The compelling link between physical activity and the body's defense system

Abstract

This review summarizes research discoveries within 4 areas of exercise immunology that have received the most attention from investigators: (1) acute and chronic effects of exercise on the immune system, (2) clinical benefits of the exercise–immune relationship, (3) nutritional influences on the immune response to exercise, and (4) the effect of exercise on immunosenescence. These scientific discoveries can be organized into distinctive time periods: 1900–1980, which focused on exercise-induced changes in basic immune cell counts and function; 1980–1990, during which seminal papers were published with evidence that heavy exertion was associated with transient immune dysfunction, elevated inflammatory biomarkers, and increased risk of upper respiratory tract infections; 1990–2010, when additional focus areas were added to the field of exercise immunology including the interactive effect of nutrition, effects on the aging immune system, and inflammatory cytokines; and 2010 to the present, when technological advances in mass spectrometry allowed system biology approaches (i.e., metabolomics, proteomics, lipidomics, and microbiome characterization) to be applied to exercise immunology studies. The future of exercise immunology will take advantage of these technologies to provide new insights on the interactions between exercise, nutrition, and immune function, with application down to the personalized level. Additionally, these methodologies will improve mechanistic understanding of how exercise-induced immune perturbations reduce the risk of common chronic diseases.

Full text

Review
The compelling link between physical activity and the body’s
defense system
David C. Nieman
a,
*, Laurel M. Wentz
b
a
Human Performance Laboratory, Appalachian State University, North Carolina Research Campus, Kannapolis, NC 28081, USA
b
Department of Nutrition and Health Care Management, Appalachian State University, Boone, NC 28608, USA
Received 12 July 2018; revised 26 August 2018; accepted 25 September 2018
Available online 16 November 2018
Abstract
This review summarizes research discoveries within 4 areas of exercise immunology that have received the most attention from investigators:
(1) acute and chronic effects of exercise on the immune system, (2) clinical benefits of the exerciseimmune relationship, (3) nutritional influen-
ces on the immune response to exercise, and (4) the effect of exercise on immunosenescence. These scientific discoveries can be organized into
distinctive time periods: 19001979, which focused on exercise-induced changes in basic immune cell counts and function; 19801989, during
which seminal papers were published with evidence that heavy exertion was associated with transient immune dysfunction, elevated inflamma-
tory biomarkers, and increased risk of upper respiratory tract infections; 19902009, when additional focus areas were added to the field of exer-
cise immunology including the interactive effect of nutrition, effects on the aging immune system, and inflammatory cytokines; and 2010 to the
present, when technological advances in mass spectrometry allowed system biology approaches (i.e., metabolomics, proteomics, lipidomics, and
microbiome characterization) to be applied to exercise immunology studies. The future of exercise immunology will take advantage of these
technologies to provide new insights on the interactions between exercise, nutrition, and immune function, with application down to the person-
alized level. Additionally, these methodologies will improve mechanistic understanding of how exercise-induced immune perturbations reduce
the risk of common chronic diseases.
2095-2546/Ó2019 Published by Elsevier B.V. on behalf of Shanghai University of Sport. This is an open access article under the CC BY-NC-ND
license. (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Aging; Exercise; Immunology; Infection; Inflammation; Mass Spectrometry; Nutrition
1. Introduction to exercise immunology
Although exercise immunology is considered a relatively
new area of scientific endeavor with 90% of papers published
after 1990,
1
some of the earliest studies were published well
over a century ago. For example, in 1902, Larrabee
2
provided
evidence that changes in white blood cell differential counts in
Boston marathon runners paralleled those seen in certain dis-
eased conditions. He also observed that “the exertion had gone
far beyond physiological limits and our results certainly show
that where this is the case we may get a considerable leukocy-
tosis of the inflammatory type.”
2
The immune system is very responsive to exercise, with the
extent and duration reflecting the degree of physiological
stress imposed by the workload. This review paper
summarizes the research discoveries within 4 areas of exercise
immunology that have received the most consideration: acute
and chronic effects of exercise on the immune system, clinical
benefits of this exerciseimmune relationship, nutritional
influences on the immune response to exercise, and the exer-
cise effect on immunosenescence (Fig. 1).
37
These scientific discoveries can be organized into distinc-
tive time periods (Fig. 2). The earliest exercise immunology
studies (19001979) focused on exercise-induced changes in
basic immune cell counts and function.
5
The human immuno-
deficiency virus was identified as the cause of the AIDS in
1984. One of the markers for AIDS diagnosis was the CD4
antigen on helper T cells that required a flow cytometer for
detection. Many medical universities acquired flow cytometers
in the 1980s, and these instruments became available to exer-
cise investigators, initiating the modern era of exercise immu-
nology research. Another impetus was the publication of a
brief review in a special issue of the Journal of the American
Peer review under responsibility of Shanghai University of Sport.
* Corresponding author.
E-mail address: niemandc@appstate.edu (D.C. Nieman).
https://doi.org/10.1016/j.jshs.2018.09.009
Cite this article: Nieman DC, Wentz LM. The compelling link between physical activity and the body’s defense system. J Sport Health Sci 2019;8:20117.
Available online at www.sciencedirect.com
Journal of Sport and Health Science 8 (2019) 201217
www.jshs.org.cn

Medical Association for the 1984 Olympic Games in Los
Angeles.
8
This review concluded there was “no clear experi-
mental or clinical evidence that exercise will alter the fre-
quency or severity of human infections... Further studies will
be needed before it can be concluded that exercise affects the
host response to infection in any clinically meaningful way.”
8
This conclusion was consistent with the existing evidence at
that time and at the same time provided a framework for future
investigations. During the same time period (19801989),
seminal papers were published with evidence that heavy exer-
tion was associated with transient immune dysfunction, ele-
vated inflammatory biomarkers, and an increased risk of upper
respiratory tract infections (URTIs).
918
For example, acute
bouts of intense and prolonged exercise were linked by several
early exercise immunology pioneer investigators to suppressed
salivary immunoglobulin A (IgA) output, decreased natural
killer cell (NK) lytic activity, reduced T- and B-cell function,
and a 2- to 6-fold increased URTI risk during the 12 week
postrace time period.
918
In 1989, the International Society of
Exercise Immunology was founded, leading to biannual con-
ferences and the highly successful Exercise Immunology
Review journal (www.isei.dk).
5
During the time period from 1990 to 2009, additional focus
areas were added to the field of exercise immunology, including
the interactive effect of nutrition,
7,19,20
effects on the aging immune
system,
2123
and influences on inflammatory cytokines.
2427
With
advances in mass spectrometry and genetic testing technology
since 2010, increasing attention is being focused on metabolomics,
proteomics, lipidomics, gut microbiome characterization, and
genomic approaches to exercise immunology, and how this infor-
mation can be used to provide personalized exercise and nutrition
guidelines.
2833
Additionally, acute and chronic exercise-induced
immune changes are now being described as important mechanistic
pathways for elucidating reduced cancer and heart disease risk
among the physically active.
3436
2. Acute and chronic effects of exercise on the immune
system
The acute immune response to exercise depends on the inten-
sity and duration of effort. For the purposes of this review, moder-
ate and vigorous exercises are differentiated using an intensity
threshold of 60% of the oxygen update and heart rate reserve, and
a duration threshold of 60 min. Exercise immunology investigators
had an early focus on the large perturbations of basic leukocyte
subsets associated with the physiological stress of athletic endeav-
or.
2,914,27
Increasing attention is being directed to the enhanced
immunosurveillance of distinct immune cell subtypes during
Fig. 1. Key research areas and basic findings in exercise immunology.
Fig. 2. Exercise immunology research can be organized into 4 distinctive periods.
202 D.C. Nieman and L.M. Wentz

exercise bouts of less than 60 min that have potential prevention
and therapeutic value.
3748
2.1. Enhanced immunosurveillance with acute exercise bouts
of less than 60 min
During moderate- and vigorous-intensity aerobic exercise
bouts of less than 60 min duration, the antipathogen activity of
tissue macrophages occurs in parallel with an enhanced recir-
culation of immunoglobulins, anti-inflammatory cytokines,
neutrophils, NK cells, cytotoxic T cells, and immature B cells,
all of which play critical roles in immune defense activity and
metabolic health (Fig. 3).
3740,4447
Acute exercise bouts pref-
erentially mobilize NK cells and CD8
+
T lymphocytes that
exhibit high cytotoxicity and tissue migrating potential.
38,46,48
Stress hormones, which can suppress immune cell function,
and proinflammatory cytokines, indicative of intense meta-
bolic activity, do not reach high levels during short duration,
moderate exercise bouts.
40
Over time, these transient, exer-
cise-induced increases in selective lymphocyte subsets
enhance immunosurveillance and lower inflammation, and
may be of particular clinical value for obese and diseased
individuals.
4143
In general, acute exercise is now viewed as an important
immune system adjuvant to stimulate the ongoing exchange of
leukocytes between the circulation and tissues.
37
An ancillary
benefit is that acute exercise may serve as a simple strategy to
enrich the blood compartment of highly cytotoxic T-cell and
NK cell subsets that can be harvested for clinical use.
38,4446
Metabolically, moderate exercise induces small, acute eleva-
tions in IL-6 that exert direct anti-inflammatory effects,
improving glucose and lipid metabolism over time.
49,50
Another benefit may include an enhanced antibody-specific
response when vaccinations are preceded by an acute exercise
bout, but more research is needed with better study designs to
control for potential confounding influences.
51
2.2. Transient immune dysfunction after heavy exertion
The measurement of immune responses to prolonged and
intensive exercise by athletes continues to receive high
attention. Taken together, the best evidence supports that
high exercise training workloads, competition events, and
the associated physiological, metabolic, and psychological
stress are linked to immune dysfunction, inflammation, oxi-
dative stress, and muscle damage.
914,24,27,5254
NK cell
and neutrophil function, various measures of T- and B-cell
function, salivary IgA output, skin delayed-type hypersensi-
tivity response, major histocompatibility complex II expres-
sion in macrophages, and other biomarkers of immune
function are altered for several hours to days during recov-
ery from prolonged and intensive endurance exercise.
5258
The contrast in the magnitude of immune responses between
a 30- to 45-min walking bout and 42.2-km marathon race is
summarized in Fig. 4.
3,4,27,40,5257
These immune changes
occur in several compartments of the immune system and
body including the skin, upper respiratory tract mucosal tis-
sue, lung, blood, muscle, and peritoneal cavity. Although
some investigators have challenged the clinical significance
and linkage between heavy exertion and transient immune
dysfunction,
58
the majority of investigators in the field of
exercise immunology have supported the viewpoint that the
immune system reflects the magnitude of physiological
stress experienced by the exerciser.
35,27,54,56,57
Recent improvements in mass spectrometry technology and
bioinformatics support have improved the capacity to use a
systems biology approach when measuring the complex inter-
actions between exercise stress and immune function within
the human athlete.
2933,5963
Metabolomics, proteomics, and
lipidomics have revealed that metabolism and immunity are
inextricably interwoven and has led to a new area of research
Fig. 3. Acute exercise stimulates the interchange of innate immune system
cells and components between lymphoid tissues and the blood compartment.
Although transient, a summation effect occurs over time, with improved
immunosurveillance against pathogens and cancer cells and decreased sys-
temic inflammation.
Fig. 4. The contrast in acute immune responses to heavy exertion (e.g., a mar-
athon race) and a 30- to 45-min walking bout. DTH = delayed-type
hypersensitivity; IgA = immunoglobulin A; Ne/Ly = neutrophil/lymphocyte
ratio; NK = natural killer; OB = oxidative burst.
Exercise immunology 203

