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Winter Viruses
Influenza- and Respiratory Syncytial Virus–Related Morbidity in Chronic Lung Disease
Marie R. Griffin, MD, MPH;
Christopher S. Coffey, PhD;
Kathleen M. Neuzil, MD, MPH;
Edward F. Mitchel, Jr, MS;
Peter F. Wright, MD;
Kathryn M. Edwards, MD
Arch Intern Med. 2002;162:1229-1236.
ABSTRACT
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Background Chronic lung disease predisposes to serious consequences of respiratory
viruses. While increasing influenza immunization rates in older adults signals
an awareness of the impact of influenza, children with asthma are infrequently
immunized. While respiratory syncytial virus (RSV) is recognized as an important
target of vaccine development for infants, its impact on adults is underappreciated.
Methods We performed a retrospective cohort study to estimate rates of hospitalizations,
deaths, outpatient visits, and antibiotic courses due to influenza and RSV
in persons with chronic lung disease in the Tennessee Medicaid program from
1995 to 1999. Differences between study event rates when influenza was cocirculating
with RSV and event rates when RSV was circulating alone were used to calculate
influenza-attributable morbidity. Differences in rates when RSV was circulating
alone and during summer months were calculated to assess the effect of RSV.
Results Influenza- and RSV-associated hospitalizations were highest at the extremes
of age. There were an estimated 8 and 23 hospitalizations per 1000 children
younger than 5 years annually due to influenza and RSV, respectively. There
were 23 and 18 hospitalizations, as well as 2 and 5 deaths per 1000 persons
65 years or older annually due to influenza and RSV, respectively. Both viruses
were associated with an excess of outpatient visits in children, and antibiotic
prescriptions in all age groups.
Conclusion Among persons with chronic lung disease, influenza virus and RSV accounted
for 15% to 33% of acute respiratory hospitalizations in children, 7% to 9%
of such hospitalizations in adults, and 9% of deaths in those 65 years or
older.
INTRODUCTION
SEASONAL PATTERNS of viruses that cause frequent respiratory tract infections
are distinct. Rhinoviruses, adenoviruses, and parainfluenza viruses occur
throughout the year, with periodic increases in frequency. Influenza virus
and respiratory syncytial virus (RSV), on the other hand, are usually confined
to winter.1 Historically, cold temperature
has been linked to health events, and winter increases in acute respiratory
disease have been shown to presage increases in overall mortality.2 The recognition of the association between influenza
epidemics and deaths over a century ago was facilitated by the explosive nature
of influenza epidemics. Although RSV is recognized to cause seasonal increases
in respiratory hospitalizations in children,3-5
its influence in adults is underappreciated. Emerging evidence suggests that
both influenza and RSV cause substantial illness at both ends of the age spectrum
during most winters.1-2,6-7
Persons with chronic lung disease contribute substantially to the overall
burden of acute respiratory hospitalizations.8-9
Such persons are at increased risk for serious morbidity related to influenza
infection, yet influenza immunization rates remain low in younger persons
with high-risk conditions, at 38% in those aged 50 to 64 years and less than
30% in children and young adults.10 The impact
that a safe and effective vaccine against RSV would have on children's health
is now well recognized; however, there are few data on the potential benefits
in adult high-risk populations. Although RSV has been convincingly associated
with exacerbations of chronic lung disease in adults,11-13
there are few data on the magnitude of this effect.
To assess the impact of influenza and RSV across the age spectrum, we
performed a retrospective cohort study of persons of all ages with chronic
lung disease enrolled in the Tennessee Medicaid program to determine rates
of acute cardiopulmonary hospitalizations, deaths, outpatient visits, and
antibiotic courses during 4 consecutive years, 1995 to 1999. We estimated
rates of these events due to influenza and RSV using active viral surveillance
to determine times when these viruses were circulating in Tennessee.
