Article

Position Statement Part two: Maintaining immune health

Abstract and Figures

The physical training undertaken by athletes is one of a set of lifestyle or behavioural factors that can influence immune function, health and ultimately exercise performance. Others factors including potential exposure to pathogens, health status, lifestyle behaviours, sleep and recovery, nutrition and psychosocial issues, need to be considered alongside the physical demands of an athlete's training programme. The general consensus on managing training to maintain immune health is to start with a programme of low to moderate volume and intensity; employ a gradual and periodised increase in training volumes and loads; add variety to limit training monotony and stress; avoid excessively heavy training loads that could lead to exhaustion, illness or injury; include non-specific cross-training to offset staleness; ensure sufficient rest and recovery; and instigate a testing programme for identifying signs of performance deterioration and manifestations of physical stress. Inter-individual variability in immunocompetence, recovery, exercise capacity, non-training stress factors, and stress tolerance likely explains the different vulnerability of athletes to illness. Most athletes should be able to train with high loads provided their programme includes strategies devised to control the overall strain and stress. Athletes, coaches and medical personnel should be alert to periods of increased risk of illness (e.g. intensive training weeks, the taper period prior to competition, and during competition) and pay particular attention to recovery and nutritional strategies.
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Position Statement
Part two: Maintaining immune health
Neil P. Walsh1, Michael Gleeson2, David B. Pyne3, David C. Nieman4, Firdaus
S. Dhabhar5, Roy J. Shephard6, Samuel J. Oliver1, Stéphane Bermon7, Alma
Kajeniene8
1School of Sport, Health and Exercise Sciences, Bangor University, UK.
2School of Sport, Exercise and Health Sciences, Loughborough University, UK.
3Department of Physiology, Australian Institute of Sport, Australia.
4Human Performance Labs, North Carolina Research Campus and Appalachian
State University, USA.
5Department of Psychiatry and Behavioural Sciences and Stanford Institute for
Immunity, Transplantation, and Infection, Stanford University, USA.
6Faculty of Physical Education and Health, University of Toronto, Canada.
7Monaco Institute of Sports Medicine and Surgery (IM2S), Monaco.
8Kaunas Sports Medicine Center and Kaunas University of Medicine, Lithuania.
CONSENSUS STATEMENT
The physical training undertaken by athletes is one of a set of lifestyle or behav-
ioural factors that can influence immune function, health and ultimately exercise
performance. Others factors including potential exposure to pathogens, health
status, lifestyle behaviours, sleep and recovery, nutrition and psychosocial issues,
need to be considered alongside the physical demands of an athlete’s training pro-
gramme.
The general consensus on managing training to maintain immune health is to start
with a programme of low to moderate volume and intensity; employ a gradual and
periodised increase in training volumes and loads; add variety to limit training
monotony and stress; avoid excessively heavy training loads that could lead to
exhaustion, illness or injury; include non-specific cross-training to offset stale-
ness; ensure sufficient rest and recovery; and instigate a testing programme for
identifying signs of performance deterioration and manifestations of physical
stress. Inter-individual variability in immunocompetence, recovery, exercise
capacity, non-training stress factors, and stress tolerance likely explains the differ-
ent vulnerability of athletes to illness. Most athletes should be able to train with
high loads provided their programme includes strategies devised to control the
overall strain and stress. Athletes, coaches and medical personnel should be alert
to periods of increased risk of illness (e.g. intensive training weeks, the taper peri-
od prior to competition, and during competition) and pay particular attention to
recovery and nutritional strategies.
64 Maintaining immune health
EIR 17 2011 - position statement part 2
Correspondence:
Neil Walsh; email: n.walsh@bangor.ac.uk; telephone: +44 1248 383480
Although exercising in environmental extremes (heat, cold, altitude) may increase
the stress response to acute exercise and elevate the extent of leukocyte trafficking
it does not appear to have marked effects on immune function other than a depres-
sion of cell-mediated immunity when training at altitude. The available evidence
does not support the contention that athletes training and competing in cold (or
hot) conditions experience a greater reduction in immune function compared with
thermoneutral conditions. Nevertheless, it remains unknown if athletes who regu-
larly train and compete in cold conditions report more frequent, severe or longer-
lasting infections. Research should identify whether the airway inflammation
associated with breathing large volumes of cold dry air or polluted air impairs air-
way defences and whether athletes (and their physicians) wrongly interpret the
sore throat symptoms that accompany exercising in cold or polluted air as an
infection.
Elite athletes can benefit from immunonutritional support to bolster immunity
during periods of physiological stress. Ensuring adequate energy, carbohydrate
and protein intake and avoiding deficiencies of micronutrients are key to main-
taining immune health. Evidence is accumulating that some nutritional supple-
ments including flavonoids such as quercetin and Lactobacillus probiotics can
augment some aspects of immune function and reduce illness rates in exercise-
stressed athletes. Limited data are non-supportive or mixed for use of N-3 polyun-
saturated fatty acids, β-glucans, bovine colostrums, ginseng, echinacea or mega-
doses of vitamin C by athletes.
Relatively short periods of total sleep deprivation in humans (up to 3 consecutive
nights without sleep) do not influence the risk of infection, and the reported
increase in natural killer cell activity with this duration of total sleep deprivation
would seem to rule out the possibility of an “open-window” for respiratory infec-
tions. Very little is known about the effects of more prolonged sleep disruption
and repeated sleep disturbances on immune function and infection incidence,
although recent studies have highlighted the importance of sleep quantity (total
duration of sleep per night) and quality (number of awakenings per night) to pro-
tect against the common cold in healthy adults.
Short- or long-term exercise can activate different components of a physiological
stress response. Prolonged intense exercise may induce negative health conse-
quences, many of which may be mediated by physiological pathways activated by
chronic stress. Psychological stress is likely additive to the effects of physical
stress and whereas short exposures to both physical or psychological stress can
have a beneficial effect on immune function, chronic exposure to stress exerts
detrimental effects on immune function and health. However, regular moderate
exercise could be an important factor in ameliorating the negative health effects of
chronic stress via the optimization and maintenance of the survival-promoting
physiological changes induced by the short-term or acute stress response. Further
research on mechanisms mediating the salubrious effects of exercise, and on the
relationship between exercise and the psychosocial stress-status of an individual,
is likely to be helpful for more fully and widely harnessing the health benefits of
exercise.
Maintaining immune health 65
EIR 17 2011 - position statement part 2
It is agreed by everyone that prevention of infection is always superior to treatment
and this is particularly true in athletes residing in countries with limited medical
facilities. Although there is no single method that completely eliminates the risk of
contracting an infection, there are several effective ways of reducing the number of
infectious episodes incurred over a given period. These means of reducing infec-
tion risk include appropriate management of training loads, use of appropriate
recovery strategies, good personal hygiene, avoiding contact with large crowds,
young children and sick people, good nutrition, getting adequate good quality
sleep and limiting other life stresses to a minimum. Part two of the position state-
ment includes sections on: training considerations (David Pyne); nutritional coun-
termeasures to exercise-induced immune perturbations (David Nieman); effects of
stress on immune function (Firdaus Dhabhar); sleep disruption and immune func-
tion (Roy Shephard); environmental extremes and the immune response to exer-
cise (Neil Walsh and Samuel Oliver) and finally, prevention and treatment of com-
mon infections (Stéphane Bermon and Alma Kajeniene).
