CLINICAL RESEARCH STUDY
Seasonality of invasive pneumococcal disease: Temporal
relation to documented influenza and respiratory
syncytial viral circulation
Thomas R. Talbot, MD, MPH,a,cKatherine A. Poehling, MD, MPH,b
Tina V. Hartert, MD, MPH,aPatrick G. Arbogast, PhD,d,e
Natasha B. Halasa, MD, MPH,bKathryn M. Edwards, MD,bWilliam Schaffner, MD,a,c
Allen S. Craig, MD,gMarie R. Griffin, MD, MPHa,c,e,f
aFrom the Departments of Medicine,bPediatrics,cPreventive Medicine, anddBiostatistics, andeCenter for Education and
Research on Therapeutics, Vanderbilt University School of Medicine, Nashville, Tennessee;
fthe Veterans Administration, Tennessee Valley Healthcare System, Geriatric Research, Education and Clinical Center
and Clinical Research Center of Excellence, Nashville; and
gthe Tennessee Department of Health, Nashville.
BACKGROUND: Seasonal fluctuation in the incidence of invasive pneumococcal disease has been
attributed to winter virus exposure (e.g., influenza and respiratory syncytial virus [RSV]). Evidence of
a direct correlation of invasive pneumococcal disease with laboratory-confirmed virus seasons, how-
ever, is limited. Using two prospective surveillance networks, the temporal relation between invasive
pneumococcal disease and isolation of circulating winter viruses was explored.
METHODS: Episodes of invasive pneumococcal disease in five Tennessee counties were collected
prospectively from January 1995 through June 2002. Virus seasons were defined using prospective
laboratory-based surveillance. Correlation between weekly identification of invasive pneumococcal
disease and laboratory isolation of RSV and influenza, as well as comparisons of the frequencies of
invasive pneumococcal disease episodes during viral and nonviral seasons were determined.
RESULTS: A total of 4147 invasive pneumococcal disease episodes were identified. Weekly fre-
quency of invasive pneumococcal disease correlated directly with the weekly frequency of isolation of
RSV (r ? 0.56, P ?0.001) and influenza (r ? 0.40, P ?0.001). The average weekly frequency of
invasive pneumococcal disease during RSV and influenza seasons was higher than during the nonviral
seasons (P ?0.001 for each year).
Supported in part by ATPM/CDC Cooperative Agreement TS-0825
and Emerging Infections grant U50/CCU416123. Dr. Hartert received
support from grants UO1HL72471 and AI001582. Dr. Halasa received
support from the NIH Vanderbilt Mentored Clinical Research Scholar
Requests for reprints should be addressed to Thomas R. Talbot, MD,
MPH, A-4103C Medical Center North, 1161 21st Avenue South, Nashville,
E-mail address: email@example.com.
0002-9343/$ -see front matter © 2005 Elsevier Inc. All rights reserved.
The American Journal of Medicine (2005) 118, 285–291
CONCLUSION: Weekly episodes of invasive pneumococcal disease correlated temporally with lab-
oratory-confirmed weekly isolation of RSV and influenza, and the incidence of invasive pneumococcal
disease was increased when these viruses were circulating in the community.
© 2005 Elsevier Inc. All rights reserved.
The epidemiology of invasive disease due to Strepto-
coccus pneumoniae exhibits a seasonal fluctuation with a
peak incidence during the winter months.1-3Although the
exact cause of such variation is not known, alterations in
environmental and host factors have been suggested as
possible causes for seasonal differences in the incidence
of pneumococcal disease.4Variations in light-dark expo-
sure have been shown to affect mouse susceptibility to
pneumococcal infection5and to correlate with seasonal
peaks in the incidence of pneumococcal disease.3Circu-
lating respiratory viruses may also play a key role in the
pathogenesis and seasonality of invasive pneumococcal
infection.6Through alterations in the host’s airway mu-
cosa, respiratory viruses can decrease the clearance of
encapsulated organisms.6In addition, influenza virus
neuraminidase potentiates the development of pneumo-
coccal pneumonia in vitro by mediating improved bacte-
Although the relation between respiratory viruses and
pneumococcal disease is widely assumed, direct correla-
tions between the epidemiology of pneumococcal disease
and circulating respiratory viruses are scarce. Utilizing two
prospective surveillance systems (one for invasive pneumo-
coccal disease and another for respiratory viruses), we in-
vestigated the relation between pneumococcal disease and
the winter respiratory viruses influenza and respiratory syn-
cytial virus (RSV) in Tennessee over a 7-year period. The
association between invasive pneumococcal disease and al-
terations in light-dark exposure was also examined.
