitalisation by up to an additional 10 days (6).
In addition to the burden of acute RVGE in children, RV infection has a large public health burden in industrialised countries, with a significant economic effect on society (eg, lost work productivity for carers, a drain on health care resources, and high costs of RV-associated hospitalisation and medical care) (9).
RV strains show considerable diversity (4), but those carrying the G1, G3, G4, or G9 types in association with P (G1P, G3P, G4P, G9P), and G2 in association with P (G2P) are the most common causes of RVGE worldwide (>93% of cases in Europe) (10). Although many different RV strains may be circulating simultaneously within a region, their prevalence differs considerably within the same geographical area from one season to the next (4). Furthermore, the detection of emerging genotypes varies from country to country and depends on the implemented surveillance methods (10).
Vaccination is the only control measure likely to have a significant effect on RVGE incidence. Clear, endorsed regional guidelines on the use of RV vaccines are needed to engage key stakeholders for vaccine introduction and to assist general practitioners and parents in the decision to vaccinate; however, as yet, following the publication of European recommendations by the European Society for Paediatric Infectious Diseases (ESPID) and the European Society for Paediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) in 2008, Latvia is the only central European country to develop national recommendations (3,11).
The aim of this review is to reinforce the present knowledge on RVGE burden to highlight the present situation in Central European Vaccination Awareness Group (CEVAG) countries and to develop a formal CEVAG position on RV vaccination.
CEVAG consists of regional experts from 12 central European countries: Bulgaria, Croatia, the Czech Republic, Estonia, Hungary, Latvia, Lithuania, Poland, Romania, Slovakia, Slovenia, and Turkey. The aim of CEVAG is to encourage the efficient and safe use of vaccines to prevent, control, and, if possible, eliminate vaccine-preventable infectious diseases. This will be addressed by raising awareness of immunisation and by compiling and distributing appropriate information. CEVAG is an established voluntary association of national representatives and legal entities, which shares an interest in promoting vaccination in central Europe. CEVAG is organisationally independent of state administration and self-administration bodies, political parties, and other civic associations and initiatives. The association does, however, cooperate with these groups during the realisation of common plans and promotion of matters of mutual interest.
BURDEN OF RVGE IN CEVAG COUNTRIES
The present burden of acute RVGE in CEVAG countries is not clearly known. Differences in surveillance programmes and detection techniques may account for the large variations in incidence rates between countries (Table 1) (12–14).
TABLE 1-a Overview o...Image Tools
In 2009, incidence rates (cases/100,000 population) of RVGE were lower in Lithuania (88.4 cases) than in Estonia (118.1 cases) or Latvia (141.1 cases) (15). In 2004–2009, prevalence rates of acute RVGE in hospitalised children varied from 19.6% to 27% in Estonia, Hungary, Romania, and the Czech Republic, to 33% to 42% in Bulgaria, Poland, Slovenia, and Turkey (12).
TABLE 1-b Overview o...Image Tools
In most CEVAG countries, the season for RVGE is from November to May, peaking between March and May (10). Significant differences in the geographical distribution of RV genotypes have been found in Bulgaria, Croatia, the Czech Republic, and Slovenia (16). In a study conducted between 2004 and 2006, the G9 genotype was identified in 2% to 35% of all samples worldwide, depending on the country. Unusual combinations, such as G1 or G4 associated with P, or G2 with P, were found in 3% to 20% of patients. The less common genotypes G8P and G10P were also identified. Double infections with 2 RV strains were observed in 1.7% to 14% of cases (16).
In Bulgaria, studies on RV testing methods began in 1979. In 2008, the National Reference Laboratory of Enteroviruses (Centre for rotavirus surveillance in Bulgaria) and the National Centre of Infectious and Parasitic Diseases (NCIPD), Sofia, joined the European Rotavirus Network. In 2010, RV testing for all cases of acute gastroenteritis in children younger than 5 years was required by the National Health Insurance Fund and in August 2011, the reporting of RVGE became mandatory.
Based on NCIPD data, in 2005–2009, RVGE was estimated to be responsible for at least one-third (33%–39%) of all hospitalisations because of acute gastroenteritis among children (A. Mangarov, unpublished data).
In 2008–2010, of all the children with RVGE, 70.7% (424/600) were ages 1 to 24 months (17). The highest prevalence rates of RVGE have been reported in the district of Sofia (44.9% in 2005 and 43.3% in 2006) and in the region of Varna (48.8% in 2007) (10), whereas in other regions prevalence rates ranged between 14.3% and 34.8%.
RV circulates throughout the year in Bulgaria (10). In 2006–2007, more cases of RVGE were observed between January and August and in 2007–2008, more cases were observed in September and January. During this time, boys were infected more frequently than girls.