Key Words: exercise; sport; immune; leukocyte; pathogen; infection; training;
overtraining; overreaching; adaptation; diet; supplement; stress; in vivo; sleep;
environment; treatment; prevention
TRAINING CONSIDERATIONS
Background
There is considerable incentive for athletes, coaches, and teams to implement practi-
cal strategies that limit the risk of training-related perturbations in immune function.
The physical training undertaken by athletes is one of a set of lifestyle or behaviour-
al factors that can influence immune function, health and ultimately exercise per-
formance. Other factors including health status, lifestyle behaviours, pathogen
transmission, nutrition and psychosocial issues, need to be considered alongside the
physical demands of an athlete’s training programme. Guidelines on prescribing
training to keep athletes healthy are sought-after in the sporting community.
The challenge of preparing guidelines for prescribing training in the absence of
specific experimental studies has been acknowledged (8, 134). There are only a
few training studies that have directly examined the relationship between training
loads and patterns of illness in highly trained athletes, and the effectiveness of
various training and lifestyle interventions – see reviews (85, 171) and the respira-
tory infections and exercise section in part one of this position statement. It is dif-
ficult to study elite athletes in their regular training environment especially during
preparations for major competition. Experimental control of training, lifestyle
and dietary practices, and other confounders such as time missed with injury can
be problematic. Investigators have generally used moderately active individuals,
often volunteers in graduate research programmes, as participants in exercise
immunology studies. The predominance of short cross-sectional studies of the
acute effects of exercise rather than long-term prospective studies of athletes in
training over weeks, months or years is another issue (85). The limited number of
experimental studies makes it difficult to develop definitive practical guidelines
for athletes, coaches, clinicians and team officials.
66 Maintaining immune health
EIR 17 2011 - position statement part 2
To overcome the shortage of studies, clinicians and scientists working with ath-
letes need to translate and apply selected findings of studies in related fields.
Research areas including clinical immunology, nutritional immunology, sports
medicine, exercise physiology, psychoneuroimmunology and sports psychology
should yield useful insights. Moderate physical activity may enhance immune
function and reduce infection incidence mainly in less fit subjects, and pre-event
fitness status can also influence the risk of illness (185). However, results from
studies involving sedentary or only moderately active individuals may not easily
translate to highly trained athletes. Guidelines for maintaining good health (as
discussed later in this part of the position statement) and training will also depend
on the experience, skills and knowledge of coaches, athletes, clinicians and scien-
tists.
In most sports it is accepted that there exists a dose-response relationship between
training and performance (7). Athletes in endurance sports generally require high
training volumes to develop the background necessary for success in high-level
competition. Sudden increases in either training volume or intensity, or in combi-
nation, may place additional pressure on immune function. Post-exercise immune
function dysfunction is most pronounced when the exercise is continuous, pro-
longed (>1.5 h), of moderate to high intensity (55–75% maximal O2uptake), and
performed with minimal nutritional support (85) (as discussed in the following
section). The risk of developing symptoms of non-functional overreaching (short-
term decrements in performance capacity where the athlete is unable to recover
fully after sufficient rest) or overtraining (long-term decrements that may take
several weeks or months to resolve) (131) can be increased by monotonous train-
ing without alternating hard and easy training days, a lack of a complete rest day
once per week, increasing loads when the total load is already high, and too many
competitions (171). In terms of planning and monitoring, integrated indices of
training loads in a multivariate model are likely to be more highly correlated with
illness than individual factors such as training load, volume or intensity (72). An
imbalance between training loads and recovery is also a major contributor to the
onset of fatigue, overtraining and illness (141). A well planned recovery pro-
gramme is essential if athletes are to stay healthy and be ready to perform at their
best.
Consensus
The general consensus on managing training to maintain immune health is to start
with a programme of low to moderate volume and intensity; employ a gradual and
periodised increase in training volumes and loads; add variety to limit training
monotony and stress; avoid excessive training distances that could lead to exhaus-
tion, illness or injury (75); include non-specific cross training to offset staleness;
ensure sufficient rest and recovery; and instigate a testing programme for identi-
fying signs of performance deterioration and manifestations of physical stress
(85, 171). Inter-individual variability in recovery, exercise capacity, non-training
stress factors, and stress tolerance likely explains the differential vulnerability of
athletes to illness (172). Most athletes should be able to train with high loads pro-
vided their programme includes strategies devised to control the overall strain and
stress (Table 1). Athletes should be encouraged to undertake intensive training in
Maintaining immune health 67
EIR 17 2011 - positon statement part 2
the knowledge that variations in performance and fatigue are symptoms to be
expected and respected, and not necessarily problems to overcome (206). Ath-
letes, coaches and medical personnel should be alert to these periods of increased
risk of illness (e.g. intensive training weeks, the taper period prior to competition,
and during competition) and pay particular attention to recovery and nutritional
strategies (151).
Controversies
Studies are often limited by: using participants with moderate fitness rather than
highly trained athletes; poor description or omission of training details; absence
of a suitable control group; and, a modest sample size that reduces statistical
power. Changes in immune function after exercise are often transient and small
in magnitude (106). Although a substantial amount of research has been conduct-
68 Maintaining immune health
EIR 17 2011 - position statement part 2
Table 1. Suggested strategies for modifying training and recovery activities to limit the risk
of training-induced impairments in immune health.
Training Descriptor Comment
Frequency Increase the frequency of shorter training sessions rather
than enduring fewer but longer sessions.
Volume Reduce the overall weekly training volume and/or volume
of individual training sessions.
Intensity Avoid prolonged intensive training sessions or activities.
Employ shorter sharper (spike) sessions mixed with lower-
intensity work.
Load (volume x intensity) Systematically manipulate the training volume
and/or intensity to manage the degree of training load.
Load increments Reduce the size of increments in frequency, volume,
intensity and load of training e.g. increases of 5-10% per
week rather than 15-30%.
Load sequencing – weekly
microcycle
Undertake two or three easy-moderate training sessions
after each high intensity session rather than the traditional
pattern of simply alternating hard – easy sessions.
Load sequencing – multi-
week macrocyle
Plan an easier recovery or adaptation week every 2nd or 3rd
week rather than using longer 3 – 6 week cycles with
increasing loads.
Recovery – session/week Implement recovery activities immediately after the most
intensive or exhaustive training sessions.