PARTICIPANTS AND METHODS
The Medicaid program has computerized files that permitted cohort assembly
and identification of medical events of interest. These files include the
enrollment file (a central registry of all enrollees), the pharmacy file (records
of prescriptions filled at the pharmacy), the inpatient file (records of hospitalizations
[including Medicare data for those jointly enrolled in this program]), and
the outpatient file (encounter records for emergency department, hospital
outpatient departments, and physician visits). In addition, Medicaid files
have been linked to state death certificates to determine date of death. Annual
differences between event rates when influenza virus was cocirculating with
RSV and event rates when RSV was circulating alone were used to calculate
influenza-attributable morbidity and mortality. Differences in event rates
when RSV was circulating alone and event rates during summer months were calculated
to assess the effect of RSV.
Vanderbilt University and the State of Tennessee Department of Health
institutional review boards reviewed and approved this study.
STUDY POPULATION
Noninstitutionalized persons enrolled in the Tennessee Medicaid program
from birth or for at least 1 year from August 1, 1995, through July 31, 1999,
were the base population. Those of black or white race contributed nearly
4 million person-years; those in other racial/ethnic groups were few and therefore
excluded. Persons with chronic lung disease (about 16% of base population)
were identified for this study. Persons were defined as having chronic lung
disease if they had at least 1 hospitalization or emergency department visit
within the past year for chronic lung disease or at least 2 prescriptions
in the past year for medications used to treat chronic lung disease. Hospital
visits with a discharge diagnosis of cystic fibrosis (International
Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM], 277 or 277.0), chronic respiratory disease of the newborn (770.7),
or chronic obstructive pulmonary disease and allied conditions (490.xx-496.xx),
including asthma (493.xx), were included. Medications included  -agonists,
ipratropium bromide, theophylline, inhaled corticosteroids, cromolyn sodium,
montelukast sodium, and zafirlukast. Persons being treated for human immunodeficiency
virus, cancer, chronic renal failure, or liver failure were excluded from
this analysis. Under a special program initiated in Tennessee in 1994, Medicaid
was expanded to include low-income persons who were uninsured as well as persons
who were unable to obtain insurance because of preexisting medical conditions.
The study population included those enrolled in Medicaid under traditional
criteria including Aid to Families with Dependent Children, Blind and Disabled,
and Aged, as well as the new group of uninsured.
OUTCOME DEFINITIONS
Study outcomes were (1) acute respiratory hospitalizations with an ICD-9-CM coded discharge diagnosis of pneumonia (480.xx-486.xx),
influenza (487.xx), acute respiratory conditions (460.xx-466.xx), other respiratory
conditions (490.xx-519.xx), as well as heart failure or myocarditis (422.xx,
427.xx, and 428.xx); (2) all-cause mortality (as determined by the Medicaid
enrollment file or death certificates); (3) all outpatient visits regardless
of diagnosis; and (4) filled outpatient antibiotic prescriptions.
VIRAL SURVEILLANCE
Two sources of viral isolation were used to define seasons. About 150
children, 5 years or younger, participated in a vaccine clinic at Vanderbilt
University during each of the 4 study years. Viral cultures for RSV, influenza,
and parainfluenza were obtained when these children developed a fever or respiratory
symptoms.5 We also identified all positive
tests for these viruses from the Vanderbilt Hospital Virology Laboratory,
the majority of which were performed in children.
The start of influenza season was defined as the first day of the first
of 2 consecutive weeks with at least 2 influenza isolates per week; the end
of the season was the last day of the second of 2 consecutive weeks with at
least 2 influenza isolates per week. Respiratory syncytial virus season was
similarly defined, but excluded time classified as influenza season. During
the 4 study years, influenza seasons were always encompassed by RSV seasons
(Figure 1). Thus, all person-time
and events in the study occurred in 1 of 3 exposure categories: RSV (during
which only RSV circulated), influenza (during which RSV and influenza cocirculated),
and summer (all time not in RSV or influenza seasons).
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Figure 1. Number of acute respiratory hospitalizations
by week and discharge diagnosis among Medicaid enrollees with chronic lung
disease for 4 successive years: 1995 to 1996, 1996 to 1997, 1997 to 1998,
and 1998 to 1999, with week 1 beginning in August and week 52 ending July
31. Brackets indicate the weeks when respiratory syncytial virus (RSV) and
influenza virus were circulating in the region of middle Tennessee. The annual
peak weeks for RSV and influenza viral isolates are indicated by asterisks.