The dominant RV genotype has changed over the years: G4P (40.6%) in 2005, G9P (84.8%) in 2006, G2P (45.1%) in 2007, GP1P (39.5%) in 2008, and G4P (47%) in 2009, although this has gradually been replaced by G2P (27%) (18,19).
In Croatia, notification of RV infection has been obligatory since 2008, but data at the national level are scarce. In 2008, according to the Croatian National Institute of Public Health (CNIPH), 7000 cases of gastroenteritis were reported; of these, 89% (6230/7000) were caused by RV, and the share of acute RVGE that year was 18% (1260/7000) (20). Of the total number of gastroenteritis cases, 20% (1400/7000) were reported in infants younger than 24 months, of whom 87% (1218/1400) were hospitalised: 495 acute RVGE (no deaths) and 723 cases of presumed viral infection (1 death).
A survey conducted by the University Hospital for Infectious Diseases (UHID) in Zagreb collected data from children hospitalised between 2006 and 2007 across 3 Croatian hospitals (UHID, Clinical Center Split and Čakovec General Hospital). A total of 715 cases of RVGE were confirmed; of these, 58.6% were from Zagreb, 30.9% from Split, and 10.5% from Čakovec (G. Tešović, unpublished data). Most cases occurred in children younger than 2 years (74.3%), boys (55%), not attending day care centres (78.2%), and living in urban communities (61.3%). For most cases (93.4%), parenteral rehydration was the treatment of choice (G. Tešović, unpublished data). There was no significant difference in the Vesikari score between children younger than 2 years and 2 years or older, but fever (>39°C) was significantly more common in the older age group (P = 0.001), whereas diarrhoea lasting >5 days was significantly more common in those younger than 2 years (P < 0.001) (G. Tešović, unpublished data). Only 1 study has reported on the prevalence of RV genotypes in Croatia (16). A total of 459 stool samples were collected from children with severe gastroenteritis, mostly younger than 5 years, admitted across 3 different health institutions/hospitals in Zagreb (CNIPH, Children's Hospital and University Hospital for Infectious Diseases) (16). The most common genotype was G1P (21.8%), followed by G2P (19.2%) and G4P (12.6%). G3P (5.0%) and G3P (1.3%) were less common (16).
In the Czech Republic, the burden of acute RVGE is still underestimated because no dedicated surveillance system has been implemented. The annual incidence rate of RVGE in children younger than 5 years was 649.1/100,000 in 2009 (3713 hospitalised) (21).
In 2009, according to the Notifications of Infectious Diseases in the Czech Republic, RV accounted for 19.6% of all gastrointestinal diseases in children younger than 5 years (R. Prymula, unpublished data).
Nosocomial RVGE accounted for 27.75% of cases between 2001 and 2005 (20). On average, children with nosocomial RVGE were 9.8 months younger than those with community-acquired RVGE (20). Nosocomial cases were more frequent in younger children who had a longer duration of hospitalisation (including intensive care) and who had experienced the illness for a longer time (20). The clinical severity of cases varied with an average of 3 to 4 days of hospitalisation (20).
In a study conducted at the University Hospital Hradec Králové, a diminishing seasonality and a shift toward spring and summer months was observed in 2008–2009, when an increasing number of cases were observed among older children and adults (parents) (R. Prymula, unpublished data).
According to the SPRIK (Surveillance for Practitioner/Paediatrician for Rotavirus Infection in Kids) study, G1P was the predominant RV genotype in children younger than 5 years in the Czech Republic (87.5% [56/64]) (23).
RVGE is a notifiable disease in Estonia, but most disease estimates are based on hospital data. Stool samples are not routinely tested for RV in ambulatory or community-based settings. Consequently, the total burden of RVGE in the community remains unknown.
According to the Estonian Health Board, there were 75.6 to 118.1/100,000 cases of RVGE each year in the period 2006–2010 (24). The highest incidence was reported in 2011 (170/100,000), when 50% to 60% of RVGE cases occurred in children ages 1 to 4 years, whereas fewer cases were reported in infants younger than 1 year (24).
Data on RVGE prevalence were collected from children younger than 5 years hospitalised between 2007 and 2008 across 3 major paediatric hospitals in the country (25). The study reported a total of 671 cases of RVGE, accounting for 5.5% of all hospitalised children younger than 15 years (25). Most cases (65%) occurred in children ages 7 to 24 months (median 17 months), most of which (76.9%) were of moderate severity (Clark score 12.1 ± 3.2). Overall, children were hospitalised for 3.2 days (±1.9 days), but those experiencing nosocomial RVGE stayed for an average of 4.2 days (±2.2). No intensive care admissions, deaths, or severe disabilities were reported (25).