Recovery - season Permit athletes at heightened risk of illness a longer period
of passive and active recovery (several weeks) after
completion of a season or major competition.
ed, several important questions remain unanswered. Are different guidelines
needed for (previously) sedentary individuals, moderately active and highly-
trained athletes? How much exercise or training is too much? Should guidelines
be general or sports-specific? Which are the best clinical signs and symptoms of
overtraining or impending illness (37)? Which diagnostic tests are useful in moni-
toring immune status (3)? A section in part one of this position statement high-
lights the strengths and weaknesses of various methods used to assess immune
status and the challenges associated with interpreting the clinical significance of
results from these tests. What is the relative effectiveness of other tactics such as
nutritional countermeasures (see section that follows), sleep (see sleep disruption
section in this part of the position statement) and recovery interventions (111,
181)? Given limitations in time, money and resources, coaches are often unable
to implement every strategy and a process of prioritising training, recovery and
behavioural interventions is necessary.
Future directions
A systematic programme of clinical and experimentally controlled research is
needed to formulate evidence-based training guidelines or recommendations to
maintain immune health in athletes. Studies are needed with both recreational
and elite athletes. Modelling studies of responses to physical training (16) should
shed light on the relative influence of training volume, intensity and loads on the
immune system. Molecular biology is already yielding some insights for identi-
fying athletes more at risk of illness (36) and should further our understanding of
how the immune system responds to various types of training. For a more
detailed account of a role for “omics” in exercise immunology, readers are direct-
ed to the “omics” section in part one of this position statement. Studies should
also address how individual variations in the risk of illness relate to training (172).
A combination of field-based diagnostic technology, experimental research,
insightful analytical approaches (99), and the clinical/practical experience of
physicians and athletes/coaches is likely to be the most effective approach for
managing the training and immunity of athletes.
NUTRITIONAL COUNTERMEASURES TO EXERCISE-
INDUCED IMMUNE PERTURBATIONS
Background
Nutrition, exercise, mental stress, and other lifestyle factors influence immune
function and the risk of certain types of infection such as upper respiratory tract
infections (URTI). In contrast to moderate physical activity, prolonged and inten-
sive exertion by athletes causes numerous changes in immunity in multiple body
compartments and an increased risk of URTI (150). Elite athletes must train
intensively to compete at the highest levels and they can benefit from immunonu-
tritional support to bolster immunity during periods of physiological stress (151).
Non-athletes engaging in moderate physical activity programmes do not require
nutritional supplements, and can obtain all needed nutrients from a healthy and
balanced diet.
Maintaining immune health 69
EIR 17 2011 - position statement part 2
Each acute bout of heavy exertion leads to physiological stress and transient but
clinically significant changes in immunity and host pathogen defence, with eleva-
tions in stress hormones, pro- and anti-inflammatory cytokines, and reactive oxy-
gen species (85, 148). Natural killer cell activity, various measures of T and B cell
function, upper airway neutrophil function, salivary IgA concentration, granulocyte
oxidative burst activity, skin delayed-type hypersensitivity response, and major his-
tocompatibility complex (MHC) II expression in macrophages are suppressed for at
least several hours during recovery from prolonged, intense endurance exercise (as
discussed in detail in part one of this position statement). These immune changes
occur in several compartments of the immune system and body (e.g., the skin,
upper respiratory tract mucosal tissue, lung, blood, muscle, and peritoneal cavity).
During the “open window” of impaired immunity (which may last between three
and 72 hours, depending on the immune measure), pathogen resistance is low-
ered, increasing the risk of subclinical and clinical infection (150). Epidemiolog-
ical studies indicate that athletes engaging in marathon and ultramarathon race
events and/or very heavy training are at increased risk of URTI (150) (as
described in the section on respiratory infections and exercise in part one of this
position statement). Together, these epidemiological and exercise immunology
studies support the viewpoint that heavy exercise workloads increase URTI risk
through altered immune function.
Consensus
Various nutritional agents have been tested for their capacity to attenuate immune
changes and inflammation following intensive exercise, thus lowering the magni-
tude of physiologic stress and URTI risk. This strategy is similar to the immunonu-
tritional support provided to patients recovering from trauma and surgery, and to
the frail elderly (151). Some question the value of using immunonutritional sup-
port for athletes because blocking the transient immune changes, oxidative stress,
and inflammation following heavy exertion interferes with important signaling
mechanisms for training adaptations (88, 182). Another viewpoint is that effica-
cious nutritional supplements only partially block exercise-induced immune dys-
function, inflammation, and oxidative stress, analogous to the beneficial use of ice
packs to reduce swelling following mild injuries (209, 225). This debate will hope-
fully spur additional research on the overall value of immunonutritional support for
athletes.
Table 2 summarizes published findings on a variety of supplements, with a focus
on those investigated by several different research groups on human athletes.
Results for most nutritional supplements tested as countermeasures to exercise-
induced inflammation, oxidative stress, and immune dysfunction following heavy
exertion have been disappointing. Early studies focused on large dose vitamin
and/or mineral supplements, and no consistent countermeasure benefit has been
observed (41, 42, 87, 157, 158). A series of studies dating back to the mid-1990s
have shown that carbohydrate supplement ingestion before and/or during pro-
longed exercise attenuates increases in blood neutrophil and monocyte counts,
stress hormones, and anti-inflammatory cytokines such as interleukin (IL)-6, IL-
10, and IL-1ra, but has little effect on decrements in salivary IgA output and T cell
70 Maintaining immune health
EIR 17 2011 - position statement part 2
and natural killer cell function (26, 41, 85, 149, 153). Thus, carbohydrate inges-
tion during heavy exercise has emerged as an effective but partial countermeasure
to immune dysfunction, with favourable effects on measures related to stress hor-
mones and inflammation, but with limited effects on markers of innate or adaptive
immunity. Glutamine and amino acid supplements are not recommended because
the best studies show no benefits when compared to placebo, perhaps due to
abundant storage pools within the body that cannot be sufficiently depleted by
exercise (85, 86, 113).
