Context Influenza and respiratory syncytial virus (RSV) cause substantial morbidity
and mortality. Statistical methods used to estimate deaths in the United States
attributable to influenza have not accounted for RSV circulation.
Objective To develop a statistical model using national mortality and viral surveillance
data to estimate annual influenza- and RSV-associated deaths in the United
States, by age group, virus, and influenza type and subtype.
Design, Setting, and Population Age-specific Poisson regression models using national viral surveillance
data for the 1976-1977 through 1998-1999 seasons were used to estimate influenza-associated
deaths. Influenza- and RSV-associated deaths were simultaneously estimated
for the 1990-1991 through 1998-1999 seasons.
Main Outcome Measures Attributable deaths for 3 categories: underlying pneumonia and influenza,
underlying respiratory and circulatory, and all causes.
Results Annual estimates of influenza-associated deaths increased significantly
between the 1976-1977 and 1998-1999 seasons for all 3 death categories (P<.001 for each category). For the 1990-1991 through
1998-1999 seasons, the greatest mean numbers of deaths were associated with
influenza A(H3N2) viruses, followed by RSV, influenza B, and influenza A(H1N1).
Influenza viruses and RSV, respectively, were associated with annual means
(SD) of 8097 (3084) and 2707 (196) underlying pneumonia and influenza deaths,
36 155 (11 055) and 11 321 (668) underlying respiratory and
circulatory deaths, and 51 203 (15 081) and 17 358 (1086) all-cause
deaths. For underlying respiratory and circulatory deaths, 90% of influenza-
and 78% of RSV-associated deaths occurred among persons aged 65 years or older.
Influenza was associated with more deaths than RSV in all age groups except
for children younger than 1 year. On average, influenza was associated with
3 times as many deaths as RSV.
Conclusions Mortality associated with both influenza and RSV circulation disproportionately
affects elderly persons. Influenza deaths have increased substantially in
the last 2 decades, in part because of aging of the population, underscoring
the need for better prevention measures, including more effective vaccines
and vaccination programs for elderly persons.
Influenza infections result in substantial morbidity and mortality nearly
every year1,2 and estimates of
this burden have played a pivotal role in formulating influenza vaccination
policy in the United States.3 However, numbers
of deaths attributable to influenza are difficult to estimate directly because
influenza infections typically are not confirmed virologically or specified
on hospital discharge forms or death certificates. In addition, many influenza-associated
deaths occur from secondary complications when influenza viruses are no longer
detectable.4,5 Nonetheless, wintertime
influenza epidemics have been shown to be associated with increased hospitalizations
and mortality for many diagnoses, including congestive heart failure, chronic
obstructive pulmonary disease, pneumonia, and bacterial superinfections.6-9
Respiratory syncytial virus (RSV) epidemics often overlap with influenza
epidemics,8,10 and RSV infections
have been associated with substantial morbidity and mortality in young children
and more recently in older adults.10-14 Like
influenza, RSV infections can precipitate both cardiac and pulmonary complications.15-17 Respiratory syncytial
virus infections are rarely diagnosed in adults, in part because available
rapid antigen-detection tests are insensitive in adults and few tests for
RSV are requested for this age group by medical practitioners.16,18 It
is likely that some deaths previously attributed to influenza are actually
associated with RSV infection.13,14,19
In this study, we provide age-specific estimates of deaths attributable
to influenza, by virus type and subtype, and to RSV using Poisson regression
models that incorporates national respiratory viral surveillance data. Recent
deliberations of the Advisory Committee on Immunization Practices (ACIP) regarding
influenza vaccination recommendations3 guided
our choice of age groups for these analyses.
Definition of Respiratory Season
Influenza and RSV typically circulate during winter months and across
calendar years. Therefore, we defined each annual respiratory season as the
period from July 1 through June 30 of the following year.
National Viral Surveillance Data
In the United States, laboratory-based surveillance for influenza viruses
is conducted from October through mid-May (calendar week 40 through week 20).
For the influenza virus surveillance periods from the 1976-1977 through 1998-1999
seasons, we obtained numbers of influenza virus isolates reported weekly by
50 to 75 World Health Organization collaborating virology laboratories in
the United States to the Influenza Branch of the Centers for Disease Control
and Prevention (CDC). The collaborating laboratories provided weekly numbers
of total respiratory specimens tested for influenza and positive-influenza
isolates by virus type and subtype20 (Table 1).