In 2007–2008, G2P was the dominant strain of RV (34.7%), causing significantly more cases than G4P (12.9%), G1P or G9P (both 4.0%), and G3P (1.6%). Yearly differences in genotype distribution were evident, with G2P (52.8%) dominating in 2007 and G4P (26.9%) in 2008. The G2P strain was also the most prevalent strain in nosocomial infections isolated in 50% of cases. One-third of strains remained nontypeable (25).
Reporting of infectious acute gastroenteritis is mandatory in Hungary where stool samples should be tested for RV in all children hospitalised with diarrhoea. Data on RVGE cases are collected from clinicians and clinical laboratories, but discrepancies have been reported between the 2 systems mainly because of underreporting by clinicians (26).
In 2008, 3801 cases of RVGE were reported (4% of all infectious diseases that year) (27). In Hungary, RVGE has the typical seasonal appearance with most cases occurring between January and March. In 2010, the number of cases ranged between 28% and 38%; the highest proportion of RVGE was in March (37%), followed by February (25%), April (14%), and January (6%) (27).
In 2007, the most prevalent RV strains (10.2%–31%) were G1P, G2P, G4P, and G9P, whereas the least common strains (0.2%–1.3%) were G1P, G2P, G3P, G4P, G6P, G8P, G9P, G9P, and G12P (28). G9P was detected in Hungary in early 2007 (29).
RVGE is a notifiable disease in Latvia, but most disease estimates are based on hospital data. Stool samples are not routinely tested for RV in ambulatory or community-based settings.
In 2010, there was a 3% increase in reported cases of RVGE compared with 2009, and a 37% increase compared with the previous 5 years. Because most reported cases (97%) are hospital based, data on the incidence and prevalence of RVGE may be underestimated. An outbreak was reported in 2010, with 210 RVGE cases (30). Incidence rates of RVGE have increased dramatically in the last decade, with a peak in 2011 (168.55/100,000; 3758 cases) (D. Zavadska, unpublished data).
Although RVGE varies between regions, in 2010 the highest incidence rates were reported in the Riga region, including the capital city and the Latgales region. Overall, RV infection accounts for one-third of all registered cases of gastroenteritis in Latvia (30). No deaths caused by RVGE have been reported during the last 10 years.
Overall, 59.2% (1931) cases of RVGE occur in children younger than 24 months, mostly between 6 and 23 months. In 2010, the youngest patient with RVGE was a 6-day-old infant and the oldest was a 92-year-old woman (30). Boys at preschool age are more affected than girls. In adults, except for those ages 40 to 49 years, RVGE is more common among women (30).
According to a tree model–based study, 2500 RVGE hospitalisations are reported every year in Latvia (31). The Latvian Society of Paediatric Infectious Diseases Specialists noticed a dramatic increase (300%) in the number of children hospitalised with RVGE between January and March 2011 compared with 2010 (30). Most cases are usually reported during the winter and spring seasons, peaking between January and May.
Laboratory-confirmed RV infections have been notifiable in Lithuania since 1994, and according to Lithuanian communicable diseases legislation, the reporting of all viral intestinal infection is mandatory (32). High incidence rates of RVGE have been reported in Lithuania, where it is recognised as an important public health problem (32).
Since 2006, incidence rates of RVGE have continued to decrease—by 12.7% in 2008–2009—which may be in part because of changes and/or availability in laboratory confirmation techniques (32). In 2009, the incidence rate was 88.4/100,000 (2782) cases (32). It is important to note that in Lithuania, laboratory-unconfirmed gastroenteritis is usually considered as RVGE, mainly because of the inherent economic difficulties within primary health care clinics that make it difficult to confirm every case.
As observed in every preceding year, in 2009, the highest incidence of RVGE was reported in children 3 years or younger (1601.2/100,000 children). In contrast <400/100,000 cases of RVGE were reported in children younger than 3 years (32).
Until 2008, the incidence of RVGE in urban populations was nearly 2 times higher than that in rural populations (32). In the urban population, the incidence rate of RVGE dropped by 21.3%, from 121.1/100,000 in 2008 to 95.3 in 2009. In the rural population, the rate dropped by only 8.8%, from 63.8/100,000 in 2008 to 58.2 in 2009 (32).
