acute gastroenteritis ( age ) , characterized by the onset of diarrhea with or without vomiting , still represents a major cause of morbidity even in industrialized countries , being mortality confined in mostly resource - constrained nations .
although generally considered a mild and self - limiting disease , age is one of the most common causes of hospitalization and is associated with a substantial disease burden . within the european union ,
surveillance studies showed that rv accounts for up to 2 thirds of admissions to hospital and emergency room visits and one third of primary care consultations for age among children under 5  years , being the greatest burden of disease consistently observed in children aged under 2 .
rvge is estimated to occur at a rate of 1 symptomatic infection in every 7 children each year , accounting for 231 deaths , more than 87,000 hospitalizations and almost 700,000 outpatient visits .
the reveal study , carried out in belgium , france , germany , italy , spain , sweden , and the uk , reported that rvge in children under 5 y of age was responsible for between 53.0% and 68.9% of cases presenting to hospitals , 35.4% and 63.3% for those seen in emergency departments , and 7.7% and 41.3% of cases seeking primary care physicians . in 2006 , 2 new live , oral , attenuated rv vaccines were licensed for infants less than 6 months of age rv vaccination was first recommended to us children in 2006 .
subsequently , in 2009 the world health organization strategic advisory group of experts ( sage ) recommended rv vaccination for all children .
worldwide a number of countries have adopted this recommendation and implemented rv vaccines in their pediatric immunisation programmes , but only in a limited number of countries in europe .
some countries , such as austria and luxembourg ( 2006 ) , belgium ( 2007 ) , finland ( 2009 ) , united kingdom and germany ( 2013 ) , norway and estonia ( 2014 ) , latvia ( 2015 ) introduced universal anti - rv vaccination until april 1st 2015 , while in other countries , such as , sweden , denmark , and romania the formal assessment for universal vaccination is under consideration . in italy , where rvge is an important cause of pediatric hospitalization , associated with high health care costs , as pointed out by several studies , among them , that of marocco et  al . is the only nationwide but limited only to the primary diagnosis , the national health care system ( nhs ) is decentralized i.e regions are expected to implement  free of charge - all the vaccinations included in the national immunization plan ( nip ) ; further , they are allowed to increase the vaccination offer providing that the additional budget is funded at regional level , either centrally or in co - payment with the citizens .
rv in not included in the current national immunization plan ( nip ) and most of the regions introduced it in co - payment , sometimes reducing the co - payment to a small amount .
sicily is the only region were rv universal mass vaccination ( umv ) free of charge was implemented in 2012 . in order to provide an epidemiological picture that can be helpful in assessing the need to adopt anti - rv universal vaccination also in italy , this study was designed to estimate the proportion of rvge among children younger than 6 y of age who were diagnosed with age and admitted to hospital in italy during the years 20052012 .
in the study time frame , 334,982 age hospital discharge records ( hdrs ) were collected in italy ( average annual number : 41,873 hospitalizations ) , in children aged < 6  years , being age the primary diagnosis ( pd ) in 50.30% ( 168,509 cases ) of these .
table  1 shows the number of hospital admissions only coded as age of any etiology in pd : 63.09% of age ( 106,326 cases ) presented the code of gastroenteritis of non - specified origin , and 33.75% of cases were viral gastroenteritis ( vge ) , that were the leading cause of admissions for gastroenteritis of specified origin ; rvge were 39,024 ( 23.16% ) , and represented 68.61% of all vge . considering the total admissions for age ( in pd ) , over the 8-years study period , a significant and consistent reduction of the total number of admissions for age , from 27,555 in 2005 to 14,988 in 2012 , ( a decrease of 45.60% - age trend - test :  coefficient=-1,939 ; p < 0.001 ) was observed . in parallel , a minor , but statistically significant , decrease for rvge of 29.72% ( from 5,824 in 2005 to 4,093 in 2012 ; rvge trend - test :  coefficient = 253 ; p = 0 .014 ) was found out . 

