the societal burden of seasonal influenza epidemics is quite heavy , with approximately 3 - 5 million cases and 250,000 - 500,000 estimated deaths worldwide every year   and a large economic impact , which includes both direct and indirect costs [ 2 , 3 ] .
conventionally , attention has been directed toward influenza a , which accounts for the majority of influenza cases in most seasons [ 4 - 7 ] .
since the 1980s , influenza b viruses have belonged to two antigenically distinct lineages , called the victoria and yamagata lineages ; this has constituted a challenge for seasonal influenza vaccines , as only one influenza b strain is included in the trivalent vaccine .
studies in the united states have shown that the frequent influenza b vaccine mismatches of recent years have been associated both with substantial increases in cases , hospitalizations and deaths ( up to 970,000 cases , with 8200 hospitalizations and 485 deaths annually , in the usa ) , and with high influenza - related medical costs and costs due to productivity loss .   despite the important role of influenza b ,
much of the published scientific literature regarding the epidemiology of influenza has focused on influenza a , and we still have a relatively poor understanding of the global epidemiology and disease burden of influenza b. several studies have reported on the burden of disease attributable to influenza b in a single season , or during consecutive seasons in a single country [ 12 , 13 ] . in order to improve our understanding of the burden and epidemiology of influenza b , we reviewed the influenza b viruses circulating in italy from 2000 to 2015 .
in italy , the influenza sentinel surveillance system ( influnet ) was implemented nationwide in the 1999 - 2000 season by the influnet working group .
influnet is based on the voluntary participation of an average of 830 ( range 648 - 902 ) general practitioners ( including paediatricians ) per year , covering about 1.5 - 2% of the national population in all italian regions .
the system aims to monitor the incidence of influenza - like illness ( ili ) and to determine the extent , timing and severity of seasonal epidemics .
gps are asked to report ili cases ( defined as acute onset of fever + respiratory symptoms + one of the following symptoms : headache , general discomfort , asthenia ) weekly ( from week 42 to week 17 ) using standardized forms .
specific information regarding age ( 0 - 14 , 15 - 64 , > 64 years ) and influenza vaccine status are also collected .
we excluded the first years of data collection and focused the analysis on influnet data collected from the 2005/2006 to 2014/2015 seasons .
influenza virological surveillance in italy is routinely carried out , between week 46 and week 17 of the following year , by the national who ( world health organization ) influenza centre at the istituto superiore di sanit ( nic - iss ) , in collaboration with a network of 15 peripheral laboratories located in 14 of the 21 italian regions .
the main objective of these activities is to rapidly characterize the influenza viruses circulating in the country and to identify antigenic variants emerging in human populations during the winter season , in order to update the vaccine composition , in collaboration with the who and ecdc ( european centre for disease prevention and control ) . during the virological surveillance period ,
sampling kits are sent out to a random sample of gps participating in the influnet surveillance system , who collect throat swabs from the first ili patients seen each week .
collected swabs are then sent to the regional reference laboratories for influenza diagnosis , and the isolated strains are characterized at the regional laboratory or directly sent to the nic - iss for further molecular and antigenic analyses .
overall results obtained throughout the country are reported to the niciss weekly by means of web - based electronic forms .
every year , approximately 2000 samples are collected , with a proportion of positive specimens of about 34% .
a web - based data collection form for the surveillance of severe confirmed hospitalised cases and deaths due to pandemic influenza was drawn up in mid - september 2009 . since then
, regional and local authorities have filled in forms during the influenza season ( october - april ) ; the data are analysed weekly at the national level ( by the iss and the ministry of health ) .
our analysis included virological surveillance data collected from the 2010/2011 to 2014/2015 seasons , as all confirmed cases during the 2009/2010 season were due to a / h1n1pdm09 virus .
in italy , the influenza sentinel surveillance system ( influnet ) was implemented nationwide in the 1999 - 2000 season by the influnet working group .
influnet is based on the voluntary participation of an average of 830 ( range 648 - 902 ) general practitioners ( including paediatricians ) per year , covering about 1.5 - 2% of the national population in all italian regions .
the system aims to monitor the incidence of influenza - like illness ( ili ) and to determine the extent , timing and severity of seasonal epidemics .
gps are asked to report ili cases ( defined as acute onset of fever + respiratory symptoms + one of the following symptoms : headache , general discomfort , asthenia ) weekly ( from week 42 to week 17 ) using standardized forms .
specific information regarding age ( 0 - 14 , 15 - 64 , > 64 years ) and influenza vaccine status are also collected .
