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. Author manuscript; available in PMC: 2015 Aug 1.
Published in final edited form as: Prev Med. 2014 Apr 24;65:58–64. doi: 10.1016/j.ypmed.2014.04.017

Physical Inactivity and Long-Term Rates of Community-Acquired Sepsis

Henry E Wang 1, John Baddley 2, Russell Griffin 3, Suzanne Judd 4, George Howard 5, John Donnelly 6, Monika M Safford 7
PMCID: PMC4101049  NIHMSID: NIHMS598595  PMID: 24768917

Abstract

OBJECTIVE

The authors sought to determine the association between physical inactivity (characterized by exercise and television watching levels) and long-term rates of community-acquired sepsis.

METHODS

Population-based cohort study of 30,183 adult (≥45 years) community-dwelling participants. Subjects reported weekly exercise (low=none, medium=1-3 times/week, high= ≥4 times/week) and daily television watching (low= <1 hour/day, medium= 1-3 hours/day, high= ≥4 hours/day) levels. The authors evaluated the association between exercise, television watching and rates of sepsis, defined as hospital treatment for a serious infection with ≥2 Systemic Inflammatory Response Syndrome (SIRS) criteria.

RESULTS

Among 30,183 participants, 1,500 experienced a sepsis event. Reported weekly exercise was: high 8,798 (29.2%), medium 10,695 (35.4%), and low 10,240 (33.9%). Where available, reported daily television watching was: low 4,615 (19.6%), medium 11,587 (49.3%) and high 7,317 (31.1%). Decreased weekly exercise was associated with increased adjusted sepsis rates (high – referent; medium HR 1.02, 95% CI 0.96-1.20; low 1.33, 1.13-1.56). Daily television watching was not associated with sepsis rates. Sepsis rates were highest among those with both low exercise and high television watching levels (HR 1.49, 95% CI: 1.10-2.01).

CONCLUSIONS

Physical inactivity may be associated with increased long-term rates of community-acquired sepsis.

Keywords: sepsis, infections, epidemiology, physical activity, diet, exercise, sedentary behavior

INTRODUCTION

Physical inactivity is prevalent in over half of United States adults, higher than other modifiable risk factors.(Macera, Jones et al. 2003) Physical activity involves a spectrum encompassing low through high metabolic activities.(Tremblay, Colley et al. 2010) An important element in this continuum is exercise, which has been associated with a host of health benefits, including reductions in coronary heart disease risk factors, cardiovascular disease, stroke and all-cause mortality.(Gibbons, Blair et al. 1983; Wood, Haskell et al. 1983; Kannel, Wilson et al. 1985; Blair, Kohl et al. 1989; Kiely, Wolf et al. 1994; Kokkinos 2012; Sluik, Buijsse et al. 2012) Another important element of physical activity is sedentary behavior, most commonly represented by television watching.(Hu, Leitzmann et al. 2001; Hu, Li et al. 2003; Grontved and Hu 2011) Television watching has been associated with increased risks of obesity, diabetes, cardiovascular disease, metabolic syndrome, cancer, psychosocial health, and all-cause mortality.(Hu, Leitzmann et al. 2001; Hu, Li et al. 2003; Dunstan, Salmon et al. 2007; Dunstan, Barr et al. 2010; Grontved and Hu 2011)

Sepsis, the syndrome of microbial infection complicated by systemic inflammation, is a major public health problem in the United States.(Dellinger, Levy et al. 2013) Each year, individuals with severe sepsis account for over 750,000 hospitalizations, 570,000 Emergency Department visits, and 200,000 deaths in the United States.(Angus, Linde-Zwirble et al. 2001; Wang, Shapiro et al. 2007) While international campaigns have highlighted the importance of early recognition and aggressive care in improving sepsis outcomes, relatively little attention has focused on the precursors of sepsis; that is, identification of the individuals at greatest risk for developing the condition.(Dellinger, Levy et al. 2013)

There are plausible connections between physical inactivity and one’s risk of developing sepsis. For example, prior human and animal studies suggest associations between physical inactivity, immune function and susceptibility to upper respiratory infections.(Friman and Wesslen 2000; Walsh, Gleeson et al. 2011; Araujo, Campos et al. 2012; Gunzer, Konrad et al. 2012; Liebetanz, Gerber et al. 2012)(Matthews, Ockene et al. 2002; Chubak, McTiernan et al. 2006; Barrett, Hayney et al. 2012) We have previously observed associations between chronic medical conditions and increased rates of sepsis, including many associated with lack of physical activity.(Wang, Shapiro et al. 2012) Television watching has been associated with poor dietary habits, and obesity - a major consequence of poor diet and physical inactivity - is also independently associated with increased rates of sepsis.(Hu, Leitzmann et al. 2001; Hu, Li et al. 2003; Wang, Griffin et al. 2013)

In this we study we sought to determine the association between physical inactivity (characterized by exercise and television watching) and long-term rates of community-acquired sepsis.