table 1.number ( percentage ) of all hospitalizations for gastroenteritis in pd among children < 6 y of age in the 20052012 period  2005200620072008200920102011201220052012unspecified etiology  infectious : icd9 cm 009009.312,569 ( 45.61%)12,500 ( 47.57%)10,619 ( 44.96%)9,191 ( 42.55%)7,743 ( 43.47%)8,794 ( 43.46%)7,145 ( 46.92%)7,013 ( 46.79%)75,574 ( 44.85% )  non - infectious : icd9 cm 558.95,244 ( 19.03%)5,352 ( 19.51%)4,684 ( 19.83%)4,223 ( 19.55%)3,428 ( 19.25%)3,604 ( 17.81%)2,289 ( 15.03%)1,928 ( 12.86%)30,752 ( 18.25%)specified etiology  viral : icd9 cm 008.62008.8 ( without rv)3,055 ( 11.09%)3,275 ( 11.94%)2,524 ( 10.69%)2,235 ( 10.35%)1,930 ( 10.84%)1,987 ( 9.82%)1,455 ( 9.55%)1,392 ( 9.29%)17,853 ( 10.59% )  rotavirus : icd9 cm 008.615,824 ( 21.14%)5,439 ( 19.83%)5,144 ( 21.78%)5,324 ( 24.65%)4,146 ( 23.28%)5,301 ( 26.2%)3,753 ( 24.65%)4,093 ( 27.31%)39,024 ( 23.16% )  bacterial : icd9 cm 001005 , 008008.5661 ( 2.4%)634 ( 2.31%)475 ( 2.1%)460 ( 2.13%)383 ( 2.15%)406 ( 2.01%)481 ( 3.16%)447 ( 2.98%)3,947 ( 2.34% )  parasitic : icd9 cm 006007202 ( 0.73%)228 ( 0.83%)174 ( 0.74%)163 ( 0.75%)181 ( 1.02%)142 ( 0.70%)154 ( 1.01%)115 ( 0.77%)1,359 ( 0.81% )  total27,55527,42823,62021,59617,81120,23415,22714,988168,509age trend - test :  coefficient = 1,939 ; p < 0.001 ; number of rvpd hospitalizations , trend - test : -coefficient = 253 ; p < 0.014 . 
 
number ( percentage ) of all hospitalizations for gastroenteritis in pd among children < 6 y of age in the 20052012 period age trend - test :  coefficient = 1,939 ; p < 0.001 ; number of rvpd hospitalizations , trend - test : -coefficient = 253 ; p < 0.014 .
figure  1a shows the trend of hospitalizations for rvge in children under 6 y of age over the study period , but including secondary diagnosis ( sd ) .
sd inclusion leads to a total of 79,344 hospitalizations associated with rv , of which 40,320 ( 50.81% ) in sd . 

figure 1.(a ) number of rvge hospitalizations ( code icd9 cm 008.61 ) in primary ( pd ) and secondary diagnosis ( sd ) among children < 6 y of age in 20052012 .
number of rvpd hospitalizations trend - test : -coefficient = 253 ; p<0.014 ; number of rvsd hospitalizations trend - test : -coefficient = 163 ; p = 0 .184 ; total number of rv hospitalizations trend - test : -coefficient = 89 ; p = 0 .630 .
rvpd : rvge hospitalizations in primary diagnosis ; rvsd : rvge hospitalizations in secondary diagnosis ; % rvpd : percentage of rvge hospitalizations in primary diagnosis ; % rvsd : percentage of rvge hopistalizations in secondary diagnosis .
( b ) hospitalization rates per 100,000 of rvge pd and sd among children < 6 y of age in 2005 - 2012 .
hospitalization rates per 100,000 of rvge pd trend - test : -coefficient=-8.21 ; p=0.010 ; hospitalization rates per 100,000 of rvge sd trend - test : -coefficient=4 .40 ; p=0.209 .
rvhrpd : hospitalization rates for rvge gastroenteritis in primary diagnosis ; rvhrsd : hospitalization rates for rvge gastroenteritis in secondary diagnosis ; rvhrtotal : hospitalization rates for rvge gastroenteritis in any diagnosis ( pd and sd ) . 