endeavor termed immunometabolism.
33,64
In a typical study
with human athletes exercising intensely for more than
2 h, significant increases in at least 300 identified metabolites
can be measured as body glycogen stores are depleted and an
extensive increase occurs in numerous and varied lipid super-
pathway metabolites, including oxidized derivatives called
oxylipins.
32,6062
Exercise-induced muscle tissue injury and
inflammation elicit a strong innate immune response involving
granulocytes, monocytes, and macrophages. Immune-specific
proteins are produced to regulate the innate immune response,
with oxylipins involved in initiating, mediating, and resolving
this process.
29,30,60,63
Most of the expressed immune-related
proteins including lysozyme C, neutrophil elastase and defen-
sin 1, proteins S100-A8/A12, cathelicidin antimicrobial pep-
tide, a-actinin-1, and profilin-1 are involved with pathogen
defense and immune cell chemotaxis and locomotion. Other
proteins including serum amyloid A-4, myeloperoxidase, com-
plements C4B and C7, plasma protease C1 inhibitor, a-2-HS-
glycoprotein, and a-1-acid glycoprotein 2 increase chronically
during recovery and are involved in the inflammatory acute
phase response.
30
This profound, exercise-induced perturbation in metabo-
lites, lipid mediators, and proteins more than likely has a direct
influence on immune function, decreasing the capacity of
immune cells to increase oxygen consumption rates after acti-
vation.
31
In response to an acute immunologic challenge such
as exercise stress, cells of the immune system must be able to
engage in growth and proliferation to generate effector cells
that produce specific molecules such as cytokines and the pro-
teins listed in the previous paragraph.
64
Immune activation is
associated with oxygen and biosynthetic demands, and
immune cells must engage in metabolic reprogramming to
generate sufficient energy to fuel these demands. Although
more research is needed, preliminary data support that immune
cell metabolic capacity is decreased during recovery from
physiologically demanding bouts of intensive exercise, result-
ing in transient immune dysfunction.
31,33
Immunonutrition
support, especially increased intake of carbohydrate and poly-
phenols, has been shown to counter these exercise-induced
decrements in immune cell metabolic capacity.
31,33
2.3. Illness risk and high exercise workloads
The potential linkage between prolonged, intensive exercise
and increased risk for illness has been an active area of research
since the 1980s.
3,6569
Early epidemiologic studies indicated that
athletes engaging in marathon and ultramarathon race events
and/or very heavy training were at increased risk of URTI.
17,67
(Table 1). For example, in a large group of 2311 endurance
runners, nearly 13.0% reported illness during the week after the
Los Angeles Marathon race compared with 2.2% of control
runners (odds ratio (OR) = 5.9; 95% confidence interval (CI):
1.918.8).
17
Forty percent of the runners reported at least
1 illness episode during the 2-month winter period before the
marathon race, and those running more than 96 km/week vs. less
than 32 km/week doubled their odds for illness. A 1-year retro-
spective study of 852 German athletes showed that URTI risk
was highest in endurance athletes who also reported significant
stress and sleep deprivation.
70
These seminal studies indicated
that illness risk may be increased when an athlete participates in
competitive events, goes through repeated cycles of unusually
heavy exertion, or experiences other stressors to the immune sys-
tem including lack of sleep and mental stress. The direct connec-
tion between exercise-induced immune changes and infection
risk has not yet been established, and will require long-term stud-
ies with large cohorts. More research is needed to more clearly
demonstrate the linkage between heavy exertion, illness symp-
toms, and pathogen-based illnesses, and the relative importance
of associated factors such as travel, pathogen exposure, exercise-
induced immune perturbations, sleep disruption, mental stress,
and nutrition support.
3,4
As illness data from additional studies mounted,
7177
several
athletic organizations including the International Olympic Com-
mittee (IOC) and the International Association of Athletics Feder-
ation (IAAF) initiated acute illness surveillance systems to
delineate the extent of the problem and underlying risk
factors.
65,7889
The stated goal was to improve illness prevention
and treatment procedures.
65,80
The IOC has also focused on the
inappropriate management of both internal (e.g., psychological
responses) and external loads (e.g., training and competition work-
loads). Load management is a key strategy, according to the IOC,
to decrease illness incidence and associated downturns in exercise
performance, interruptions in training, missed competitive events,
and risk of serious medical complications. The wealth of acute ill-
ness epidemiologic data collected during international competition
events has revealed that 2%18% of elite athletes experience ill-
ness episodes, with higher proportions for females and those
engaging in endurance events (Table 1).
7889
At least one-half of
the acute illness bouts involve the respiratory tract, with other
affected systems including the digestive tract, skin tissues, and the
genitourinary tract.
65
Significant illness risk factors include female
gender, high levels of depression or anxiety, engaging in unusu-
ally intensive training periods with large fluctuations, international
travel across several time zones, participation in competitive
events especially during the winter, lack of sleep, and low diet
energy intake.
65,6892
The decrease in exercise performance after
an URTI can last 24 days, and runners who unwisely start an
enduranceracewithsystemicURTIsymptomsare23 times less
likely to complete the race.
65,92,93
Paralympic athletes have unique
preexisting medical conditions that predispose them to an
increased risk of illness, and the incidence rate of illness is high in
the Summer (10.013.2 episodes per 1000 athlete-days) and Win-
ter (18.7 episodes per 1000 athlete-days) Paralympic Games.
94
Athletes must train hard for competition and are interested in
strategies to keep their immune systems robust and illness rates
low despite the physiologic stress experienced. The ultimate objec-
tive is to achieve performance goals with little interruption from ill-
ness and fatigue from training-induced subclinical immune
dysfunction. Several training, hygienic, nutritional, and psychologi-
cal strategies are recommended, and these require the coordinated
involvement of the medical staff, coaches, and athletes.
4,6,65,95
The
medical staff should develop and implement an illness prevention
program, with a focus on full preventative precautions for high-
risk individuals such as female endurance athletes. Adjustments to
204 D.C. Nieman and L.M. Wentz

Table 1.
Research on the relationship between vigorous exercise and illness.
Investigator Study population Research design Key finding
Peters and Bateman
67
141 ultramarathon runners and 124 controls
(aged 1865 years)
Participants reported 2-week recall of ill-
ness symptoms after 56-km race
Illness incidence 2£higher in runners after
race vs. controls (33% vs. 15%).
Nieman et al.
21
1828 marathon runners and 134 runner controls
(aged 36.9 §0.2 years)
Participants reported illness symptoms 2
months before and 1 week after March
42.2-km race
Illness incidence 6£higher in runners who
finished race vs. controls (13% vs. 2%). Run-
ners training 97 km/week vs.
<32 km/week at higher URTl risk.
Heath et al.
69
530 runners (aged 39.4 years) Participants reported training log and ill-
ness symptoms every month for 1 year
Running >485 miles/year (780 km/year)
increased risk of illness.
Konig et al.
70
852 German athletes (aged 23.6 §9.5 years) Participants retrospectively reported ill-
ness episodes over past 12 months
Illness incidence 2£higher in endurance
sports (OR = 2.2); 2£higher with stress
(OR = 2.0); and nearly 2£with sleep depri-
vation (OR = 1.7).
Spence et al.
71
20 elite triathletes/cyclists, 30 recreational tri-
athletes/cyclists, 20 sedentary controls (aged
1834 years)
Participants followed for 5 months in
summer/autumn; reported daily illness
symptoms
Illness incidence 4£higher in elite athletes
and 2£greater in controls vs. recreational
athletes. Higher number of illness days in
elite athletes (311 days) and control (137
days) and recreational (92 days).
Gleeson et al.
72
75 endurance trained university students (aged
1835 years)
Participants followed for 4 months in
winter; reported weekly illness
symptoms
Greater illness incidence in high and
medium vs. low training groups (2.4 §2.6
episodes and 2.6 §2.2 episodes vs. 1.0 §1.7
episodes).
Rama et al.
73
19 elite swimmers vs. 11 nonathlete controls
(aged 17.6 §1.0 years)
Participants followed for 7 months in
winter; reported daily illness symptoms
67% of illness episodes occurred during high
volume training in swimmers vs. no illness in
control at same time points.
Hellard et al.
74
28 elite swimmers (aged 1630 years) Participants followed for 4 years; moni-
tored weekly for illness
Illness increased 1.08£(95%CI: 1.011.16)
every 10% increase in resistance training and
1.10£(95%CI: 1.011.19) for every 10%
increase in high-load training.
Svendsen et al.
75
42 elite cross-country skiers (aged 24 §4 years) Participants followed for 8 years;
reported illness symptoms daily for
10 days after the Tour de Ski race
Illness incidence was 3£higher in skiers
who raced the Tour de Ski vs. non-compet-
ing skiers (48% vs. 16%).
Raysmith and Drew
77
33 international track and field athletes Participants reported illness symptoms
during 6 months preceding competition
for 5 years
Illness incidence was 23%; one-half of ill-
nesses occurred 2 months before competi-
tion. Better performing athletes had a lower
incidence of illness.
Drew et al.
78
132 elite athletes preparing for the Olympics 3 months before competition, partici-
pants reported illness symptoms during a
1-month time period
Illness symptoms in 100% athletes (46%
upper respiratory). Risk factors were female
sex, low energy availability.
Prien et al.,
79
Timpka
et al.
80
1551 elite athletes preceding World Champion-
ship competition
Participants retrospectively reported ill-
ness symptoms during 4 weeks preceding
competition
Illness incidence ranged from 5% to 13%.
Engebretsen et al.,
81,82
Palmer-Green and
Elliott,
83
Soligard et al.
84,85
27,245 elite athletes during an international
Olympic competition
Medical staff reported illness symptoms
during competition event (<4 weeks)
Illness incidence ranged from 5% to 18%;
Risk factor was female sex.
Mountjoy et al.,
86,87
Prien et al.
79
5293 elite aquatics athletes during the interna-
tional World Championships
Medical staff reported illness symptoms
during competition event (<4 weeks)
Illness incidence ranged from 7% to 13%.
Alonso et al.,
88,89
Timpka et al.
80
3305 elite track and field athletes during the
international World Championships
Medical staff reported illness symptoms
during competition event (<4 weeks)
Illness incidence ranged from 2% to 7%;
10£greater illness incidence in endurance
events vs. speed/power events.
Abbreviations: CI = confidence interval; OR = odds ratio; URTI = upper respiratory tract infections.
Exercise immunology 205

the guidelines can be applied based on how each individual athlete
responds. Here is a summary of the most important guidelines pro-
vided from consensus statements:
4,6,65,95
2.3.1. Training and competition load management
a. Develop a detailed, individualized training and competi-
tion plan that also provides for sufficient recovery using
sleep, nutrition, hydration, and psychological strategies.
b. Use small increments when changing the training load
(typically less than 10% weekly).
c. Develop a competition event calendar that is based on the
health of the athlete.
d. Monitor for early signs and symptoms of over-reaching,
overtraining, and illness.
e. Avoid intensive training when ill or experiencing the early
signs and symptoms of illness (which can make the illness
more severe and prolonged).
f. Participate in ongoing illness surveillance systems by sport
agencies.
2.3.2. Hygienic, lifestyle, nutritional, and behavioral
strategies
a. Minimize pathogen exposure by avoiding close contact
with infected individuals in crowded, enclosed spaces, and
not sharing drinking or eating implements. Avoid exercise
sessions in poorly ventilated clubs and gymnasium facili-
ties. The medical staff should isolate infected athletes.
b. Limit hand-to-face contact (i.e., self-inoculation) and wash
hands regularly and effectively. The medical staff should
educate the athletes to minimize pathogen spread to others
(e.g., sneezing and coughing into the crook of the elbow).
c. Follow other hygienic practices to limit all types of infec-
tions including safe sex and the use of condoms, wearing
open footwear when using public facilities to limit skin
infections, using insect repellents, and covering the arms
and legs with clothing at dawn or dusk.
d. Maintain vaccines needed for home and foreign travel,
with a focus on annual influenza vaccination.
e. Follow strategies that facilitate regular, high-quality sleep.
f. Avoid excessive alcohol intake.
g. Consume a well-balanced diet with sufficient energy to
maintain a healthy weight, with a focus on grains, fruits,
and vegetables to provide sufficient carbohydrate and pol-
yphenols that reduce exercise-induced inflammation and
improve viral protection.
2.3.3. Psychological load management
a. Follow stress management techniques that decrease the
extraneous load of life hassles and stresses.
b. Develop coping strategies that minimize the internalized
impact of negative life events and emotions.
c. Periodically monitor psychological stresses using avail-
able instruments.
3. Clinical influences of immune responses to chronic
exercise
Each bout of moderate physical activity promotes improved
but transient immunosurveillance and, when repeated on a reg-
ular basis, confers multiple health benefits including decreased
illness incidence and dampened systemic inflammation.
95
3.1. J-curve relationship between exercise and URTIs
Table 2 summarizes published evidence from randomized
clinical trials and epidemiologic studies on the inverse rela-
tionship between moderate exercise training and URTI inci-
dence. The randomized clinical trials (8 weeks to 1 year in
length) are consistent in demonstrating that study participants
assigned to moderate exercise programs experience reduced
URTI incidence and duration.
21,96100
The magnitude of
reduction in URTI symptom days with near-daily moderate
exercise in these randomized clinical trials (typically
40%50%) exceeds levels reported for most medications and
supplements, and bolsters public health guidelines urging indi-
viduals to be physically active on a regular basis. The protec-
tive effect of moderate activity on illness incidence contrasts
with the increased illness risk linked with prolonged and inten-
sive exercise, as summarized in the J-curve model (Fig. 5).
95
The IOC consensus group provided support for the J-curve
model, but cautioned that the right side of the model may not
apply to elite athletes on the highest level, where high training
loads are not consistently associated with an increased risk of
illness.
65
Retrospective and prospective epidemiologic studies have
measured illness incidence in large groups of individuals
engaging in self-selected and varied physical activity work-
loads (Table 2).
101104
Collectively, the epidemiologic studies
summarized in Table 2 consistently show reduced URTI rates
(weighted mean, 28%) in high vs. low physical activity and fit-
ness groups. Fig. 6 summarizes the results from a group of
1002 adults (aged 1885 years; 60% female and 40% male)
studied for 12 weeks (one-half during the winter, one-half dur-
ing the fall), with monitoring of URTI symptoms and severity
using the validated Wisconsin Upper Respiratory Symptom
Survey.
103,105
The number of days with URTI was 43% lower
in subjects engaging in an average of 5 or more days per week
of aerobic exercise (20 min bouts or longer) compared with
those who were largely sedentary (1 day/week), and 46%
lower when comparing subjects in the highest vs. lowest tertile
for perceived physical fitness. This relationship persisted, even
after adjustment for confounders such as age, education level,
marital status, gender, body mass index (BMI), and perceived
mental stress.
Physical activity may lower rates of infection for other types
of viral and bacterial diseases, but more data are needed. Sev-
eral epidemiologic studies suggest that regular physical activity
is associated with decreased mortality and incidence rates for
influenza and pneumonia.
106109
These findings are in accor-
dance with rodent-based studies demonstrating a positive link
between chronic exercise and improved host responses to influ-
enza and pneumonia infection.
110113
These data must be
206 D.C. Nieman and L.M. Wentz

