the annual winter surge in antibiotic utilization , ambulatory visits , hospitalization and mortality associated with respiratory illness has been attributed primarily to influenza virus infection . 
 , 
 , 
  increasingly the contribution of other viruses , particularly respiratory syncytial virus ( rsv ) to respiratory morbidity in older adults is being recognized . 

, 
 , 
 , 
 , 
  rsv is a leading cause of hospitalization for respiratory tract infection in young children . 
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 , 

, 
  previous studies have estimated the mortality associated with influenza and rsv in adults , 
  and prospective surveillance studies of hospital admissions and ambulatory visits for laboratoryconfirmed illness have elucidated the burden of illness and clinical spectrum of disease in certain settings . 

, 

  in canada , detailed records of all hospital discharges have been captured in a national database since 1994 .
we aimed to use a statistical model to estimate the excess admissions attributable to these viruses at the national level and to determine the burden of illness associated with influenzaattributable illness in adults by age and by season , while estimating and controlling for the effects of other respiratory viruses , particularly rsv .
weekly hospital admissions for persons over 19  years of age were extracted from the canadian institute of health information patientspecific hospitalization morbidity database ( hmdb ) 
  for the period september 1994 to august 2000 .
the hmdb contains all cases separated ( discharge or death ) from a hospital in canada .
each discharge record identifies the most responsible diagnosis ( mrd ) for the length of stay and up to 15 additional diagnostic fields .
diagnoses for this period were coded in accordance with the international classification of disease , ninth modification ( icd9cm ) . 
 
the impact of influenza was estimated for various diagnostic groups , selected to illustrate their association with influenza .
the diagnostic group of all primary respiratory admissions ( mrd of icd9 460496 ) was further divided into the following respiratory groups : influenza 487 , pneumonia 480486 , acute respiratory infection 460466 , chronic obstructive pulmonary disease ( copd ) 494496 , and asthma 493 . as congestive heart failure ( chf ) 428 was the only diagnostic category for which a strong association with influenza was found , it was included as a separate group .
the remaining nonrespiratory mrd admissions were divided into two categories where a secondary respiratory admission denoted a nonrespiratory mrd admission with a respiratory complication noted in any of the 15 additional diagnostic fields .
influenzacertified deaths ( icd9 487 ) were obtained from the canadian vital statistics death database . 
 
respiratory virus identifications were obtained from the respiratory virus detection surveillance system , public health agency of canada , which collects weekly data from selected laboratories on numbers of tests performed and numbers positive for influenza a , influenza b , rsv , piv , and adenovirus .
these specimens are submitted by clinicians in the course of clinical care and by sentinel physicians participating in the national influenza surveillance system fluwatch . 

 
denominators for the population at risk were obtained from statistics canada census and intercensus estimates . 

 
weekly admissions , by diagnostic category and age group , were modeled using the poisson regression model framework developed to estimate influenzaattributable hospitalization among children . 
 
poisson regression , similar to multiple linear regression , allows for natural variation in count data 
  and has been used in similar studies . 