Ascertainment of invasive pneumococcal disease
Surveillance for invasive pneumococcal disease has
been performed in Tennessee as part of the Centers for
Disease Control and Prevention’s (CDC) Active Bacte-
rial Core Surveillance program of the Emerging Infec-
tions Network.8Since January 1, 1995, pneumococcal
surveillance in Tennessee has encompassed five urban
counties surrounding the state’s four major metropolitan
centers (Memphis, Nashville, Knoxville, and Chatta-
nooga), covering a total population of 2,283,929 persons
(40% of the state’s population).9Case finding was active
and laboratory based, focusing on acute care microbiol-
ogy and reference laboratories that process sterile site
specimens for residents in the surveillance areas. Inva-
sive pneumococcal disease was defined as a disease in
which S. pneumoniae was isolated from a normally sterile
site (blood, surgical aspirate, bone, cerebrospinal, pleu-
ral, peritoneal, pericardial, or joint fluid).8,10In the event
that S. pneumoniae was isolated concurrently from mul-
tiple sites from one subject, the overall episode was
counted as a single case of invasive disease. The study
interval extended from January 1, 1995, through June 30,
2002. This study was approved by the Vanderbilt Uni-
versity Institutional Review Board.
For each episode of invasive pneumococcal disease iden-
tified through the surveillance program, information on de-
mographic characteristics, comorbid conditions, disease
type (isolated bacteremia, meningitis, other invasive dis-
ease), body source of pneumococcal isolate, and illness
outcome was abstracted from clinical records by trained
program nurses using standardized definitions and abstrac-
tion criteria.10An audit of the surveillance process in
Tennessee revealed incomplete reporting rates from one
institution between 1995 and 1999. Through active audit of
this institution’s records and laboratory databases, previ-
ously unreported episodes of invasive pneumococcal dis-
ease were identified and case report forms were completed
and added to the main surveillance database.
Definition of winter virus seasons
Vanderbilt University has conducted surveillance of win-
ter respiratory viruses (including influenza A and B, and
RSV) since 1973, utilizing data from the Vanderbilt Pedi-
atric Vaccine Clinic and the Vanderbilt University Hospital
Virology Laboratory. In the Pediatric Vaccine Clinic, which
has provided primary and acute care for more than 150
children each year of surveillance, nasopharyngeal speci-
mens were routinely obtained during all visits associated
with fever or respiratory symptoms.11The virology labora-
tory receives various respiratory specimens (e.g., nasopha-
ryngeal aspirates, bronchopulmonary washings) collected
from symptomatic inpatients and outpatients seen at
Vanderbilt University Medical Center. The specimens col-
lected from both the pediatric vaccine clinic and the virol-
ogy laboratory are processed for viral culture or rapid an-
tigen testing for RSV or influenza, based on the primary
medical provider’s selection.
The start of the influenza season was defined as the
first day of the first of 2 consecutive weeks with at least
2 influenza isolates (detected either by culture or antigen
testing) per week. Once 2 consecutive weeks passed
without at least 2 influenza isolates per week, the influ-
286The American Journal of Medicine, Vol 118, No 3, March 2005
enza season was declared over, with the end date of the
season defined as the last day prior to this 2-week period.
The RSV season was similarly defined. Weeks were
defined using CDC criteria in which the first Sunday in
January of each year serves as the first day of week 1.
During the 7 study years, RSV season encompassed the
influenza season. Therefore, all person-time and events in
the study were classified as one of the following: RSV-
only season (when only RSV circulated), influenza sea-
son (when influenza and RSV circulated), and nonviral
season (when neither influenza nor RSV circulated). The
RSV-only and influenza seasons comprised the winter
virus season for each year. To include each individual
winter respiratory season within 1 year of study, study
periods began on July 1 and ended on June 30 of the
following year. As the surveillance period in Tennessee
began on January 1, 1995, episodes identified after this
date and before the start of the 1995–1996 study year
(July 1, 1995) occurred during the period named “early
The first analysis, using correlation coefficients, tested
whether the patterns of isolation of invasive pneumococcal
disease were similar to the patterns of RSV and influenza
identification, and did not use the above definitions of viral
seasons. The relation between weekly frequency of isolation
of invasive pneumococcal disease cases with weekly fre-
quency of laboratory identification of RSV and influenza
was assessed using the Pearson correlation coefficient (r).