METHODS

Study Design

This study utilized data from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a national, population-based, longitudinal cohort. The study received approved by the Institutional Review Board of the University of Alabama at Birmingham.

Selection of Participants

REGARDS is one of the largest ongoing national cohorts of community-dwelling individuals in the US, encompassing 30,239 individuals ≥45 years old.(Howard, Cushman et al. 2005) Designed to evaluate reasons for geographic and racial variations in stroke mortality, REGARDS includes individuals from all regions of the continental US. The study oversampled participants in the Southeastern US, with 21% of the cohort originating from the coastal plains of North Carolina, South Carolina and Georgia (the “buckle” of the stroke belt), and 35% originating from the remainder of North Carolina, South Carolina and Georgia plus Tennessee, Mississippi, Alabama, Louisiana and Arkansas (the “stroke belt”). The cohort is 42% African American and 45% male, and 69% of individuals are >60 years old. REGARDS does not include Hispanics, where stroke mortality disparities are small-to-non-existent.

REGARDS enrolled participants during 2003-7. The study obtained baseline data for each participant through phone interviews and in-person evaluations. Baseline data included medical history, functional status, health behaviors, physical characteristics (height, weight), physiologic measures (blood pressure, pulse, electrocardiogram), and an inventory of medications. Each participant provided blood and urine specimens. Participants completed self-administered questionnaires regarding diet, family history of diseases, psychosocial factors and prior residences. On a semi-annual basis, REGARDS contacted each participant to determine the date, location and attributed reason for all emergency department visits and hospitalizations during the follow-up interval. If the participant died, the study team reviewed death certificates and related medical records and interviewed proxies to ascertain the circumstances of the participant’s death.

Identification of Sepsis Events

We reviewed all reported hospitalizations and Emergency Department visits attributed by participants to a serious infection. We identified serious infections using taxonomies developed by Angus, et al.(Angus, Linde-Zwirble et al. 2001) Two trained abstractors independently reviewed all pertinent medical records to confirm the presence of a serious infection on initial hospital presentation. The abstractors also confirmed if the serious infection was a major reason for hospitalization. Medical record review included clinical and laboratory information from the first 28-hours of hospitalization, a time period encompassing Emergency Department and up to one full day of inpatient treatment. The abstractors adjudicated discordances, with additional physician-level review as needed.

Using international consensus definitions, we defined community-acquired sepsis as hospital treatment for an infection with two or more systemic inflammatory response syndrome (SIRS) criteria, including 1) heart rate >90 beats/minute, 2) fever (temperature >38.3°C or <36°C), 3) tachypnea (>20 breaths/min) or PCO2<32 mmHg, and 4) leukocytosis (white blood cells [WBC] >12,000 or <4,000 cells/mm3 or >10% band forms). Presentation to the hospital consisted of the time of Emergency Department triage or admission to inpatient unit (for participants admitted directly to the hospital). To allow for acute changes in the participant’s condition during early hospitalization, we used vital signs and laboratory test results for the initial 28-hours of hospitalization. Our study focused on individuals presenting to the hospital or Emergency Department with community-acquired sepsis. We did not include “hospital-acquired” sepsis developing at later points of hospitalization. We did not include organ dysfunction in the definition of sepsis. Initial review of 1,349 hospital records indicated excellent inter-rater agreement for presence of a serious infection (kappa=0.92) and the presence of sepsis (kappa=0.90) upon hospital presentation.

We included all sepsis events identified during the 10-year timeframe 2003-2012.

Definition of Exercise and Television Watching

We defined physical inactivity in terms of exercise and television watching. During their initial phone interview for the REGARDS study, participants reported their weekly frequency of exercise based upon the question, “How many times per week do you engage in intense physical activity, enough to work up a sweat?” The study categorized weekly exercise as none, 1-3 times per week, and 4 or more times per week. Participants reported weekly television or video watching frequency on a written survey administered during the initial in-person examination. Television and video watching categories included none, 1-6 hours/week, 1 hour/day, 2 hours/day, 3 hours/day, and 4+ hours/day.