Controversies and future directions
The growing realization that extra vitamins, minerals, and amino acids do not pro-
vide countermeasure benefits for healthy and well-fed athletes during heavy train-
EIR 17 2011 - position statement part 2
Immunonutrition
Supplement
Proposed Rationale Recommendation Based On
Current Evidence
Vitamin E Quenches exercise-induced reactive oxygen
species (ROS) and augments immunity
Not recommended; may be pro-
oxidative with heavy exertion
Vitamin C Quenches ROS and augments immunity Not recommended; not consistently
different from placebo
Multiple vitamins and
minerals
Work together to quench ROS and reduce
inflammation
Not recommended; not different
from placebo; balanced diet is
sufficient
Glutamine Important immune cell energy substrate that is
lowered with prolonged exercise
Not recommended; body stores
exceed exercise-lowering effects
Branched chain amino
acids (BCAAs)
BCAAs (valine, isoleucine, and leucine) are
the major nitrogen source for glutamine
synthesis in muscle
Not recommended; data
inconclusive, and rationale based on
glutamine is faulty
Carbohydrate Maintains blood glucose during exercise,
lowers stress hormones, and thus counters
immune dysfunction
Recommended; up to 60 g per hour
of heavy exertion helps dampen
immune inflammatory responses,
but not immune dysfunction
Bovine colostrums Mix of immune, growth, and hormonal factors
improve immune function and the
neuroendocrine system, and lower illness risk
Jury still out, with mixed results
Probiotics Improve intestinal microbial flora, and thereby
enhance gut and systemic immune function
Jury still out, with mixed results
N-3 PUFAs (fish oil) Exerts anti-inflammatory effects post-exercise Not recommended; no different from
placebo
-glucan Receptors found on immune cells, and animal
data show supplementation improves innate
immunity and reduces infection rates
Not recommended; human study
with athletes showed no benefits
Herbal supplements (e.g.,
Ginseng, Echinacea)
Contain bioactive molecules that augment
immunity and counter infection
Not recommended; humans studies
do not show consistent support
within an athletic context
Quercetin In vitro studies show strong anti-
inflammatory, anti-oxidative, and anti-
pathogenic effects. Animal data indicate
increase in mitochondrial biogenesis and
endurance performance, reduction in illness
Recommended, especially when
mixed with other flavonoids and
nutrients; human studies show
strong reduction in illness rates
during heavy training and mild
stimulation of mitochondrial
biogenesis and endurance
performance in untrained subjects;
anti-inflammatory and anti-oxidative
effects when mixed with green tea
extract and fish oil
al
Table 2. Summary of rationale and findings for selected immunonutritional supplements.
Maintaining immune health 71
ing has shifted the focus to other types of nutritional components. In vitro/cell
culture, animal, and epidemiological research indicate that advanced supplements
such as probiotics, bovine colostrum, β-glucan, flavonoids and polyphenols such
as quercetin, resveratrol, curcumin, and epigallicatechin-3-gallate (EGCG), N-3
polyunsaturated fatty acids (N-3 PUFAs or fish oil), herbal supplements, and
unique plant extracts (e.g., green tea extract, blackcurrant extract, tomato extract
with lycopene, anthocyanin-rich extract from bilberry, polyphenol-rich pome-
granate fruit extract), warrant well-conducted studies with athletes to determine if
they are effective countermeasures to exercise-induced immune dysfunction and
risk of URTI (6, 124, 144, 152, 155). Limited data are non-supportive or mixed
for use of N-3 PUFAs (156), probiotics (221), bovine colostrums (202), ginseng
(196), or Echinacea (196) by athletes.
An evolving hypothesis is that the immune system is so diverse that a mixture of
these advanced supplements, perhaps within a carbohydrate beverage, will proba-
bly perform better than one supplement by itself (6, 156). The “pharma” approach
of using large doses of a single molecule is not as effective as a “cocktail” strate-
gy for nutritional supplements.
A secondary hypothesis is that the primary immune target of nutrient supplements
should be the nonspecific, innate arm of the immune system to enhance immuno-
surveillance against a wide variety of pathogens in athletes. If the nutritional sup-
plement improves natural killer cell, macrophage, and granulocyte function
before and/or after heavy exertion, then risk of infection is more effectively coun-
tered than when the target is the slower moving adaptive immune components
(154, 155, 159).
Some nutritional supplements exert impressive effects in vitro and in animal-
based models, but then fail when studied under double-blinded, placebo-con-
trolled conditions in human athletes. A prime example is β-glucan, a polysaccha-
ride found in the bran of oat and barley cereal grains, the cell wall of baker's
yeast, certain types of fungi, and many kinds of mushrooms. Rodent studies indi-
cate that oat β-glucan supplements offset the increased risk of infection associated
with exercise stress through augmentation of macrophage and neutrophil func-
tion, but these results were not upheld in a study of human cyclists (144, 159).
The physiologic effects of dietary polyphenols such as quercetin, EGCG, curcum-
in, lycopene, resveratrol, luteolin, and tiliroside are of great current interest to
exercise immunologists due to their antioxidative, anti-inflammatory, anti-patho-
genic, cardioprotective, anticarcinogenic, and mitochondrial stimulatory activities
(151, 152). Several recent quercetin supplementation studies in human athletes
have focused on potential influences as a countermeasure to post-exercise inflam-
mation, oxidative stress, and immune dysfunction, in improving endurance per-
formance, and in reducing illness rates following periods of physiologic stress
(162). When quercetin supplementation is combined with other polyphenols and
food components such as green tea extract, isoquercetin, and fish oil, a substantial
reduction in exercise-induced inflammation and oxidative stress occurs in ath-
letes, with chronic augmentation of innate immune function (155). Quercetin
72 Maintaining immune health
EIR 17 2011 - position statement part 2
supplementation (1,000 mg/day for two to three weeks) also reduces illness rates
in exercise-stressed athletes (154). Animal studies support a role for quercetin as
an exercise mimetic for mitochondrial biogenesis, and recent data in untrained
human subjects indicate modest enhancement in skeletal muscle mitochondrial
density and endurance performance (162). Quercetin has multiple bioactive
effects that support athletic endeavour, and research continues to define optimal
dosing regimens and adjuvants that amplify these influences (152, 162).
Summary remarks
Endurance athletes must train hard for competition and are interested in strategies
to keep their immune systems robust and to avoid illness despite the physiologic
stress they experience. The ultimate goal is to provide athletes with a sports drink
or supplement bar containing carbohydrate and a cocktail of advanced supple-
ments that will lower infection risk, exert significant and measurable influences
on their innate immune systems, and attenuate exercise-induced oxidative stress
and inflammation. The athlete can combine this strategy with other approaches
that help maintain immunity and health.
EFFECTS OF STRESS ON IMMUNE FUNCTION – IMPLI-
CATIONS FOR THE EFFECTS OF EXERCISE ON HEALTH
Understanding the psychological, biological, and health effects of exercise in the
context of stress and stress physiology is important for several reasons: First, the
process of exercising induces a physiological stress response and increases circu-
lating concentrations of noradrenaline (norepinephrine), adrenaline (epinephrine),
cortisol, and other stress-related factors including cytokines (93, 166). An acute or
short-term stress response can have beneficial effects. However, intense pro-
longed exercise may induce negative health consequences, many of which may be
mediated by physiological pathways activated by chronic stress (85). Secondly,
exercise, when performed under the appropriate conditions, could be a factor in
ameliorating the deleterious health effects of chronic stress and increased allostat-
ic load (viz. the physiological cost that results from ongoing adaptive efforts to
maintain homeostasis in response to stressors) (128, 223). A novel and important
mechanism mediating the salubrious effects of exercise could be through its opti-
mization of the beneficial, survival-promoting effects of the short-term or acute
stress response (44). Thirdly, the psychosocial stress status of an individual may
be important for determining whether a given exercise regimen is salubrious or
harmful.