Correlations with mean daily hours of darkness by week
during the study period was also examined using data from
Davidson County obtained via the United States Naval
Observatory.12All correlations were examined with a lag
time from detection of viral pathogens and determination of
hours of darkness to invasive pneumococcal disease iden-
tification of 1, 2, 3, and 4 weeks.
The second analysis attempted to quantify the differ-
ences between the burden of pneumococcal disease during
RSV and influenza seasons and during the time when these
viruses were not circulating. Comparisons between winter
respiratory virus season and nonviral season frequencies of
invasive pneumococcal disease per week were performed
using the one-sample test of proportion, comparing the
observed proportion of annual cases during the virus season
with the expected proportion of cases during the virus sea-
son while presuming no relation existed between circulation
of winter viruses and invasive pneumococcal disease. Anal-
yses were conducted using Stata, version 7.0 (Stata Corpo-
ration, College Station, Texas).
Epidemiology of invasive pneumococcal disease
During the 7 years of surveillance, 4147 episodes of
invasive pneumococcal disease were detected. The median
age of persons with invasive pneumococcal disease was
44.0 years, with 30.1% (n ? 1250) of episodes occurring in
persons younger than 18 years and 28.5% (n ? 1180)
occurring in those aged 65 years or older. Males comprised
55% (n ? 2273) of all episodes. Isolated bacteremia ac-
counted for a majority of episodes (n ? 3497 [84%]), with
meningitis seen in 251 (6%) and other invasive disease
found in 399 (10%).
pneumococcal disease (green solid line) from January 1, 1995, through June 30, 2002.
Weekly isolation of winter respiratory viruses RSV (red dashed line) and influenza (blue dotted line) and frequency of invasive
287 Talbot et alRespiratory Syncytial Virus, Influenza, and Pneumococcal Disease
Correlation between episodes of invasive
pneumococcal disease and circulation of influenza
The viral surveillance system detected 3458 RSV-posi-
tive and 633 influenza-positive test results (antigen or cul-
ture) during the study period. The relative frequency of
positive test results did not reflect the actual level of viral
activity as RSV tests were performed more commonly. The
onset of the influenza season ranged from late November to
early February, with a mean (?SD) duration of 8 ? 3 weeks
(range, 4 to 11 weeks). The onset of the RSV season ranged
from late September to early November and averaged 29 ?
6 weeks (range, 17 to 38 weeks). During most years, peak
influenza activity and peak RSV activity occurred within 3
weeks of each other; in early 1995 and 1998–1999, how-
ever, the peak influenza season occurred 2 months after the
peak RSV season.
Each study year, the incidence of invasive pneumococcal
disease peaked when influenza and RSV circulated together
(Figure 1). The weekly frequency of invasive pneumococcal
disease correlated significantly with the weekly frequency of
laboratory isolation of RSV (r ? 0.56, P ?0.001) and influ-
of viral pathogens to the identification of invasive pneumococ-
cal disease cases was incorporated into the analysis (Table 1),
the correlation with circulation of RSV changed little. How-
ever, the correlation with influenza decreased as the lag be-
tween isolation of influenza and detection of invasive pneu-
mococcal disease episodes increased. The correlation between
the incidence of invasive pneumococcal disease and isolation
years or older than in those younger than 18 years. Influenza
and invasive pneumococcal disease episodes for subjects
younger than 18 years were weakly correlated and statistically
significant only for lags of 1 and 3 weeks.
January 1, 1995, through June 30, 2002.
Average hours of darkness by week (red dashed line) and frequency of invasive pneumococcal disease (blue solid line) from
pneumococcal disease, by age strata
Correlation of weekly laboratory isolation of respiratory syncytial virus and influenza with identified episodes of invasive
Virus isolated Age group
Lag between viral isolation and detection of invasive pneumococcal disease episodes
None1 week2 weeks 3 weeks4 weeks
Correlation coefficient (P value)
RSV ? respiratory syncytial virus.
288The American Journal of Medicine, Vol 118, No 3, March 2005
Correlation between invasive pneumococcal
disease episodes and average hours of darkness
The weekly frequency of invasive pneumococcal disease
detection also correlated significantly with the average daily
hours of darkness per week (Figure 2, Table 2). The corre-
lation with hours of darkness was greater in subjects aged
18 years or older (r ? 0.60 vs. r ? 0.37 in those younger
than 18 years). The strength of the correlation between
invasive pneumococcal disease and the average hours of
darkness, however, increased with increasing lag time from
determination of darkness hours to isolation of S.
pneumoniae (Table 2). The average hours of darkness also
correlated significantly with the weekly frequency of labo-
ratory isolation of RSV (r ? 0.69, P ?0.001) and influenza
(r ? 0.37, P ?0.001).