carefully balanced with published reports of increased infec-
tious disease severity when vigorous exercise was engaged in
during active influenza or other viral infections.
114116
There is
also increasing support for improved antibody responses to
influenza immunization in elderly adults who engage in regular
exercise training regimens.
117119
3.2. Reduced systemic inflammation in physically active and
lean individuals
Each exercise bout causes transient increases in total white
blood cells, granulocyte-related proteins, and a variety of
plasma cytokines including interleukin-6 (IL-6), IL-8, IL-10,
IL-18, IL-1 receptor antagonist (IL-1ra), granulocyte colony
stimulating factor, and monocyte chemoattractant protein
1.
30,40,52
The magnitude of change in these inflammation-related
biomarkers depends on the overall exercise workload. Acute
phase proteins including C-reactive protein (CRP) are also
increased after heavy exertion, but increases are delayed in
comparison with most cytokines.
30,52
Despite regular increases
in these inflammation biomarkers during each intense exercise
Fig. 5. J-curve model of the relationship between the exercise workload contin-
uum and risk for upper respiratory tract infection (URTI). Other factors such as
travel, pathogen exposure, sleep disruption, mental stress, and dietary patterns
may influence this relationship. This figure was adapted from Nieman.
95
Table 2.
Research on the relationship between moderate exercise and illness.
Investigator Study population Research design Key finding
Randomized controlled trials
Nieman et al.
96
36 mildly obese sedentary
women (aged 34.4 §1.1 years)
Randomized to 15 weeks of moderate
intensity (45 min/day £5 days/week)
walking program or observational
control
Fewer days with illness symptoms
reported in walkers vs. controls (5.1 §
1.2 days vs. 10.8 §2.3 days).
Nieman et al.
21
32 sedentary women (aged 73.4
§1.2 years); 12 highly condi-
tioned women (aged 72.5 §1.8
years)
Sedentary women randomized to a
12-week moderate intensity (30- to
40-min/day £5 days/week) walking
program or stretching (45 min/day £
5 days/week) in fall season
Illness incidence 8% in highly condi-
tioned, 21% in walkers, and 50% in
controls.
Nieman et al.
97
91 obese women (aged 45.6 §
1.1 years)
Randomized to a 12-week moderate
intensity (45 min/day £5 days/week)
walking program or stretching
45 min/day £4 days/week
Fewer days with illness symptoms
reported in walkers vs. controls (5.6 §
0.9 days vs. 9.4 §1.1 days).
Chubak et al.
98
115 postmenopausal women
(aged 60.7 §6.9 years)
Randomized to 1 year of moderate inten-
sity exercise (45 min/day £5 days/week)
or stretching control (45 min/day £
1 day/week)
Illness incidence 30% in exercise vs.
48% in controls. Three-fold decreased
risk of illness in exercise group vs. con-
trol in final 3 months.
Barrett et al.
99,100
373 male and female older adults
(aged 59.3 §6.6 years (2012);
49.9 §11.8 years (2018))
Randomized to 8 week moderate-inten-
sity sustained exercise (group sessions;
home practice) or observational control
Pooled datasets: proportional reductions
of incidence, days-of-illness, and global
severity were 14%, 23%, and 31% for
exercise compared with controls.
Epidemiologic studies
Mathews et al.
101
547 male and female adults (aged
48.0 §12.4 years)
Participants followed for 1 year; inter-
viewed for physical activity and illness
symptoms every 90 days
29% decreased illness risk in upper vs.
lower quartile of activity.
Fondell et al.
102
1509 male and female adults
(aged 2060 years)
Participants followed for 4 months; base-
line questionnaire on physical activity;
illness symptoms assessed every 3 weeks
18% decreased illness risk in high vs.
low physical activity.
Nieman et al.
103
1002 male and female adults
(aged 1885 years)
Participants followed for 12 weeks in
winter and autumn seasons; baseline
questionnaire on physical fitness levels;
daily illness symptoms checklist
46% decrease in total day with illness in
high vs. low physical fitness tertile. 43%
decrease in those who reported
5 days/week aerobic activity vs.
<1 day/week.
Zhou et al.
104
1413 male and female adults
(aged 38.9 §9.0 years)
Participants retrospectively reported fre-
quency of illness and physical activity
over the past year
26% decreased illness risk in high vs.
low physical activity.
Exercise immunology 207

bout, physically fit individuals have lower resting levels in con-
trast with those who are overweight and unfit. Fig. 7 compares
serum CRP (4.4-fold difference) and plasma IL-6 (1.3-fold) in
large groups of obese individuals (n=950; mean BMI =
31.7 kg/m
2
) and endurance athletes (n=383; mean BMI =
23.0 kg/m
2
) studied over the course of the past 2 decades in the
author’s laboratory. There is increasing evidence that regular
exercise training has an overall anti-inflammatory influence
mediated through multiple pathways including improved
control of inflammatory signaling pathways, release of muscle
myokines that stimulate production of IL-1ra and IL-10
(perhaps by blood mononuclear immune cells), a decrease in
dysfunctional adipose tissue and improved oxygenation,
enhanced innate immune function, and an improved balance of
oxylipins.
7,33,50,55,120
The persistent increase in inflammation biomarkers is
defined as chronic or systemic inflammation, and is linked
with multiple disorders and diseases including obesity, arthri-
tis, atherosclerosis and cardiovascular disease, chronic kidney
disease, liver disease, metabolic syndrome, insulin resistance
and type 2 diabetes mellitus, sarcopenia, arthritis, bone resorp-
tion and osteoporosis, chronic obstructive pulmonary disease,
dementia, depression, and various types of cancers.
121127
Obesity induces a constant state of low-grade inflammation
characterized by activation and infiltration of proinflammatory
immune cells such as macrophages and granulocytes, and a
dysregulated production of acute-phase proteins, reactive oxy-
gen species, metalloproteinases, oxylipins, adipokines, and
proinflammatory cytokines.
124,128
Many of the inflammation
biomarkers increased transiently after intense and prolonged
exercise bouts are chronically expressed at lower levels in
obese individuals (resting state).
Epidemiologic studies consistently show reduced white blood
cell count, CRP, IL-6, IL-18, tumor necrosis factor alpha, and
other inflammatory biomarkers in adults with higher levels of
physical activity and fitness, even after adjustment for potential
confounders such as BMI.
129131
Forexample,inastudyof
1002 community-dwelling adults (aged 1885 years), a general
linear model analysis showed that BMI had the strongest effect
on CRP followed by gender (greater in females), exercise fre-
quency, age, and smoking status.
129
Another study of 1293 mid-
dle-aged Danes showed that cardiorespiratory fitness was
inversely associated with CRP, IL-6, and IL-18, and was only
partly explained by lower levels of abdominal obesity.
130
Most randomized, controlled trials, however, have failed to
demonstrate that inflammation is decreased by a clinically sig-
nificant level with exercise training in the absence of weight
loss.
132136
There are several potential explanations for these
null findings when compared with epidemiologic studies,
including the small reported changes in aerobic fitness and
activity levels, the short duration of the intervention trials, and
issues with compliance. In general, moderate exercise training
is unlikely to lower chronic inflammation at the individual
level unless the exercise workload is increased to more than
300 min per week and significant weight loss is experienced.
3.3. Exerciseimmune linkages to reduced chronic disease
Do exercise-induced perturbations in immunity help to
explain altered risks of cancer, heart disease, type 2 diabetes,
arthritis, nonalcoholic fatty liver disease, and other chronic
conditions? Research in this area is still emergent, but there is
increasing evidence that the circulation surge in cells of the
innate immune system with each exercise bout and the anti-
inflammatory and antioxidant effect of exercise training have
a summation effect over time in modulating tumorigenesis,
atherosclerosis, and other disease processes.
36,137139
Low
8.2
9
8
7
6
5
4
3
2
1
0
5.0
4.4
URTI days-fitness tertiles
Days with URTI during 12-week period
URTI days-exercise tertiles
8.6
5.5
4.9
46% ↓ 3.8 days 43% ↓ 3.7 days
Medium High
Fig. 6. The upper tertiles of fitness and exercise frequency are associated with
reduced numbers of days with upper respiratory tract infections (URTI). Data
from Nieman et al.
103
4.93
2.34
1.02
0.92
p < 0.001
p < 0.001
0
0
1
2
3
4
5
CRP (mg/L)
2
4
6
8
10
Obese (n = 950,
BMI = 31.7 ± 5.2)
Athletes (n = 383,
BMI = 23.0 ± 2.4)
Obese (n = 950,
BMI = 31.7 ± 5.2)
Athletes (n = 383,
BMI = 23.0 ± 2.4)
IL-6 (pg/mL)
Fig. 7. C-reactive protein (CRP) and interleukin-6 (IL-6) values for obese and
athletic groups (data expressed as mean §SD). Data are from ongoing studies
in the first author’s lab during the past 2 decades. BMI = body mass index.
208 D.C. Nieman and L.M. Wentz