Although the word “stress” generally has negative connotations, stress is a famil-
iar and ubiquitous aspect of life, being a stimulant for some, and a burden for
many. Numerous definitions have been proposed for stress, each focusing on
aspects of an internal or external challenge/stimulus, on stimulus perception, or
on a physiological response to the stimulus (190). An integrated definition pro-
poses that stress is a constellation of events, consisting of a stimulus (stressor),
that precipitates a reaction in the brain (stress perception), that activates physio-
Maintaining immune health 73
EIR 17 2011 - position statement part 2
logical fight or flight systems in the body (stress response) (46). The stress
response induces the release of the principal stress hormones (noradrenaline,
adrenaline, and cortisol/corticosterone) as well as a myriad of neurotransmitters,
hormones, peptides, cytokines and other factors. Since virtually every cell in the
body expresses receptors for one or more of these factors, all cells and tissues can
receive biological signals that alert them regarding the presence of a stressor. The
only way that a stressor can affect brain, body, and health is by inducing biologi-
cal changes through a physiological stress response.
Although stress can be harmful when it is chronic or long lasting (43, 82, 128), a
short-term fight-or-flight stress response has salubrious adaptive effects (44, 45,
50). Therefore, the duration of stress is an important factor in determining its
effects on immune function and health. Acute stress has been defined as stress that
lasts for a period of minutes to hours, and chronic stress as stress that persists for
several hours per day for weeks or months (46). Dysregulation of the circadian
cortisol rhythm is one marker that is related to the deleterious effects of chronic
stress (46, 192). It is important to note that there are significant individual differ-
ences in stress perception, processing, and coping that mediate differences in the
intensity and duration of a physiological response to a given stressor (32, 49, 50,
92). It is known that chronic or long-term stressors can have adverse effects on
health, many of which may be mediated through immune mechanisms. However,
it is important to recognize that a psycho-physiological stress response is one of
nature's fundamental survival mechanisms (44). Without a fight-or-flight stress
response, a lion has no chance of catching a gazelle, just as the gazelle has no
chance of escape. During such short-term stress responses observed in nature,
physiological systems act in synchrony to enable survival. Therefore, it was
hypothesized that just as the stress response prepares the cardiovascular, muscu-
loskeletal and neuroendocrine systems for fight or flight, under certain conditions,
stress may also prepare the immune system for challenges (e.g. wounding or
infection) that may be imposed by a stressor (e.g. predator or surgical procedure)
(48, 50). Short duration stressors induce a redistribution of immune cells within
the body and immune function is significantly enhanced in organs like the skin to
which leukocytes traffic during acute stress. Studies have also identified mecha-
nisms involving dendritic cell, neutrophil, macrophage, and lymphocyte traffick-
ing, maturation, and function through which acute stressors may enhance innate
as well as adaptive immunity.
Effects of acute versus chronic stress on immune cell distribution
Effective immunoprotection requires rapid redistribution and recruitment of
leukocytes into sites of surgery, wounding, infection, or vaccination. Numerous
studies have shown that stress and stress hormones induce significant changes in
absolute numbers and relative proportions of leukocytes in the blood (9, 48, 52,
69, 194). An acute stress-induced redistribution of leukocytes within different
body compartments is perhaps one of the most under-appreciated effects of stress
(51). Acute stress induces an initial increase followed by a decrease in blood
mononuclear leukocyte numbers (48, 187). Stress conditions that result in activa-
tion of the sympathetic nervous system induce an increase in circulating leuko-
cyte numbers (both mononuclear and polymorphonuclear cells). These conditions
74 Maintaining immune health
EIR 17 2011 - position statement part 2
may occur during the beginning of a stress response, very short duration stress
(order of minutes), mild psychological stress, or during exercise. In contrast,
stress conditions that result in the activation of the hypothalamic-pituitary-adrenal
axis induce a decrease in circulating mononuclear cell (viz. lymphocyte and
monocyte) numbers. These conditions often occur during the later stages of a
stress response, exposure to long duration acute stressors (order of hours), or dur-
ing severe stress or prolonged and/or intense exercise. An elegant example comes
from Schedlowski et al. who measured changes in blood T cell and natural killer
(NK) cell numbers as well as plasma catecholamine and cortisol levels in para-
chutists 2 hours before, immediately after, and 1 hour after a jump (193). Results
showed a significant increase in T cell and NK cell numbers immediately (min-
utes) after the jump that was followed by a significant decrease an hour later. An
early increase in plasma catecholamines preceded early increases in lymphocyte
numbers, whereas the more delayed rise in plasma cortisol preceded the later
decrease in lymphocyte numbers (193). Importantly, changes in NK cell activity
and antibody-dependent cell-mediated cytotoxicity closely paralleled changes in
blood NK cell numbers, thus suggesting that changes in leukocyte numbers may
be an important mediator of apparent changes in leukocyte “functional activity.”
A similar profile of changes in lymphocyte and monocyte numbers has been char-
acterized in patients experiencing surgery stress and has been related to successful
postsurgical recovery (187).
Thus, an acute stress response induces biphasic changes in blood leukocyte num-
bers. Soon after the beginning of stress (order of minutes) or during mild acute
stress, or exercise, the body’s “soldiers” (leukocytes), exit their “barracks”
(spleen, lung, marginated pool and other organs) and enter the “boulevards”
(blood vessels and lymphatics). This results in an increase in blood leukocyte
numbers, the effect being most prominent for NK cells and polymorphonuclear
granulocytes. As the stress response continues, leukocytes exit the blood and take
position at potential “battle stations” (such as the skin, lung, gastro-intestinal and
urinary-genital tracts, mucosal surfaces, and lymph nodes) in preparation for
immune challenges which may be imposed by the actions of the stressor (45, 48,
50). Such a redistribution of leukocytes results in a decrease in blood mononu-
clear leukocyte numbers. Thus, acute stress induces a redistribution of several
leukocyte subsets from the barracks, through the boulevards, and to potential bat-
tle stations within the body. It is important to note that in addition to leukocyte
redistribution, acute stressors also enhance immune function through additional
mechanisms involving dendritic cell, neutrophil, macrophage, and lymphocyte
trafficking, maturation, and function (215).
In contrast to acute stress, chronic stress induces deleterious changes in leukocyte
numbers. First, exposure to chronic stress results in lower resting-state immune
cell numbers that would imply a diminished capacity to mount immune responses
(46). Secondly, exposure to chronic stress decreases the magnitude of acute
stress-induced immune cell redistribution (46). In effect, chronic stress reduces
the number of “soldiers” in the body’s army, and reduces the capacity of the
remaining leukocytes to mobilize from “boulevards to battle stations” during a
fight-or-flight response.