Comparison of frequency of invasive
pneumococcal disease during winter virus and
Average weekly frequencies of invasive pneumococcal
disease during the winter virus seasons were significantly
higher each year (P ?0.001 for each study year, except
early 1995 where P ?0.05) than during the nonviral seasons
(Table 3). This increase was more pronounced during peri-
ods when influenza and RSV circulated concurrently (P
?0.05 for each period), but was still present when RSV
circulated alone (P ?0.01 for each period except 1995–
1996 and 1999–2000; Figure 3). When stratified by age, the
weekly frequency of invasive pneumococcal disease re-
mained significantly higher during the winter virus season
each year in adults 18 years of age or older, and every year
except 2001–2002 in those younger than 18 years (Table 3).
Despite a decline in the incidence of invasive pneumococcal
disease in the 2001–2002 study year, the weekly frequency
of invasive pneumococcal disease was still significantly
higher during the 2001–2002 winter virus season in subjects
of all ages (10.4 vs. 5.3 cases per week, P ?0.001) and in
those 18 years or older (8.6 vs. 3.5 cases per week, P
Seasonal fluctuation in the incidence of pneumococcal dis-
ease has been ascribed to a wide variety of factors, including
Correlation of weekly mean daily hours of darkness with identified weekly episodes of invasive pneumococcal disease, by
Lag between week of darkness hours assessment and detection of invasive pneumococcal disease episodes
None 1 week 2 weeks3 weeks 4 weeks
Correlation coefficient (P value)
respiratory viruses, by age strata*
Comparison of weekly frequency of episodes of invasive pneumococcal disease in relation to the circulation of winter
All agesAge ?18 years Age ?18 years
Weekly Frequency of Invasive Disease
Mean Episodes of Invasive Pneumococcal Disease Per Week
*P ?0.001 for winter virus season with nonviral season comparisons, except for † where P ?0.05 and ‡ where P ? 0.85.
289Talbot et alRespiratory Syncytial Virus, Influenza, and Pneumococcal Disease
changes in ambient temperature and humidity,3variations in
atmospheric pollutants,1and changes in host behavior, such
as increased crowding in the winter. Exposure to seasonal
respiratory viruses has also been implicated in the patho-
genesis of pneumococcal disease.6Although the association
between respiratory viral infection and invasive pneumo-
coccal disease is assumed, correlations of the incidence of
invasive pneumococcal disease with direct surveillance of
circulating respiratory viruses are scarce. In a study of 480
cases of invasive pneumococcal disease detected in Houston
over a 3-year period,1Kim et al found a temporal associa-
tion between pneumococcal disease and the isolation of
influenza alone, RSV alone, and all respiratory viruses com-
bined (influenza, RSV, parainfluenza, picornaviruses, and
adenoviruses) in adults. In children, however, invasive dis-
ease correlated only with isolation of adenoviruses alone
and all respiratory viruses combined, except influenza. Cal-
endar-based seasons were also used to describe an increased
incidence of invasive pneumococcal disease from October
to March. Our investigation, which included more than
4100 episodes of invasive pneumococcal disease and
spanned about 7 years of active surveillance in four urban
centers, revealed that patterns of invasive pneumococcal
disease occurrence were similar to patterns of occurrence of
RSV and influenza-related illness. Similar to Kim et al’s
results, this effect was less pronounced in children than in
To help quantify the differences between the burden of
pneumococcal disease during RSV and influenza seasons
and during the time when these viruses were not circulating,
we used laboratory-confirmed viral surveillance to define
winter respiratory virus seasons, as opposed to calendar-
based seasons, which provided a more precise ascertainment
of annual virus circulation. This definition accounts for
annual variations in the timing and duration of circulation of
RSV and influenza virus that would not be reflected when
using a calendar-based definition.
The lack of any discernable increase in the correlation
between virus isolation and pneumococcal disease when a
lag time from virus detection to invasive pneumococcal
disease identification was incorporated in the analysis was
curious, especially in light of data suggesting a direct role of
viral infection in the development of pneumococcal disease.