Obesity, the metabolic syndrome, and most common
chronic diseases such as atherosclerosis, specific types of can-
cer, and type 2 diabetes are characterized in part by high
inflammation, oxidative stress, and immune dysfunction.
137
Exercise training counters these elements of the disease pro-
cess, stimulating many cellular and molecular changes
throughout body tissues that promote anti-inflammatory and
antioxidant responses, and augment immunosurveillance. For
example, IL-1bis a proinflammatory cytokine that is involved
in disease pathogenesis, and the release of IL-6 from the
exercising muscle induces high levels of plasma IL-1ra during
recovery that competitively inhibits IL-1bsignaling.
137
Exer-
cise training also downregulates Toll-like receptor 4 expres-
sion, a key transmembrane receptor that is activated by
numerous ligands including oxidized low-density lipoproteins
and involved in obesity-induced insulin resistance and type 2
diabetes, and atherosclerosis.
137
Inflammation involves several types of immune cells,
including macrophages and neutrophils, and is an important
mediator of oxidative stress. Reactive oxygen species (ROS)
or reactive nitrogen species (RNS), are double-edged mole-
cules. ROS/RNS can function as important inflammatory
effectors in supporting immune system clearance of pathogens
and repair of damaged muscle tissue, or they can amplify
chronic inflammation (e.g., during obesity) and induce tissue
damage. Oxinflammation is a term used to describe the com-
plex interactions between oxidative stress and inflamma-
tion.
138
Exercise training decreases oxidative stress by
augmenting antioxidant defenses consisting of enzymes such
as catalase, superoxide dismutase, and glutathione peroxidase,
and nonenzymatic antioxidants including glutathione.
137,138
Exercise training has immunomodulating effects that may
alter the cross-talk between the immune system and tumori-
genesis. For example, exercise may increase intra-tumoral
cytotoxic T-cell infiltration and reduce regulatory T-cell
infiltration, enhance the recirculation and function of tumor-
specific NK cells, and decrease inflammatory influences that
support cancer cell growth.
139
In general, exercise promotes the recirculation of key immune
cells and mediates an anti-inflammatory and antioxidant state
through multiple mechanisms. Although many information gaps
exist, these exercise-induced effects may help to counter the
development of chronic metabolic diseases and are likely multi-
plied when body fat mass is reduced.
3.4. Exercise, gut immune function, and the microbiome
The gastrointestinal tract is colonized by trillions of micro-
organisms that include a gene set 150 times larger than that of
the human genome.
140
The most abundant bacterial phyla are
the Firmicutes (»60%) and Bacteriodetes (»20%), with low
proportions of Actinobacteria, Proteobacteria, and Verrucomi-
crobia. One-third of the adult gut microbiota is similar
between most individuals, but diversity is associated with a
healthier status. The gut bacteria composition and diversity is
influenced by a variety of factors, including dietary and exer-
cise habits, age, gender, genetics, ethnicity, antibiotics, health,
and disease.
The gut microbiota influences human health and immune
function, in part through the fermentation of indigestible food
components in the large intestine. The microbiome and
derived metabolites including short chain fatty acids and bio-
transformed bile acids have been shown to influence immune
function both within the gut and systematically.
141
Although
research in this area is emerging, recent studies indicate that
exercise and physical fitness diversifies the gut microbiota,
enhancing the number of benign microbial communities.
142,143
The underlying mechanisms are still being explored, with no
clear consensus, in part owing to confounding from diet, exer-
cise workload and intensity, and body composition. More
human research is needed to establish whether the positive
linkage between long-term exercise training and a diverse
microbiome translates to improved immune function in physi-
cally fit individuals and athletes.
144,145
4. Nutritional interactions on exercise-induced immune
changes
Several comprehensive reviews have been published on the
value of nutritional support as countermeasures to exercise-
induced immune dysfunction, inflammation, and oxidative
stress.
4,6,7,33
The most effective nutritional strategies for ath-
letes, especially when evaluated from a multiomics perspective,
include increased intake of carbohydrates and polyphenols.
4.1. Carbohydrates attenuate postexercise inflammation
During the 1990s, several studies reported that carbohy-
drate ingestion (3060 g/h) during prolonged endurance exer-
cise (90 min and longer) was linked with lower postexercise
plasma stress hormone levels and inflammation.
20,146150
These results have been confirmed by many subsequent studies
(Table 3).
31,151165
A consistent finding is that carbohydrate
intake during prolonged and intense exercise, whether from
6%8% beverages or sugar-dense fruits such as bananas (with
water), is associated with higher plasma glucose and insulin
levels; lower plasma stress hormones (epinephrine and corti-
sol), adrenocorticotropic hormone, and growth hormone;
diminished fatty acid mobilization and oxidation; and reduced
inflammation as measured by a variety of biomarkers includ-
ing skeletal muscle IL-6 and IL-8 messenger ribonucleic acid
(mRNA), blood neutrophil and monocyte cell counts, cyto-
kines such as IL-6, IL-1ra, and IL-10, and granulocyte phago-
cytosis (Table 3 and Fig. 8). The effect of carbohydrate
ingestion in attenuating postexercise inflammation is strong
(about 30%40%), especially when contrasted with water-
only intake in overnight fasted athletes.
7,27,3133,164,166
4.2. Polyphenols counter exercise-induced immune changes
Fruits contain a mixture of sugars and a wide variety of bio-
logically active polyphenols. Polyphenols, in particular flavo-
noids, have attracted much attention owing to their bioactivity
and related health benefits, and new evidence using metabolo-
mics supports their value as potential countermeasures to exer-
cise-induced immune changes.
6,7,31,33
Exercise immunology 209

Table 3.
Research showing the effect of carbohydrates on inflammation and immune biomarkers after >90 min of endurance exercise.
Investigator Study population Exercise protocol Carbohydrate intervention Postexercise immune response
Nieman et al.,
146
Nehlsen-Cannarella
et al.,
20
Henson et al.
147
30 male and female marathon run-
ners (aged 41.5 §2.0 years) random-
ized to CHO or placebo
2.5-h run at
75%80%VO
2max
6% CHO or placebo beverage
consumed before, during, and
after exercise
CHO "glucose; #cortisol; #total leukocytes, neutrophils,
monocytes, and lymphocytes; #IL-6, IL-1ra vs. placebo group.
Placebo "T cells and NK cells immediately after running;
#3-h recovery vs. the CHO group.
Nieman et al.,
148
Nieman et al.,
149
Henson et al.
150
10 male and female triathletes (aged
34.0 §2.1 years) in cross-over
design
2.5-h cycle and run at
75%VO
2max
6% CHO or placebo beverage
consumed before, during, and
after exercise
CHO "glucose, insulin; #cortisol, growth hormone; #neutrophils,
monocytes, lymphocytes; #granulocyte, monocyte phagocytosis and
oxidative burst activity; #neutrophil/lymphocyte ratio;
#NK cell cytotoxicity; #IL-6, IL-1ra vs. placebo trial.
Henson et al.
151
15 Olympic female rowers (aged
22.4 §0.5 years) in a cross-over
design
2-h rowing session 6% CHO or placebo beverage
consumed before, during, and
after exercise
CHO "glucose; #total leukocytes, neutrophils, and monocytes;
#phagocytosis; #IL-1ra vs. placebo trial.
Nieman et al.
152
16 marathon runners (aged 50.1 §
1.5 years) in a cross-over design
3-h run at 70%VO
2max
6% CHO or placebo beverage
consumed before and during
exercise
CHO "glucose, insulin; #cortisol; #total leukocytes, monocytes,
lymphocytes, and granulocytes; #plasma IL-6, IL-10, IL-1ra;
#skeletal muscle IL-6, IL-8 mRNA vs. placebo trial.
Bishop et al.
153
9 trained male cyclists (aged 25.0 §
2.0 years) in a cross-over design
2-h cycle at 75%VO
2max
6.4% CHO or placebo bever-
age consumed before, during,
and after exercise
CHO "glucose; #cortisol; #neutrophils vs. placebo trial.
Keller et al.
154
8 untrained men (aged 24.0 §1.0
years) in a cross-over design
3-h cycle at 60% maximal
workload
6% CHO or placebo beverage
consumed during exercise
CHO "glucose; #free fatty acids; #plasma IL-6,
#adipose tissue IL-6 mRNA vs. placebo trial.
Febbraio et al.
155
7 men (aged 22.1 §3.8 years) in
cross-over design
2-h cycle at 65%VO
2max
6.4% CHO or placebo bever-
age consumed before and
during exercise
CHO "glucose; #free fatty acids; #IL-6 vs. placebo trial.
Henson et al.
156
48 male and female marathon run-
ners (aged 42.5 §2.4 years) random-
ized to CHO or placebo
42-km marathon 6% CHO or placebo beverage
consumed before and during
exercise
CHO "glucose, insulin; #cortisol; #total leukocytes,
neutrophils, and monocytes vs. placebo group.
Davison and Gleeson
157
6 moderately trained men (aged 25.0
§2.0 years) in a cross-over design
2.5-h cycle at 60%VO
2max
6% CHO or placebo beverage
consumed before and during
exercise
CHO "glucose; #cortisol; #ACTH; #total leukocytes,
neutrophils; "bacterial-stimulated neutrophil
degranulation vs. placebo trial.
Lancaster et al.
158
7 moderately trained men (aged 25.0
§1.0 years) in a cross-over design
2.5-h cycle at 65%VO
2max
6.4%, 12.8% CHO or placebo
beverage consumed before
and during exercise
CHO "glucose; #cortisol; #growth hormone;
#total leukocytes, neutrophils, monocytes;
#CD4
+
T cell IFN-gand CD8
+
T cell IFN-glymphocytes.
No significant difference between CHO concentrations.
Li and Gleeson
159
9 men (aged 28.7 §1.6 years) in a
cross-over design
90-min cycle at 60%VO
2max
10% CHO or placebo bever-
age consumed before and
during exercise
CHO "glucose; #cortisol, epinephrine, ACTH, growth hormone;
#total leukocytes, monocytes, lymphocytes; #IL-6 vs. placebo trial.
Nieman et al.
160
15 trained male cyclists (aged 29.2 §
6.0 years) in a cross-over design
2.5-h cycle at 75%VO
2max
6% CHO or placebo beverage
consumed before, during, and
after exercise
CHO "glucose, insulin; #cortisol, epinephrine;
#total leukocytes, neutrophils; #IL-6, IL-10,
IL-1ra vs. placebo trial.
Nieman et al.
161
12 trained male cyclists (aged 21.0 §
1.0 years) in a cross-over design
2-h cycle at 75%VO
2max
6% CHO or placebo beverage
consumed before and during
exercise
CHO "glucose, insulin; #cortisol; #total leukocytes,
neutrophils, and monocytes vs. placebo trial.
Scharhag et al.
162
14 trained male cyclists/triathletes
(aged 25.0 §5.0 years) in a
cross-over design
4-h cycle at 70% anaerobic
threshold
6%, 12% CHO, or placebo
beverage consumed before
and during exercise
6% and 12% CHO "glucose; #cortisol; #total leukocytes,
neutrophils, and monocytes vs. placebo trial. 12% CHO
#CRP and NK cells vs. placebo trial.
Nieman et al.
163
14 trained male cyclists (aged 37.0 §
7.1 years) in a cross-over design
75-km time trial 6% CHO beverage or
matched CHO banana
No difference in immune and inflammation measures
(e.g., IL-6, granulocyte and monocyte phagocytosis)
(continued on next page)
210 D.C. Nieman and L.M. Wentz

Many of the earlier studies reported few discernable
immune-related influences of increased polyphenol intake for
athletes, but research design deficiencies portrayed a misun-
derstanding of polyphenol bioavailability and metabolism, and
the appropriate outcome measures. Polyphenol absorption, dis-
position, metabolism, and excretion is complex and requires
both untargeted and targeted metabolomics procedures to mea-
sure small molecule shifts in humans after increased intake.
167
A high proportion of ingested polyphenols from fruits, vegeta-
bles, and other plant foods pass through the small intestine
unabsorbed and reach the colon, where bacterial degradation
produces smaller phenolics that can reabsorbed into the circu-
lation after undergoing phase 2 conjugation in the liver.
33
The
biotransformed, gut-derived phenolics circulate throughout the
body, exerting a variety of bioactive effects that are important
to athletes including anti-inflammatory, antiviral, antioxida-
tive, and immune cell signaling effects.
167172
Several studies using metabolomics and ex vivo cell cultures
comparing ingestion of bananas with intake of water only or a
6% sugar beverage during prolonged and intensive cycling have
shown large-fold increases in at least 18 banana-related metabo-
lites.
31,163,164
Banana flesh contains many unique molecules
including serotonin, dopamine, phenolics, and xenobiotics.
Soon after ingestion, plasma levels of metabolites derived from
banana flesh molecules increase, and may confer anti-inflamma-
tory effects by countering cyclooxygenase-2 (COX-2) mRNA
expression the morning after heavy exertion.
31
In general, evolving data support the intake of fruits such as
dates, raisins, and bananas by athletes during training to pro-
vide the sugars and polyphenols that exert anti-inflammatory
influences that may enhance metabolic recovery. Future stud-
ies using system-wide approaches such as metabolomics, lipi-
domics, and proteomics will improve scientific understanding
regarding the complex and multilevel interactions between
exercise, nutrition, and the immune and metabolic systems.
Fig. 8. Carbohydrate ingestion before and during exercise attenuates postexer-
cise inflammation.
Table 3. (Continued)
Investigator Study population Exercise protocol Carbohydrate intervention Postexercise immune response
consumed before and during
exercise
between banana and CHO beverage; higher
FRAP and plasma dopamine with banana.
Nieman et al.
164
20 trained male cyclists (aged 39.2 §
1.9 years) in a cross-over design
75-km time trial Banana, pear, or water con-
sumed before and during
exercise
Banana and pear "glucose, RER; #cortisol, IL-10;
#neutrophil/ lymphocyte ratio; "antioxidant capacity
(sulfated phenolics, FRAP), #fatty acid mobilization and
oxidation metabolites vs. water trial. "in fruit-specific metabolites.
Shanely et al.
165
20 trained male cyclists (aged 48.5 §
2.3 years) in a cross-over design
75-km time trial 6% CHO beverage or
matched CHO watermelon
consumed before and during
exercise
No difference in inflammation measures (e.g., cytokines and immune
cell counts) between watermelon and CHO beverage; watermelon
"antioxidant capacity (FRAP, ORAC); "citrulline, arginine,
nitrate vs. CHO beverage.
Nieman et al.
31
20 trained male and female cyclists
(aged 39.1 §2.4 years) in a cross-
over design
75-km time trial 6% CHO beverage, 2 types of
banana, or water consumed
before and during exercise
Bananas and CHO beverage "glucose, fructose; #cortisol;
#IL-6, IL-10, IL-1ra; #total leukocytes; #9+13 HODES;
#fatty acid mobilization and oxidation metabolites vs.
water trial. Both banana trials #COX2 mRNA expression;
"amino acid and xenobiotics metabolites.
Abbreviations: ACTH = adrenocorticotropic hormone; CHO = carbohydrate; COX2 = cyclo-oxygenase 2; CRP = C-reactive protein; FRAP = ferric reducing ability of plasma; HODES = hydroxyoctadecadienoic
acid; IFN-g= interferon gamma; IL-1ra = interleukin-1 receptor antagonist; mRNA = messenger ribonucleic acid; NK = natural killer; ORAC = oxygen radical absorbance capacity; RER = respiratory exchange
ratio; VO
2max
= maximal oxygen uptake.
Exercise immunology 211