a regression approach facilitated the simultaneous estimation of the effects of influenza , rsv , piv , and other viral activity on weekly respiratory admissions while controlling for other factors such as seasonality , holidays , the extended 3week christmas period , population growth , and secular trends toward generally reduced admission rates .
influenzaattributed admissions were calculated as the difference between modelpredicted admissions and the modelpredicted admissions under the hypothetical absence of influenza ( influenza activity variable set to zero ) .
the positive predictive value was calculated for the 4  weeks of peak viral activity for each year as the number of influenzaattributable admissions divided by the total number of admissions . 
general form of the poisson regression model used to model admissions for a variety of causespecific and agespecific groups .
proxy variables for viral activity were developed similar to those used in the pediatric models .
the three surrogate measures for influenza activity  influenza deaths , influenza ( mrd ) admissions ( by age group ) , and laboratoryconfirmed influenza identifications
 described a very similar weekly pattern of activity . to account for seasontoseason differences in the total number of specimens tested and for the relative severity of the strains circulating , the proxy variable for influenza activity ( denoted as inflbase ) was calculated as influenzaattributed admissions ( mrd ) for each age group .
this process normalized annual influenza laboratory confirmations to the annual level of hospital admissions , reflecting the variation in relative severity of the various strains and strain types ( h3n2 , h1n1 , and b ) by age group .
hence , inflbase was similar to weekly laboratoryconfirmed influenza identifications , with additional weight given to strains that resulted in higher morbidity and mortality rates .
for adults , the contribution of influenza b to the proxy variable for influenza activity was minimal .
as no adult mrd category was strongly correlated with rsv identifications , the rsv proxy used in the pediatric model ( rsvattributed bronchiolitis admissions ) was used as the rsv proxy for the adult models .
this rsv proxy corrected for a general increase in the number of samples sent for laboratory identification , particularly from pediatric patients .
it is worth noting that the seasonal pattern of piv activity among adults was distinct from that for children . while the pediatric piv proxy ( related to croup admissions and likely piv1 ) was initially tested with the adult models , its effect was not statistically significant .
these negative identifications were assumed to be due to either other respiratory influenzalike infections , which we termed 
the very strong association of the negative results with influenza and rsv confirmations necessitated the estimation and removal of false negatives . using a similar poisson regression model , negative samples attributed to influenza , rsv , piv , or adenovirus
other ili. results for adenovirus were combined with  other ili to simplify reporting . while the proxies for rsv , piv , and 
other ili have limitations , their inclusion in the model was primarily to assess and reduce the potential for bias in the estimates of influenzaattributed admissions .
hence , results presented here are the results of numerous regression models , and each estimated rate is an independent estimate . where calculated ,
95% confidence intervals are modeledbased . as a reminder that any bias or uncertainty , due in part to potentially omitted confounders or poor proxy variables for viral activity , is not captured in these calculations ,
a linear link function was chosen to maintain a linear relationship between viral activity and attributed hospitalizations ( a doubling of influenza activity results in a doubling of influenzaattributed admissions , not , for example , all respiratory admissions ) . to compensate for the use of linear link , dummy variables were used for the trend instead of a population offset , and the study period was kept short , so that monthly seasonality could be assumed to be constant over this period .
as an alternative to the mbci , influenzaattributed admissions were estimated using slightly different model forms ( for example , including season specific coefficients for influenza activity , or the removal of the  other ili covariate ) , providing a range , which was somewhat larger than the confidence intervals .
weekly hospital admissions for persons over 19  years of age were extracted from the canadian institute of health information patientspecific hospitalization morbidity database ( hmdb ) 
  for the period september 1994 to august 2000 .
the hmdb contains all cases separated ( discharge or death ) from a hospital in canada .
each discharge record identifies the most responsible diagnosis ( mrd ) for the length of stay and up to 15 additional diagnostic fields .
diagnoses for this period were coded in accordance with the international classification of disease , ninth modification ( icd9cm ) . 
 
the impact of influenza was estimated for various diagnostic groups , selected to illustrate their association with influenza .
the diagnostic group of all primary respiratory admissions ( mrd of icd9 460496 ) was further divided into the following respiratory groups : influenza 487 , pneumonia 480486 , acute respiratory infection 460466 , chronic obstructive pulmonary disease ( copd ) 494496 , and asthma 493 . as congestive heart failure ( chf ) 428 was the only diagnostic category for which a strong association with influenza was found , it was included as a separate group .
the remaining nonrespiratory mrd admissions were divided into two categories where a secondary respiratory admission denoted a nonrespiratory mrd admission with a respiratory complication noted in any of the 15 additional diagnostic fields .
influenzacertified deaths ( icd9 487 ) were obtained from the canadian vital statistics death database . 
 
respiratory virus identifications were obtained from the respiratory virus detection surveillance system , public health agency of canada , which collects weekly data from selected laboratories on numbers of tests performed and numbers positive for influenza a , influenza b , rsv , piv , and adenovirus .
these specimens are submitted by clinicians in the course of clinical care and by sentinel physicians participating in the national influenza surveillance system fluwatch . 

 
denominators for the population at risk were obtained from statistics canada census and intercensus estimates . 


weekly admissions , by diagnostic category and age group , were modeled using the poisson regression model framework developed to estimate influenzaattributable hospitalization among children . 
 
poisson regression , similar to multiple linear regression , allows for natural variation in count data 
  and has been used in similar studies . 