Weekly RSV data were obtained from the National Respiratory and Enteric
Virus Surveillance System for the 1990-1991 through 1998-1999 seasons. During
this period, 63 to 72 clinical and public health laboratories in 44 states
reported to CDC weekly numbers of specimens tested for RSV by antigen-detection
and viral-isolation methods and numbers of positive results.21 We
used the results of both antigen-detection and isolation tests to determine
the circulation pattern of RSV. The weekly percentages of specimens that tested
positive for both influenza and RSV were used in estimating the association
of virus circulation with weekly deaths in the United States (Table 1).
Mortality Data and Outcomes
National mortality data were obtained from the National Center for Health
Statistics (NCHS).22 Deaths were categorized
using the International Classification of Diseases, Ninth
Revision (ICD-9) codes for NCHS mortality data obtained from 1976 through
1998.23 The International
Classification of Diseases, 10th Revision (ICD-10) was used for classifying
NCHS mortality data obtained for 1999.24 Analyses
were based on the underlying cause-of-death because it represents the disease
or injury that initiated the chain of morbid events that led directly to the
death.25 The change from ICD-9 to ICD-10 in January 1999 resulted in
a 30% decrease in the number of coded underlying pneumonia deaths.26 Therefore, all analyses of underlying pneumonia and
influenza deaths were carried out using data collected through the 1997-1998
season, which limited the analyses to ICD-9 coded
deaths.
The 3 death categories modeled were underlying pneumonia and influenza
deaths (ICD-9 codes 480-487), underlying respiratory
and circulatory deaths (ICD-9 codes 390-519 and ICD-10 codes I00-I99, J00-J99), and all-cause deaths (all ICD codes). Underlying pneumonia and influenza deaths exclude
some deaths, such as those related to exacerbations of underlying cardiac
and pulmonary conditions, which are associated with both influenza and RSV
infections.6,18 Influenza-associated
all-cause death estimates have been previously used to represent the full
spectrum of deaths associated with influenza infections.1,2 However,
these estimates include deaths such as those caused by fires and motor vehicle
crashes, which are not directly associated with respiratory viral infections.
Therefore, we also modeled a third category of deaths, underlying respiratory
and circulatory deaths (which includes pneumonia and influenza deaths), to
provide an estimate of deaths that was more directly associated with viral
respiratory infections. These estimates would be expected to be more sensitive
than estimates using underlying pneumonia and influenza deaths and more specific
than estimates using all-cause deaths.
For the influenza model, we developed an age-specific Poisson regression
model that used weekly influenza circulation data. Deaths were stratified
into the following 5 age groups: younger than 1 year, 1 to 4 years, 5 to 49
years, 50 to 64 years, and 65 years or older. Influenza-associated deaths
were estimated for influenza A(H1N1), A(H3N2), and B viruses. The viral circulation
terms represented percentages of specimens testing positive for each of the
3 influenza virus types and subtypes during a particular week. Estimates of
the weekly age-specific population size were used to account for changes in
population trends over time. The US population estimates by age group were
obtained from the US Census Bureau.27
For the influenza and RSV model, we used a model identical to the influenza
model except it included an additional coefficient for RSV viral circulation.
The full model was written as follows:
Y = α exp{β0 + β1[t] + β2[t2] + β3[sin(2π/52)] + β4[cos(2π/52)] + β5[A(H1N1)] + β6[A(H3N2)]
+ β7[B] + β8[RSV]}
where Y represents the number of deaths during a particular week for
a specific age group, α is the offset term and is equal to the log of
the age-specific population size, β0 represents the intercept, β1 accounts for the linear time trend, β2 accounts for
nonlinear time trends, β3 and β4 account for
seasonal changes in deaths, and β5 through β8 represent
coefficients associated with the percentage of specimens testing positive
for a given week.
We fit the influenza model to national influenza surveillance data available
from the 1976-1977 through 1998-1999 seasons. The influenza and RSV model
was fit to data available from the 1990-1991 through 1998-1999 seasons, when
both weekly influenza and RSV data were available (PROC GENMOD, SAS, version
8.2; SAS Institute Inc, Cary, NC).
Annual Influenza and RSV Laboratory Surveillance
National influenza and RSV surveillance data are summarized in Table 1. Influenza isolate data were available
for the 1976-1977 through 1998-1999 seasons. A mean of 27 360 specimens
(range, 13 275-52 505) was tested for influenza viruses during each
of the influenza surveillance periods (October through May). During weeks
that testing for influenza occurred, an average of 12% of specimens tested
positive for influenza. Influenza A(H1N1), A(H3N2), and B viruses, respectively,
comprised 15%, 60%, and 25% of the positive influenza isolates. From the 1990-1991
through 1997-1998 season, the annual mean number of specimens tested for RSV
was 107 711 (range, 67 374-133 648) with an average of 17 220
specimens (16%) testing positive each season for RSV.