In 2009, the incidence of RVGE varied between regions, with the highest rates reported in Panevezys (143.3/100,000), Vilnius (141.7), and Silute (134.4) (32). In 2009, 72.1% of RVGE cases were reported as sporadic, occurring at home, whereas for the remaining cases, the source of infection was unknown. Some cases were detected in health care facilities and sanatoriums (2.9%), child care facilities (1.7%), and others (2.7%). During 2009, 45 outbreaks of diarrhoea of viral aetiology (40 due to RV) were recorded in Lithuania (32).
During 2008–2009, an increase in RVGE was observed between January and May (eg, 16.7 cases in March), whereas low numbers were observed at the end of the summer and autumn (eg, 1.5 cases per day in September) (32). In 2009, RVGE morbidity was lowest between June and December, less than the average daily rate (32).
In Lithuania, a natural fluctuation exists among RV strains: G3P was the most prevalent genotype circulating in 2005–2006 and 2009–2010, G4P in 2007–2008, and G1P in 2008–2009 (33).
In Poland, infectious gastroenteritis in children younger than 2 years is a notifiable disease, with obligatory reporting of individual cases, hospital and outpatient outbreaks, and laboratory positive stool testing results. Since 2001, RV has been on the list of alert pathogens monitored by law in all hospital settings. Testing for RV infection is widely performed in hospitals, but not in ambulatory care, mainly using rapid latex tests. Up to 32,000 cases of viral gastroenteritis were reported in 2009; half of these cases occurred in children younger than 2 years (P. Grzesiowski, unpublished data).
During 2008–2011, according to official statistics, a total of 22,747 cases of RVGE were hospitalised in 2008, 21,376 in 2009, 20,170 in 2010, and 29,618 in 2011 (80/100,000). Cumulative incidence rates of hospitalisation caused by community-acquired RV in Polish children by 5 years of age amounted to 1 in 651, with mean duration of hospital stay of 9.5 days for children younger than 5 years (7). According to official statistics during the 3-year period 2008–2010, 130 hospital outbreaks were reported. No child fatalities have been reported in Poland as a result of either gastroenteritis or RVGE (P. Grzesiowski, unpublished data).
The ongoing SPRIK study has provided data on RV-type distribution among outpatients for 2006–2007. In Poland, G9P was the most common type (71.1%; 54/76) (23).
In Romania, reporting of gastroenteritis is not mandatory and because testing for RV is not routine practice, RVGE may be underestimated (26). In 2008, a study was conducted with 684 children (median age 8 months) admitted with acute gastroenteritis to the Emergency Pediatric Hospital “Grigore Alexandrescu” in Bucharest. A total of 87 children (12.7%) were infected with RV (34). Children experiencing RVGE were 2.36 times more likely to have a longer hospital stay (>6 days) than those with other acute diarrhoeal disease (34). Most cases occurred in April (40%) and November (25%) (34).
Between November 2008 and October 2010, a survey was conducted to determine the etiologic cause of acute diarrhoea in children younger than 5 years hospitalised in the 2nd Pediatric Clinic of Cluj Napoca. Of the 1262 children enrolled, 316 (25%) stool samples were RV positive, and of these, 77% were younger than 2 years. RVGE had a seasonal distribution, with peaks in the winter and early spring (35). No published data are available on RV genotypes in Romania.
In Slovakia, cases of RVGE are reported to the Epidemiological Information System. In 2011, Epidemiological Information System recorded 3222 cases of RVGE in children younger than 5 years (1125.64/100,000); of these, 1025 (1703.68/100,000) occurred in infants younger than 1 year and 2197 (971.81/100,000) in those ages 1 to 4 years (36).
In a study conducted at the Paediatric Department Teaching Hospital in Trenčín from 2006 to 2009, gastroenteritis was reported in 21% (824/3850) of children younger than 5 years hospitalised in the area of Trenčín; of these, RVGE accounted for 39% (324/824) (37). Overall, in the period 2006–2009, 30.6% of nosocomial RVGE cases occurred in the Trenčín area (37). Based on the data collected between 2001 and 2009, RVGE peaked in March and April for children younger than 5 years (P. Šimurka, unpublished data).
RV is a notifiable disease in Slovenia, where a passive reporting system exists. Incidence rates of RVGE were 80.5/100,000 cases in 2009 (38). Overall, in 2005–2009, most cases of RVGE (78.1%) were notified in children younger than 5 years and only 18.1% in those younger than 1 year (38). Hospitalised cases were at their highest in 2007 (74.8/100,000, 1510 cases) and lowest in 2009, at 51.36/100,000 (1049 cases) (38).
Cases of RVGE usually increase during the winter months, with most being reported in January and February (2004–2008 figures). In 2009, however, the highest rates of RVGE were registered during the spring months (March–April) in children younger than 1 year (∼1400 cases) and 1 to 4 years (∼1300 cases) (38).