Covariates

Sociodemographic characteristics included age, sex, race, geographic region, self-reported annual household income and self-reported education (years of school). To account for the sampling strategy used to recruit the REGARDS cohort, we defined geographic region as participant residence in the stroke “buckle,” stroke “belt” and elsewhere, as described previously.(Howard 1999; Howard, Cushman et al. 2005)

Health behaviors included tobacco and alcohol use, and exercise. We defined smoking status as current, past and never. We defined alcohol use according to the National Institute on Alcohol Abuse and Alcoholism classification; i.e., moderate (1 drink per day for women or 2 drinks per day for men) and heavy alcohol use (>1 drink per day for women and >2 drinks per day for men).(2005)

Television watching has been associated with poor dietary habits.(Hu, Leitzmann et al. 2001; Hu, Li et al. 2003) We characterized diet in terms of adherence to a Mediterranean Diet pattern, which has been associated with improved health outcomes, including reductions in cardiovascular disease and death.(Estruch, Ros et al. 2013) REGARDS participants completed a comprehensive food questionnaire documenting the frequency of consumption of items in nine food groups or components, including cereals, vegetables, fruits and nuts, legumes, fish, monounsaturated to saturated fat ratio, and moderate alcohol consumption, meat and dairy food products. We assigned a value of 1 for intake greater or equal than the median for food groups contributing to greater adherence to a Mediterranean diet; specifically, cereals, vegetables, fruits and nuts, legumes, fish, monounsaturated to saturated fat ratio, and moderate alcohol consumption. We also assigned a value of 1 for meat and dairy food product consumption less than the median. We summed the food group scores to yield an overall score ranging from 0 to 9, with higher scores indicating greater adherence to the Mediterranean Diet.

Obesity included individuals with elevated body mass index (BMI) or waist circumference (WC). Following standardized protocols, REGARDS examiners measured weight, height and WC of each participant at the beginning of the study. We defined elevated BMI as values >30 kg/m2, which is the cutoff for obesity in the United States.(2012) Examiner measured WC at a point midway between the lowest rib and the iliac crest with the subject standing. We defined elevated WC as values >102 cm for males and >88 cm for females.(Janssen, Katzmarzyk et al. 2002)

Chronic medical conditions included diabetes, hypertension, history of myocardial infarction, history of stroke, chronic kidney disease, and chronic lung disease. Diabetes included a fasting glucose ≥126 mg/L (or a glucose ≥200 mg/L for those not fasting) or the use of insulin or oral hypoglycemic agents. Hypertension consisted of systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or the self-reported use of antihypertensive agents. Participants self-reported history of myocardial infarction or stroke. Chronic kidney disease included individuals with an estimated glomerular filtration rate <60 ml/min/1.73 m2, calculated using the CKD-EPI equation.(Levey, Stevens et al. 2009) Because REGARDS did not collect information on pulmonary conditions such as asthma and chronic obstructive pulmonary disease, we defined participant use of pulmonary medications as a surrogate for chronic lung disease. Obtained from each participant’s medication inventory, pulmonary medications included beta agonists, leukotriene inhibitors, inhaled corticosteroids, combination inhalers, and other pulmonary medications such as ipratropium, cromolyn, aminophylline and theophylline.

Data Analysis

We conceptualized exercise and television watching as the primary exposures of interest in the analysis. Using a chi-square test, we first examined demographic, health behavioral and clinical characteristics differences between categories of exercise and television watching.

To estimate the associations between exercise, television watching and sepsis, we fit a series of multivariable Cox proportional hazards models. We limited the analysis to the first sepsis episode. Person-time at risk consisted of the time (days) from first in-person examination to the first episode of sepsis or the last follow-up interview, whichever came first. We defined exercise levels as low (none), medium (1-3 times/week) and high (≥4 times/week). We defined television watching levels as low (<1 hour/day), medium (1-3 hours/day) and high (≥4 hours/day). Multivariable adjustment accounted for demographic characteristics (age, sex, race, income, education, geographic region), health behaviors (smoking and alcohol use, exercise), obesity, adherence to a Mediterranean diet, and chronic medical conditions (diabetes, hypertension, myocardial infarction, stroke, chronic kidney disease, chronic lung disease).