It is important to note that, while a temporal relation be-
tween virus isolation and identification of cases of pneumo-
coccal disease was shown in our study, conclusions regard-
ing the role of these viruses in the pathogenesis of
pneumococcal disease cannot be directly inferred. However,
this temporal association in conjunction with existing data
implicating viral pathogens in the development of pneumo-
coccal infection,6,7and recent studies identifying an effect
of pneumococcal vaccination on the incidence of viral pneu-
monia,13suggest a causal relation between these pathogens
and highlight the need to examine further the complex
interactions between these pathogens.
The temporal relation between viral isolation and inva-
sive pneumococcal disease noted here may be due to asso-
ciations with other seasonal phenomena. For example, in
our investigation, the weekly frequency of invasive pneu-
mococcal disease also correlated strongly with alterations in
the average daily hours of darkness, a finding that has been
noted previously.3Alterations of host immune responses by
changes in daily light exposure have been postulated to
affect susceptibility to various pathogens,3,5,14,15which
could explain the seasonal alterations in both the incidence
of invasive pneumococcal disease as well as RSV and
Our investigation has several potential limitations. Other
than variations in daily light-dark exposure, we did not
examine other factors hypothesized to cause seasonal fluc-
tuations in pneumococcal incidence, such as ambient tem-
perature or air pollution. In addition, the surveillance area
for pneumococcal disease included four geographically dis-
tinct counties of one state, but the viral surveillance data
only covered one of these areas. If RSV and influenza
circulation differed in the other surveillance counties, then
the defined dates of the winter virus seasons may be incor-
rect. Data for other respiratory viral pathogens were also not
included in our surveillance program. Epidemiologic data,
however, indicate that many of these pathogens circulate
throughout the year (e.g., the rhinoviruses and adenovi-
ruses)16or have a seasonal peak later in the year (e.g.,
parainfluenza and metapneumovirus),16,17suggesting that
the role of these pathogens in the seasonal fluctuation of
pneumococcal disease may be less than the viruses that peak
in the winter season. Nonetheless, surveillance of these
respiratory pathogens should be considered in future inves-
Specific descriptive data were not available for all per-
sons with a positive test result for RSV or influenza. Chil-
dren likely comprised a majority of these persons since one
of the viral surveillance programs centered in a pediatric
clinic and awareness of RSV as an etiology of winter re-
95-96 96-97 97-98 98-99 99-00 00-01 01-02
Year (July 1 - June 30)
disease in five urban counties in Tennessee, by relation to winter
virus season, all ages. Black diamonds indicate the period when
respiratory syncytial virus (RSV) and influenza co-circulated; dark
gray triangles indicate the period when RSV circulated without
influenza; and light gray circles indicate the nonviral season. P
?0.01 for all comparisons between virus season and nonviral
season frequencies, except for * where P ?0.05, † where P ?
0.07, and ‡ where P ? 1.0.
Mean weekly frequency of invasive pneumococcal
290The American Journal of Medicine, Vol 118, No 3, March 2005
spiratory illness is greater for children than adults.18-21 Download full-text
Nonetheless, the epidemiology of the circulating viruses in
the pediatric population likely serves as an adequate surro-
gate for the active respiratory viruses in the community.
Finally, cases of influenza and RSV were defined using
either isolation in viral culture or antigen detection by poly-
merase chain reaction (PCR) to indicate circulation of these
viruses in the community. False-positive cases of viral in-
fection diagnosed solely by positive PCR data may have
been included; however, the influenza and RSV antigen
tests are over 90% specific,22leaving the likelihood of
false-positive diagnoses quite low.
Using data from two large surveillance systems, we have
provided evidence of a temporal relation between circulat-
ing respiratory viruses (influenza and RSV) and invasive
pneumococcal disease. RSV, influenza, and invasive pneu-
mococcal disease appear to have strong winter peaks that
correlate closely with each other as well as with the average
hours of darkness. Further studies should investigate
whether these respiratory viruses have a causal role in the
pathogenesis of pneumococcal disease, whether strategies
aimed at reducing viral respiratory diseases, such as influ-
enza vaccination, will also affect the incidence of invasive
pneumococcal disease, and the specific role of alterations in
the light-dark cycle upon host susceptibility to both viral
and bacterial pathogens.
The authors would like to acknowledge and thank Carol
A. Clay, RN, Diane Kent, RN, and Yuwei Zhu for their
work with the viral surveillance project, and Brenda G.
Barnes, RN, all members of the Tennessee Active Bacterial
Core Surveillance network, and the CDC Emerging Infec-
tions Program, in particular Carolyn Wright and Tami
Skoff, for their support and guidance on this project.
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