a regression approach facilitated the simultaneous estimation of the effects of influenza , rsv , piv , and other viral activity on weekly respiratory admissions while controlling for other factors such as seasonality , holidays , the extended 3week christmas period , population growth , and secular trends toward generally reduced admission rates .
influenzaattributed admissions were calculated as the difference between modelpredicted admissions and the modelpredicted admissions under the hypothetical absence of influenza ( influenza activity variable set to zero ) .
the positive predictive value was calculated for the 4  weeks of peak viral activity for each year as the number of influenzaattributable admissions divided by the total number of admissions . 
general form of the poisson regression model used to model admissions for a variety of causespecific and agespecific groups .
proxy variables for viral activity were developed similar to those used in the pediatric models .
the three surrogate measures for influenza activity  influenza deaths , influenza ( mrd ) admissions ( by age group ) , and laboratoryconfirmed influenza identifications
 described a very similar weekly pattern of activity . to account for seasontoseason differences in the total number of specimens tested and for the relative severity of the strains circulating
, the proxy variable for influenza activity ( denoted as inflbase ) was calculated as influenzaattributed admissions ( mrd ) for each age group .
this process normalized annual influenza laboratory confirmations to the annual level of hospital admissions , reflecting the variation in relative severity of the various strains and strain types ( h3n2 , h1n1 , and b ) by age group .
hence , inflbase was similar to weekly laboratoryconfirmed influenza identifications , with additional weight given to strains that resulted in higher morbidity and mortality rates . for adults ,
as no adult mrd category was strongly correlated with rsv identifications , the rsv proxy used in the pediatric model ( rsvattributed bronchiolitis admissions ) was used as the rsv proxy for the adult models .
this rsv proxy corrected for a general increase in the number of samples sent for laboratory identification , particularly from pediatric patients .
it is worth noting that the seasonal pattern of piv activity among adults was distinct from that for children . while the pediatric piv proxy ( related to croup admissions and likely piv1 ) was initially tested with the adult models , its effect was not statistically significant .
these negative identifications were assumed to be due to either other respiratory influenzalike infections , which we termed  other ili , or to falsenegative results .
the very strong association of the negative results with influenza and rsv confirmations necessitated the estimation and removal of false negatives . using a similar poisson regression model , negative samples attributed to influenza , rsv , piv , or adenovirus
other ili. results for adenovirus were combined with  other ili to simplify reporting . while the proxies for rsv , piv , and  other ili have limitations , their inclusion in the model was primarily to assess and reduce the potential for bias in the estimates of influenzaattributed admissions .
hence , results presented here are the results of numerous regression models , and each estimated rate is an independent estimate . where calculated ,
95% confidence intervals are modeledbased . as a reminder that any bias or uncertainty , due in part to potentially omitted confounders or poor proxy variables for viral activity , is not captured in these calculations ,
a linear link function was chosen to maintain a linear relationship between viral activity and attributed hospitalizations ( a doubling of influenza activity results in a doubling of influenzaattributed admissions , not , for example , all respiratory admissions ) . to compensate for the use of linear link , dummy variables were used for the trend instead of a population offset , and the study period
was kept short , so that monthly seasonality could be assumed to be constant over this period . as an alternative to the mbci
, influenzaattributed admissions were estimated using slightly different model forms ( for example , including season specific coefficients for influenza activity , or the removal of the  other ili covariate ) , providing a range , which was somewhat larger than the confidence intervals .
of an average 170  000 adult primary respiratory admissions per year , 14  00017  000 admissions ( or 810% ) could be attributed to influenza , corresponding to an annual rate of 6080 per 100  000 adult population .
rsv , piv and adenovirus each accounted for 23% of the annual adult respiratory admissions , and  other ili another 4% . in total
annual rates of admissions attributed to these viruses are summarized by age group in table  1 , where the range includes the range of variation that was observed by using slightly different model forms plus their 95% mbci .
the influenzaattributed rate corresponding to the model given in figure  1 was 65/100  000 adult population per year ( 95% mbci 6367 ) , and ranged from 20 to 92/100  000 for mild and severe seasons , respectively . 
estimated average annual rate of respiratory admissions for adults attributed to influenza , rsv , piv , adenovirus and other influenza like illness for 1994/19981999/2000 , canada rsv , respiratory syncytial virus ; piv , parainfluenza ; ili , influenzalike infection . * three of six seasons unusually severe for influenza .
average annual rates of admission attributable to influenza , rsv , parainfluenza , and  other ili by 5year age groups show that hospitalization rates are steady for all viruses until age 5054 and then increase steadily ( figure  2 ) . by age 6569
there are over 100 hospitalizations per 100  000 population attributable to influenza and 80/100  000 attributable to rsv . by age 85 the average influenzaattributable hospitalization rate
had increased to 650/100  000 , while the effects of rsv remained relatively stable in older adults at 100/100  000 . 
hospital admission rates attributable to viral agent and 5year age group for six respiratory seasons ( 1994/19951999/2000 ) .
pneumonia was the main diagnostic category for influenzaattributable admissions at all ages ( table  2 ) .
rsvattributed hospitalizations were most commonly associated with a diagnosis of pneumonia in younger adults , but in those 65  years rsv was often associated with copd , and other primary respiratory conditions ( bronchitis , emphysema ) as well as pneumonia .  estimated annual number of hospitalizations attributed to influenza , rsv , piv , and other influenzalike illness by most responsible diagnoses for 1994/19981999/2000 , canada rsv , respiratory syncytial virus ; piv , parainfluenza ; ili , influenzalike infection ; ari , acute respiratory infections ; copd , chronic obstructive pulmonary disease . * significant at 5% level of significance . 