we excluded the first years of data collection and focused the analysis on influnet data collected from the 2005/2006 to 2014/2015 seasons .
influenza virological surveillance in italy is routinely carried out , between week 46 and week 17 of the following year , by the national who ( world health organization ) influenza centre at the istituto superiore di sanit ( nic - iss ) , in collaboration with a network of 15 peripheral laboratories located in 14 of the 21 italian regions .
the main objective of these activities is to rapidly characterize the influenza viruses circulating in the country and to identify antigenic variants emerging in human populations during the winter season , in order to update the vaccine composition , in collaboration with the who and ecdc ( european centre for disease prevention and control ) . during the virological surveillance period ,
sampling kits are sent out to a random sample of gps participating in the influnet surveillance system , who collect throat swabs from the first ili patients seen each week .
collected swabs are then sent to the regional reference laboratories for influenza diagnosis , and the isolated strains are characterized at the regional laboratory or directly sent to the nic - iss for further molecular and antigenic analyses .
overall results obtained throughout the country are reported to the niciss weekly by means of web - based electronic forms .
every year , approximately 2000 samples are collected , with a proportion of positive specimens of about 34% .
a web - based data collection form for the surveillance of severe confirmed hospitalised cases and deaths due to pandemic influenza was drawn up in mid - september 2009 . since then
, regional and local authorities have filled in forms during the influenza season ( october - april ) ; the data are analysed weekly at the national level ( by the iss and the ministry of health ) .
our analysis included virological surveillance data collected from the 2010/2011 to 2014/2015 seasons , as all confirmed cases during the 2009/2010 season were due to a / h1n1pdm09 virus .
from the 2005/2006 to 2014/2015 seasons , an estimated average number of approximately 4,800.000 ili cases were reported to the surveillance system ( tab .
the national database that was used for the analysis included 40,000 ili cases , with testing of samples from cases that occurred between 2000/2001 and 2011/2012 . during the study period
, several waves of infections by influenza a and b viruses were observed in italy ( fig .
1 ) . in detail , 11,488 influenza cases were confirmed in the study period : 9,842 influenza a cases and 1,646 influenza b cases .
influenza a and b viruses co - circulated during most influenza seasons , with numbers of influenza b infections approaching or exceeding those of influenza a virus during three seasons in the study period considered ( 2001/02 , 2007/08 and 2012/13 ) .
the number of samples tested for influenza viruses by pcr in italy increased by a factor of 1.5 over this period , from an average of 2,774 per season in the period 2000 - 2007 to an average of 4,312 per season in 2008 - 2012 .
influenza b appeared to be relatively more frequent among older children ; a(h1n1)pdm2009 among young and older adults , and a(h3n2 ) among the elderly . on average , the proportion of influenza b cases on the total of tested samples was 23% ( range < 1 - 78% ) ( fig .
2 ) . distribution of estimated influenza - like illness cases and cumulative incidence by season , italy , 2005/2006  2014/2015 . distribution of confirmed severe cases , by influenza virus , italy , 2010/2011  2014/2015 .
number of influenza a and b virus infections , italy , 2000/2001  2011/2012 . influenza b circulation as a proportion of the total percentage of all circulating influenza strains , italy 2001/2002  2010/2011 seasons . from 2010/2011 to 2014/15 , on a total of 1,545 severe confirmed influenza cases reported to the surveillance system ( tab .
i ) , 102 were confirmed influenza b virus - infected individuals admitted to icu ; 2 were pregnant ( both in the third trimester ) ; 7 needed extracorporeal membrane oxygenation ( ecmo ) treatment , and 24 died .
the median age was 63 years ( range 0 - 92 ) , 58 were male , and 16 were vaccinated almost 15 days before symptom onset .
the median age of the individuals who died was 76 ( range 39 - 85 ) . of the 102 severe influenza b patients , 73 belonged to groups recommended for vaccination ( 65 years and older or a clinical risk group ) , but only 16 had actually received the seasonal influenza vaccination . most of the influenza b cases were reported during the 2012/2013 season , when the b virus co - circulated with the a / h1n1pdm09 .
from 2010/2011 to 2014/15 , on a total of 1,545 severe confirmed influenza cases reported to the surveillance system ( tab .
i ) , 102 were confirmed influenza b virus - infected individuals admitted to icu ; 2 were pregnant ( both in the third trimester ) ; 7 needed extracorporeal membrane oxygenation ( ecmo ) treatment , and 24 died .
the median age was 63 years ( range 0 - 92 ) , 58 were male , and 16 were vaccinated almost 15 days before symptom onset .