5. Exercise influences immunosenescence
Immunosenescence is defined as immune dysregulation
with aging and is related to an increased susceptibility to infec-
tions, autoimmune diseases, neoplasias, metabolic diseases,
osteoporosis, and neurologic disorders. Recent evidence sup-
ports that immunity can be remodeled during the aging process
as a result of interactions with the environment and lifestyle
and is instrumental in shaping immune status in later
life.
173175
Immune system interactions with pathogens, the
host microbiome, nutritional and exercise influences, mental
stress, and many other extrinsic factors are considered as cru-
cial modulators of the immunosenescence process.
Early cross-sectional studies compared immune function in
highly conditioned and sedentary elderly men and women.
31,176
One study contrasted immune function in 30 sedentary elderly
women and 12 age-matched, highly conditioned elderly women
who were active in state and national senior game and road race
endurance events.
31
The highly conditioned elderly women had
significantly higher levels of NK cells and T-lymphocyte func-
tion and reduced illness rates compared with the 30 sedentary
elderly women. Another study compared immune function in
17 elderly runners who had trained for about 17 years and 19
elderly controls, and reported significantly higher T lymphocyte
function in the elderly runners.
176
These studies stimulated many additional studies on the
effects of exercise training on immunosenescence. Data sup-
port that habitual exercise is capable of regulating the immune
system and delaying the onset of immunosenescence, and has
been associated with the following:
31,175,177179
Enhanced vaccination responses,
Lower numbers of exhausted/senescent T cells,
Increased T-cell proliferative capacity,
Lower circulatory levels of inflammatory cytokines (i.e.,
decreased “inflamm-aging”),
Increased neutrophil phagocytic activity,
Lowered inflammatory response to bacterial challenge,
Greater NK cell cytotoxic activity, and
Longer leukocyte telomere lengths.
6. Conclusion
This review summarized research discoveries within
4 areas of exercise immunology: acute and chronic effects of
exercise on the immune system, clinical benefits of the exerci-
seimmune relationship, nutritional influences on the immune
response to exercise, and the exercise effect on immunosenes-
cence. The immune system is very responsive to exercise,
with the extent and duration reflecting the degree of physiolog-
ical stress imposed by the workload. Key exercise immunol-
ogy discoveries since 1980 include the following.
Acute exercise (moderate-to-vigorous intensity, less than
60 min) is now viewed as an important immune system
adjuvant to stimulate the ongoing exchange of distinct and
highly active immune cell subtypes between the circulation
and tissues. In particular, each exercise bout improves the
antipathogen activity of tissue macrophages in parallel with
an enhanced recirculation of immunoglobulins, anti-inflam-
matory cytokines, neutrophils, NK cells, cytotoxic T cells,
and immature B cells. With near daily exercise, these acute
changes operate through a summation effect to enhance
immune defense activity and metabolic health.
In contrast, high exercise training workloads, competition
events, and the associated physiological, metabolic, and
psychological stress are linked with transient immune per-
turbations, inflammation, oxidative stress, muscle damage,
and increased illness risk. Metabolomics, proteomics, and
lipidomics have revealed that metabolism and immunity
are inextricably interwoven, providing new insights on
how intense and prolonged exercise can cause transient
immune dysfunction by decreasing immune cell metabolic
capacity.
Illness risk may be increased when an athlete competes,
goes through repeated cycles of unusually heavy exertion,
and experiences other stressors to the immune system. The
wealth of acute illness epidemiologic data collected during
international competition events has revealed that
2%18% of elite athletes experience illness episodes, with
higher proportions for females and those engaging in endur-
ance events. Other illness risk factors include high levels of
depression or anxiety, participation in unusually intensive
training periods with large fluctuations, international travel
across several time zones, participation in competitive
events especially during the winter, lack of sleep, and low
diet energy intake.
The IOC has also focused on load management of both
internal (e.g., psychological responses) and external factors
(e.g., training and competition workloads), and lifestyle
strategies (e.g., hygiene, nutritional support, vaccination,
regular sleep) to reduce illness incidence and associated
downturns in exercise performance, interruptions in train-
ing, missed competitive events, and risk of serious medical
complications.
Randomized clinical trials and epidemiologic studies con-
sistently support the inverse relationship between moderate
exercise training and incidence of URTI. These data led to
the development of the J-curve model that links URTI risk
with the exercise workload continuum. Several epidemio-
logic studies also suggest that regular physical activity is
associated with decreased mortality and incidence rates for
influenza and pneumonia.
Regular exercise training has an overall anti-inflammatory
influence mediated through multiple pathways. Epidemio-
logic studies consistently show decreased levels of inflam-
matory biomarkers in adults with higher levels of physical
activity and fitness, even after adjustment for potential con-
founders such as BMI.
There is increasing evidence that the circulation surge in
cells of the innate immune system with each exercise bout
and the anti-inflammatory and antioxidant effect of exercise
training have a summation effect over time in modulating
tumorigenesis, atherosclerosis, and other disease processes.
212 D.C. Nieman and L.M. Wentz

Recent studies indicate that exercise and physical fitness
diversifies the gut microbiota, but more human research is
needed to determine potential linkages to immune function
in physically fit individuals and athletes.
The most effective nutritional strategies for athletes, especially
when evaluated from a multiomics perspective, include
increased intake of carbohydrates and polyphenols. A consis-
tent finding is that carbohydrate intake during prolonged and
intense exercise, whether from 6%8% beverages or sugar-
dense fruits such as bananas is associated with reduced stress
hormones, diminished blood levels of neutrophils and mono-
cytes, and dampened inflammation. Gut-derived phenolics cir-
culate throughout the body after increased polyphenol intake,
exerting a variety of bioactive effects that are important to ath-
letes including anti-inflammatory, antiviral, antioxidative, and
immune cell signaling effects.
Immunosenescence is defined as immune dysregulation
with aging. Emergent data support that habitual exercise is
capable of improving regulation of the immune system and
delaying the onset of immunosenescence.
The future of exercise immunology will take advantage of
advances in mass spectrometry and genetic testing technology,
with increased utilization of metabolomics, proteomics, lipido-
mics, microbiome characterization, and genomics. Use of these
system-wide approaches will provide new insights on the inter-
actions between exercise, nutrition, and immune function, with
application down to the personalized level. Additionally, these
methodologies will improve mechanistic understanding of how
exercise-induced immune changes reduce risk for common
chronic diseases.
Authors’ contributions
DCN and LMW conducted the literature review and wrote
the manuscript. Both authors have read and approved the final
version of the manuscript, and agree with the order of presen-
tation of the authors.
Competing interests
Both authors declare that they have no competing interests.
References
1. Van Dijk JG, Matson KD. Ecological immunology through the lens of
exercise immunology: new perspective on the links between physical
activity and immune function and disease susceptibility in wild animals.
Integr Comp Biol 2016;56:290–303.
2. Larrabee RC. Leukocytosis after violent exercise. J Med Res (NS)
1902;7:76–82.
3. Walsh NP, Gleeson M, Shephard RJ, Gleeson M, Woods JA, Bishop NC,
et al. Position statement. Part one: immune function and exercise. Exerc
Immunol Rev 2011;17:6–63.
4. Walsh NP, Gleeson M, Pyne DB, Nieman DC, Dhabhar FS, Shephard RJ,
et al. Position statement. Part two: maintaining immune health. Exerc
Immunol Rev 2011;17:64–103.
5. Shephard RJ. Development of the discipline of exercise immunology.
Exerc Immunol Rev 2010;16:194–222.
6. Bermon S, Castell LM, Calder PC, Bishop NC, Blomstrand E, Mooren
FC, et al. Consensus statement immunonutrition and exercise. Exerc
Immunol Rev 2017;23:8–50.
7. Nieman DC, Mitmesser SH. Potential impact of nutrition on immune sys-
tem recovery from heavy exertion: a metabolomics perspective.
Nutrients 2017;9. pii: E513. doi:10.3390/nu9050513.
8. Simon HB. The immunology of exercise: a brief review. JAMA
1984;252:2735–8.
9. Mackinnon LT. Changes in some cellular immune parameters following
exercise training. Med Sci Sports Exerc 1986;18:596–7.
10. Mackinnon LT, Chick TW, van As A, Tomasi TB. The effect of
exercise on secretory and natural immunity. Adv Exp Med Biol 1987;
216A:869–76.
11. Hoffman-Goetz L, Keir R, Thorne R, Houston ME, Young C. Chronic
exercise stress in mice depresses splenic T lymphocyte mitogenesis
in vitro.Clin Exp Immunol 1986;66:551–7.
12. Hoffman-Goetz L, Thorne RJ, Houston ME. Splenic immune responses
following treadmill exercise in mice. Can J Physiol Pharmacol
1988;66:1415–9.
13. Pedersen BK, Tvede N, Hansen FR, Andersen V, Bendix T, Bendixen G,
et al. Modulation of natural killer cell activity in peripheral blood by
physical exercise. Scand J Immunol 1988;27:673–8.
14. Tvede N, Pedersen BK, Hansen FR, Bendix T, Christensen LD, Galbo H,
et al. Effect of physical exercise on blood mononuclear cell subpopula-
tions and in vitro proliferative responses. Scand J Immunol
1989;29:383–9.
15. Nieman DC, Tan SA, Lee JW, Berk LS. Complement and immunoglobu-
lin levels in athletes and sedentary controls. Int J Sports Med
1989;10:124–8.
16. Nieman DC, Johanssen LM, Lee JW. Infectious episodes in runners
before and after a roadrace. J Sports Med Phys Fitness 1989;29:
289–96.
17. Nieman DC, Johanssen LM, Lee JW, Arabatzis K. Infectious episodes in
runners before and after the Los Angeles Marathon. J Sports Med Phys
Fitness 1990;30:316–28.
18. Cannon JG, Kluger MJ. Endogenous pyrogen activity in human plasma
after exercise. Science 1983;220:617–9.
19. Peters EM, Goetzsche JM, Grobbelaar B, Noakes TD. Vitamin C supplemen-
tation reduces the incidence of postrace symptoms of upper-respiratory-tract
infection in ultramarathon runners. Am J Clin Nutr 1993;57:170–4.
20. Nehlsen-Cannarella SL, Fagoaga OR, Nieman DC, Henson DA, Butter-
worth DE, Schmitt RL, et al. Carbohydrate and the cytokine response to
2.5 h of running. J Appl Physiol (1985) 1997;82:1662–7.
21. Nieman DC, Henson DA, Gusewitch G, Warren BJ, Dotson RC, Butter-
worth DE, et al. Physical activity and immune function in elderly
women. Med Sci Sports Exerc 1993;25:823–31.
22. Nieman DC, Henson DA. Role of endurance exercise in immune senes-
cence. Med Sci Sports Exerc 1994;26:172–81.
23. Shinkai S, Konishi M, Shephard RJ. Aging, exercise, training, and the
immune system. Exerc Immunol Rev 1997;3:68–95.
24. Northoff H, Berg A. Immunologic mediators as parameters of the reac-
tion to strenuous exercise. Int J Sports Med 1991;12(Suppl. 1):S9–15.
25. Cannon JG, Meydani SN, Fielding RA, Fiatarone MA, Meydani M, Far-
hangmehr M, et al. Acute phase response in exercise. II. Associations
between vitamin E, cytokines, and muscle proteolysis. Am J Physiol
1991;260:R1235–40.
26. Rohde T, MacLean DA, Richter EA, Kiens B, Pedersen BK. Prolonged
submaximal eccentric exercise is associated with increased levels of
plasma IL-6. Am J Physiol 1997;273:E85–91.
27. Nieman DC. Immune response to heavy exertion. J Appl Physiol (1985)
1997;82:1385–94.
28. Colbey C, Cox AJ, Pyne DB, Zhang P, Cripps AW, West NP. Upper
respiratory symptoms, gut health and mucosal immunity in athletes.
Sports Med 2018;48(Suppl. 1):S65–77.
29. Markworth JF, Vella L, Lingard BS, Tull DL, Rupasinghe TW, Sinclair
AJ, et al. Human inflammatory and resolving lipid mediator responses to
resistance exercise and ibuprofen treatment. Am J Physiol Regul Integr
Comp Physiol 2013;305:R1281–96.
30. Nieman DC, Groen AJ, Pugachev A, Vacca G. Detection of functional
overreaching in endurance athletes using proteomics. Proteomes 2018;6.
pii: E33. doi:10.3390/proteomes6030033.
Exercise immunology 213

