Influenza and COPD Mortality Protection as

Pleiotropic, Dose-Dependent Effects of

Statins*
Floyd J. Frost, Hans Petersen, Kristine Tollestrup and Betty Skipper

Chest 2007;131;1006-1012
DOI 10.1378/chest.06-1997

The online version of this article, along with updated information

and services can be found online on the World Wide Web at:
http://www.chestjournal.org/content/131/4/1006.full.html

CHEST is the official journal of the American College of Chest

Physicians. It has been published monthly since 1935. Copyright 2007
by the American College of Chest Physicians, 3300 Dundee Road,
Northbrook, IL 60062. All rights reserved. No part of this article or PDF
may be reproduced or distributed without the prior written permission
of the copyright holder.
(http://www.chestjournal.org/site/misc/reprints.xhtml) ISSN:0012-3692

Downloaded from www.chestjournal.org by guest on September 14, 2009

© 2007 American College of Chest Physicians
 CHEST Original Research
NOVEL PHARMACOTHERAPY

Influenza and COPD Mortality

Protection as Pleiotropic, Dose-
Dependent Effects of Statins*
Floyd J. Frost, PhD; Hans Petersen, MS; Kristine Tollestrup, PhD; and
Betty Skipper, PhD

Background: Published data on antiinflammatory and immunomodulatory effects of statins

suggest they may reduce mortality risks associated with an unchecked immune response to
selected infections, including influenza and COPD. We assessed whether statin users had
reduced mortality risks from these conditions.
Methods: We conducted a matched cohort study (n ⴝ 76,232) and two separate case-control
studies (397 influenza and 207 COPD deaths) to evaluate whether statin therapy is associated
with increased or decreased mortality risk and survival time using health-care encounter data for
members of health maintenance organizations. For the cohort study, baseline illness risks from
all causes prior to initiation of statin therapy were used to statistically adjust for the occurrence
of outcomes after initiation of treatment.
Results: For moderate-dose (> 4 mg/d) statin users, this cohort study found statistically significant
reduced odds ratios (ORs) of influenza/pneumonia death (OR, 0.60; 95% confidence interval [CI],
0.44 to 0.81) and COPD death (OR, 0.17; 95% CI, 0.07 to 0.42) and similarly reduced survival
hazard ratios. Findings were confirmed with the case-control studies. Confounding factors not
considered may explain some of the effects observed.
Conclusions: This study found a dramatically reduced risk of COPD death and a significantly
reduced risks of influenza death among moderate-dose statin users.
(CHEST 2007; 131:1006 –1012)

Key words: COPD; epidemiology; 3-hydroxy-3-methylglutaryl coenzyme A; influenza; mortality; statins

Abbreviations: CCI ⫽ Charleson comorbidity index; CI ⫽ confidence interval; HMO ⫽ health maintenance organi-
zation; ICD-9-CM ⫽ International Classification of Disease, Ninth Revision, Clinical Modification; LPD ⫽ Lovelace
Patient Database; OR ⫽ odds ratio

S tatin therapy has demonstrated cardiovascular

disease risk reduction that has exceeded expecta-
tions based solely on observed reduction of blood
lipid levels.1–3 Evidence suggests that statins, in
addition to lipid reduction, may provide other posi-
tive pleiotropic effects.4 – 6 The disease-risk reduction
mechanisms of statins are not completely under-
stood, but prominent among their positive pleiotro-
pic effects are immunomodulatory and antiinflam-
*From the Health and Environmental Epidemiology Program
(Dr. Frost and Mr. Petersen), Lovelace Respiratory Research
Institute; and Department of Family and Community Medicine
(Drs. Tollestrup and Skipper), University of New Mexico School
of Medicine, Albuquerque, NM.
This work was performed at Lovelace Respiratory Research
Institute.
The authors have no conflicts of interest to disclose.
matory actions. Statins appear to positively affect
life-threatening infections associated with cytokine
dysregulation, such as bacterial sepsis.7–11 Statins
have also been shown to reduce C-reactive protein
levels, known markers for increased cardiovascular
events.12–14
A current global concern is mortality risk from a
Manuscript received August 10, 2006; revision accepted October
10, 2006.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
Correspondence to: Floyd J. Frost, PhD, Health and Environ-
mental Epidemiology Program, Lovelace Respiratory Research
Institute, 2425 Ridgecrest Dr SE, Albuquerque, NM 87108;
e-mail: ffrost@LRRI.org
DOI: 10.1378/chest.06-1997