The prevalence of RV genotypes has been changing in recent years: G4P was the most widespread in 1988–1994 (52%); from 1999 to 2008, G1P was the most common, with rates approaching 100% in 1999–2001 and >64% in 2001–2008; G9P emerged as the second most frequent strain in 2005–2006 (23%) (39–41). In 2007–2008, G4P and G2P were less common (≤3%) (39–41).
In Turkey, notification of RVGE is not mandatory and testing methods are not routinely used. Consequently, laboratory surveillance is undertaken rarely and epidemiology data on RVGE are probably underestimated. Since the Management and Control of Diarrhoeal Diseases programme initiated in 1986, the number of deaths caused by diarrhoeal diseases has declined significantly. As a result, from 1999, diarrhoeal diseases have dropped from second to seventh as the leading cause of child deaths (N. Salman, unpublished data).
In a study conducted between 2005 and 2006 among children younger than 5 years with acute gastroenteritis hospitalised across 4 cities in Turkey (Adana, Ankara, Istanbul, and Izmir), RVGE accounted for 53% (179/338) of cases. The highest proportion was observed in Izmir (67.4%) and the lowest in Adana (32.4%). Most of those with RVGE were younger than 2 years (83.8%), 43.5% were younger than 1 year, and 11.7% were younger than 6 months (42). The median duration of hospitalisation was 3 days, regardless of the RV status (42).
A similar study published in 2011 evaluated RVGE incidence among children hospitalised with acute gastroenteritis across 4 centres in the Bursa province (43). Hospitalisation rates owing to acute RVGE were 22.5%, 27%, and 12.5% in children younger than 1, 2, and 5 years, respectively (43). RV positivity was significantly higher in hospitalised acute gastroenteritis cases than in outpatient cases (28.5% vs 21%, respectively), and in both, boys were more affected (60%) than girls (43). Eighty-six percent of those hospitalised and 76% of outpatients were younger than 5 years (43). Approximately half of the cases were seen in the January–March period. In January, half of the hospitalised cases and one-third of the outpatient cases resulted from acute RVGE (43). It was estimated that the annual acute RVGE-related hospitalisation incidence was 629/100,000 in children younger than 1 year, 553/100,000 in those younger than 2 years, and 293/100,000 in those younger than 5 years (43).
In 2003, a marked seasonality of RVGE was observed in Izmir, with a peak incidence from January to March and no reported cases in August (44). In 2005–2006, RVGE was most frequently observed across the country between October and April, peaking in February (>70%) (42). In 2005–2006, G1P was the most prevalent strain (76%), followed by G2P (12.8%) (44); G9P was reported in 3.9% of samples from children (42).
PRESENTLY AVAILABLE RV VACCINES IN EUROPE
The 2 available, live, oral-attenuated RV vaccines were licensed in 2006: the 2-dose monovalent (G1P) human RV vaccine (Rotarix; GlaxoSmithKline Biologicals, Rixensart, Belgium) and the 3-dose pentavalent (G1, G2, G3, G4, and P) bovine-human reassortant RV vaccine (RotaTeq, Sanofi Pasteur, Lyon, France), both of which have undergone central registration at the European Medicines Agency (4). Both vaccines are equally well tolerated and efficacious against the RVGE(3) G1–G4 and G9 genotypes, but differ in their antigen composition and immunisation schedule (4,45).
The 2-dose monovalent vaccine is scheduled for infants ages 2 to 4 months (first dose at 6 weeks and second dose at 24 weeks, preferably before 16 weeks of age) (4). The 3-dose pentavalent vaccine is administered to infants at 2, 4, and 6 months (first dose between 6 and 12 weeks and subsequent doses at intervals of 4–10 weeks) (4).
Vaccination should not be initiated for infants older than 12 months because there is a potentially higher risk of intussusception (IS) after this age, and consequently, it should not be used in catch-up vaccination campaigns (4).
Immunogenicity and Effectiveness of RV Vaccines
The clinical efficacy and effectiveness of the RV vaccines have been demonstrated mainly in the United States, Europe, and Latin America (2,4). The monovalent vaccine has achieved high efficacy (up to 96.1%) against severe RVGE caused by the 5 most common strains circulating in developed countries (G1P, G2P, G3P, G4P, and G9P), and high effectiveness (up to 80.3%) in some Asian and Latin American countries (3). During the first 2 years of life, 2 doses of the monovalent vaccine provide sustained protection against any RVGE (79%), severe RVGE (≥11 Vesikari score) (90%), RVGE hospitalisations (96%), and gastroenteritis hospitalisations (72%) (46).