We evaluated the [exercise X television watching] interaction in the multivariable model. We also examined interactions between exercise, television watching, and age, sex, race and geographic region. We fit a model separately assessing the associations of sepsis for different joint combinations of exercise and television watching. We tested the proportional hazards assumption of the Cox model using log-log plots and Schoenfeld residuals. We evaluated for potential collinearity between exercise and television watching by evaluating variance inflation factors. We conducted all analyses using Stata 12.2 (Stata, Inc, College Station, Texas).

RESULTS

From February 5, 2003 through December 31, 2012, among 30,183 participants, 2,553 experienced a serious infection, including 1,500 who experienced a hospitalization for community-acquired sepsis. The most common infection types associated with first sepsis events were pneumonia, kidney and urinary tract infections, and abdominal infections. (Table 1)

TABLE 1.

Infection types associated with first hospitalizations for sepsis. Total of 1,500 first sepsis events.

Infection Type Number of
First Sepsis
Hospitalizations
N (%)
Pneumonia 592 (39.5)
Kidney and Urinary Tract Infections 251 (16.7)
Abdominal 230 (15.3)
Bronchitis, Influenza and other Lung Infections 137 (9.1)
Skin and Soft Tissue 121 (8.1)
Sepsis 98 (6.5)
Fever of Unknown Origin 29 (1.9)
Catheter (IV / Central / Dialysis) 6 (0.4)
Surgical Wound 10 (0.7)
Meningitis 5 (0.3)
Unknown/Other 21 (1.4)
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Weekly exercise data were available for 29,733 of 30,183 (98.5%) participants. Reported weekly exercise among REGARDS participants included: high exercise (≥4 times/week) 8,798 (29.2%), medium (1-3 times/week) 10,695 (35.4%), and low (none) 10,240 (33.9%). (Table 2) Exercise frequency was lower for older, female and black individuals, as well as those with lower annual income and education. Although exercise frequency was lower for current smokers, exercise frequency was higher among moderate and heavy alcohol users. Diet was similar between exercise levels. Exercise frequency was lower among those with obesity and chronic medical conditions.

TABLE 2.

Baseline characteristics of REGARDS participants, stratified by quantity of weekly exercise. Weekly exercise levels available for 29,733 of 30,183 (98.5%) participants.

Variable High Exercise
(≥4 times/week)
(n=8,798)
(col %)		 Medium Exercise
(1-3 times/week)
(n=10,695)
(col %)		 Low Exercise
(none)
(n=10,240)(col %)		 P-value
Demographics
  Age
    <50 years 5.1 6.0 4.1 <0.001
    50-59 24.7 29.4 24.5
    60-69 39.4 37.6 36.1
    70-79 24.7 21.6 25.7
    ≥80 6.2 5.4 9.5
  Sex
    Male 54.0 45.3 36.6 <0.001
    Female 46.0 54.7 63.4
  Race
     White 63.2 58.5 54.6 <0.001
     Black 36.8 41.5 45.4
  Geographic Region
    Non-Belt 43.7 44.6 45.1 0.35
    “Stroke Belt” 34.8 34.5 34.6
    “Stroke Buckle” 21.5 20.8 20.3
  Income
    <$20,000 15.9 15.0 23.3 <0.001
    $20,000-34,000 23.4 23.3 25.8
    $35,000-74,000 30.9 32.0 26.1
    ≥$75,000 17.6 18.6 11.5
    Unknown 12.3 11.1 13.3
  Education
    Less than High School 11.6 9.9 15.8 <0.001
    High School Graduate 25.6 23.6 28.4
    some College 26.1 27.1 27.3
    College Graduate 36.7 39.4 28.5
    Missing 0.0 0.1 0.1
Health Behaviors
  Tobacco Use
    Never 43.7 47.8 43.5 <0.001
    Past 42.7 38.5 39.1
    Current 13.2 13.3 17.1
    Missing 0.4 0.4 0.3
  Alcohol Use
    None 57.5 59.2 67.0 <0.001
    Moderate 35.8 35.4 27.4
    Heavy 4.9 3.5 3.4
    Missing 1.8 1.9 2.1
Obesity (abnormal BMI or WC) 44.2 53.2 61.8 <0.001
  Missing 0.2 0.1 0.2
Mediterranean Diet Score (median, IQR) 5 (3-6) 4 (3-6) 4 (3-5) <0.001*
  Missing (%) 27.4 27.8 33.0
Chronic Medical Conditions
  Chronic Kidney Disease 8.4 9.1 14.8 <0.001
  Chronic Lung Disease 7.8 8.5 11.1 <0.001
  Diabetes 19.3 20.9 27.2 <0.001
  Hypertension 54.4 57.2 65.3 <0.001
  Myocardial Infarction 12.0 10.9 14.5 <0.001
  Stroke 5.3 4.9 8.9 <0.001
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*

From Kruskall-Wallis test.