Maintaining immune health 75
EIR 17 2011 - position statement part 2
Acute stress psychophysiology as an endogenous adjuvant
It has been proposed that a psycho-physiological stress response is nature’s fun-
damental survival mechanism that could be harnessed therapeutically to augment
immune function during vaccination, wound healing or infection (54). These
adjuvant-like immuno-enhancing effects of acute stress may have evolved
because many stressful situations (aggression, accident) result in immune activa-
tion (wounding, infection) and vice versa. Interestingly, in modern times, many
medical procedures involving immune activation (vaccination, surgery) also
induce a stress response. In keeping with the above hypothesis, studies have
shown that patients undergoing knee surgery, who show a robust and adaptive
immune cell redistribution profile during the acute stress of surgery, also show
significantly enhanced recovery (187). Similarly, an elegant series of adjuvant
effects of acute mental stress or exercise can enhance vaccine-induced humoral
and cell-mediated immunity in human subjects (60, 62) (for review see: (61)).
Although acute stress- (or exercise-) induced immunoenhancement may serve to
increase immunoprotection during vaccination, infection, or wounding, it may
also exacerbate immunopathology if the enhanced immune response is directed
against innocuous or self-antigens, or becomes dysregulated following prolonged
activation as seen during chronic stress.
Numerous studies have been conducted to elucidate mechanisms mediating acute
stress-induced enhancement of immune function. Viswanathan and Dhabhar
(216) used a subcutaneously implanted surgical sponge model to elucidate the
effects of stress on the kinetics, magnitude, subpopulation, and chemoattractant
specificity of leukocyte trafficking to a site of immune activation or surgery.
Results showed that an acute stress-induced increase in leukocyte trafficking cou-
pled with specific chemokines and cytokines released during the initiation cas-
cades of inflammation can alter the course of different (innate versus adaptive,
early versus late, acute versus chronic) protective or pathological immune
responses (216). Since the skin is one target organ to which leukocytes traffic dur-
ing stress, studies were conducted to examine whether skin immunity is enhanced
when immune activation/antigen exposure occurs following a stressful experi-
ence. Studies showed that acute stress experienced at the time of novel or primary
antigen exposure results in a significant enhancement of the ensuing skin immune
response (54). Compared to controls, mice restrained for 2.5 hours before pri-
mary immunization with keyhole limpet haemocyanin (KLH) showed a signifi-
cantly enhanced immune response when re-exposed to KLH nine months later.
This immunoenhancement was mediated by an increase in numbers of memory
and effector helper T cells in sentinel lymph nodes at the time of primary immu-
nization. Further analyses showed that the early stress-induced increase in T cell
memory was followed by a robust increase in infiltrating lymphocyte and
macrophage numbers months later at a novel site of antigen re-exposure.
Enhanced leukocyte infiltration was driven by increased levels of the Type-1
cytokines, interleukin (IL)-2, interferon-γ(IFN-γ) and tumour necrosis factor-α
observed at the site of antigen re-exposure. Other investigators have similarly
reported stress-induced enhancement of Type-1 cytokine driven cell-mediated
immunity (13, 189, 222) and Type-2 cytokine driven humoral immunity (Type-2
cytokines include for example IL-4 and IL-10) (30, 222). Viswanathan et al. (215)
76 Maintaining immune health
EIR 17 2011 - position statement part 2
further showed that important interactive components of innate (dendritic cells
and macrophages) and adaptive (surveillance T cells) immunity are mediators of
the stress-induced enhancement of a primary immune response. Although much
work remains to be done, to identify further molecular, cellular, and physiological
mechanisms, studies have also identified endocrine and immune mediators of
these effects showing that corticosterone and adrenaline are important systemic
mediators and IFN-γis an important local mediator of immunoenhancement
induced by acute stress (47, 53).
Effects of chronic stress on immune function
The immuno-suppressive and dysregulatory effects of chronic stress have been
reviewed extensively (2, 33, 64, 82, 101). Chronic stress is known to dysregulate
immune responses (82) by altering the cytokine balance from Type-1 to Type-2
cytokine-driven responses (83) and accelerating immunosenescence (65), and to
suppress immunity by decreasing numbers (46), trafficking (46), and function of
protective immune cells while increasing regulatory/suppressor T cells (192).
Through these effects, chronic stressors are thought to exacerbate pro-inflamma-
tory diseases and increase susceptibility to infections and cancer (44). Exercise
and cancer is discussed in detail in part one of the position statement.
Importance of relationship between stress and exercise
Understanding the psychological, physiological, and health effects of exercise in
the context of stress and stress physiology is critical for several important reasons:
First, the process of exercising invariably induces a physiological stress response
and results in higher circulating concentrations of noradrenaline, adrenaline, cor-
tisol, other stress-related factors, and even cytokines (93, 166). Exercise-induced
pain, exhaustion, or injury could also induce psychological stress. Moreover,
intense prolonged exercise (85) or exercising under extreme environmental condi-
tions (218), may lead to chronic exposure to stress hormones which may make the
individual susceptible to the deleterious health effects of chronic stress. Thus,
short- or long-term exercise can activate different components of a physiological
stress response. The relative concentrations of exercise-induced stress-related
hormones, cytokines and other factors induced in the body are likely to depend on
a host of factors including the genetic makeup, psycho-physiological health, and
fitness of the individual, as well as the type, intensity, duration, and chronicity of
exercise. Since immune cells and organs have receptors for, and respond to, the
myriad of stress-related physiological factors that are released during exercise,
many effects of exercise on the immune system are likely to be mediated by these
factors. Secondly, when performed under appropriate conditions, exercise could
be a significant factor in ameliorating the deleterious health effects of chronic
stress (169, 223). The type, intensity, duration and frequency of exercise and the
conditions under which it should be performed in order to effectively reduce the
stress burden of different individuals need to be understood and defined clearly. It
is likely that one would need different strokes for different folks, i.e., running
could serve as a “de-stressor” for some while others would benefit from aerobics,
swimming, dancing or yoga. The most desirable results are likely to arise when
the physical as well as psychosocial aspects of the exercise are matched with fac-
tors such as the fitness, capability, temperament, personality, etc., of the exercis-
Maintaining immune health 77
EIR 17 2011 - position statement part 2
ing individual. Thirdly, the psychosocial stress status of an individual may affect
the relationship between exercise and health positively or negatively. For exam-
ple, a chronically stressed individual may react differently to the effects of exer-
cise, and may have lower thresholds for exercise-induced wear and tear compared
to someone who is not chronically stressed. This is an area of research that is ripe
for investigation and is relevant for the well-being of recreational and elite ath-
letes, as well as armed forces and other professions for whom exercise is a critical
aspect of training and job-performance.