ppv is positive predictive value  =  influenzaattributable admissions / total admissions over four peak weeks of influenza activity . 

nonrespiratory , excludes congestive heart failure above , and admissions with any secondary respiratory complication .
although a pneumonia mrd accounted for the largest proportion of influenzaattributable admissions ( 40% for seniors ) , a pneumonia mrd admission was no more predictive of influenza during peak activity than other respiratory mrds .
of admissions for a chronic condition without any accompanying respiratory diagnosis , only admissions with an mrd of chf were found to be associated with the level of influenza activity . for other admissions where the mrd was nonrespiratory , an increase in admissions with respiratory complications
was observed during periods of influenza activity , while admissions without any indication of respiratory complications decreased , as would be expected if some elective admissions were cancelled because of influenza , and other patients were admitted with influenza , but for other reasons ( table  2 ) .
the net reduction on all nonrespiratory mrd admissions during periods of influenza activity was estimated to be only 01% of annual admissions .
agespecific influenzaattributed rates , by an arbitrary classification of each season into mild , moderate , and severe , were plotted ( figure  3 ) to show the yeartoyear variation in hospitalization rates .
the three severe seasons ( 1997/98 , 1998/99 and 1999/2000 ) were primarily h3n2 ( a / sydney ) , the moderate seasons ( 1994/95 and 1996/97 ) were also h3n2 seasons , while for the mild season ( 1995/96 ) , h3n2 circulated very late in the season , and h1n1 was identified earlier in the season . in the oldest age groups rates varied by as much as sixfold . however , over all six interpandemic seasons , the same pattern of increasing hospitalization rates with older age was observed .
the severe season curve is smoothest , as the study period included three severe seasons , two moderate , and only one mild season . 
the excellent model fit is illustrated in figure  4 where weekly respiratory admissions in adults over 65  years are plotted along with their predicted values , and the modelestimated baseline .
the spike in admissions over the christmas period is seen in the baseline curve , though not in influenzaattributed admissions .
the seasonal pattern of influenzaattributed admissions is contrasted with admissions attributed to other viruses . 
weekly admissions for primary respiratory conditions and the attribution to influenza and other influenza like viruses among seniors aged 65 + , canada .
the large burden of influenza in older adults , as indicated by utilization of hospital resources , is confirmed in this national study over six winter seasons .
notably , we have taken an approach that captures the burden of illness associated with institutional care that is hidden in clinical presentations not explicitly coded or recognized as being attributable to influenza infection , and have sought to account for the effect of other circulating respiratory viruses , particularly rsv .
we also demonstrate a large seasontoseason variation in influenza burden in which agerelated risk is preserved among older adults .
this variation highlights the need for the development of a nimble surge capacity in institutions during the winter respiratory season .
previous work has demonstrated that influenza is probably the primary determinant of annual increases in winterseason mortality 
 , 
  and quantified the burden of mortality attributable to influenza and rsv . 