1006 Original Research

Downloaded from www.chestjournal.org by guest on September 14, 2009

© 2007 American College of Chest Physicians
potential influenza pandemic.15,16 The H5N1/97
strain has exhibited potent ability to elevate proin-
flammatory cytokines.17,18 Preparation for the next
pandemic in the Unites States has focused on devel-
opment of vaccines and antiviral drugs. However,
progress toward developing an effective, abundantly
For editorial comment see page 950
available vaccine has been disappointing. Estimates
for the time from drug discovery to market in the
United States range from 5 to 15 years,19,20 suggest-
ing new antiviral drugs will arrive too late to protect
against a pandemic resulting from the current influ-
enza strains. Alternatively, Dr. David Fedson21 has
suggested that existing approved drugs may provide
protection from influenza/pneumonia death. One
such class of drugs suggested is statins.21 Two studies
(Mortenson et al,5 Mancini et al6) suggest that statins
may provide protection from community-acquired
pneumonia and COPD.
That these diseases can be controlled through
attenuation of the immune response is understand-
able.22–27 A recent study28 reports that H5N1 influ-
enza deaths have been primarily the result of a
rapidly escalating immune response, outpacing the
ability of current antiviral drugs to provide sufficient
protection. Cellular damage resulting from cytokine
dysregulation could be reduced if statins are able to
effectively modulate these immune responses. This
study compared influenza and COPD mortality risks
for low-dose and moderate-dose statin users and
nonusers.
Materials and Methods
We conducted a matched cohort study and two case-control
studies to evaluate whether statin use is associated with a reduced
risk of death from pneumonia/influenza or COPD. For the
case-control studies, two groups of cases and control subjects
were selected based on two outcomes: pneumonia/influenza and
COPD. This research protocol was reviewed and ruled exempt
under the Code of Federal Regulations protection of human
subjects.29 The Lovelace Patient Database (LPD), a deidentified,
longitudinal, health-care research database comprised of com-
plete health-care encounter data for members of several moder-
ate-sized health maintenance organizations (HMOs), was the
data source for these studies. The participating HMOs operate
integrated health-care delivery systems. The HMO population
considered for this study consisted of approximately 150,000
enrollees per year.
Matched Cohort Study
A file of patients with pharmacy benefits during enrolled
periods between January 1, 1992, and December 31, 2003, was
compiled using pharmacy dispensing data. Cases were individuals
with at least 90 days of cumulative statin exposure prior to death
www.chestjournal.org
Downloaded from www.chestjournal.org by guest on September 14, 2009
© 2007 American College of Chest Physicians
or disenrollment (n ⫽ 19,058). All data after December 31, 2003,
were censored. Data extracted for analysis included the follow-
ing: dispensing date, national drug code (uniquely identifying the
drug), quantity dispensed, days supply, dosage, and dates of
HMO enrollment and disenrollment. Patients using any one or
more distinct statin drugs for a minimum of 90 cumulative days
were considered to be statin exposed. Based on our data, the
usual minimum prescribed statin dose was 10 mg/d. Statin
exposure was further classified into low daily dose (⬍ 4 mg/d) and
moderate daily dose (ⱖ 4 mg/d). Daily dose was defined to be the
mean milligrams per day for a 3-month to 1-year period following
initiation of statin therapy, depending on available enrollment.
Ninety-four percent of the moderate-daily-dose group was HMO
enrolled at least 1 year after initiation of statin therapy, and 75%
of the low-daily-dose group was enrolled for at least 1 year
following initiation of statin therapy. Three HMO members
without a history of statin therapy (the unexposed group) were
matched to each statin-exposed individual based on sex, birth
year, and HMO enrollment period. Both cases and comparison
group members were required to have at least 90 days of
enrollment following initiation of the patient’s statin therapy.
Enrollment period matching of statin-exposed and nonexposed
individuals permitted observation of health-care events for both
groups during closely comparable time periods (ie, 90 days
following statin initiation until death or disenrollment). Health-
care utilization and hospital discharge data for the statin-exposed
and comparison individuals prior to (phase 1) and after (phase 2)
initiation of statin therapy were extracted from the LPD. All
participants survived phase 1. The Charlson comorbidity index
(CCI), an estimate of mortality risk during the subsequent year
based on outpatient International Classification of Disease, Ninth
Revision Clinical Modification (ICD-9-CM) diagnosis codes, was
calculated for both statin-exposed and unexposed patients for
matching 12-month periods during phase 1.30
Deaths were based on a patient’s hospital discharge status of
deceased. Causes of death were taken from the primary, second-
ary, and tertiary discharge diagnoses. Grouped causes of death
used in the cohort analyses included several broad categories of