Television watching data were available for 23,519 of 30,183 (77.9%) participants. Reported television watching among REGARDS participants included: low (≤1 hour/day) 4,615 (19.6%), medium (1-3 hours/day) 11,587 (49.3%) and high (≥4 hours/day) 7,317 (31.1%). (Table 3) Television watching levels were higher for older, female and black individuals, as well as those with lower annual income and education. Television watching was higher among current smokers. Most moderate and heavy alcohol users reported medium television watching levels. Television watching levels were higher among those with obesity and chronic medical conditions.

TABLE 3.

Baseline characteristics of REGARDS participants, stratified by quantity of daily television watching. Television watching levels available for 23,519 of 30,183 (77.9%) participants.

Low
Television
Watching
(≤1 hour/day)
(n=4,615)
(col %)		 Medium
Television
Watching
(1-3 hours/day)
(n=11,587)
(col %)		 High Television
Watching
(≥4 hours/day
(n=7,317)
(col %)		 P-value
Demographics
  Age
    <50 years 6.2 4.1 4.2 <0.001
    50-59 29.1 24.6 23.6
    60-69 36.6 37.8 39.9
    70-79 21.7 25.8 25.3
    ≥80 6.4 7.7 7.0
  Sex
    Male 44.5 48.2 39.5 <0.001
    Female 55.5 51.8 60.5
  Race
    White 69.0 70.9 49.0 <0.001
    Black 31.0 29.1 51.0
  Geographic Region
    Non-Belt 44.6 43.2 43.6 0.001
    “Stroke Belt” 33.8 34.0 36.0
    “Stroke Buckle” 21.5 22.8 20.4
  Income
    <$20,000 14.0 12.6 26.9 <0.001
    $20,000-34,000 19.3 24.0 28.0
    $35,000-74,000 30.7 33.4 25.2
    ≥$75,000 24.1 18.2 7.4
    Unknown 11.9 11.8 12.5
  Education
    Less than High School 9.0 8.1 17.3 <0.001
    High School Graduate 21.5 24.0 32.3
    Some College 23.2 28.4 27.1
    College Graduate 46.2 39.5 23.3
    Missing 0.0 0.0 0.1
Health Behaviors
  Tobacco Use
    Never 52.4 45.6 38.4 <0.001
    Past 37.4 42.2 41.6
    Current 9.8 11.8 19.7
    Missing 0.5 0.4 0.3
  Alcohol Use
    None 58.9 57.6 64.9 <0.001
    Moderate 35.8 36.4 28.8
    Heavy 3.9 4.4 4.1
    Missing 1.3 1.7 2.2
Obesity (abnormal BMI or WC) 43.3 49.6 61.2 <0.001
  Missing 0.1 0.1 0.2
Mediterranean Diet Score (median, IQR) 5 (3-6) 4 (3-6) 4 (3-5) <0.001
  Missing 12.1 10.2 13.2
Chronic Medical Conditions
  Chronic Kidney Disease 8.1 10.1 13.1 <0.001
  Chronic Lung Disease 8.5 8.6 11.3 <0.001
  Diabetes 17.0 19.0 27.2 <0.001
  Hypertension 49.7 56.5 65.8 <0.001
  Myocardial Infarction 10.7 11.8 14.0 <0.001
  Stroke 4.4 4.8 8.2 <0.001
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*

From Kruskall-Wallis test.

Median follow-up time was 6.6 years (IQR 5.1-8.1). Sepsis incidence was highest among those who reported no weekly exercise or ≥4 hours of daily television watching. (Table 4) On multivariable analysis, low exercise was independently associated with increased rates of sepsis, even after adjustment for demographics, tobacco and alcohol use, obesity, diet and chronic medical conditions. (Table 5) Television watching was not associated with rates of sepsis after adjustment for confounders.

TABLE 4.

Sepsis incidence rates by exercise and television watching category.