, 
  thompson et  al . estimated influenzaattributable admissions using poisson regression to model all respiratory admissions , and included a proxy for influenza activity but not other viral activity . 
 
other ili activity resulted in only a marginal reduction in the number of admissions attributable to influenza .
notably , the inclusion of a proxy variable for  other ili reduced the number of admissions attributed to rsv and these broader uncertainties due to model form are reflected in the broad ranges given in table  1 .
a number of other model refinements contributed to a better model fit , and allowed us to estimate influenzaattributable admissions for subgroups with a smaller number of weekly admissions .
our influenza proxy based on the number of specimens confirmed positive for influenza , rather than proportion positive , captured peak influenza activity better , with implications for the selection of indicators of annual influenza activity . as evident in figure  4 , the baseline curve is not entirely sinusoidal , and the additional seasonal parameters captured the early autumn increase in asthma admissions , and holiday indicators captured the excess admissions over the christmas period . that subgroup estimates ( finer age or diagnostic groups ) were consistent with group totals substantiates model validity .
it is difficult to assess whether studies that have used the periseasonal baseline approach 
 , 
  were able to adequately correct for the seasonality of other viral agents or even other causes of seasonality .
although the largest adult burden of influenza and rsv occurs in adults 65  years of age ( 270340 and 30110 admissions/100  000 population per year , respectively ) , the agerelated increase in admissions begins in adults at age 50 .
further analyses of comorbidities should identify whether age > 50 itself places a person at risk , or whether the risk is limited to persons with chronic illness .
the united states includes this younger age group in its targeted annual influenza immunization program 
  because of an increased prevalence of highrisk conditions , as 50 is the age at which routine assessment and other preventive services are recommended , and because agebased strategies are thought to be more successful in increasing vaccine coverage than patient selection strategies based on medical conditions .
however , in most of the 50 countries with governmentfunded national influenza immunization programs , including canada , this group is not recommended for annual vaccine . 
 
targets for influenza vaccine coverage rates in persons over 65 have been met for 2001 
  in this country , suggesting that improving protection of this population will not be achieved through immunization alone .
other strategies to decrease the burden of influenza in the elderly include immunization of careproviders and other contacts , antiviral prophylaxis and treatment , and other infection control measures . 

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  our study adds to the growing body of literature indicating that rsv is a significant cause of respiratory illness in older persons , 
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  and is an appreciable cause of hospitalization as early as the sixth decade of life . in a review of etiologic studies of adult pneumonia hospitalizations , han et  al . 

 
estimated that 29% of hospitalizations for pneumonia in adults over 65  years in the us are associated with rsv . while we found similar numbers of rsvattributable admissions in patients with chf , pneumonia , copd and asthma as did falsey et  al . in a prospective laboratoryconfirmed study , 
  we also identified rsvattributable admissions among unspecified acute respiratory admissions ( icd9 465 ) and acute as well as chronic bronchitis ( table  2 ) .
improved case finding by clinicians and surveillance for rsvassociated illness in this age group would increase the accuracy of disease burden estimates .
our study is limited by the lack of laboratory viral identification data specific to the hospitalized population by age group , and the expected poor test sensitivity for viral confirmation 
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  complicated by a delay between onset of symptoms on clinical presentation . 
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  samples negative for influenza , rsv , piv , and adenovirus are an incomplete surrogate for the many other viruses that circulate annually ; however , working with this series was illustrative of the low sensitivities for routine laboratory tests as well as the potential for other viruses to cause considerable morbidity .
piv and adenovirus likely contribute to considerable adult respiratory morbidity , as well as other viruses such as rhinovirus and metapneumovirus that are known to cause illness in children .
all authors revised the manuscript critically , and all approved the final version that was submitted .
 
 objective   we sought to estimate agespecific hospitalization rates attributed to influenza and other virus for adults . 
 
 methods   admissions from canada s national hospitalization database ( canadian institute of health information ) , from 1994/95 to 1999/2000 , were modeled as a function of proxy variables for influenza , respiratory syncytial virus ( rsv ) and other viral activity , seasonality and trend using a poisson regression model and stratified by age group . 
 
 results   the average annual influenzaattributed hospitalization rate for all adults , 20  years of age or older , over the study period , which included three severe seasons , was an estimated 65/100  000 population ( 95% ci 6367 ) . among persons aged 65 and over , 270340 admissions per 100  000 population per year were attributed to influenza , while 30110 , 6090 and 130350 per 100  000 were attributed to rsv , parainfluenza ( piv ) and other respiratory viruses , respectively . 
 although marked seasontoseason variation in agespecific hospitalization rates attributable to influenza was observed in persons 50  years of age and older , increasing risk with age was preserved at all time periods . 
 
 conclusions   influenza , rsv , piv and other respiratory viruses were all associated with morbidity requiring hospitalization , while influenza was responsible for peak respiratory admissions . 
 the burden of health care utilization associated with respiratory viruses is appreciable beginning in the sixth decade and increases significantly with age . 
Introduction
Methods
Sources of data
Statistical analysis
Results
Discussion
Author contribution