The pentavalent vaccine has been demonstrated to reduce G1–G4/G9 RVGE-related hospitalisations and emergency visits by up to 95.5% after 3 years post-3-dose vaccination (3). Compared with other age groups, in Africa and Asia, the efficacy of the pentavalent vaccine against severe RVGE was significantly lower during the first year of life (64.2%) and before 2 years (48.3%) (3).
Both presently available vaccines should be effective in protecting against the most common RV genotypes circulating in central Europe (G1P, G2P, G3P, G4P, and G9P) (11).
The safety profile of the monovalent vaccine is based on extensive clinical data from the largest vaccine clinical trial programme, enrolling >90,000 participants across Europe, Latin America, Asia, Africa, and the United States (47). No increased risk of IS was found after the use of the monovalent vaccine in a phase III clinical trial involving 60,000 subjects in Latin America and Finland (47). Postmarketing surveillances in Europe and Latin America have, however, identified a possible small increased risk of IS because a number of cases have been identified shortly after 1 dose (3). Depending on the population evaluated, between 1 and 2 additional cases per 100,000 vaccinated infants are temporally at risk for developing IS (3). Fortunately, most children who experience clinically significant IS make a full recovery without complications following appropriate treatment (3). The small risk of adverse events as a result of vaccination should be put in perspective of the far greater risk of harm caused by leaving a child unvaccinated (3). Porcine circovirus type 1 (PCV1) DNA has been detected in the monovalent vaccine, and fragments of DNA from both PCV1 and PCV2 were later discovered in the pentavalent vaccination. There is no evidence to suggest that these findings pose a safety risk.
The potential risks and benefits of RV vaccination in infants who are immunocompromised or have a preexisting gastrointestinal chronic infection should always be assessed by physicians (4).
Contraindications include hypersensitivity to any of the vaccine components and history of IS or intestinal malformations that could predispose to IS (4). Vaccination should be postponed in infants experiencing acute gastroenteritis or serious febrile illness (4).
RV vaccines can be simultaneously administered with other vaccines commonly used in the infant immunisation programme, as well as in breast-feeding infants and in premature infants (<37 weeks’ gestation) (4).
Cost-of-Illness and Cost-Effectiveness Studies
The cost of RV vaccination has been identified as an impediment to RV universal mass vaccination (UMV) in many European countries (3). Competing demands in many central European countries may contribute to the lack of regional cost-effectiveness studies that could facilitate the implementation of RV UMV (3). It has been noted that routine RV immunisation programmes in the region may bring substantial medical and economic benefits, but more data are needed to support the demand for mandatory immunisation (3).
A retrospective analysis of acute RVGE in hospitalised children younger than 5 years in 3 cities in Poland during the period 1994–1996 estimated the cost of each disease episode to be 1258 Polish Zloty (PLN) (308 Euros). In contrast, the cost of nosocomial RV was approximately 27,300 PLN (6693 Euros). Total costs of acute RVGE were estimated to be in the region of 11,214,742 PLN (2,749,470 Euros) (48).
According to a tree model–based study conducted in Latvia, the estimated costs associated with each child hospitalised because of RVGE is 315 Euros and for each general practitioner visit it is 12 Euros (31). Overall, in Latvia, the cost burden of RVGE is in the range 937,500 to 997,500 Euros per year.
To evaluate the cost-effectiveness of vaccination against RV in Estonia, a Markov cohort model was constructed to follow an approximate Estonian annual birth cohort of 16,000 children until the age of 5 (49). According to the model, approximately 90% of RVGE cases would be prevented by vaccination and all RVGE deaths would most likely be avoided. Compared with the nonvaccination arm, 55 to 57 quality-adjusted life-years are gained because of vaccination during the 5-year period. From the perspective of a third-party payer, the incremental cost-effectiveness ratio of either RV vaccine, compared with no vaccination, would be 13,000 to 30,000 Euros. The key effect factors of these cost-effectiveness results were the cost of vaccines and the number of cases needing hospitalisation. Vaccinating against RV would prevent a considerable number of RVGE cases in Estonia; however, vaccination costs exceed treatment cost savings 4-fold.
RV Vaccination Coverage in CEVAG Countries
Vaccine coverage has increased steadily over the years in most of the CEVAG member countries (Table 2); however, many barriers still exist that delay the implementation of RV UMV (3). The burden of disease is still unrecognised by health authorities, notification is less than optimal, and other competing immunisation priorities hinder the introduction of RV into the National Immunisation Programme (NIP) (3). Moreover, budget restrictions exist in many of these countries: RV vaccines are available exclusively on the private market and, with the exception of Latvia and Slovakia, there are no reimbursement programmes. In the Czech Republic, immunisation coverage is still low, but the wider implementation of vaccination for younger children may have a significant effect on both nosocomial- and community-acquired RVGE (20).