Annual US Deaths by Underlying Diagnosis
From the 1976-1977 through 1998-1999 seasons, there was an annual mean
of 69 140 (range, 47 133-90 895) underlying pneumonia and influenza
deaths, 1 135 724 (range, 1 069 560-1 203 728)
underlying respiratory and circulatory deaths, and 2 126 740 (range,
1 879 039-2 407 494) all-cause deaths. The numbers of
deaths in each of these categories increased linearly during this period.
From the 1976-1977 through 1997-1998 seasons, underlying pneumonia and influenza
deaths increased by 83%, substantially more than underlying respiratory and
circulatory deaths or all-cause deaths (11% and 28%, respectively). From the
1990-1991 through 1998-1999 seasons, there was an annual mean of 82 239
(range, 74 872-90 895) underlying pneumonia and influenza deaths,
1 158964 (range, 1098 086-1203 728) underlying respiratory
and circulatory deaths, and 2 277 268 (range, 2 135 976-2 407 494)
all-cause deaths.
Annual Influenza-Associated Deaths From the 1976-1977 Through 1998-1999
Seasons Using the Influenza Model
The mean annual estimates of underlying pneumonia and influenza deaths,
underlying respiratory and circulatory deaths, and all-cause deaths associated
with influenza were 5977, 25 420, and 34 470 (Table 2). Each of these 3 estimates increased significantly during
the study period (P<.001 for trend for all 3 death
categories).
Annual Influenza- and RSV-Associated Deaths From the 1990-1991 Through
1998-1999 Seasons Using the Influenza and RSV Model
For underlying pneumonia and influenza deaths, we estimated an annual
mean of 8097 (SD, 3084; range, 3515-13 033) influenza-associated deaths,
representing 9.8% (8097/82 239) of these deaths (Table 3). Influenza A(H1N1), A(H3N2), and B viruses were associated
with annual means of 381 (SD, 617; range, 0-1742), 6613 (SD, 3928; range,
944-12 941), and 1103 (SD, 1030; range, 53-2619) deaths, respectively.
Respiratory syncytial virus was associated with an annual mean of 2707 (SD,
196; range 2336-2880) deaths or 3.3% (2707/82 239) of all such deaths.
The year-to-year variation in influenza-associated deaths was higher than
the year-to-year variation in RSV-associated deaths.
For underlying respiratory and circulatory deaths, we estimated an annual
mean of 36 155 (SD, 11 055; range, 17 056-51 296) influenza-associated
deaths, representing 3.1% (36 155/1 158 964) of these deaths.
Influenza A(H1N1), A(H3N2), and B viruses were associated with annual means
of 1960 (SD, 3372; range, 0-10 080), 28 940 (SD, 14 848; range,
4435-50 855), and 5255 (SD, 4513; range, 253-12 067) deaths, respectively.
Respiratory syncytial virus was associated with an annual mean of 11 321
(SD, 668; range, 10 047-12 385) deaths or 1.0% (11 321/1 158 964)
of all such deaths.
For all-cause deaths, we estimated an annual mean of 51 203 (SD,
15 081; range, 25 570-71 416) influenza-associated deaths,
representing 2.2% (51 203/2 277 268) of these deaths. Influenza
A(H1N1), A(H3N2), and B viruses were associated with annual means of 2836
(SD, 4909; range, 0-14 727), 40 017 (SD, 20 656; range, 6033-70 701),
and 8349 (SD, 7105; range, 404-19 030) deaths, respectively. Respiratory
syncytial virus was associated with an annual mean of 17 358 (SD, 1086;
range, 15 464-19 262) deaths or 0.8% (17 358/2 277 268)
of all such deaths. Influenza-associated deaths again showed higher year-to-year
variability than did RSV-associated deaths.
Age-Specific Annual Influenza and RSV-Associated Deaths From the 1990-1991
Through 1998-1999 Seasons Using the Influenza and RSV Model
In children younger than 1 year, RSV was associated with annual means
of 124 underlying pneumonia and influenza deaths, 211 underlying respiratory
and circulatory deaths, and 214 all-cause deaths (Table 4). In this age group, influenza viruses were associated with
annual means of 13 underlying pneumonia and influenza deaths, 26 underlying
respiratory and circulatory deaths, and 88 all-cause deaths. There were more
influenza-associated deaths relative to RSV-associated deaths among children
aged 1 to 4 years for all 3 death categories.