Activity Person-Time
(person-years)		 First Sepsis
Events		 Incidence
(Sepsis events per
1,000 person years)
Exercise
  High (≥4 times/week) 55,471 379 6.8 (6.2-7.6)
  Medium (1-3 times/week) 68,283 452 6.6 (6.0-7.3)
  Low (none) 60,099 642 10.7 (9.9-11.5)
Television Watching
  Low (≤1 hour/day) 29,969 204 6.8 (5.9-7.8)
  Medium (2-3 hours/day) 74,742 543 6.6 (6.0-7.3)
  High (≥4 hours/day) 44,578 469 10.7 (9.9-11.5)
Overall 186,420 1,498 8.0 (7.6-8.4)
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TABLE 5.

Multivariable hazard ratios for associations between exercise, television watching and first-sepsis events. Total of 1,500 first-sepsis events. Television watching and exercise were both included in the models.

Activity Unadjusted
Model		 Add
demographics,*
tobacco and
alcohol use		 Add obesity Add diet Add chronic
medical
conditions**
Quantity of Exercise
  High (≥4 times/week) Referent Referent Referent Referent Referent
  Medium (1-3 times/week) 0.93 (0.80-
1.09)		 1.04 (0.89-1.21) 1.01 (0.86-
1.18)		 1.02 (0.86-
1.20)		 1.02 (0.86-
1.20)
  Low (none) 1.53 (1.33-
1.71)		 1.53 (1.31-1.76) 1.43 (1.24-
1.66)		 1.43 (1.22-
1.67)		 1.33 (1.13-
1.56)
Quantity of Television
Watching
  Low (≤1 hour/day) Referent Referent Referent Referent Referent
  Medium (2-3 hours/day) 1.04 (0.88-
1.22)		 0.91 (0.77-1.08) 0.89 (0.76-
1.05)		 0.92 (0.77-
1.10)		 0.94 (0.79-
1.13)
  High (≥4 hours/day) 1.43 (1.21-
1.69)		 1.22 (1.03-1.45) 1.17 (0.99-
1.40)		 1.24 (1.03-
1.49)		 1.16 (0.95-
1.40)
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*

Age decile, sex, race, geographic region, income, education.

**

Chronic kidney disease, chronic lung disease, diabetes, hypertension, myocardial infarction, stroke.

The [exercise X television watching] interaction was not statistically significant. Interaction between exercise and age, sex, race and geographic region were not statistically significant. Interaction between television watching and age, sex, race and geographic region were also not statistically significant. When examining the joint association between exercise and television watching, individuals reporting both low exercise and high television watching exhibited the highest adjusted rates of sepsis. (Table 6)

TABLE 6.

Multivariable hazard ratios for joint associations between exercise and television watching levels and first-sepsis events. Total of 1,500 first-sepsis events.

Exercise and Television Watching Level Unadjusted
HR (95% CI)
for Sepsis		 Adjusted*
HR (95% CI)
for Sepsis
High exercise (≥4 times/week) + Low television watching (≤1 hour/day) Referent Referent
High exercise + Medium television watching (2-3 hours/day) 1.00 (0.75-1.33) 0.84 (0.61-1.15)
High exercise + High television watching (≥4 hours/day) 1.31 (0.96-1.79) 1.06 (0.75-1.50)
Medium exercise (1-3 times/week) + Low television watching (≤1 hour/day) 0.89 (0.64-1.25) 0.92 (0.63-1.33)
Medium exercise + Medium television watching (2-3 hours/day) 0.98 (0.74-1.29) 0.95 (0.70-1.28)
Medium exercise + High television watching (≥4 hours/day) 1.17 (0.87-1.58) 0.98 (0.70-1.37)
Low exercise (none) + Low television watching (≤1 hour/day) 1.41 (1.01-1.98) 1.15 (0.78-1.09)
Low exercise + Medium television watching (2-3 hours/day) 1.43 (1.09-1.89) 1.11 (0.81-1.51)
Low exercise + High television watching (≥4 hours/day) 2.22 (1.70-2.90) 1.49 (1.10-2.01)
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*

Adjusted for age decile, sex, race, geographic region, income, education, obesity, Mediterranean diet score, and history of chronic kidney disease, chronic lung disease, diabetes, hypertension, myocardial infarction or stroke.