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OTHER COVARIATES
We ascertained these additional characteristics from computerized Medicaid
files: age group (<5, 5-14, 15-49, 50-64, and  65 years), sex, residence
(urban [Tennessee's 4 largest cities], other standard metropolitan statistical
area, or rural), and race (black or white).
STATISTICAL ANALYSIS
Persons entered the study on the first day after July 31, 1995, that
they met entry criteria, and were followed up until loss of enrollment, death,
or July 31, 1999. Crude age-specific rates of hospitalization due to acute
cardiopulmonary events were calculated by dividing the number of these hospitalizations
in the age group by the age-specific person-years during influenza, RSV, and
summer seasons, and expressed per 1000 person-years of follow-up for persons
with chronic lung disease. Differences between these crude rates during influenza
and RSV seasons were calculated as measures of influenza-attributable risk.
Differences between rates during RSV and summer seasons were calculated as
a measure of risk attributable to RSV. Standardized rate differences were
calculated as the weighted average of the strata-specific differences in rates,
where the weights were defined as the corresponding strata-specific person-years
in all seasons combined.
The excess number of hospitalizations due to influenza per 1000 persons
with chronic lung disease was estimated separately in all strata by multiplying
the strata-specific differences in rates for influenza and RSV seasons by
the proportion of the corresponding study year classified as influenza season.
The excess number of hospitalizations due to RSV per 1000 persons with chronic
lung disease was computed by multiplying the strata-specific differences in
rates for RSV and summer seasons by the proportion of the study years classified
as either RSV or influenza season (RSV circulated during both these seasons).
Standardized estimates were calculated with a weighted average of strata-specific
values, as was done for the standardized differences in rates. Confidence
intervals were computed based on large sample properties.14
Similar analyses were performed for deaths (expressed per 10 000 person-years),
outpatient visits, and antibiotic courses. Estimates of virus-specific hospitalization
and mortality rates were divided by total event rates (Table 1) to determine the proportion of hospitalizations and deaths
due to theses viruses.
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Table 1. Demographic Characteristics and Health Care Utilization Among
Persons With Chronic Lung Disease by Age Group, 1995-1999, Tennessee Medicaid
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RESULTS
VIRAL SURVEILLANCE
The 2 viral surveillance systems detected 1105 RSV-positive cultures,
253 influenza-positive tests (antigen or culture), and 77 positive parainfluenza
type 1, 2, or 3 cultures during the 4 study years. The relative frequency
of positive tests does not reflect the actual level of viral activity since
RSV tests were done more commonly. The onset of influenza season ranged from
late November to late January with an average duration of 12 weeks (Figure 1). The onset of RSV season ranged
from late September to early November and averaged 26 weeks in duration. The
1995 to 1996 season was exceptionally long due to cocirculation of 2 influenza
A strains and a late influenza B outbreak. During the first 2 years, peak
influenza activity closely followed peak RSV activity, as indicated in Figure 1; whereas, the 2 peaks were more
widely separated in the subsequent 2 years. There were few influenza isolates
outside the defined influenza season. By definition, RSV activity occurred
during both RSV and influenza seasons with means of 9.6, 11.2, and 0.3 positive
tests per week in RSV, influenza, and summer seasons, respectively. Parainfluenza
isolates were distributed throughout the year but were on average higher in
summer (0.5 per week) than during RSV (0.3 per week) or influenza (0.2 per
week) seasons.
STUDY POPULATION
Persons with asthma and other chronic pulmonary diseases contributed
625 509 person-years of follow-up and are the subject of this study.
Because Medicaid preferentially enrolls children and persons 65 years or older,
36% of the study population were younger than 15 years, and 13% were 65 years
or older (Table 1). The higher
prevalence of males among children reflects the increased prevalence of asthma
in boys, whereas the predominance of women in the older age groups reflects
the higher enrollment of women in the Medicaid program. Thirty-one percent
of the population resided in urban areas, 25% in other standard metropolitan
statistical areas, and 44% in more rural locations, though this differed by
age group.