Among underlying pneumonia and influenza deaths, 90% (7326/8097) of
influenza-associated deaths and 88% (2388/2707) of RSV-associated deaths occurred
among persons aged 65 years or older. For underlying respiratory and circulatory
deaths, 90% (32 651/36 155) of influenza-associated deaths and 78%
(8811/11 321) of RSV-associated deaths occurred among persons aged 65
years or older. For all-cause deaths, 43 979 and 9812 all-cause deaths
were attributable to influenza and RSV, respectively.
Age-Specific Mortality Rates
Annual mean influenza-associated mortality rates for underlying pneumonia
and influenza deaths, underlying respiratory and circulatory deaths, and all-cause
deaths were 3.1, 13.8, and 19.6 per 100 000 person-years, respectively
(Table 5). Similarly, annual mean
RSV-associated mortality rates for these death categories were 1.0, 4.3, and
6.6 per 100 000 person-years, respectively. The relative risks (RRs)
and 95% confidence intervals (CIs) comparing influenza mortality rates with
RSV mortality rates for the 3 death categories were 3.0 (95% CI, 2.9-3.1),
3.2 (95% CI, 3.1-3.3), and 2.9 (95% CI, 2.9-3.0), respectively.
Annual mean influenza-associated mortality rates for underlying pneumonia
and influenza deaths in persons younger than 1 year, 1 to 4 years, 5 to 49
years, 50 to 64 years, and 65 years or older were 0.3, 0.2, 0.2, 1.3, and
22.1 deaths per 100 000 person-years, respectively. The RSV-associated
mortality rates for underlying pneumonia and influenza deaths in persons younger
than 1 year, 1 to 4 years, 5 to 49 years, 50 to 64 years, and 65 years or
older were 3.1, 0.1, <0.1, 0.5, and 7.2 deaths per 100 000 person-years,
respectively. For children younger than 1 year, the RR for RSV vs influenza
mortality rates was 9.5 (95% CI, 5.4-16.9) for underlying pneumonia and influenza
deaths and 8.1 (95% CI, 5.4-12.2) for underlying respiratory and circulatory
deaths. For all-cause deaths, the RR among this age group was substantially
lower (RR, 2.4; 95% CI, 1.9-3.1).
Age-Specific Mortality Rates Among Persons 65 Years or Older
Periseason influenza rate-difference models10 were
fit to the 1976-1977 through the 1998-1999 seasons and revealed substantial
differences in relative influenza-attributable mortality rates among elderly
persons. Persons aged 85 years or older were 32 times more likely to die of
an influenza-associated underlying pneumonia and influenza death compared
with persons aged 65 to 69 years (RR, 32.1; 95% CI, 31.3-32.9). Persons aged
85 years or older were 16 times more likely to die of an influenza-associated
all-cause death compared with persons aged 65 to 69 years (RR, 14.8; 95% CI,
14.6-14.9). However, there were no statistically significant increases in
any of the 5-year age-specific mortality rates from the 1976-1977 through
the 1998-1999 seasons (P>.05 for all).
The number of persons aged 65 years or older increased substantially
between the 1976-1977 and 1998-1999 seasons.27 During
the 1990s, the growth rate for the number of persons aged 50 to 64 years also
increased substantially relative to the period from 1976 through 1990.27
Morbidity and mortality associated with seasonal epidemics of influenza
in the United States have provided the impetus for public health policies
and strategies to control influenza infections, particularly among specific
target groups.3 Mortality associated with influenza
can vary dramatically by season and models developed to assess influenza-associated
mortality date back to 1847.28 These approaches
have been feasible because well-defined peaks in deaths occur in association
with influenza outbreaks in temperate countries. In the recent past, the CDC
has used a linear regression model, applied to either complete national mortality
data or more immediately available mortality surveillance data from 122 cities,
to estimate annual deaths associated with influenza.1,2 The
influenza and RSV model presented in this study will be used to provide future
estimates of influenza-associated mortality in the United States, because
the model permits estimates of influenza subtype-specific mortality and also
simultaneously estimates RSV-associated mortality.
Our results indicate that US influenza-associated deaths have increased
substantially from the 1976-1977 through 1998-1999 seasons. We believe this
is explained in part by the aging of the US population. Between 1976 and 1999,
the number of persons aged 85 years or older doubled in the United States.29 We found that persons in this age group were 16 times
more likely to die of an influenza-associated all-cause death than persons
aged 65 to 69 years during a period in which all-cause age-specific death
rates have remained stable. Other studies have also shown that influenza-attributable
mortality rates increased rapidly with age among persons aged 65 years or
older.30-32 For
example, Nordin et al32 found that persons
aged 75 years or older were 3 to 9 times more likely to die from influenza
infections than persons aged 65 to 74 years. Another important factor contributing
to the increase in influenza-associated deaths during the 1990s was the predominance
of influenza A(H3N2) viruses, the most virulent of the recently circulating
influenza viruses. Influenza A(H3N2) viruses were 1 of the predominant strains
in 8 of 9 seasons we analyzed during the 1990s.