disease: infectious diseases (ICD-9-CM 001–139), cancer (ICD-
9-CM 140 –239), nervous system (ICD-9-CM 320 –389), circula-
tory system (ICD-9-CM 340 – 459), digestive system (ICD-9-CM
520 –579), respiratory system (ICD-9-CM 460 –519), and exter-
nal causes (ICD-9-CM 800⫹). Up to three causes of death were
considered for the analyses, with only one cause included in any
particular analysis. Respiratory disease deaths were further cate-
gorized as follows: (1) pneumonia and influenza deaths (ICD-
9-CM 480 – 487); (2) unspecified pneumonia and influenza
deaths (ICD-9-CM 486 – 487); and (3) COPD deaths (ICD-
9-CM 490 – 496).
Logistic regression was used to estimate the odds ratio (OR) of
death for statin users (either low or moderate daily dose)
compared to nonusers. Similarly, proportional hazards analysis
was used to estimate differences in survival times. The compar-
isons were adjusted for duration of enrollment before (phase 1)
initiation of statin therapy of their matched statin-exposed indi-
vidual, the CCI during phase 1 (ⱖ 2 vs ⬍ 2), the number of
different medications taken during phase 1 (0 to ⱖ 18), and
receiving three or more influenza vaccinations after initiation of
statin therapy (phase 2). Analyses for each cause of death were
conducted for both low- and moderate-daily-dose statin groups.
The large number of strata (n ⫽ 19,058) rendered stratified
analysis unnecessary.
Case-Control Studies
Statin-exposed individuals in the cohort study exhibited more
cardiovascular comorbidities than matched patients not receiving
CHEST / 131 / 4 / APRIL, 2007 1007
statins due to the intended primary indication for statins. Since
adjustment for these comorbidities in the cohort model could
have inadvertently affected other outcomes, we conducted two
confirmatory case-control studies. Cases and control subjects
(n ⫽ 64,362) were again drawn from the LPD. We required both
cases and control subjects to be HMO enrolled for at least 12
months. Cases for the pneumonia/influenza study consisted of
patients with a hospital discharge of deceased and mention of
pneumonia or influenza (ICD-9-CM 486 – 487); cases for the
COPD study were patients with a deceased-labeled hospital
discharge and mention of COPD (ICD-9-CM 490 – 496). Control
subjects for the pneumonia/influenza study were surviving pa-
tients with one or more inpatient or outpatient visits for either
specified pneumonia or influenza/pneumonia (ICD-9-CM 480 –
487). Control subjects for the COPD study were surviving
patients with two or more inpatient or outpatient visits with
mention of COPD (ICD-9-CM 490 – 496). Both cases and control
subjects were restricted to those born before 1956 to increase the
likelihood of including statin users.
ORs were estimated using logistic regression (SAS Proc Logis-
tic; SAS Institute; Cary, NC). Three categories of statin adher-
ence were used: none, low daily dose (⬍ 4 mg/d), and moderate
daily dose (ⱖ 4 mg/d). Adjustments were made for sex, birth year,
and duration of phase 2 enrollment in all models.
Results
Matched Cohort Study
Table 1 lists the characteristics of the patients in
the matched cohort. Among the 19,058 HMO mem-
bers with a statin pharmacy fill, 11,583 patients
(60.8%) received at least 4 mg/d during phase 2.
Statin daily dose was lowest in members born after
1945 (p ⬍ 0.001). Statin users had a higher mean
number of different medications received in phase 1.
A higher fraction of moderate-daily-dose users (ⱖ 4
mg/d) had three or more influenza vaccinations in
phase 2. Significantly more statin users (both mod-
erate- and low-daily-dose groups) had CCI scores
ⱖ 2 (9.2%) than nonusers (4.4%), suggesting signif-
icantly more comorbidities and a higher risk of death
during phase 2.
ORs for death from the seven broad disease
categories for low-daily-dose (⬍ 4 mg/d) and mod-
erate-daily-dose (ⱖ 4 mg/d) statin users are shown in
Table 2. As expected, deaths due to circulatory
diseases (ICD-9-CM 340 – 459) were significantly
elevated for all statin users. Deaths due to nervous
system diseases (ICD-9 320 –389) were significantly
elevated for all statin users. Deaths from these
conditions were also elevated (not significantly) for
patients with moderate-daily-dose statin use.
ORs for deaths from three categories of respira-
tory diseases—pneumonia/influenza (ICD-9-CM
480 – 487), unspecified pneumonia and influenza
(ICD-9-CM 486 – 487), and COPD (ICD-9-CM
490 – 496)—are provided in Table 3. In each of these
categories, patients with a moderate daily dose had
significantly reduced ORs of death. For COPD
deaths, statin users with a moderate daily dose had a
reduced OR of 0.17 (95% confidence interval [CI],
0.07 to 0.42). The ORs of death in the cohort study
from COPD and influenza were nearly identical for
both male and female subjects (data not shown).
There is possibly a greater influenza/pneumonia
protective effect for female than male subjects.
Adjusting for the co-occurrence of COPD changed
the ORs for influenza from 0.49 (95% CI, 0.26 to
0.76) to 0.63 (95% CI, 0.35 to 1.14).
Alternatively, we calculated the proportional haz-
ards regression using SAS Proc PHREG (SAS Insti-
tute), adjusted for the same variables used in the
logistic regression (Table 4). We examined survival
times for both low- and moderate-daily-dose statin