BASELINE HEALTH CARE UTILIZATION
Total acute respiratory hospitalization rates were lowest in children
aged 5 to 14 years, were similar in those younger than 5 years and those 15
to 49 years, and increased markedly in older age groups (Table 1). Whereas hospitalizations for pneumonia and acute respiratory
conditions, including bronchiolitis, predominated in children, chronic lung
disease and congestive heart failure constituted a greater proportion of admissions
in older age groups. Death rates increased with age. Patients of all ages
had a high frequency of both outpatient visits and antibiotic prescriptions
filled.
SEASONAL DIFFERENCES IN ACUTE RESPIRATORY HOSPITALIZATIONS
In all 4 years, acute respiratory hospitalizations were higher in winter
than summer weeks and peaked during influenza seasons (Figure 1). The distribution of hospitalizations was similar in all
age groups and except for those aged 5 to 14 years, rates were highest in
influenza season, when by definition, influenza and RSV cocirculated (Figure 2A). The excess hospitalization rates
(Figure 2B) account for the fact
that influenza seasons averaged 12 weeks, whereas RSV circulated an average
of 26 weeks. There were an estimated 8, 0, 3, 13, and 23 excess hospitalizations
due to influenza per 1000 persons with chronic lung disease per year in the
age groups younger than 5, 5 to 14, 15 to 49, 50 to 64, and 65 years or older,
respectively. In addition, there were an estimated 23, 5, 3, 11, and 18 excess
hospitalizations due to RSV per 1000 persons with chronic lung disease in
these 5 age groups, respectively. For children younger than 5 years, RSV accounted
for about 3 times the number of hospitalizations as influenza. Thirty-three
percent of all acute respiratory hospitalizations were due to one of these
viruses (Table 2). We detected
no excess hospitalizations due to influenza in those aged 5 to 14 years, but
RSV accounted for 15% of all such hospitalizations. In older age groups, influenza
and RSV accounted for a remarkably similar estimated number of hospitalizations.
Both influenza and RSV individually accounted for 3% to 5% of all cardiopulmonary
hospitalizations in those 15 years or older (Table 2).
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Figure 2. Adjusted age-specific rates, per
1000 persons with chronic lung disease, of acute respiratory hospitalizations
(A), outpatient visits (C), and antibiotic prescriptions (E) by summer, respiratory
syncytial virus (RSV), and influenza seasons and excess of acute respiratory
hospitalizations (B), outpatient visits (D), and antibiotic prescriptions
(F) attributable to influenza virus and RSV, Tennessee Medicaid program August
1995 to July 1999. Rates were adjusted for year, race, sex, and residence.
Calculation of excess events included terms for rate differences between seasons
and duration of virus circulation.
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Table 2. Acute Respiratory Hospitalization Rate Differences Between
Seasons, Estimated Hospitalizations, and Cardiopulmonary Hospitalizations
Attributable to Winter Viruses by Age Group, 1995-1999, Tennessee Medicaid*
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SEASONAL DIFFERENCES IN ALL-CAUSE MORTALITY
Among those with chronic lung disease 65 years or older, there were
23.8 (95% confidence interval, 10.1-37.5) and 46.5 (95% confidence interval,
23.7-69.3) deaths due to influenza and RSV, respectively, per 10 000
persons (Table 3 note deaths expressed
per 10 000 not per 1000). During the study years, the excess in deaths
during the winter respiratory virus seasons represented 9% of deaths from
all causes in this age group. There was also an estimated 15.3 deaths per
10 000 among those aged 50 to 64 years from RSV. There was insufficient
power to detect excess deaths of 1 per 10 000 or lower in the other age
groups.
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Table 3. All-Cause Mortality Rate Differences Between Seasons and Estimated
and Total Deaths Attributable to Winter Viruses by Age Group, 1995-1999, Tennessee
Medicaid*
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SEASONAL DIFFERENCES IN OUTPATIENT VISITS
Seasonal variation in outpatient visits was more evident in children
than in adults (Figure 2C). A significant
excess in outpatient visits due to influenza was observed only in those younger
than 65 years and ranged from 66 to 173 per 1000 persons with chronic lung
disease per year, with the highest excess in those younger than 5 years. Significant
excesses in outpatient visits attributable to RSV were observed only in those
younger than 15 years, and were 515 and 401 per 1000 persons with chronic
lung disease per year in those younger than 5 years and 5 to14 years, respectively
(Figure 2D).