 
( a ) number of rvge hospitalizations ( code icd9 cm 008.61 ) in primary ( pd ) and secondary diagnosis ( sd ) among children < 6 y of age in 20052012 .
number of rvpd hospitalizations trend - test : -coefficient = 253 ; p<0.014 ; number of rvsd hospitalizations trend - test : -coefficient = 163 ; p = 0 .184 ; total number of rv hospitalizations trend - test : -coefficient = 89 ; p = 0 .630 .
rvpd : rvge hospitalizations in primary diagnosis ; rvsd : rvge hospitalizations in secondary diagnosis ; % rvpd : percentage of rvge hospitalizations in primary diagnosis ; % rvsd : percentage of rvge hopistalizations in secondary diagnosis .
( b ) hospitalization rates per 100,000 of rvge pd and sd among children < 6 y of age in 2005 - 2012 .
hospitalization rates per 100,000 of rvge pd trend - test : -coefficient=-8.21 ; p=0.010 ; hospitalization rates per 100,000 of rvge sd trend - test : -coefficient=4 .40 ; p=0.209 .
rvhrpd : hospitalization rates for rvge gastroenteritis in primary diagnosis ; rvhrsd : hospitalization rates for rvge gastroenteritis in secondary diagnosis ; rvhrtotal : hospitalization rates for rvge gastroenteritis in any diagnosis ( pd and sd ) .
overall , the percentage of hospital admissions for rvge in pd has gradually and significantly decreased from 57.93% in 2005 to 43.18% in 2012 . on the contrary
, the incidence of rvge sd admissions has increased from 42.07% in 2005 to 56.82% in 2012 .
the annual incidence rates of rv hospitalizations among children < 6 y of age are shown in figure  1 b. the average hospitalization rate ( hr ) was 296/100,000 children : 146/100,000 children for rvge in pd and 150/100,000 children for rvge in sd . since 2008 the hrs for rvge in sd exceeds those for rvge in pd , with the highest peak in 2010 ( total rv hr : 339/100,000 children ) .
the decrease of the hrs for rvge in pd is 8.21 per year ( p = 0 .01 ) , while considering the trend of hrs for rvge in any diagnosis ( pd and sd ) it is not statistically significant ( p = 0 .487 ) . most rvge hospitalizations ( 80.79% ) occurred in children younger than 3 y ( table  2 ) , mainly infants 2  years ( 1223 months ) had the highest number of cases ( 33.67% ) , followed by children aged up to 3 y ( 2435 months ) , with 18.45% of annual hospitalizations , then children aged 011 months ( 28.67% ) . 
 table 2.temporal distribution of rotavirus infections in italy .
distribution ( absolute and relative ) by age groups of the hospitalizations for rotavirus gastroenteritis ( code icd-9 cm 008.61 ) in pd in children aged < 6 y over the 20052012 period  age groups  < 1 y of age1 year2  years3  years4  years5  years  011 months1223 months2435 months3647 months4859 months6071 months  n%n%n%n%n%n%total20051,59927.461,95733.601,05718.1562210.683676.302223.815,82420061,49927.561,89834.9099418.2855910.282945.411953.595,43920071,49829.121,69432.9393918.2552410.192915.661983.855,14420081,51428.441,73332.551,01118.9956210.563025.672023.795,32420091,24630.051,37533.1681219.593939.482034.901172.824,14620101,55729.371,84534.8093317.604879.192905.471893.575,30120111,11929.821,25233.3667017.853719.892075.521343.573,75320121,15628.241,38633.8678419.153859.412125.181704.154,0932005201211,18828.6713,14033.677,20018.453,90310.002,1665.551,4273.6639,024n/% = number / percentage of all hospitalizations in the given year for the specified age group . 