31. Nieman DC, Gillitt ND, Sha W, Esposito D, Ramamoorthy S. Metabolic
recovery from heavy exertion following banana compared to sugar bev-
erage or water only ingestion: a randomized, crossover trial. PLoS One
2018;13:e0194843. doi:10.1371/journal.pone.0194843.
32. Nieman DC, Gillitt ND, Sha W. Identification of a targeted metabolo-
mics panel for measuring metabolic perturbation in response to heavy
exertion. Metabolomics 2018;14:147. doi:10.1007/s11306-018-1444-7.
33. Nieman DC, Lila MA, Gillitt ND. Immunometabolism: a multi-omics
approach to interpreting the influence of exercise and diet on the immune
system. Ann Rev Food Sci Tech 2019;10:341–63.
34. Koelwyn GJ, Wennerberg E, Demaria S, Jones LW. Exercise in regula-
tion of inflammation-immune axis function in cancer initiation and pro-
gression. Oncology (Williston Park) 2015;29:908–20.
35. Bigley AB, Spielmann G, LaVoy EC, Simpson RJ. Can exercise-related
improvements in immunity influence cancer prevention and prognosis in
the elderly? Maturitas 2013;76:51–6.
36. Antunes BM, Cayres SU, Lira FS, Fernandes RA. Arterial thickness and
immunometabolism: the mediating role of chronic exercise. Curr Cardiol Rev
2016;12:47–51.
37. Adams GR, Zaldivar FP, Nance DM, Kodesh E, Radom-Aizik S, Cooper
DM. Exercise and leukocyte interchange among central circulation, lung,
spleen, and muscle. Brain Behav Immun 2011;25:658–66.
38. Bigley AB, Rezvani K, Chew C, Sekine T, Pistillo M, Crucian B, et al.
Acute exercise preferentially redeploys NK-cells with a highly-differentiated
phenotype and augments cytotoxicity against lymphoma and multiple mye-
loma target cells. Brain Behav Immun 2014;39:160–71.
39. Gupta P, Bigley AB, Markofski M, Laughlin M, LaVoy EC. Autologous
serum collected 1 h post-exercise enhances natural killer cell cytotoxic-
ity. Brain Behav Immun 2018;71:81–92.
40. Nieman DC, Henson DA, Austin MD, Brown VA. Immune response to a
30-minute walk. Med Sci Sports Exerc 2005;37:57–62.
41. Viana JL, Kosmadakis GC, Watson EL, Bevington A, Feehally J, Bishop
NC, et al. Evidence for anti-inflammatory effects of exercise in CKD.
J Am Soc Nephrol 2014;25:2121–30.
42. Evans ES, Hackney AC, McMurray RG, Randell SH, Muss HB, Deal
AM, et al. Impact of acute intermittent exercise on natural killer cells in
breast cancer survivors. Integr Cancer Ther 2015;14:436–45.
43. Ferrandi PJ, Fico BG, Whitehurst M, Zourdos MC, Bao F, Dodge KM,
et al. Acute high-intensity interval exercise induces comparable levels of
circulating cell-free DNA and interleukin-6 in obese and normal-weight
individuals. Life Sci 2018;202:161–6.
44. Simpson RJ, Kunz H, Agha N, Graff R. Exercise and the regulation of
immune functions. Prog Mol Biol Transl Sci 2015;135:355–80.
45. Simpson RJ, Bigley AB, Agha N, Hanley PJ, Bollard CM. Mobilizing
immune cells with exercise for cancer immunotherapy. Exerc Sport Sci
Rev 2017;45:163–72.
46. LaVoy EC, Bollard CM, Hanley PJ, Blaney JW, O’Connor DP, Bosch
JA, et al. A single bout of dynamic exercise enhances the expansion of
MAGE-A4 and PRAME-specific cytotoxic T-cells from healthy adults.
Exerc Immunol Rev 2015;21:144–53.
47. Turner JE, Spielmann G, Wadley AJ, Aldred S, Simpson RJ, Campbell
JP. Exercise-induced B cell mobilization: preliminary evidence for an
influx of immature cells into the bloodstream. Physiol Behav
2016;164:376–82.
48. Campbell JP, Riddell NE, Burns VE, Turner M, van Zanten JJ, Drayson
MT, et al. Acute exercise mobilizes CD8+ T lymphocytes exhibiting an
effector-memory phenotype. Brain Behav Immun 2009;23:767–75.
49. Karstoft K, Pedersen BK. Exercise and type 2 diabetes: focus on metabo-
lism and inflammation. Immunol Cell Biol 2016;94:146–50.
50. Pedersen BK. Anti-inflammatory effects of exercise: role in diabetes and
cardiovascular disease. Eur J Clin Invest 2017;47:600–11.
51. Grande AJ, Reid H, Thomas EE, Nunan D, Foster C. Exercise prior to
influenza vaccination for limiting influenza incidence and its related
complications in adults. Cochrane Database Syst Rev 2016;22:
CD011857. doi:10.1002/14651858. CD011857.pub2.
52. Peake JM, Della Gatta P, Suzuki K, Nieman DC. Cytokine expression
and secretion by skeletal muscle cells: regulatory mechanisms and exer-
cise effects. Exerc Immunol Rev 2015;21:8–25.
53. Peake JM, Neubauer O, Della Gatta PA, Nosaka K. Muscle damage and
inflammation during recovery from exercise. J Appl Physiol (1985)
2017;122:559–70.
54. Peake JM, Neubauer O, Walsh NP, Simpson RJ. Recovery of the
immune system after exercise. J Appl Physiol (1985) 2017;122:1077–87.
55. Simpson RJ, Kunz H, Agha N, Graff R. Exercise and the regulation of
immune functions. Prog Mol Biol Transl Sci 2015;135:355–80.
56. Pedersen BK, Hoffman-Goetz L. Exercise and the immune system: regu-
lation, integration, and adaptation. Physiol Rev 2000;80:1055–81.
57. Siedlik JA, Benedict SH, Landes EJ, Weir JP, Vardiman JP, Gallagher
PM. Acute bouts of exercise induce a suppressive effect on lymphocyte
proliferation in human subjects: a meta-analysis. Brain Behav Immun
2016;56:343–51.
58. Campbell JP, Turner JE. Debunking the myth of exercise-induced
immune suppression: redefining the impact of exercise on immunological
health across the lifespan. Front Immunol 2018;9:648. doi:10.3389/
fimmu.2018.00648.
59. Balfoussia E, Skenderi K, Tsironi M, Anagnostopoulos AK, Parthimos
N, Vougas K, et al. A proteomic study of plasma protein changes under
extreme physical stress. J Proteomics 2014;98:1–14.
60. Markworth JF, Maddipati KR, Cameron-Smith D. Emerging roles of pro-
resolving lipid mediators in immunological and adaptive responses to
exercise-induced muscle injury. Exerc Immunol Rev 2016;22:110–34.
61. Nieman DC, Shanely RA, Gillitt ND, Pappan KL, Lila MA. Serum meta-
bolic signatures induced by a three-day intensified exercise period persist
after 14 h of recovery in runners. J Proteome Res 2013;12:4577–84.
62. Nieman DC, Shanely RA, Luo B, Meaney MP, Dew DA, Pappan KL. Metab-
olomics approach to assessing plasma 13- and 9-hydroxy-octadecadienoic
acid and linoleic acid metabolite responses to 75-km cycling. Am J Physiol
Regul Integr Comp Physiol 2014;307:R68–74.
63. Whitham M, Parker BL, Friedrichsen M, Hingst JR, Hjorth M, Hughes
WE, et al. Extracellular vesicles provide a means for tissue crosstalk dur-
ing exercise. Cell Metab 2018;27:237–51.
64. Hotamisligil GS. Foundations of immunometabolism and implications
for metabolic health and disease. Immunity 2017;47:406–20.
65. Schwellnus M, Soligard T, Alonso JM, Bahr R, Clarsen B, Dijkstra HP,
et al. How much is too much? (Part 2) International Olympic Committee
consensus statement on load in sport and risk of illness. Br J Sports Med
2016;50:1043–52.
66. Meeusen R, Duclos M, Foster C, Fry A, Gleeson M, Nieman D, et al.
European College of Sport Science; American College of Sports Medi-
cine. Prevention, diagnosis, and treatment of the overtraining syndrome:
joint consensus statement of the European College of Sport Science and
the American College of Sports Medicine. Med Sci Sports Exerc
2013;45:186–205.
67. Peters EM, Bateman ED. Ultramarathon running and upper respiratory
tract infections. An epidemiological survey. S Afr Med J 1983;64:582–4.
68. Nieman DC. Exercise immunology: practical applications. Int J Sports
Med 1997;18(Suppl. 1):S91–100.
69. Heath GW, Ford ES, Craven TE, Macera CA, Jackson KL, Pate RR.
Exercise and the incidence of upper respiratory tract infections. Med Sci
Sports Exerc 1991;23:152–7.
70. Konig D, Grathwohl D, Weinstock C, Northoff H, Berg A. Upper
respiratory tract infection in athletes: influence of lifestyle, type of
sport, training effort, and immunostimulant intake. Exerc Immunol
Rev 2000;6:102–20.
71. Spence L, Brown WJ, Pyne DB, Nissen MD, Sloots TP, McCormack JG,
et al. Incidence, etiology, and symptomatology of upper respiratory ill-
ness in elite athletes. Med Sci Sports Exerc 2007;39:577–86.
72. Gleeson M, Bishop N, Oliveira M, Tauler P. Influence of training load on
upper respiratory tract infection incidence and antigen-stimulated cyto-
kine production. Scand J Med Sci Sports 2013;23:451–7.
73. Rama L, Teixeira AM, Matos A, Borges G, Henriques A, Gleeson M,
et al. Changes in natural killer cell subpopulations over a winter training
season in elite swimmers. Eur J Appl Physiol 2013;113:859–68.
74. Hellard P, Avalos M, Guimaraes F, Toussaint JF, Pyne DB. Training-
related risk of common illnesses in elite swimmers over a 4-yr period.
Med Sci Sports Exerc 2015;47:698–707.
214 D.C. Nieman and L.M. Wentz