SEASONAL DIFFERENCES IN ANTIBIOTIC COURSES
There was a consistent winter excess of antibiotic prescriptions in
all age groups (Figure 2E). The
estimated increase in antibiotic prescriptions attributed to influenza ranged
from 64 to 108 prescriptions per 1000 persons with chronic lung disease (Figure 2F). Excess antibiotic prescriptions
attributable to RSV were higher, ranging from 190 per 1000 in those 65 years
or older to 641 per 1000 in those younger than 5 years.
COMMENT
In this comprehensive examination of winter virus-related illness among
persons with chronic lung disease, both influenza and RSV were associated
with a high burden of disease in all age groups. Respiratory syncytial virus,
recognized to be the leading cause of lower respiratory tract infection in
infants and young children,15 was associated
with a greater burden of hospitalizations in children younger than 15 years
than was influenza. However, in adults, the burden of hospitalizations due
to influenza and RSV was remarkably similar, consistent with other recent
reports.2, 8, 16 In
addition, both viruses were associated with relatively high mortality in older
adults, and with considerable outpatient morbidity in all age groups. Influenza
morbidity and mortality reported here does not take into account influenza
vaccination, and thus underestimates events that would occur in the absence
of immunization. In 1999, 65.5% of persons in Tennessee 65 years or older
reported influenza immunization17; rates were
likely lower in younger groups, including those with high-risk conditions.
Approximately 98% of infants are infected with RSV in their first year
of life,18 resulting in hospitalization rates
of 3% to 4%.3-4 In their next
2 years of life, the majority of children have less severe symptomatic reinfections,
as do 40% of older children and adults who are exposed to sick family members.18 Our estimate that RSV causes 25% of all acute respiratory
hospitalizations in children younger than 5 years with chronic lung disease
is consistent with a prior estimate that RSV causes 23% of lower respiratory
tract disease in children younger than 5 years.18
Our study provides the first evidence from a large population-based
group of adults with chronic lung disease that influenza and RSV account for
similar rates of excess acute respiratory hospitalizations. In addition, in
this population, RSV was associated with substantial mortality in adults.
Although RSV epidemics with associated morbidity and mortality have been documented
in nursing homes,19-20 RSV in
noninstitutionalized elderly persons is less well studied. A review of 8 hospital-based
studies estimated that RSV is responsible for 2% to 9% of all pneumonia admissions
among elderly persons, a frequency similar to influenza,16
and also consistent with our results. There are several reasons why RSV may
be underappreciated in adults. Because lower quantities of virus are shed
at time of illness, RSV is harder to detect in adults than children. Unlike
bronchiolitis in children, there is no specific syndrome that clinically distinguishes
RSV infection in adults. Finally, the long RSV season and the imposition of
influenza epidemics on this season makes the contribution of RSV more difficult
to visualize (Figure 1).
Influenza accounted for excess hospitalizations in all age groups except
the 5 to 14 years group. Thus, in children with lung disease, as in healthy
children, the greatest burden of hospitalizations due to influenza appears
to occur in the very young.21-22
Reported hospitalization rates due to influenza in persons 65 years and older
range from 1 to more than 10 per 1000.23-24
Thus, our rates of 3 per 1000 in younger adults and 13 to 23 per 1000 in older
adults with medically treated chronic lung disease appear to be reasonable
estimates.
Both influenza and RSV were associated with a substantial number of
outpatient visits in children, but not adults. We measured all outpatient
visits, regardless of associated diagnosis because of uncertainty about the
quality of diagnostic information. Since chronic lung disease results in frequent
outpatient visits (Table 1), it
is possible that acute illness caused cancellations of regularly scheduled
visits as well as an increase in sick visits resulting in no net increase
in visits among older adults. Respiratory syncytial virus was associated with
a greater excess of outpatient visits in children than influenza, consistent
with the prominence of this pathogen in association with asthma exacerbations
in young children.25 In all age groups, there
was a substantial excess of antibiotic prescriptions (Figure 2), which may be a more specific indicator of excess illness
due to viral respiratory infections than outpatient visits. Respiratory syncytial
virus and influenza are associated with otitis media in children,5 and with exacerbations of asthma and chronic pulmonary
disease in children and adults,26-29
all of which may result in antibiotic treatment. Our estimates indicate that
RSV and influenza infections accounted for 20% to 24% of antibiotic use in
children and 12% to 14% of use in adults with chronic lung disease.