 
distribution ( absolute and relative ) by age groups of the hospitalizations for rotavirus gastroenteritis ( code icd-9 cm 008.61 ) in pd in children aged < 6 y over the 20052012 period n/% = number / percentage of all hospitalizations in the given year for the specified age group .
rvge hospitalizations seasonal peak was during december - march every year , with maximum values of 2,850 cases in pd during 2006 and 3,139 cases in sd over 2008 y ( data by italian hdd database ; data not shown ) . in rvge sd cases , 26,675 ( 66.16% ) main diagnoses
2 ) : the most frequent were dehydration ( 49.77% ) syncopations and convulsions ( 6.59% ) and acidosis and electrolyte fluid disorders ( 5.35% ) .
the main ( 52% ) drg code for rvge sd was 298 ( symptoms concerning nutrition and metabolism < 18  years ) . 
 figure 2.number ( n ) and frequency ( % ) of other diseases in pd in rvge sd cases . 
 
number ( n ) and frequency ( % ) of other diseases in pd in rvge sd cases .
total hospital charges for the admissions for rv in the overall period were approximately  112 million .
they , however , decreased from  7,238,739 in 2005 to  3,158,220 in 2012 , considering only pd .
hospital admission rates for rv age in children aged < 6 y still remain a relevant topic in italy . the hospital discharge data ( hdd ) analysis confirmed that rvge still represents the greatest proportion of hospitalized vge , in agreement with previous results either in italy and in other parts of europe or usa . as in the study time frame
the rv vaccine coverage ( estimated less than 10% ) did not reach yet significant levels to affect the overall epidemiology of the disease , the figures reported here can be considered as a pre - vaccination picture . a progressive reduction of all hospitalizations for acute diarrhea in children , in the study period , which is more evident for age of unspecified etiology and of bacterial and parasitic origin was observed .
indeed , we provided evidence that there was a switch in the position of rv age diagnosis from pd to sd .
vitale et  al , using the markov model and considering a cohort of 555,791 births in 2011 in italy , in the absence of vaccination , estimated an average of 14,000 hospitalizations per year by using the rvge hospital rates collected within the reveal study ; in our study , an average of 9,918 hospitalizations per year for rv in any diagnosis was found out . whereas an underestimation of hospitalizations through the hdd by around 4050% was reported ,
even if calculated from a different setting , our findings are consistent with those reported .
our findings support the need of including both pd and sd , which also includes nosocomial infection forms and the incidence of which was estimated in italy by 5.3% in children under 30 months , in rv hospitalizations analysis .
the most frequent pd in cases of sd rvge were : dehydration , acidosis and vomiting ( 54% ) , infections of the upper and lower respiratory tract ( respectively 11% and 13% ) , seizures or other neurological symptoms ( 7% ) and urinary tract infection ( 6% ) , in agreement with previous reports .
although further studies would be needed to confirm the hypothesis , a consistent part of admissions such as dehydration , gastrointestinal disorders , febrile seizures and electrolyte abnormalities reported in main diagnosis could be associated with the rv etiology ; this would also partially justify the under estimation of rvge hospitalization figures
. it can be assumed that variations in coding rv hospitalizations in the studied years might be related to the introduction of strategies of containment of the sanitary expense , being some icd9-cm codes leading to a more specialized management and reimbursement . even though the study was not intended as an economic analysis of rvge hospitalizations ,
however , figures obtained were just a rough indicator of real healthcare costs when compared to more accurate calculations . limitations of the study .
indeed , regional data are not detailed even if the regional differences in the payment of rvge hopitalizations may influence the coverage of rv vaccines and the age hospitalizations . in conclusion ,
rvge hospitalization figures in italy are still relevant and generate significant costs to the nhs .
as observed in other countries , the introduction of rv umv in italy might consistently reduce morbidity and associated medical costs .
this is a retrospective population - based study , conducted among all pediatric patients aged < 6 y hospitalized for age in italy , between january 1st 2005 and december 31st 2012 .