75. Svendsen IS, Gleeson M, Haugen TA, Tønnessen E. Effect of an intense
period of competition on race performance and self-reported illness in
elite cross-country skiers. Scand J Med Sci Sports 2015;25:846–53.
76. Svendsen IS, Taylor IM, Tønnessen E, Bahr R, Gleeson M. Training-
related and competition-related risk factors for respiratory tract and gas-
trointestinal infections in elite cross-country skiers. Br J Sports Med
2016;50:809–15.
77. Raysmith BP, Drew MK. Performance success or failure is influenced by
weeks lost to injury and illness in elite Australian track and field athletes:
a 5-year prospective study. J Sci Med Sport 2016;19:778–83.
78. Drew M, Vlahovich N, Hughes D, Appaneal R, Burke LM, Lundy B,
et al. Prevalence of illness, poor mental health and sleep quality and low
energy availability prior to the 2016 Summer Olympic Games. Br J
Sports Med 2018;52:47–53.
79. Prien A, Mountjoy M, Miller J, Boyd K, van den Hoogenband C, Gerrard
D, et al. Injury and illness in aquatic sport: how high is the risk? A com-
parison of results from three FINA World Championships. Br J Sports
Med 2017;51:277–82.
80. Timpka T, Jacobsson J, Bargoria V, P
eriard JD, Racinais S, Ronsen O,
et al. Preparticipation predictors for championship injury and illness:
cohort study at the Beijing 2015 International Association of Athletics
Federations World Championships. Br J Sports Med 2017;51:271–6.
81. Engebretsen L, Steffen K, Alonso JM, Aubry M, Dvorak J, Junge A,
et al. Sports injuries and illnesses during the Winter Olympic Games
2010. Br J Sports Med 2010;44:772–80.
82. Engebretsen L, Soligard T, Steffen K, Alonso JM, Aubry M, Budgett R,
et al. Sports injuries and illnesses during the London Summer Olympic
Games 2012. Br J Sports Med 2013;47:407–14.
83. Palmer-Green D, Elliott N. Sports injury and illness epidemiology: Great
Britain Olympic Team (TeamGB) surveillance during the Sochi 2014
Winter Olympic Games. Br J Sports Med 2015;49:25–9.
84. Soligard T, Steffen K, Palmer-Green D, Aubry M, Grant ME, Meeuwisse
W, et al. Sports injuries and illnesses in the Sochi 2014 Olympic Winter
Games. Br J Sports Med 2015;49:441–7.
85. Soligard T, Steffen K, Palmer D, Alonso JM, Bahr R, Lopes AD, et al.
Sports injury and illness incidence in the Rio de Janeiro 2016 Olympic Sum-
mer Games: a prospective study of 11274 athletes from 207 countries. Br J
Sports Med 2017;51:1265–71.
86. Mountjoy M, Junge A, Alonso JM, Engebretsen L, Dragan I, Gerrard D,
et al. Sports injuries and illnesses in the 2009 FINA World Champion-
ships (Aquatics). Br J Sports Med 2010;44:522–7.
87. Mountjoy M, Junge A, Benjamen S, Boyd K, Diop M, Gerrard D,
et al. Competing with injuries: injuries prior to and during the 15th
FINA World Championships 2013 (aquatics). Br J Sports Med
2015;49:37–43.
88. Alonso JM, Tscholl PM, Engebretsen L, Mountjoy M, Dvorak J, Junge
A. Occurrence of injuries and illnesses during the 2009 IAAF World Ath-
letics Championships. Br J Sports Med 2010;44:1100–5.
89. Alonso JM, Edouard P, Fischetto G, Adams B, Depiesse F, Mountjoy M.
Determination of future prevention strategies in elite track and field:
analysis of Daegu 2011 IAAF Championships injuries and illnesses sur-
veillance. Br J Sports Med 2012;46:505–14.
90. Wentz LM, Ward MD, Potter C, Oliver SJ, Jackson S, Izard RM, et al.
Increased risk of upper respiratory infection in military recruits who
report sleeping less than 6 hour per night. Mil Med 2018;183:e699–704.
91. Drew MK, Vlahovich N, Hughes D, Appaneal R, Peterson K, Burke L,
et al. A multifactorial evaluation of illness risk factors in athletes prepar-
ing for the Summer Olympic Games. J Sci Med Sport 2017;20:745–50.
92. Van Tonder A, Schwellnus M, Swanevelder S, Jordaan E, Derman W,
Janse van Rensburg DC. A prospective cohort study of 7031 distance
runners shows that 1 in 13 report systemic symptoms of an acute illness
in the 8-12 day period before a race, increasing their risk of not finishing
the race 1.9 times for those runners who started the race: SAFER study
IV. Br J Sports Med 2016;50:939–45.
93. Gordon L, Schwellnus M, Swanevelder S, Jordaan E, Derman W. Recent
acute prerace systemic illness in runners increases the risk of not finish-
ing the race: SAFER study V. Br J Sports Med 2017;51:1295–300.
94. Janse Van Rensburg DC, Schwellnus M, Derman W, Webborn N. Illness
among Paralympic athletes: epidemiology, risk markers, and preventa-
tive strategies. Phys Med Rehabil Clin N Am 2018;29:185–203.
95. Nieman DC. Is infection risk linked to exercise workload? Med Sci
Sports Exerc 2000;32(Suppl. 7):S406–11.
96. Nieman DC, Nehlsen-Cannarella SL, Markoff PA, Balk-Lamberton AJ,
Yang H, Chritton DB, et al. The effects of moderate exercise training on
natural killer cells and acute upper respiratory tract infections. Int J
Sports Med 1990;11:467–73.
97. Nieman DC, Nehlsen-Cannarella SL, Henson DA, Koch AJ, Butterworth
DE, Fagoaga OR, et al. Immune response to exercise training and/or
energy restriction in obese women. Med Sci Sports Exerc 1998;30:679–86.
98. Chubak J, McTiernan A, Sorensen B, Wener MH, Yasui Y, Velasquez
M, et al. Moderate-intensity exercise reduces the incidence of colds
among postmenopausal women. Am J Med 2006;119:937–42.
99. Barrett B, Hayney MS, Muller D, Rakel D, Ward A, Obasi CN, et al.
Meditation or exercise for preventing acute respiratory infection: a ran-
domized controlled trial. Ann Fam Med 2012;10:337–46.
100. Barrett B, Hayney MS, Muller D, Rakel D, Brown R, Zgierska AE, et al.
Meditation or exercise for preventing acute respiratory infection
(MEPARI-2): a randomized controlled trial. PLoS One 2018;13:
e0197778. doi:10.1371/journal.pone.0197778.
101. Matthews CE, Ockene IS, Freedson PS, Rosal MC, Merriam PA, Hebert
JR. Moderate to vigorous physical activity and risk of upper-respiratory
tract infection. Med Sci Sports Exerc 2002;34:1242–8.
102. Fondell E, Lagerros YT, Sundberg CJ, Lekander M, B€
alter O, Rothman
KJ, et al. Physical activity, stress, and self-reported upper respiratory
tract infection. Med Sci Sports Exerc 2011;43:272–9.
103. Nieman DC, Henson DA, Austin MD, Sha W. Upper respiratory tract
infection is reduced in physically fit and active adults. Br J Sports Med
2011;45:987–92.
104. Zhou G, Liu H, He M, Yue M, Gong P, Wu F, et al. Smoking, leisure-
time exercise and frequency of self-reported common cold among the
general population in northeastern China: a cross-sectional study. BMC
Public Health 2018;18:294. doi:10.1186/s12889-018-5203-5.
105. Barrett B, Brown R, Mundt M, Safdar N, Dye L, Maberry R, et al. The
Wisconsin Upper Respiratory Symptom Survey is responsive, reliable,
and valid. J Clin Epidemiol 2005;58:609–17.
106. Williams PT. Reduced total and cause-specific mortality from walking
and running in diabetes. Med Sci Sports Exerc 2014;46:933–9.
107. Williams PT. Dose-response relationship between exercise and respira-
tory disease mortality. Med Sci Sports Exerc 2014;46:711–7.
108. Wu S, Ma C, Yang Z, Yang P, Chu Y, Zhang H, et al. Hygiene behaviors
associated with influenza-like illness among adults in Beijing, China: a
large, population-based survey. PLoS One 2016;11: e0148448.
doi:10.1371/journal.pone.0148448.
109. Wong CM, Lai HK, Ou CQ, Ho SY, Chan KP, Thach TQ, et al. Is exer-
cise protective against influenza-associated mortality? PLoS One 2008;3:
e2108. doi:10.1371/journal.pone.0002108.
110. Sim YJ, Yu S, Yoon KJ, Loiacono CM, Kohut ML. Chronic exercise
reduces illness severity, decreases viral load, and results in greater anti-
inflammatory effects than acute exercise during influenza infection.
J Infect Dis 2009;200:1434–42.
111. Warren KJ, Olson MM, Thompson NJ, Cahill ML, Wyatt TA, Yoon KJ,
et al. Exercise improves host response to influenza viral infection in
obese and non-obese mice through different mechanisms. PLoS One
2015;10: e0129713. doi:10.1371/journal.pone.0129713.
112. Stravinskas Durigon T, MacKenzie B, Carneiro Oliveira-Junior M, San-
tos-Dias A, De Angelis K, Malfitano C, et al. Aerobic exercise protects
from Pseudomonas aeruginosa-induced pneumonia in elderly mice.
J Innate Immun 2018;10:279–90.
113. Olivo CR, Miyaji EN, Oliveira ML, Almeida FM, Louren¸co JD, Abreu
RM, et al. Aerobic exercise attenuates pulmonary inflammation
induced by Streptococcus pneumoniae.J Appl Physiol (1985)
2014;117:998–1007.
114. Parker S, Brukner P, Rosier M. Chronic fatigue syndrome and the athlete.
Sport Med Train Rehab 1996;6:269–78.
Exercise immunology 215