Our definition of chronic lung disease was a pragmatic one that included
persons who were hospitalized in the past year with a discharge diagnosis
of chronic lung disease and persons who received at least 2 prescriptions
for medications used primarily for asthma and chronic obstructive pulmonary
disease. This definition constituted about 16% of noninstitutionalized persons
enrolled in the Tennessee Medicaid program and included a wide spectrum of
patients with chronic lung disease. All patients in this study were enrolled
in Medicaid and thus may be poorer and sicker than other populations. However,
previous estimates of influenza-attributable disease in this population were
similar to those of persons enrolled in health maintenance organizations.30 In addition, during the study period, about 25% of
persons in Tennessee were enrolled in this program.
We assumed study events that occurred during the 6 months when influenza
and RSV were circulating in excess of events that occurred in the remainder
of the year were due to these 2 viruses. This assumes that other viruses were
distributed equally during these two 6-month time periods. Viral surveillance
data indicated that parainfluenza occurred more frequently in summer months
during the study years. This would have the effect of our underestimating
the winter excess. Uneven distribution of other respiratory viruses such as
coronaviruses and rhinoviruses, which are also associated with exacerbations
of asthma and chronic lung disease, but were not part of our viral surveillance,
would also affect the accuracy of our estimates. However, other respiratory
viruses tend to be distributed throughout the year, and likely account for
a substantial portion of exacerbations not due to RSV or influenza.11 It is unknown whether other winter factors, such
as temperature, humidity, or time spent indoors increase respiratory illness
independent of their role in the spread of respiratory viruses. To the degree
that there are other independent "winter" factors that cause respiratory illness,
our figures would overestimate viral-associated disease. Our definition of
seasons relied on viral surveillance from the middle Tennessee region, primarily
in children. Thus, these definitions were rough estimates of when these viruses
were circulating in the state. Misclassification of seasons likely resulted
in underestimation of the effect of these 2 viruses.
Morbidity from influenza and RSV will vary by year and for influenza
with the number of persons vaccinated and the vaccine effectiveness. Our estimates
of the burden of illness due to winter viruses are consistent with many other
smaller and primarily hospital-based investigations. Among persons with chronic
lung disease, we estimate these viruses are responsible for 15% to 33% of
acute respiratory hospitalizations in children, 7% to 9% of such hospitalizations
in adults, and 8% to 9% of total adult deaths. In addition, infections with
these viruses cause a substantial increase in outpatient visits and antibiotic
courses. These data reinforce the importance of influenza immunization in
persons with pulmonary disease of all ages. In addition, the data suggest
that vaccines against RSV and other strategies to decrease morbidity associated
with RSV will be important for adults as well as children.
AUTHOR INFORMATION
Accepted for publication October 2, 2001.
This study was supported in part by an unrestricted educational grant
from GlaxoSmithKline, Research and Development, Greenford, England, and a
cooperative agreement with the Centers for Disease Control and Prevention,
Atlanta, Ga (UR6 CCU417579).
We would like to thank Yuwei Zhu for analysis of viral isolation data
and Cindy Naron for editorial assistance.
Corresponding author and reprints: Marie R. Griffin, MD, MPH, Vanderbilt
University School of Medicine, Department of Preventive Medicine, A-1124 MCN,
Nashville, TN 37232 (e-mail: marie.griffin{at}mcmail.vanderbilt.edu).
From the Departments of Preventive Medicine (Drs Griffin and Coffey
and Mr Mitchel), Medicine (Dr Griffin), and Pediatrics (Drs Wright and Edwards),Vanderbilt
University School of Medicine and the Geriatric Research Education and Clinical
Center, and Nashville Veterans Affairs Medical Center (Dr Griffin), Nashville,
Tenn; and the Department of Medicine, University of Washington, Seattle (Dr
Neuzil). Dr Coffey is now with the Department of Biostatistics, University
of Alabama, Birmingham.
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