the median age of the individuals who died was 76 ( range 39 - 85 ) . of the 102 severe influenza b patients , 73 belonged to groups recommended for vaccination ( 65 years and older or a clinical risk group ) , but only 16 had actually received the seasonal influenza vaccination .
most of the influenza b cases were reported during the 2012/2013 season , when the b virus co - circulated with the a / h1n1pdm09 .
our results on influenza b virus infections in italy are timely , in view of the recent introduction of a tetravalent influenza vaccine containing influenza b viruses of both the victoria and yamagata lineages .
our study reveals that influenza b virus was the predominant overall cause of influenza in two of the 13 influenza seasons from 2000/01 through 2012/13
. however , circulation of the b virus during the inter - pandemic season was always demonstrated .
similar patterns of influenza b virus circulation have been described in the us , europe and hong kong [ 12 - 13 ] . in italy , the proportion of influenza b cases in the study period averaged 23% ( range < 1 - 78% ) , a value similar to the european ( 23% ( 1 - 60% ) ) and us ( 24% ( < 1 - 44% ) ) averages . in our study , < 1% of all ili cases are tested for influenza each season , and very few b viruses were antigenically and genetically characterized , thus reducing the opportunity to identify the co - circulation of the two lineages in italy .
however , evidence from two northern italian regions clearly demonstrated a complete or partial mismatch in the 2001/2002 , 2004/2005 , 2005/2006 , 2007/2008 , 2008/2009 , 2010/2011 , and 2011/2012 seasons ; this was almost always due to co - circulation of the two lineages [ 15 - 17 ] .
influenza is generally recognised as an important disease which causes high excess mortality among the elderly , although children have been shown to play an important role in its transmission [ 18 - 19 ] .
unlike the influenza a(h3n2 ) virus , the b virus predominantly infects children and young adults and is generally recognised as a mild influenza virus .
a large study conducted in the us reported that 25% of all influenza - related mortality could be attributed to influenza b virus .
this is higher than the percentage seen in the present study , in which influenza b infections accounted for 6% of all influenza virus - related deaths ( 24/428 ) during the period considered , but is similar to figures reported for scotland . among those admitted to icu with influenza b infections ,
influenza immunisation is recommended in italy for specific groups with an increased risk of complications following influenza infection ( e.g. > 65 years old , > 6 months with chronic conditions , healthcare personnel , pregnant women in their second or third trimester etc . ) .
only 16% of those treated in icu who should have been vaccinated had received the seasonal influenza vaccine , and 70% of those treated in icu were included in the target categories of national recommendations .
the magnitude of the problem created by mismatching between circulating influenza b strains and the influenza b lineage contained in the vaccine varies by season .
the most striking recent examples occurred during the 2005 - 2006 and 2007 - 2008 seasons . in 2005 - 2006 , the influenza b component of the northern hemisphere influenza vaccine was of the b / yamagata lineage , but 81- 91% of the circulating influenza b viruses antigenically characterized in the us and europe were of the b / victoria lineage , and influenza b was found in 34 - 60% of all samples .
similarly , in 2007 - 2008 , the influenza b component of the vaccine was of the b / victoria lineage , but 98 - 99% of the circulating influenza b viruses characterized in the us and europe belonged to the b/ yamagata lineage . unfortunately , as very few b influenza viruses in italy were genotyped , information on the antigenic characteristics of circulating b viruses was not available at the national level .
our study demonstrates that influenza b virus infections are associated with substantial morbidity and that influenza surveillance and interventions including vaccination and treatment are still suboptimal .
incorporating viral and epidemiological data will help obtain more accurate estimates of influenza disease burden and result in a better selection of strategies for influenza prevention and control .
 summarywe describe the burden of influenza b infections in italy over a 12-year study period . influenza a and b viruses co - circulated throughout the period , with numbers of influenza b cases approaching or exceeding those of influenza a during three influenza seasons . 
 influenza b virus infections led to fewer admissions to an intensive care unit ( icu ) and a lower mortality rate than influenza a from 2010 to 2015 . 
 however , only 16% of those admitted to icu with influenza b had been immunized . 
 this highlights the need for consistent influenza vaccination for identified risk groups . 
 our study demonstrates that influenza b virus infections are associated with substantial morbidity and that influenza surveillance and interventions including vaccination and treatment are still suboptimal . 
 our findings have important public health implications . 
 incorporating virus and epidemiological data will help obtain more accurate estimates of influenza disease burden and result in a better selection of influenza prevention and control strategies . 