Examination of log-log plots, Kaplan-Meier predicted survival plots, and Schoenfeld residuals verified that exercise and television watching satisfied the proportional hazards assumption. On collinearity analysis, the tolerance and variance inflation factor were 0.99 was 1.01, respectively, suggesting no collinearity between exercise and television watching.

DISCUSSION

In this study we observed associations between low weekly exercise and long-term rates of community-acquired sepsis. This relationship persisted even after adjustment for a range of potential confounders, indicating that the associations were not merely mediated by factors such as obesity and diet. While we did not observe an independent association between television watching and sepsis events, individuals reporting both low weekly exercise and high levels of daily television watching exhibited the highest rates of sepsis. These findings underscore the potential links between physical inactivity and long-term rates of sepsis.

In interpreting these results, one must consider that levels of television watching and exercise were based upon self-reports and may not encompass the full spectrum of sedentary behaviors.(Katzmarzyk, Church et al. 2009; Tremblay, Colley et al. 2010; Clark, Healy et al. 2011) Our analysis also assumed connections between baseline exercise and television watching and sepsis events over a 10-year span. However, REGARDS provided the best available data and presented one of the few opportunities to evaluate the connections between physical inactivity and long-term sepsis rates.

There are plausible connections between exercise and sepsis rates. Exercise has been associated with a host of immunologic alterations such as the reduction of Toll-like receptors expression on monocytes and macrophages, and inhibition of monocyte and macrophage infiltration of adipose.(Flynn and McFarlin 2006; Gleeson, McFarlin et al. 2006; Gleeson, Bishop et al. 2011) Sepsis is characterized by hyper-inflammatory response to microbial infection, and exercise is believed to have anti-inflammatory effects, including the increased production of anti-inflammatory cytokines.(3).(Gleeson, Bishop et al. 2011) Exercise and physical activity are associated with reduced levels of inflammatory markers, including high sensitivity C-reactive protein (hsCRP); we previously found that elevated hsCRP is associated with increased sepsis risk.(Geffken, Cushman et al. 2001; Abramson and Vaccarino 2002; Ford 2002; Yu, Ye et al. 2009)(Wang, Shapiro et al. 2012) Endothelial cell activation has been implicated in sepsis pathophysiology, and exercise is believed to mitigate endothelial dysfunction and inflammation.(Aird 2003; Ribeiro, Alves et al. 2010; Wang, Shapiro et al. 2013) Increased exercise and physical activity have been associated with reductions in cardiovascular disease, stroke, cancer, diabetes and dementia; these chronic medical conditions are known risk factors for sepsis.(Blair, Goodyear et al. 1984; Blair, Kohl et al. 1989; Warburton, Nicol et al. 2006; Kokkinos 2012) (Wang, Shapiro et al. 2012) Human trials have linked exercise with reduced acute respiratory infections.(Matthews, Ockene et al. 2002; Chubak, McTiernan et al. 2006; Barrett, Hayney et al. 2012)

Our observations suggested heightened sepsis rates among those with both low weekly exercise and high daily levels of television watching. As the most common form of sedentary behavior, television watching has been associated with increased risk of diabetes, cardiovascular disease, chronic kidney disease and obesity, factors that we have previously associated with increased sepsis risk.(Hu, Leitzmann et al. 2001; Mayer-Davis and Costacou 2001; Hu, Li et al. 2003; Dunstan, Salmon et al. 2005; Dunstan, Salmon et al. 2007; Lynch, White et al. 2010; Grontved and Hu 2011; Inoue, Sugiyama et al. 2012) In contrast to the anti-inflammatory effect of exercise, sedentary behavior has been associated with increases in serum markers of inflammation, including hsCRP.(Healy, Matthews et al. 2011) As discussed previously, we have identified an association with elevated hsCRP and risk of sepsis.(Wang, Shapiro et al. 2012)

While our study does not verify a causal relationship between physical inactivity and sepsis, the observations highlight the potential role of preventive health as a strategy for reducing long-term rates of sepsis. Current sepsis clinical and scientific initiatives focus upon the acute care and course of the condition. Relatively little attention has focused upon the identification of individuals at greatest risk for developing sepsis nor upon strategies for sepsis prevention. Some of the most important public health gains have originated from efforts to prevent deadly health conditions such as cardiovascular disease and stroke. A similar approach could result in major reductions in sepsis morbidity and mortality. Along these lines, exercise and television watching may present important and novel opportunities for reducing rates of sepsis because of their modifiable nature and widespread prevalence in the United States. Less than half of the United States adults participate in regular moderate-to-vigorous physical activity.(Sapkota, Bowles et al. 2005) US adults watch an average of 29-34 hours of television per week.(Grontved and Hu 2011) Given the pervasive nature of physical inactivity, organized efforts targeting these risk factors could result in significant advancements in sepsis care and prevention.