Table 1—Characteristics of Patients in the Matched Cohort Study*

Statin Use (n ⫽ 19,058)

No Statin
Characteristics Low Daily Dose Moderate Daily Dose Use

Cohort 7,475 (39.2) 11,583 (60.8) 57,174

Born 1946 to 1955 2,272 (30.4) 2,806 (24.2) 15,234 (26.6)
Born 1921 to 1945 4,746 (63.5) 8,054 (69.5) 38,400 (67.2)
Born in 1920 or before 457 (6.1) 723 (6.2) 3,540 (6.2)
Male 3,637 (48.7) 6,292 (54.3) 29,787 (52.1)
Female 3,838 (51.3) 5,291 (45.7) 27,387 (47.9)
Mean No. of medications prior to statin use 7,475 (9.5†) 11,583 (8.4†) 57,174 (6.2†)
CCI score ⱖ 2 during phase 1 7,475 (10.7) 11,583 (12.1) 57,174 (5.6)
Three or more influenza vaccinations in phase 2 7,475 (2.2) 11,583 (4.1) 57,174 (1.9)
Pneumonia or influenza (ICD-9-CM 480–487) deaths 11 (0.12) 18 (0.14) 94 (0.15)
Unspecified pneumonia and influenza (ICD-9-CM 8 (0.13) 16 (0.12) 80 (0.13)
486–487) deaths
COPD (ICD-9-CM 490–496) deaths 8 (0.09) 5 (0.04) 84 (0.14)
*Data are presented as No. (%).
†Mean.

1008 Original Research

Downloaded from www.chestjournal.org by guest on September 14, 2009

© 2007 American College of Chest Physicians
 Table 2—Inpatient Deaths by Disease and Statin Daily Dose in the Matched Cohort*
All Statin Users Statin Use ⬍ 4 mg/d Statin Use ⱖ 4 mg/d
Causes (n ⫽ 19,058) (n ⫽ 7,475) (n ⫽ 11,583)

Infectious diseases (ICD-9-CM 001–139) 1.04 (0.66–1.65); 25 1.03 (0.48–2.22); 9 1.05 (0.59–1.87); 16
Cancer (ICD-9-CM 140–239) 0.91 (0.68–1.21); 58 1.22 (0.77–2.06); 22 0.76 (0.55–1.15); 36
Nervous system (ICD-9-CM 320–389) 1.59 (1.00–2.52); 28 1.80 (0.77–4.16); 9 1.51 (0.87–2.63); 19
Circulatory (ICD-9-CM 390–459) 1.35 (1.09–1.67); 124 1.50 (1.07–2.12); 50 1.26 (0.96–1.66); 74
Respiratory (ICD-9-CM 460–519) 0.89 (0.65–1.21); 52 1.34 (0.84–2.14); 26 0.66 (0.43–1.01); 26
Digestive (ICD-9-CM 520–579) 0.56 (0.34–0.0.92†); 19 0.52 (0.22–1.23); 6 0.60 (0.33–1.08); 13
External causes (ICD-9-CM 800⫹) 1.07 (0.70–1.65); 29 1.28 (0.64–2.52); 12 0.96 (0.56–1.67); 17
*Data are presented as OR (95% CI); No. of deaths. Data are adjusted for the number of days enrolled before and after statin initiation of the
statin-exposed individual. Individuals can be counted more than once if multiple conditions are cited as one of the first three discharge diagnoses.
All study members had ⱖ 90 days of enrollment after initiation of statin therapy.
†p ⬍ 0.05.