EXISTING RECOMMENDATIONS FOR RV VACCINATION
In 2009, the World Health Organization's (WHO's) Strategic Advisory Group of Experts on immunisation recommended the global inclusion of RV vaccination into all NIPs for all infants and strongly recommended it in countries where diarrhoeal deaths account for ≥10% of mortality among children younger than 5 years (2).
WHO recommends that the first dose of RV vaccine be administered at age 6 to 15 weeks and the last dose be administered no later than 32 weeks (2). When coadministered with diphtheria, tetanus, and pertussis vaccines, both doses of the monovalent vaccine should be administered with the first and second doses of diphtheria, tetanus, and pertussis vaccines, rather than the second and third doses because this ensures maximum immunisation coverage and reduces the potential for late administration beyond the approved age window (2).
Although mortality caused by diarrhoea is low in Western countries, high morbidity has led to ESPID and ESPGHAN recommending the introduction of UMV with RV vaccines to all western European infants and children (11). These European recommendations stipulate that the first dose of vaccine should not be given >12 weeks and that the full course should be completed by 24 weeks, with no catch-up vaccination (11).
In 2009, the US Advisory Committee on Immunisation Practices issued an updated universal recommendation for both RV vaccines: the maximum age for first dose is 14 weeks and 6 days (the previous recommendation was 12 weeks), and the maximum age for the last dose is 32 weeks (50).
The discrepancies in scheduling must be considered when interpreting new results of observational research on IS and on both licensed RV vaccines, and when optimising immunisation schedules for RV vaccines in central European countries (3).
Existing Recommendation From CEVAG Countries
Bulgaria has recommended RV vaccination for infants ages 6 to 24 weeks and in Poland between 2 and 4 months (Table 2). Croatia has recently introduced vaccination for at-risk groups (eg, children born prematurely <33 weeks and those with congenital heart, metabolic, chronic renal and liver diseases, or with severe neurological disorders). In Latvia, RV vaccination was introduced into the NIP in January 2011 at 2 and 4 months of age, and recommendations have been provided by specialists at the Latvian Society of Paediatric Infectious Diseases. RV vaccination is presently fully reimbursed in at least 2 municipalities in Latvia, and reimbursement will be nationally implemented from January 2014, according to Latvian Cabinet Regulations. No official recommendations or guidelines exist for RV vaccination in Estonia, Hungary, Romania, and Turkey.
Differences in national recommendations reflect not only cost issues associated with vaccination but also variations in the burdens of RV and acute RVGE reported in each country. In countries where epidemiological information is incomplete or where RV is not routinely diagnosed, there may not yet be adequate justification for recommending the inclusion of RV vaccination in the universal schedule (51). In these countries, recommendations from professional societies can provide physicians with guidance on which patients would most benefit from RV vaccination.
The CEVAG position for RV vaccination follows the ESPID/ESPGHAN recommendations summarised below (11):
* Recommendation 1: RV vaccination should be offered to all healthy infants in Europe.
* Recommendation 2: Both RV vaccines licensed for use in Europe can be administered separately or concomitantly with inactivated, injectable childhood vaccines. RV vaccination can be integrated into the majority of European vaccination schedules.
* Recommendation 3: In European countries where oral poliovirus vaccine is still in use, concomitant administration with RV vaccine is not suggested.
* Recommendation 4: The first dose of RV vaccine should be given between the age of 6 and 12 weeks, and the full schedule (2 doses for the monovalent; 3 doses for the pentavalent vaccine) should be completed by the age of 6 months.
* Recommendation 5: For special populations of infants, such as premature infants or those with HIV infection, RV vaccination may be considered at calendar age according to recommendations for healthy infants, at the discretion of the physician.
* Recommendation 6: For infants with immunodeficiency, RV vaccination is not recommended.
* Recommendation 7: Continued monitoring for serious adverse events should be in place for RV vaccination.
Presently, there is a lack of information on the burden of RV disease in central Europe and consequently, the real situation of acute RVGE in most CEVAG countries may be underestimated. No recent reports exist on RV prevalence in children younger than 5 years and most disease estimates are based on hospital data. In addition, estimates of the prevalence of RV in severe gastroenteritis are limited to inpatients; estimates among outpatients are lacking. Although the WHO recommend testing of stool samples for surveillance of RV effect, such testing is not typically carried out for diagnostic purposes. Most CEVAG countries do not perform routine laboratory testing, and noncomprehensive surveillance networks are implemented (12). This is true in Romania where there is no routine RV testing. In Slovakia, the low estimates of RV incidence may be because of an inadequate surveillance system, with only 1% of stool samples being tested for RV (12). In Poland, there is no commitment to increase state funding and there is a lack of active surveillance (12). Despite the high diarrhoea-related mortality rate observed in Turkey, there are limited studies describing the prevalence of RV (40).