Conclusion
Exercise and stress are intricately linked. Exercise induces a physiological stress
response. Intense and/or prolonged exercise may induce negative health conse-
quences, many of which may be mediated by physiological pathways activated by
chronic stress. However, moderate exercise could be an important factor in ame-
liorating the negative health effects of chronic stress. Moreover, the stress status
of an individual could in turn affect the degree and extent of the salubrious effects
of exercise. One important mechanism mediating the salubrious effects of exer-
cise could be the optimization and maintenance of the survival-promoting physio-
logical changes induced by the short-term or acute stress response. Further
research into the effects of exercise and stress on immune function and health, on
mechanisms mediating the salubrious effects of exercise, and on the relationship
between exercise and the psychosocial stress-status of an individual, is likely to
be helpful for harnessing the health benefits of exercise more fully and widely.
SLEEP DISRUPTION AND IMMUNE FUNCTION
Background
There seems quite a close interaction between immune function and sleep. In lab-
oratory animals the intracerebral infusion of interleukin (IL)-1, interferon-γ(IFN-
γ) or tumour necrosis factor-α(TNF-α) tends to induce sleep (112, 164), and
studies of circulating cytokine levels in patients with excessive daytime sleepiness
suggest that these same factors influence human sleep patterns (91, 214). Associ-
ations have also been observed between abnormalities of immune function and
various forms of sleep disruption of interest to the exercise scientist. Issues
include sleep deprivation, shift work, and disturbances of the circadian rhythm
associated with global travel. However, it has been difficult to determine whether
the observed changes in immune responses reflect a disturbance of sleep per se,
disturbances of the circadian periodicity of hormone secretions (114, 145, 213), a
general stress response, or a cognitive reaction to loss of sleep.
The following is a brief review of the impact of various types of sleep disturbance
upon immune responses, noting the practical significance for the physically active
individual.
78 Maintaining immune health
EIR 17 2011 - position statement part 2
Sleep deprivation
Sleep deprivation may be acute (for example, because of the anxiety associated
with international competition, or the demands of extended military combat (20)),
or chronic (due to pain, or the obstructed breathing associated with severe obesity
or airway congestion due to respiratory infection). Although abnormalities of
immune function have been described in these various situations, they reflect in
part such factors as overall anxiety, very prolonged exercise, and a shortage or
excess of food rather than a direct influence of sleep deprivation upon the immune
system.
Animal studies have failed to demonstrate consistent immunological responses,
perhaps because of problems in enforcing wakefulness in rats and mice. In labora-
tory studies of humans, some authors have noted alterations of immune function
after 4-5 hours of sleep disturbance, but others have not seen changes unless par-
ticipants remained awake for several days. One study found that keeping healthy
volunteers awake between 22:00 and 03:00 led to decreases in both total natural
killer (NK) cell activity and activity per NK cell, total lymphokine activated killer
cell activity and activity per precursor cell (CD16+56+ cells and CD25+ cells),
together with a decrease in concanavalin-stimulated IL-2 production (100). After
a night of recovery sleep, NK cell activity was restored, but IL-2 levels remained
depressed. By using actigraphy to monitor sleep, a recent study showed decreased
NK cell mobilization in response to a cognitive stress test in healthy women who
had experienced disrupted sleep (224). Indeed, wrist-mounted actigraph move-
ment monitors may present a simple and inexpensive method to monitor sleep
quantity and quality in athletes and soldiers. Sleep deprivation from 23:00 to
03:00 has also been shown to induce markers of inflammation, particularly in
women; this is thought to be secondary to an activation of nuclear factor-kappa B,
and an up-regulation of pro-inflammatory genes (103). In consequence, increases
in lipopolysaccharide-stimulated production of IL-6 and TNF-αhave been
observed (102), together with increased levels of C-reactive protein (132). CD4+,
CD16+, CD56+ and CD57+ lymphocyte counts were decreased after one night
without sleep (57), in a manner reminiscent of exposure to other forms of stress
(166). More prolonged sleep deprivation leads to increases in leukocyte, granulo-
cyte and monocyte counts and the proportion of lymphocytes in the S phase of the
cell cycle (57), with enhanced NK cell activity, interferon production and IL-1
and IL-2 like activity, and increased levels of C-reactive protein (57, 132, 165).
However, some authors have found that the increase of NK cell activity is a rela-
tively late phenomenon, seen after 64 h (57) but not 40 h of sleep deprivation
(138). Recovery of the various immune parameters follows a similar pattern to the
restoration of neuro-behavioural function, suggesting a relationship between
immunological change and biological pressures to sleep.
Laboratory studies have also shown small decrements in parameters such as max-
imal oxygen intake (39) and endurance exercise performance (163) following one
or more nights without sleep. One practical consequence is that an individual who
attempts to maintain a given submaximal exercise intensity must use a larger frac-
tion of maximal aerobic power, thereby potentially exaggerating normal immune
responses to vigorous exercise.
Maintaining immune health 79
EIR 17 2011 - position statement part 2
Shift work
Shift work is of two main types- an 8-h rotating shift (which requires repeated
displacements of the individual’s circadian rhythm), and prolonged periods of
night work (which increase a person’s total exposure to light, often with disrup-
tions of normal social life). Adverse effects seem linked mainly to prolonged peri-
ods of night work (40). Such employment is associated with an increased risk of
breast, prostate and colon cancers (34, 40). Plainly, the socio-economic, demo-
graphic, dietary and lifestyle characteristics of shift workers could contribute to
this risk. Exposure to light during the night hours decreases body concentrations
of melatonin, thus stimulating the hypothalamic-pituitary-gonadal axis, and caus-
ing an increased production of testosterone and/or oestrogen (95, 207). Other
investigators have postulated that prolonged night work alters the balance of
cytokines that regulate tumour growth. In their view, a chronic decrease in NK
cells and cytotoxic, tumour-infiltrating lymphocytes leads to a decreased produc-
tion of tumour inhibiting cytokines (IL-1, IL-2, IFN-γand TNF-α) and an
increased production of tumour stimulating cytokines such as IL-10 (12, 24, 56,
123).
Disturbances of circadian rhythm
Athletes need to adjust their circadian rhythms as a consequence of latitudinal
travel. The normal, free-running cycle has a length of 25-27 h. Disturbances are
thus greater for an eastward displacement of 6 h (where the circadian clock must
be adjusted by moving 18 h forward) than for a corresponding westward journey
(where the circadian balance is restored by a 6-h shift). Various determinants of
physical performance show a circadian fluctuation (198), and such characteristics
may be less than optimal during the daytime until adjustment is complete. How-
ever, for many athletes the temporary disturbance of cognitive function is more
important than any deterioration of physical performance. Current attempts to
speed circadian adjustments are based on pre-travel exposure to bright light at the
new hour of waking, immediate adoption of the new schedule of meals and exer-
cise on arrival, and (for some physicians) the ingestion of melatonin (73). Given
the known interactions between cytokines and sleepiness, there seems scope for
future studies that attempt to speed circadian adaptations by manipulating
cytokine levels.