LIMITATIONS

Television watching and exercise may not encompass the full spectrum of sedentary behaviors.(Katzmarzyk, Church et al. 2009; Tremblay, Colley et al. 2010; Clark, Healy et al. 2011) Participants may not have accurately reported their weekly exercise or television watching levels. We also did not have information on the duration or intensity of exercise or the patterns of television watching. We could not account for changes in exercise of television watching levels over time. Additional study using more precise measures of physical activity would be appropriate. Our study reflects participants from the US population; the optimal methods for defining and assessing physical inactivity may vary internationally.

REGARDS did not measure global physical activity, which may have stronger connections with sepsis rates than self-reported exercise or television watching levels.(Wareham, Jakes et al. 2003; Bull, Maslin et al. 2009) Measurement of activity among REGARDS participants using accelerometers is the objective of a separate study.

While we adjusted for a range of potential confounders, the associations between exercise levels, television watching and sepsis rates may have been influenced by other variables such as vaccination or access to healthcare. Low-level exercise may also indicate individuals less willing to use and access preventive services or timely acute care.

REGARDS is not a surveillance study, and thus we may not have identified all sepsis events. However, misclassification of sepsis events should be similar between exercise and television watching categories, and thus the analysis should present underestimates of the true association. By design, the REGARDS cohort includes only African Americans and whites, and thus these results may not generalize to other ethnic groups.

CONCLUSION

In this analysis of the REGARDS cohort, individuals reporting low weekly levels of exercise (especially those with high daily levels of television watching) exhibited increased adjusted long-term rates of community-acquired sepsis. Physical inactivity may provide a target for sepsis prevention.

HIGHLIGHTS.

  • Sepsis is a major public health problem.

  • No studies have linked physical inactivity with long-term sepsis rates.

  • We studied 30,183 subjects in the national REGARDS cohort.

  • Low weekly exercise (<1 hr/day) was associated with increased sepsis rates.

FINANCIAL SUPPORT AND ACKNOWLEDGEMENTS

This study was supported by award R01-NR012726 from the National Institute for Nursing Research, UL1-RR025777 from the National Center for Research Resources, as well as by grants from the Center for Clinical and Translational Science and the Lister Hill Center for Health Policy of the University of Alabama at Birmingham. The parent REGARDS study was supported by cooperative agreement U01-NS041588 from the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Department of Health and Human Services. The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. Representatives of the funding agencies have been involved in the review of the manuscript but not directly involved in the collection, management, analysis or interpretation of the data.

The authors thank the other investigators, the staff, and the participants of the REGARDS study for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at http://www.regardsstudy.org and http://www.regardssepsis.org.

Footnotes

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AUTHORSHIP

HEW and MMS conceived the study. HEW and MMS organized and oversaw data collection. HEW, MMS and GH obtained funding for the study. HEW and RG conducted the analysis, and all authors contributed to review of results. HEW drafted the manuscript, and all authors contributed to its editorial review and revision. HEW assumes responsibility for the work as a whole.

CONFLICTS OF INTEREST

Dr. Safford reports the following potential conflicts of interest: Amgen - salary support to study patterns of statin use in Medicare and other large databases; diaDexus - salary support for a research grant on lipids and CHD outcomes; diaDexus - consulting to help with FDA application; NIH, AHRQ - salary support for research grants

Drs. Wang, Griffin, Baddley, Judd and Howard do not report any related conflicts of interest.

Contributor Information

Henry E. Wang, Department of Emergency Medicine, University of Alabama School of Medicine.

John Baddley, Division of Infectious Diseases, Department of Medicine, University of Alabama School of Medicine.

Russell Griffin, Department of Epidemiology, School of Public Health, University of Alabama at Birmingham.

Suzanne Judd, Department of Biostatistics, School of Public Health, University of Alabama at Birmingham.

George Howard, Department of Biostatistics, School of Public Health, University of Alabama at Birmingham.

John Donnelly, Department of Epidemiology, School of Public Health, University of Alabama at Birmingham.

Monika M. Safford, Division of Preventive Medicine, Department of Medicine, University of Alabama School of Medicine.

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