groups vs unexposed. The moderate-daily-dose haz-
ard ratio was 0.13 (95% CI, 0.05 to 0.32) for COPD,
and for influenza/pneumonia it was 0.51 (95% CI,
0.30 to 0.89), similar to the ORs from the logistic
regression analysis. For all statin users, the hazard
ratio was 0.23 (95% CI, 0.13 to 0.42) for COPD and
0.61 (95% CI, 0.41 to 0.92) for influenza/pneumonia.
Moderate-daily-dose statin users without diagnosed
COPD had a hazard ratio of 0.54 (95% CI, 0.31 to
0.93) for influenza/pneumonia.
Case-Control Studies
Table 5 lists the characteristics of patients in the case-
control studies. We identified 397 members who died in
the hospital with a discharge diagnosis of unspecified
pneumonia/influenza (ICD-9-CM 486–487) and 54,136
surviving members with either an inpatient or outpatient
diagnosis with these codes. Similarly, we identified 207
members who died in the hospital with a diagnosis of
COPD (ICD-9-CM 490–496) and 9,622 surviving
members with either an inpatient or outpatient diagno-
sis of COPD. We classified patients into three age cohorts:
those born in or before 1920, from 1921 to 1945, and from
1946 to 1955.
Cases compared with surviving control subjects in
the pneumonia/influenza study were significantly
more likely to have been born prior to 1921 (Table
6). Men were at higher risk of influenza/pneumonia
death (OR, 1.35; 95% CI, 1.11 to 1.65). For influen-
za/pneumonia deaths among moderate-daily-dose
statin users, the OR of statin exposure was 0.62 (95%
CI, 0.43 to 0.91) but was not significantly reduced for
lower statin exposure (⬍ 4 mg/d). The OR for statin
exposure among COPD deaths was significantly
lower for moderate-daily-dose statin users (OR, 0.19;
95% CI, 0.08 to 0.47), whereas the OR of statin
exposure for low-daily-dose statin users (⬍ 4 mg/d)
was not statistically distinguishable from those with
no statin use.
Due to the limited population size, there was some
subject overlap between the cohort and case/control
studies. Seventy-seven percent of the statin-exposed
patients were included exclusively in the cohort
study. Forty-five percent of influenza cases in the
influenza case/control study were included exclu-
sively, and 17% of COPD cases in the COPD
case/control study were included exclusively.
Discussion
This study found a dramatically reduced risk of
death from COPD among statin users and a signifi-

Table 3—ORs for Inpatient Death Due to Pneumonia/Influenza, Unspecified Pneumonia and Influenza, and COPD
in the Matched Cohort*

Inpatient Cause of Death All Statin Users Statin Use ⬍ 4 mg/d Statin Use ⱖ 4 mg/d

Pneumonia (ICD-9-CM 480–487) 0.73 (0.47–1.13) 0.89 (0.32–1.39) 0.49 (0.26–0.76)‡

Unspecified pneumonia and influenza (ICD-9-CM 486–487) 0.76 (0.51–1.13) 0.83 (0.28–1.54) 0.60 (0.26–0.82)‡
COPD (ICD-9-CM 490–496) 0.29 (0.16–0.52)‡ 0.58 (0.17–0.92)‡ 0.17 (0.07–0.42)‡
Unspecified pneumonia and influenza (ICD-9-CM 486–487)† 0.68 (0.42–1.11) 0.84 (0.35–2.01) 0.63 (0.35–1.14)
*Data are presented as OR (95% CI). Results were adjusted for days enrolled during phase 1 and phase 2, a CCI score ⱖ 2, and the number of
different medications taken during phase 1 and for having three or more influenza vaccinations during phase 2; required ⱖ 90 days of enrollment
after statin use (cases and control subjects).
†Adjusted for the co-occurrence of COPD.
‡p ⬍ 0.05.