115. Folsom RW, Littlefield-Chabaud MA, French DD, Pourciau SS, Mistric L,
Horohov DW. Exercise alters the immune response to equine influenza virus
and increases susceptibility to infection. Equine Vet J 2001;33:664–9.
116. Roberts JA. Viral illnesses and sports performance. Sports Med
1986;3:298–303.
117. Kohut ML, Arntson BA, Lee W, Rozeboom K, Yoon KJ, Cunnick JE,
et al. Moderate exercise improves antibody response to influenza immu-
nization in older adults. Vaccine 2004;22:2298–306.
118. de Ara
ujo AL, Silva LC, Fernandes JR, Matias Mde S, Boas LS,
Machado CM, et al. Elderly men with moderate and intense training life-
style present sustained higher antibody responses to influenza vaccine.
Age (Dordr) 2015;37:105. doi:10.1007/s11357-015-9843-4.
119. Kohut ML, Cooper MM, Nickolaus MS, Russell DR, Cunnick JE.
Exercise and psychosocial factors modulate immunity to influenza
vaccine in elderly individuals. J Gerontol A Biol Sci Med Sci 2002;57:
M557–62.
120. Ringseis R, Eder K, Mooren FC, Kr€
uger K. Metabolic signals and innate
immune activation in obesity and exercise. Exerc Immunol Rev
2015;21:58–68.
121. Beavers KM, Beavers DP, Newman JJ, Anderson AM, Loeser RF,
Nicklas BJ, et al. Effects of total and regional fat loss on plasma CRP
and IL-6 in overweight and obese, older adults with knee osteoarthritis.
Osteoarthritis Cartilage 2015;23:249–56.
122. Rahmati M, Mobasheri A, Mozafari M. Inflammatory mediators in osteo-
arthritis: a critical review of the state-of-the-art, current prospects, and
future challenges. Bone 2016;85:81–90.
123. Antunes BM, Cayres SU, Lira FS, Fernandes RA. Arterial thickness and
immunometabolism: the mediating role of chronic exercise. Curr Car-
diol Rev 2016;12:47–51.
124. Apostolopoulos V, de Courten MP, Stojanovska L, Blatch GL, Tan-
galakis K, de Courten B. The complex immunological and inflamma-
tory network of adipose tissue in obesity. Mol Nutr Food Res
2016;60:43–57.
125. Kiecolt-Glaser JK, Derry HM, Fagundes CP. Inflammation: depression
fans the flames and feasts on the heat. Am J Psychiatry 2015;172:1075–91.
126. Akchurin OM, Kaskel F. Update on inflammation in chronic kidney dis-
ease. Blood Purif 2015;39:84–92.
127. Rajendran P, Chen YF, Chen YF, Chung LC, Tamilselvi S, Shen CY,
et al. The multifaceted link between inflammation and human diseases.
J Cell Physiol 2018;233:6458–71.
128. Guzik TJ, Skiba DS, Touyz RM, Harrison DG. The role of infiltrating
immune cells in dysfunctional adipose tissue. Cardiovasc Res
2017;113:1009–23.
129. Shanely RA, Nieman DC, Henson DA, Jin F, Knab AM, Sha W. Inflam-
mation and oxidative stress are lower in physically fit and active adults.
Scand J Med Sci Sports 2013;23:215–23.
130. Wedell-Neergaard AS, Krogh-Madsen R, Petersen GL, Hansen AM,
Pedersen BK, Lund R, et al. Cardiorespiratory fitness and the metabolic
syndrome: roles of inflammation and abdominal obesity. PLoS One
2018;13: e0194991. doi:10.1371/journal.pone.0194991.
131. Parsons TJ, Sartini C, Welsh P, Sattar N, Ash S, Lennon LT, et al. Physi-
cal activity, sedentary behavior, and inflammatory and hemostatic
markers in men. Med Sci Sports Exerc 2017;49:459–65.
132. Church TS, Earnest CP, Thompson AM, Priest EL, Rodarte RQ, Saun-
ders T, et al. Exercise without weight loss does not reduce C-reactive
protein: the INFLAME study. Med Sci Sports Exerc 2010;42:708–16.
133. Arsenault BJ, C^
ot
e M, Cartier A, Lemieux I, Despr
es JP, Ross R, et al.
Effect of exercise training on cardiometabolic risk markers among seden-
tary, but metabolically healthy overweight or obese post-menopausal
women with elevated blood pressure. Atherosclerosis 2009;207:530–3.
134. You T, Arsenis NC, Disanzo BL, Lamonte MJ. Effects of exercise train-
ing on chronic inflammation in obesity: current evidence and potential
mechanisms. Sports Med 2013;43:243–56.
135. Beavers KM, Brinkley TE, Nicklas BJ. Effect of exercise training on
chronic inflammation. Clin Chim Acta 2010;411:785–93.
136. Fedewa MV, Hathaway ED, Ward-Ritacco CL. Effect of exercise training
on C reactive protein: a systematic review and meta-analysis of randomized
and non-randomized controlled trials. Br J Sports Med 2017;51:670–6.
137. Lancaster GI, Febbraio MA. The immunomodulating role of exercise in
metabolic disease. Trends Immunol 2014;35:262–9.
138. Valacchi G, Virgili F, Cervellati C, Pecorelli A. OxInflammation: from
subclinical condition to pathological biomarker. Front Physiol
2018;9:858. doi:10.3389/fphys.2018.00858.
139. Koelwyn GJ, Wennerberg E, Demaria S, Jones LW. Exercise in regula-
tion of inflammation-immune axis function in cancer initiation and pro-
gression. Oncology (Williston Park) 2015;29:908–22.
140. Codella R, Luzi L, Terruzzi I. Exercise has the guts: how physical activ-
ity may positively modulate gut microbiota in chronic and immune-based
diseases. Dig Liver Dis 2018;50:331–41.
141. Rizzetto L, Fava F, Tuohy KM, Selmi C. Connecting the immune sys-
tem, systemic chronic inflammation and the gut microbiome: the role of
sex. J Autoimmun 2018;92:12–34.
142. Estaki M, Pither J, Baumeister P, Little JP, Gill SK, Ghosh S, et al. Car-
diorespiratory fitness as a predictor of intestinal microbial diversity and
distinct metagenomic functions. Microbiome 2016;4:42. doi:10.1186/
s40168-016-0189-7.
143. Barton W, Penney NC, Cronin O, Garcia-Perez I, Molloy MG, Holmes
E, et al. The microbiome of professional athletes differs from that of
more sedentary subjects in composition and particularly at the functional
metabolic level. Gut 2018;67:625–33.
144. Cook MD, Allen JM, Pence BD, Wallig MA, Gaskins HR, White BA,
et al. Exercise and gut immune function: evidence of alterations in colon
immune cell homeostasis and microbiome characteristics with exercise
training. Immunol Cell Biol 2016;94:158–63.
145. Bermon S, Petriz B, Kaj_
enien_
e A, Prestes J, Castell L, Franco OL. The
microbiota: an exercise immunology perspective. Exerc Immunol Rev
2015;21:70–9.
146. Nieman DC, Fagoaga OR, Butterworth DE, Warren BJ, Utter A, Davis
JM, et al. Carbohydrate supplementation affects blood granulocyte and
monocyte trafficking but not function after 2.5 h or running. Am J Clin
Nutr 1997;66:153–9.
147. Henson DA, Nieman DC, Parker JC, Rainwater MK, Butterworth DE, War-
ren BJ, et al. Carbohydrate supplementation and the lymphocyte proliferative
response to long endurance running. Int J Sports Med 1998;19:574–80.
148. Nieman DC, Nehlsen-Cannarella SL, Fagoaga OR, Henson DA, Utter A,
Davis JM, et al. Effects of mode and carbohydrate on the granulocyte
and monocyte response to intensive, prolonged exercise. J Appl Physiol
(1985) 1998;84:1252–9.
149. Nieman DC, Nehlsen-Cannarella SL, Fagoaga OR, Henson DA, Utter A,
Davis JM, et al. Influence of mode and carbohydrate on the
cytokine response to heavy exertion. Med Sci Sports Exerc 1998;30:671–8.
150. Henson DA, Nieman DC, Blodgett AD, Butterworth DE, Utter A, Davis
JM, et al. Influence of exercise mode and carbohydrate on the immune
response to prolonged exercise. Int J Sport Nutr 1999;9:213–28.
151. Henson DA, Nieman DC, Nehlsen-Cannarella SL, Fagoaga OR, Shannon
M, Bolton MR, et al. Influence of carbohydrate on cytokine and phago-
cytic responses to 2 h of rowing. Med Sci Sports Exerc 2000;32:1384–9.
152. Nieman DC, Davis JM, Henson DA, Walberg-Rankin J, Shute M, Dumke
CL, et al. Carbohydrate ingestion influences skeletal muscle cytokine
mRNA and plasma cytokine levels after a 3-h run. JApplPhysiol(1985)
2003;94:1917–25.
153. Bishop NC, Walsh N, Scanlon GA. Effect of prolonged exercise and car-
bohydrate on total neutrophil elastase content. Med Sci Sports Exerc
2003;35:1326–32.
154. Keller C, Keller P, Marshal S, Pedersen BK. IL-6 gene expression in
human adipose tissue in response to exercise¡effect of carbohydrate
ingestion. J Physiol 2003;550:927–31.
155. Febbraio MA, Steensberg A, Keller C, Starkie RL, Nielsen HB, Krustrup
P, et al. Glucose ingestion attenuates interleukin-6 release from contract-
ing skeletal muscle in humans. J Physiol 2003;549:607–12.
156. Henson DA, Nieman DC, Pistilli EE, Schilling B, Colacino A, Utter AC,
et al. Influence of carbohydrate and age on lymphocyte function follow-
ing a marathon. Int J Sport Nutr Exerc Metab 2004;14:308–22.
157. Davison G, Gleeson M. Influence of acute vitamin C and/or carbohydrate
ingestion on hormonal, cytokine, and immune responses to prolonged
exercise. Int J Sport Nutr Exerc Metab 2005;15:465–79.
216 D.C. Nieman and L.M. Wentz

158. Lancaster GI, Khan Q, Drysdale PT, Wallace F, Jeukendrup AE, Drayson
MT, et al. Effect of prolonged exercise and carbohydrate ingestion on
type 1 and type 2 T lymphocyte distribution and intracellular cytokine
production in humans. J Appl Physiol (1985) 2005;98:565–71.
159. Li TL, Gleeson M. The effects of carbohydrate supplementation during
the second of two prolonged cycling bouts on immunoendocrine
responses. Eur J Appl Physiol 2005;95:391–9.
160. Nieman DC, Davis JM, Henson DA, Gross SJ, Dumke CL, Utter AC,
et al. Muscle cytokine mRNA changes after 2.5 h of cycling: influence of
carbohydrate. Med Sci Sports Exerc 2005;37:1283–90.
161. Nieman DC, Henson DA, Gojanovich G, Davis JM, Murphy EA, Mayer
EP, et al. Influence of carbohydrate on immune function following 2 h
cycling. Res Sports Med 2006;14:225–37.
162. Scharhag J, Meyer T, Auracher M, Gabriel HH, Kindermann W. Effects
of graded carbohydrate supplementation on the immune response in
cycling. Med Sci Sports Exerc 2006;38:286–92.
163. Nieman DC, Gillitt ND, Henson DA, Sha W, Shanely RA, Knab AM,
et al. Bananas as an energy source during exercise: a metabolomics
approach. PLoS One 2012;7:e37479. doi:10.1371/journal.pone.0037479.
164. Nieman DC, Gillitt ND, Sha W, Meaney MP, John C, Pappan KL, et al.
Metabolomics-based analysis of banana and pear ingestion on exercise
performance and recovery. J Proteome Res 2015;14:5367–77.
165. Shanely RA, Nieman DC, Perkins-Veazie P, Henson DA, Meaney MP, Knab
AM, et al. Comparison of watermelon and carbohydrate beverage on exer-
cise-induced alterations in systemic inflammation, immune dysfunction, and
plasma antioxidant capacity. Nutrients 2016;8:E518. doi:10.3390/nu8080518.
166. Nieman DC. Influence of carbohydrate on the immune response to inten-
sive, prolonged exercise. Exerc Immunol Rev 1998;4:64–76.
167. Kay CD, Pereira-Caro G, Ludwig IA, Clifford MN, Crozier A. Antho-
cyanins and flavanones are more bioavailable than previously perceived:
a review of recent evidence. Annu Rev Food Sci Technol 2017;8:155–80.
168. Ahmed M, Henson DA, Sanderson MC, Nieman DC, Gillitt ND, Lila MA.
The protective effects of a polyphenol-enriched protein powder on exercise-
induced susceptibility to virus infection. Phytother Res 2014;28:1829–36.
169. Amin HP, Czank C, Raheem S, Zhang Q, Botting NP, Cassidy A, et al.
Anthocyanins and their physiologically relevant metabolites alter the
expression of IL-6 and VCAM-1 in CD40L and oxidized LDL chal-
lenged vascular endothelial cells. Mol Nutr Food Res 2015;59:1095–106.
170. Edwards M, Czank C, Woodward GM, Cassidy A, Kay CD. Phenolic
metabolites of anthocyanins modulate mechanisms of endothelial func-
tion. J Agric Food Chem 2015;63:2423–31.
171. Di Gesso JL, Kerr JS, Zhang Q, Raheem S, Yalamanchili SK, O’Hagan
D, et al. Flavonoid metabolites reduce tumor necrosis factor-asecretion
to a greater extent than their precursor compounds in human THP-1
monocytes. Mol Nutr Food Res 2015;59:1143–54.
172. Warner EF, Smith MJ, Zhang Q, Raheem KS, O’Hagan D, O’Connell
MA, et al. Signatures of anthocyanin metabolites identified in humans
inhibit biomarkers of vascular inflammation in human endothelial cells.
Mol Nutr Food Res 2017;61: 1700053. doi:10.1002/mnfr.201700053.
173. M€
uller L, Pawelec G. Aging and immunity-impact of behavioral inter-
vention. Brain Behav Immun 2014;39:8–22.
174. Pascoe AR, Fiatarone Singh MA, Edwards KM. The effects of exercise
on vaccination responses: a review of chronic and acute exercise inter-
ventions in humans. Brain Behav Immun 2014;39:33–41.
175. Simpson RJ, Lowder TW, Spielmann G, Bigley AB, LaVoy EC, Kunz
H. Exercise and the aging immune system. Ageing Res Rev 2012;11:
404–20.
176. Shinkai S, Kohno H, Kimura K, Komura T, Asai H, Inai R, et al. Physical
activity and immune senescence in men. Med Sci Sports Exerc
1995;27:1516–26.
177. Nieman DC, Henson DA. Role of endurance exercise in immune senes-
cence. Med Sci Sports Exerc 1994;26:172–81.
178. Turner JE, Brum PC. Does regular exercise counter T cell immunosenes-
cence reducing the risk of developing cancer and promoting successful
treatment of malignancies. Oxid Med Cell Longev 2017;2017: 4234765.
doi:10.1155/2017/4234765.
179. Simpson RJ, Kunz H, Agha N, Graff R. Exercise and the regulation of
immune functions. Prog Mol Biol Transl Sci 2015;135:355–80.
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