A high proportion of acute RVGE occurs in children ages 9 to 13 months and overall, children <2 to 3 years are most affected by diarrhoea lasting >5 days who also spend more days in hospital (20,42–44). Compared with most other CEVAG countries, in 2008, Turkey reported more deaths (>10) caused by acute RVGE in children younger than 5 years (188 deaths, 3/100,000) and in Romania (14 deaths, 1/100,000). For the remaining CEVAG countries, however, <10 deaths were reported in the same age group, which may be owing to better access to adequate health care facilities.
The burden of disease is clearly linked to the high rate of hospitalisations. Based on data collected from the Czech Republic, Hungary, Poland, Romania, Slovakia, and Slovenia, it has been estimated that there are approximately 35,500 hospitalisations, 1,250,000 outpatient visits, and 6,323,000 house calls each year (26). The risk of a longer duration of hospitalisation is higher in children experiencing acute RVGE than in those affected by other acute diarrhoeal diseases (34). The average age of nosocomial RVGE tends to be lower than community-acquired RVGE (18.3 vs 26.7 months, respectively) (20). In Turkey, acute RVGE is more frequently associated with hospitalised patients (28.5%) than outpatients (21%) (43). In Bulgaria, Croatia, and Turkey, boys are more frequently infected with RV than girls (A. Mangarov, unpublished data).
All these estimates have a significant economic effect because of the high costs of RV-associated hospitalisation and medical treatment, and lost work productivity for parents and carers. These are medically and financially justifiable reasons to vaccinate, which is implicitly recognised by the WHO in their 2009 recommendation that RV vaccination should be included in all NIPs (3); however, except for cost-of-illness studies in Poland and Latvia and a cost-effectiveness study in Estonia, no other economic studies have been conducted in any other CEVAG countries. In the absence of detailed cost-effectiveness studies, the relatively high direct cost makes it challenging for national health systems to incorporate RV vaccination into their UMV programmes. Carrying out such studies could provide economic justification for RV immunisation programmes and provide information on the effect of RVGE on children's quality of life in the region.
Where implemented, RV UMV has dramatically reduced the burden of acute RVGE (3). High vaccine coverage rates following RV UMV has been associated with a marked reduction in gastroenteritis hospital admissions, supportive of both direct vaccine protection, as well as with indirect herd protection. In Austria, with vaccination coverage rates increasing to 87% in 2008 following UMV in 2007, the number of hospitalised cases was reduced by 74% in children eligible for vaccination (ages 90 days–20 months). A reduction in hospitalised cases was also observed in children younger than 90 days, attributable to partial vaccination of these children. Furthermore, RVGE hospitalisation rates decreased even in children not eligible for vaccination according to their age, suggesting herd immunity induced by UMV (52). In most central European countries, however, vaccination coverage remains too low to have a significant effect on the burden of acute RVGE (3). Furthermore, RV vaccination can elicit a degree of herd-immunity effect because the incidence of severe RVGE has been reduced to minimum levels in countries with UMV (3).
Although paediatricians in most countries express strong support for RV UMV, they should also focus on making clear, strong statements on the value and importance of vaccines for children in terms of saving lives and improving quality of life rather than detailed cost analysis. Emphasis should be made on the number of days in hospital that would be prevented and treatments avoided because of vaccination rather than exact costs saved.
The most common RV strains presently circulating in the region include G1P, G2P, G4P, and G9P; however, the dominance of certain genotypes can change dramatically from year to year and from country to country. A vaccination programme with broad genotype coverage may help to decrease the burden of acute RVGE in CEVAG countries (10).
In conclusion, endorsed regional guidelines on the use of RV vaccines are needed to engage stakeholders and to assist general practitioners and parents in the decision to vaccinate. The availability of efficacious vaccines with favourable safety profiles offers a route towards substantially reducing the associated burden of acute RVGE (3). Evaluation of the overall benefits of introducing RV vaccination in central Europe should be based on region-specific estimates of incidence rates, the number of cases treated, the cost burden of treatment, and the secondary societal costs from lost earnings of parents and caregivers (3). Because the first RV infection is usually the most severe, it is important to protect against RVGE from the youngest possible age. More complete information on the cost, extent, and severity of acute RVGE in CEVAG countries could provide the justification needed to include RV vaccination in UMVs.