www.chestjournal.org CHEST / 131 / 4 / APRIL, 2007 1009

Downloaded from www.chestjournal.org by guest on September 14, 2009

© 2007 American College of Chest Physicians
 Table 4 —Proportional Hazards Survival Analysis
Influenza Hazard COPD Hazard
Variables Ratio (95% CI) Ratio (95% CI)
All users 0.61 (0.41–0.92)* 0.23 (0.13–0.42)*
Low compliance 0.81 (0.44–1.51) 0.45 (0.21–0.94)*
Moderate compliance 0.51 (0.30–0.89)* 0.13 (0.05–0.32)*
Without COPD-related
deaths
Low compliance 0.99 (0.54–1.80)
Moderate compliance 0.54 (0.31–0.93)*
*p ⬍ 0.05.
cantly reduced risk of death from influenza/pneumo-
nia. Since the reductions were observed in both the
cohort and case-control studies, it is unlikely they
could be due to artifacts of either study design or the
analysis.
These findings suggest that moderate-dose statin
use reduces the risk of influenza/pneumonia death
and strongly suggest that statins reduce the risk of
COPD death. Both findings are in general agree-
ment with prior studies.5,6 A potential concern,
confounding by indication, is an unlikely explanation
since it would affect both low- and moderate-dose
statin users.
Mancini et al6 examined two cohorts of patients
ⱖ 65 years old with diagnosed COPD. The first
cohort included COPD patients who underwent
revascularization. The second cohort included peo-
ple with COPD and no recorded myocardial infarc-
tion, and who had a prescription for nonsteroidal
antiinflammatory drugs during the first 18 months of
a 24-month study period. Exposure to statins was
defined as filling at least one statin prescription prior
to the index date, with exposure treated as a binary
variable and omitting reference to average dose
information. Outcomes for both cohorts were ana-
lyzed using logistic regression and adjusted for ap-
proximately 16 factors. Statin use exhibited an ad-
justed mortality risk ratio of 0.50 (95% CI, 0.43 to
0.58) for the first cohort and 0.63 (95% CI, 0.54 to
0.74) for the second cohort. The study of Mancini et
al6 differed from ours both in its complexity of design
and its method for assessing statin exposure. How-
ever, despite these differences, the results are in
general agreement with our findings.
Our study differs markedly from prior studies of
pneumonia and COPD in the methods used to assess
statin exposure. Overall, practical statin therapy
compliance is thought to be poor,31 suggesting as-
sessment of the daily dose in studies of statin health
effects is critical. Studies attempting to quantify the
pleiotropic effects of statins for other conditions
without adequate consideration of daily dose may
risk reaching false-negative conclusions. Our data
suggest that consideration of dose is critical in
assessing the efficacy of statin therapy.
There are several potential limitations of this
study, including the potential for misclassification of
disease outcomes. Diagnoses were based on assigned
ICD-9-CM codes and are rarely confirmed by iden-
tification of a pathogen or antibody response to a
pathogen. It is also possible that some drug dispens-
ings were not identified due, for example, to admin-
istrative anomalies such as dual insurance coverage.
To maximize study power, we considered all drugs in
the statin class together. However, different statins
could possess different modes of action, with result-
ing variations in outcomes. Moderate daily dose was
defined as an average of ⱖ 4 mg/d. In practice, this
definition would be considered poor compliance.
Finally, deaths occurring outside the hospital were
not captured. This potential for underassessment is
believed to be minimal for influenza/pneumonia
owing to the acute nature and protracted convales-
cence of the infection. However, this could represent
a confounding factor for both the COPD and the
influenza studies. These errors might tend to reduce
the power of the study either to detect an effect or its
ability to estimate the magnitude of an effect.

Table 5—Characteristics of Patients in the Case-Control Studies*

Unspecified Pneumonia/Influenza COPD

Characteristics Cases (n ⫽ 397) Control (n ⫽ 54,136) Cases (n ⫽ 207) Control (n ⫽ 9,622)

Cohort
Born 1946 to 1955 29 (7.3) 38,726 (71.5) 3 (1.5) 1,327 (13.8)
Born 1921 to 1945 133 (33.5) 11,278 (20.8) 106 (51.2) 5,943 (61.8)
Born in 1920 or before 235 (59.2) 4,132 (7.6) 98 (47.3) 2,352 (24.4)
Male 202 (50.9) 25,189 (46.5) 106 (51.2) 4,837 (50.3)
Female 195 (49.1) 28,947 (53.5) 101 (48.8) 4,787 (50.3)
Daily dose
Low (⬍ 4 mg/d) 1 (0.3) 237 (0.4) 6 (2.9) 450 (4.7)
Moderate (ⱖ 4 mg/d) 30 (7.6) 3,310 (6.1) 5 (2.4) 1,171 (12.2)
*Data are presented as No. (%).