the data source was the italian hdd obtained from ministry of health ( processing national hdd , ministry of health , general directorate for health planning , vi office ) .
this database contains administrative and health data regarding hospital admissions , that all public and privately - owned hospitals in italy are legally required to report . for each admission ,
a pd is reported ; this represents the clinical condition which took up the greatest amount of resources and therefore involved the greatest cost for the hospital .
the clinical information is coded by the international icd9-cm system ( international classification of diseases , 9th revision , clinical modification ) , currently used in italy .
gastroenteritis codes include the following : 
 - unspecified etiology gastroenteritis of presumed infectious etiology ( 009009.3 ) and presumed noninfectious etiology ( 558.9);- gastroenteritis with specified etiology : vge ( 008.6169 ) , bacterial gastroenteritis ( 001005 and 008008.5 ) and parasitic gastroenteritis ( 006007 ) .
- unspecified etiology gastroenteritis of presumed infectious etiology ( 009009.3 ) and presumed noninfectious etiology ( 558.9 ) ; - gastroenteritis with specified etiology : vge ( 008.6169 ) , bacterial gastroenteritis ( 001005 and 008008.5 ) and parasitic gastroenteritis ( 006007 ) .
we included all admissions with at least one gastroenteritis related main or secondary discharge diagnosis .
for each of these hospitalizations , we obtained the following data : age , month of admission , costs related to admissions .
each hospitalization cost , on average , has been estimated , according to the theoretical remuneration of admission reported in each hdr provided by diagnosis related group ( drg ) system . even if a specific drg rates for rvge is not available ,
the 3 possible drg codes to which the disease can be referred to ( 184 : esophagitis , gastroenteritis etc . ,  785 ;  298 : symptoms concerning nutrition and metabolism < 18  years ,  1,190 ; 422 : diseases of viral origin and fever of unknown origin ,  1,660 ) were considered .
data provided by the ministry of the health did not contain any patient identifiers and was therefore completely anonymous . hence notification of the study to ethics committees was not applicable , nor was informed consent of patients required . the frequency of hospitalization with a pd of gastroenteritis was calculated as the ratio between patients with any age code in pd over the total aggregate observed in the database . as the rvges are the only vaccine - preventable , for these frequencies and hospitalization rates also in sd were analyzed , to obtain their overall epidemiological picture .
hrs were calculated for every year as the ratio between the number of hospital discharges and the resident populations aged < 6 y per 100,000 .
population data for 20052012 period was obtained from italian institute of statistics ( istat ) , which registers the national population , by age group , as of the january 1 for each year .
the statistical significance of temporal trend of hrs was determined using the analysis of the slope of the regression line between hrs and years of observation .
the authors are grateful to professor flavia carle , general directorate for health planning , vi office , ministry of health , for providing data useful to carry out the analysis .
this research was conducted independently and publishing costs only were supported by an unrestricted grant from glaxosmithkline s.p.a .
 age severity is linked to etiology , and rotavirus ( rv ) accounts for most of severe cases . in 2009 
 the world health organization recommended rv vaccination for all children . 
 worldwide a number of countries implemented rv vaccination in their pediatric immunisation programmes , but only a limited number in europe . 
 this study was designed to estimate the proportion of rvge among children aged < 6 y who were diagnosed with age and admitted to hospitals in italy during the years 20052012 . 
 a total of 334,982 hospital discharge forms were collected , being 79,344 hospitalizations associated with rv . 
 the average hospitalization rate ( hr ) was 146/100,000 children for rvge in primary diagnosis ( pd ) and 150/100,000 children for rvge in secondary diagnosis ( sd ) . since 2008 
 the rvge hospitalization figures and rates ( hrs ) in sd exceed those in pd . 
 the majority of rvge hospitalizations ( 33.67% ) were reported among children aged  2  years . despite some limitations due to the hospital discharge database ( hdd ) synthetic contents and low potential for clinical interpretation , the analysis of national hdd , including pd and sd , documents that rv still represents a consistent cause of pediatric hospitalizations in italy . 