The influenza and RSV model confirmed that influenza A(H3N2) viruses
were associated with the highest attributable mortality rates, followed by
RSV, influenza B, and influenza A(H1N1) viruses. The annual effect of RSV
on mortality was relatively stable, although the numbers of deaths associated
with influenza viruses varied substantially, depending on the predominant
circulating virus type or subtype. In this study, RSV was the most common
viral cause of death in children younger than 5 years, particularly in children
younger than 1 year. However, RSV-associated mortality rates were higher in
elderly persons and substantially more RSV-associated deaths occurred among
elderly persons than among young children.
Determining the most appropriate death category for characterizing the
burden of influenza on mortality is difficult. Pneumonia and influenza deaths
are highly correlated with the circulation of influenza, and these estimates
are useful for monitoring year-to-year trends and variability in the severity
of influenza seasons. However, this death category underestimates the total
burden of influenza because many deaths are caused by other secondary complications
of influenza (eg, congestive heart failure).7 Traditionally,
all-cause deaths have been used to estimate the total burden of influenza
on mortality.1,2 However, this
death category is also not ideal because it includes deaths that are not causally
linked with respiratory viral infections. Therefore, we analyzed underlying
respiratory and circulatory deaths to provide a more specific estimate of
the total burden of influenza and RSV on mortality. Our estimate of annual
mean influenza-associated underlying respiratory and circulatory deaths was
36 155 (29% lower than the annual mean all-cause estimate).
The Poisson regression models used to estimate influenza- and RSV-associated
deaths were more complex compared with previous influenza models, but the
models also provided more specific estimates, including independent estimates
of deaths associated with influenza and RSV. The model we used in this study
is capable of incorporating additional factors that could not be included
in the previous CDC model, such as temperature, that might independently influence
winter season mortality. Therefore, we believe this new model represents a
step forward in current efforts to better understand the burden of viral respiratory
infections on mortality.
We applied the new model to age groups relevant to policy deliberations
by ACIP regarding influenza-vaccination recommendations for persons younger
than 5 years and persons 50 to 64 years.3 Currently,
ACIP recommends annual influenza vaccination for all persons aged 65 years
or older. Because most influenza-associated deaths occur in persons aged 65
years or older, understanding age-specific effects within this age group is
also of considerable interest. As a first step, we fit simple periseason rate
difference models among those aged 65 years or older by 5-year age intervals
and demonstrated increases with age in influenza-associated mortality. Future
research will focus attention on ACIP discussions regarding age-specific vaccination
policy.
We believe the results of this study have important policy implications.
Deaths associated with viral respiratory infections have increased substantially
during the past decade and it appears that they will continue to increase
as the population continues to age. Increased numbers of patients with serious
respiratory infections may further stress hospital systems that are already
struggling to cope with wintertime surges in patient visits during influenza
seasons. For example, during the 1997-1998 season, a severe influenza outbreak
in Los Angeles County resulted in a dramatic increase in hospitalizations
and the need to divert patients to other facilities. This problem may have
been less severe if more bed capacity had been available.33
Vaccinating elderly persons will continue to be the primary strategy
for preventing influenza-associated deaths. Studies directly comparing outcomes
in vaccinated vs unvaccinated groups have shown that the currently available
trivalent inactivated influenza vaccine is approximately 68% effective in
preventing deaths from complications of influenza infections.34-36 However,
the effectiveness of influenza vaccines in preventing deaths among elderly
persons with associated chronic conditions is significantly lower,7,35 underscoring the need for influenza
vaccines that are more immunogenic in elderly persons.37,38 Recent
studies have also raised the question of whether vaccinating young children
against influenza may decrease transmission rates and thus decrease influenza-associated
morbidity and mortality among elderly persons,39,40 but
the effectiveness of this approach remains uncertain.
Although the importance of RSV among young children is well recognized,41,42 we found that more than 78% of RSV-associated
underlying respiratory and circulatory deaths occured among persons aged 65
years or older. This finding highlights the need for an effective RSV vaccine
in both young children and elderly persons.12,16,18,43 A
number of candidate RSV vaccines are being developed including vaccines based
on cold-adapted live attenuated RSV strains44,45 and
subunit vaccines intended for use in RSV nonnaive populations.46 Effective
and safe vaccines for use among persons aged 65 years or older are needed
to decrease deaths associated with RSV infection.
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