1010 Original Research

Downloaded from www.chestjournal.org by guest on September 14, 2009

© 2007 American College of Chest Physicians
 Table 6 —Case-Control Study: Influenza/Pneumonia (ICD-9-CM 486 – 487) Patients (Outpatient or Inpatient) vs
Deaths*
Covariates
Cohort
Born 1946 to 1955
Born 1921 to 1945
Born in 1920 or before
Female
Male
Statin daily dose
None
Low (⬍ 4 mg/d)
Moderate (ⱖ 4 mg/d)
*Data are presented as OR (95% CI). All subjects were enrolled in the HMO for at least 12 mo.
†p ⬍ 0.05
These studies alone are not proof that the ob-
served associations are causal. We lack specific evi-
dence that statins reduce the risks of influenza
mortality. Although statins might be effective in
lowering the risks of death from other causes of
pneumonia, the current study cannot assess reduced
risks during periods when the influenza virus is
circulating. Our data suggest that statin-related re-
duction in influenza/pneumonia mortality is not ex-
plained by reduction of COPD-related mortality
risks. It remains unclear whether statins will reduce
influenza mortality risks for young people who are
most likely to be severely affected by an avian
influenza pandemic.
The magnitude of the risk reduction for influenza/
pneumonia death we observed was less than that
reported by Mortenson et al.5 Because statins appear
to provide significant protection from COPD-associ-
ated death, the prevalence of COPD in a study
population could significantly affect the magnitude
of the influenza/pneumonia protective effect ob-
served. If a larger proportion of patients in the study
by Mortenson et al5 also had COPD, this could have
had the effect of inflating the estimated protective
effects of statin exposure for influenza/pneumonia
death. Another uncertainty is the duration of statin
therapy needed to affect risk reduction. A study32 of
107 hypercholesterolemic patients treated with sim-
vastatin for 6 weeks showed a significant decline in
cytokine levels; however, greater reductions were
observed after 6 months.
Even if statins are not able to significantly reduce
the risk of death from avian influenza, their use
could significantly extend the time between disease
onset and death. This additional survival time could
increase the effectiveness of antiinfluenza drugs,
providing a longer time to reduce mortality risks. So
far, antiinfluenza drugs have not demonstrated an
www.chestjournal.org
Downloaded from www.chestjournal.org by guest on September 14, 2009
© 2007 American College of Chest Physicians
Influenza/Pneumonia COPD Inpatient
Inpatient Death Death
1.00 1.00
17.07 (11.39–25.59)† 8.47 (2.68–26.73)†
79.14 (53.71–116.60)† 18.04 (5.71–57.03)†
1.00 1.00
1.35 (1.11–1.65)† 1.06 (0.81–1.40)
1.00 1.00
0.26 (0.04–2.13) 0.60 (0.26–1.36)
0.62 (0.43–0.91)† 0.19 (0.08–0.47)†
ability to significantly reduce the level of avian
influenza human death.28 There remain, unfortu-
nately, many uncertainties about the effectiveness of
statins as an approach to preventing or delaying
death from avian influenza. However, given the lack
of effective alternatives, resolving these uncertainties
should be a high priority.
References
1 Heart Protection Study Collaborators Group. MRC/BHF
Heart Protection Study of cholesterol lowering with simva-
statin in 20,536 high-risk individuals: a randomized placebo-
control trial. Lancet 2002; 360:7–22
2 Maron DJ, Fazio S, Linton MF. Current perspectives on
statins. Circulation 2000; 101:207–213
3 Palinski W. New evidence for beneficial effects of statins
unrelated to lipid lowering. Arterioscler Thromb Vasc Biol
2001; 21:3–5
4 Davignon J, Leiter LA. Ongoing clinical trials of the pleiotro-
pic effects of statins. Vasc Health Risk Manage 2005; 1:29 – 40
5 Mortenson EM, Restrepo MI, Anzueto A, et al. The effect of
prior statin use on 30-day mortality for patients hospitalized
with community-acquired pneumonia. Respir Res 2005; 6:82.
Available at: http://respiratory-research.com/content/6/1/82.
Accessed November 21, 2006
6 Mancini GB, Etminan M, Zhang B, et al. Reduction of
morbidity and mortality by statins, angiotensin-converting
enzyme inhibitors, and angiotensin receptor blockers in pa-
tients with chronic obstructive pulmonary disease. J Am Coll
Cardiol 2006; 47:2554 –25560
7 Almog Y, Shefer A, Novack V, et al. Prior statin therapy is
associated with a decreased rate of severe sepsis. Circulation
2004; 110:880 – 885
8 Liappis AP, Kan VL, Rochester CG, et al. The effect of statins
on mortality in patients with bacteremia. Clin Infect Dis
2001; 33:1352–1357
9 Kruger P, Fitzsimmons K, Cook D, et al. Statin therapy is
associated with fewer deaths in patients with bacteremia.
Intensive Care Med 2006; 32:75–79
10 Warnholtz A, Genth-Zotz S, Munzel T. Should treatment of
sepsis include statins [editorial]? Circulation 2005; 111:1735–
1737
CHEST / 131 / 4 / APRIL, 2007 1011
11 Merx MW, Liehn EA, Graf J, van de Sandt A, et al. Statin
treatment after onset of sepsis in a murine model improves
survival. Circulation 2005; 112:117–124
12 Fessler MB, Young SK, Jeyaseelan S, et al. A role for
hytoxy-methylgutaryl coenzyme A reductase in pulmonary
inflammation and host defense. Am J Respir Crit Care Med
2005; 171:606 – 615
13 Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy,
LDL cholesterol, C-reactive protein, and coronary artery
disease. N Engl J Med 2005; 352:29 –38
14 Blake GJ, Ridker PM. Are statins anti-inflammatory? Curr
Control Trials Cardiovasc Med 2000; 1:161–165
15 Centers for Disease Control and Prevention. Key facts about
avian influenza (bird flu) and avian influenza A (H5N1) virus.
Available at: http://www.cdc.gov/flu/avian/gen-info/facts.htm.
Accessed November 17, 2006
16 Simonsen L, Clarke MJ, Schonberger LB, et al. Pandemic
versus epidemic influenza mortality: a pattern of changing age
distribution. J Infect Dis 1998; 178:53– 60
17 Chan MCW, Cheung CY, Chui WH et al. Proinflammatory
cytokine responses induced by influenza A (H5N1) viruses in
primary human alveolar and bronchial epithelial cells. Respir
Res 2005; 6:135 Available at: http://respiratory-research.com/
content/6/1/135. Accessed November 21, 2006
18 Zhou J, Law HKW, Cheung CY, et al. Differential expression
of chemokines and their receptors in adult and neonatal
macrophages infected with human or avian influenza viruses.
J Infect Dis 2006; 194:61–70
19 Beeley N. A revolution in drug discovery [editorial]. BMJ
2000; 321:581–582
20 Cantor DJ. CRS Report for Congress. Prescription Drug
User Fee Act of 1992: effects on bringing new drugs to
market. Available at: http://countingcalifornia.cdlib.org/crs/
pdf/97– 838.pdf. Accessed November 17, 2006
21 Fedson DS. Pandemic influenza: a potential role for statins in
treatment and prophylaxis. Clin Infect Dis 2006; 43:199 –205
22 Takanashi S, Hasegawa Y, Kanehira Y, et al. Interleukin-10
level in sputum is reduced in bronchial asthma, COPD and in
1012
Downloaded from www.chestjournal.org by guest on September 14, 2009
© 2007 American College of Chest Physicians
smokers. Eur Respir J 1999; 14:309 –314
23 de Torres JP, Cordoba-Lanus E, Lopez-Aguilar C, et al.
C-reactive protein levels and clinically important predictive
outcomes in stable COPD patients. Eur Respir J 2006;
902–907
24 Dev D, Wallace E, Sankaran R, et al. Value of C-reactive
protein measurement in exacerbations of chronic obstructive
pulmonary disease. Respir Med 1998; 92:644 – 667
25 Mayo J, Ghezzo H, Cosio MG. Lymphocyte population and
apoptosis in the lungs of smokers and their relation to
emphysema Eur Respir J 2001; 17:946 –953
26 Cosio MG, Majo J, Cosio MG. Inflammation of the airways
and lung parenchyma in COPD: role of T cells. Chest 2002;
121(Suppl 5):160S–165S
27 Agusti A, Macnee W. Donaldson K, et al. Hypothesis: does
COPD have an autoimmune component? Thorax 2003; 58:
832– 834
28 de Jong MD, Simmons CP, Thanh TT, et al. Fatal outcome of
human influenza A (H5N1) is associated with high viral load
and hypercytokinemia. Nat Med 2006; 12:1203–1207
29 National Institutes of Health, Office of Human Subjects
Research. Code of Federal Regulations: Title 45, Public
Welfare; Title 46, Protection of Human Subjects, 2005.
Available at: http://ohsr.od.nih.gov/guidelines/45cfr46.htm.
Accessed November 21, 2006
30 Charleson ME, Pompei P, Ales KL, et al. A new method of
classifying prognostic comorbidity in longitudinal studies:
development and validation. J Chronic Dis 1987; 40:373–383
31 Wei L, Wang J, Thompson P, et al. Adherence to statin
treatment and readmission of patients after myocardial infarc-
tion: a six-year follow up study. Heart 2002; 88:229 –233
Available at: http://heart.bmjjournals.com/cgi/content/full/88/
3/229. Accessed November 17, 2006
32 Rezaie-Majd A, Maca T, Bucek R, et al. Simvastatin reduces
expression of cytokines interleukin-6, interleukin-8, and
monocyte chemoattractant protein-1 in circulating monocytes
from hypercholesterolemic patients. Arterioscler Thromb
Vasc Biol 2002; 22:1194 –1199
Original Research
 Influenza and COPD Mortality Protection as Pleiotropic,
Dose-Dependent Effects of Statins *
Floyd J. Frost, Hans Petersen, Kristine Tollestrup and Betty Skipper
Chest 2007;131; 1006-1012
DOI 10.1378/chest.06-1997
This information is current as of September 14, 2009

Updated Information Updated Information and services, including

& Services high-resolution figures, can be found at:
http://www.chestjournal.org/content/131/4/1006.full.html

References This article cites 28 articles, 14 of which can be

accessed free at:
http://www.chestjournal.org/content/131/4/1006.full.
html#ref-list-1
Citations This article has been cited by 6 HighWire-hosted
articles:
http://www.chestjournal.org/content/131/4/1006.full.
html#related-urls
Open Access Freely available online through CHEST open access
option
Permissions & Licensing Information about reproducing this article in parts
(figures, tables) or in its entirety can be found online at:
http://www.chestjournal.org/site/misc/reprints.xhtml
Reprints Information about ordering reprints can be found online:
http://www.chestjournal.org/site/misc/reprints.xhtml
Email alerting service Receive free email alerts when new articles cite this
article. Sign up in the box at the top right corner of the
online article.
Images in PowerPoint Figures that appear in CHEST articles can be
format downloaded for teaching purposes in PowerPoint slide
format. See any online article figure for directions

Downloaded from www.chestjournal.org by guest on September 14, 2009

© 2007 American College of Chest Physicians