The normal circadian variation of immune responses reflects parallel changes in
hormone secretion (213). Total circulating lymphocytes present essentially a mir-
ror image of plasma cortisol concentrations, peaking around 20:00-21:00 when
cortisol is at its nadir. Most authors also agree that circulating counts for individ-
ual leukocyte subsets are highest during sleep, although the timing of peak con-
centrations is disputed. Haus et al. (96) and Ritchie et al. (183) reported increased
eosinophil, monocyte, lymhocyte, T and B cell counts between 24:00 and 02:00.
Others also found the largest numbers of B and NK cells in the early morning (70,
80). On the other hand, Abo et al. (1) and Bertouch et al. (10) found the acrophase
for B cells in the evening, with the T cell and the CD4+/CD8+ ratios conforming
to a similar pattern (70, 71, 109). Plasma IL-6 concentrations rise with the onset
of sleep (176). Plasma IL-1 concentrations peak around midnight, followed by a
peaking of IL-2 and a decline of NK cell activity, these various changes apparent-
80 Maintaining immune health
EIR 17 2011 - position statement part 2
ly being linked to the onset of slow-wave sleep. Responsiveness to pokeweed
mitogen but not phytohaemagglutinin is increased during the sleeping hours (136,
137, 139). The maximum stimulation of cytolytic activity by IFN-γis seen in the
early morning, but the inhibitory effect of cortisol peaks at night; moreover, oral
melatonin given around 18:00 augments the response to IFN-γ(79). There are
also circadian variations in serum immunoglobulin concentrations (178) and the
in vitro production of cytokines in whole blood (98, 168).
Clinical significance and future directions
Stimulation of inflammatory processes in those experiencing chronic sleep dis-
ruption may increase the risk of chronic disorders such as atherosclerosis, dia-
betes mellitus, Crohn’s disease, and rheumatoid arthritis (208). Suggestions that
immune disturbances increase the risk of cancer in shift workers also merit fur-
ther exploration.
Sleep deprivation appears to reduce the antibody response to viruses in experi-
mental animals and very prolonged periods of total sleep deprivation (typically
about 20 consecutive days without sleep) result in lethal bloodstream infection
and mortality in animals (21, 67, 211). However, much shorter periods of total
sleep deprivation in humans (e.g. 3 consecutive nights without sleep) do not seem
to influence the risk of infection, and the reported increase in NK cell activity
with this duration of total sleep deprivation (57) would seem to rule out the possi-
bility of an “open-window” for respiratory infections (147).
There is a pressing need to study whether disturbances to sleep quantity (total
duration of sleep per night) or quality (number of awakenings per night) may have
an adverse effect on immune health of the athlete or soldier. One recent study
showed little effect of one night of total sleep deprivation on selected immune
indices at rest and after exercise (181). However, very little is known about the
effects of more prolonged sleep disruption or repeated sleep disturbances on
immune function and infection incidence. One recent landmark study, albeit in
healthy adults, showed that those who self-reported poor sleep quantity and/or
quality exhibited increased symptoms of the common cold after intra-nasal inocu-
lation with rhinovirus (31). Adults who slept for less than 7 h per night were
almost 3-times more likely to develop symptoms of the common cold than those
who slept more than 8 h per night. These findings highlight the importance of
sleep quantity and quality in protecting humans against upper respiratory tract
infections. Athlete and military support staff should consider monitoring sleep
quantity and quality using a small, inexpensive and non-invasive movement sen-
sor such as an actigraph. The utility of pharmacological and non-pharmacological
interventions to improve sleep quantity and/or quality in those who frequently
experience sleep disruption should be investigated alongside objective measures
of immune status and infection incidence.
Maintaining immune health 81
EIR 17 2011 - position statement part 2
ENVIRONMENTAL EXTREMES AND THE IMMUNE
RESPONSE TO EXERCISE
Background
Athletes, military personnel, mountaineers and those in physically demanding
occupations are often required to reside in, or to perform vigorous physical activ-
ity in, adverse environmental conditions. Potential adverse conditions include
extremes of heat and humidity, cold, high altitude and air pollutants. Lay people
commonly believe that a hot bath or sauna can have therapeutic effects for all
manner of ailments and that getting cold and wet increases the incidence of the
common cold. Leading exercise immunologists have suggested that physical
activity performed in stressful environments poses a greater than normal threat to
immune function (199, 201), but this remains controversial (218).
This section summarises what we do and do not know about the immune response
to exercise in environmental extremes, outlining some controversies and direc-
tions for future research. For a comprehensive review, readers are directed else-
where (218).
Heat stress and immune function
Consensus
Exercising in hot conditions in which core temperature rises by 1°C compared
with thermoneutral conditions (where core temperature rise is <1°C) augments
anticipated increases in circulating stress hormones including catecholamines and
cytokines, with associated elevations in circulating leukocyte counts (38, 180).
Controlled studies that have clamped the rise in core temperature by undertaking
moderate intensity endurance exercise in cool water demonstrate a significant
contribution of the rise in core temperature to the development of the leukocytosis
and cytokinaemia of exercise (38, 180). However, with the exception of a reduc-
tion in stimulated lymphocyte responses after exercise in the heat (197), and in
exertional heat illness (EHI) patients (core temperature >40°C) (59), laboratory
studies show a limited effect of exercise in the heat on: neutrophil function,
monocyte function, natural killer cell activity (NKCA) and mucosal immunity
(116-118, 129, 135, 205). Therefore, most of the available evidence does not sup-
port the contention that exercising in the heat poses a greater threat to immune
function compared with thermoneutral conditions. It is also worth mentioning that
individuals exercising in the heat tend to fatigue sooner (compared with perform-
ing the same exercise in thermoneutral conditions), so that their exposure to exer-
cise stress in the heat tends to be self-limiting (89).
Controversies and future directions
The findings from tightly restricted laboratory studies that have evoked only mod-
est increases in core temperature (peak <39°C) become somewhat redundant
when one considers that core temperature often exceeds 40°C in athletes and sol-
diers whilst exercising in the heat (59, 184). Although field studies provide the
opportunity to investigate the effects of severe heat stress on immune function,
these studies often lack adequate experimental control. Somewhat surprisingly,
clinically significant outcomes such as in vivo immune responses and infection
82 Maintaining immune health
EIR 17 2011 - position statement part 2
incidence have not been compared between athletes and soldiers training in hot
and humid conditions and those training in thermoneutral conditions. In this
regard, the next best evidence we have comes from studies showing that whole-
body heating with saunas reduces upper respiratory tract infection (URTI) inci-
dence (66) and hot water immersion improves clinical outcomes for cancer
patients (105).
Without doubt the most exciting ongoing controversy in this sub-discipline of
exercise-immunology centres on whether the immune system is involved in the
aetiology of exertional heat stroke (EHS). Unlike the more mild EHI, EHS is a
life threatening acute heat illness characterised by hyperthermia (core tempera-
ture >40°C) and neurological abnormalities that can develop after exposure to
high ambient temperature and humidity (142). The putative involvement of
immune dysregulation in the aetiology of EHS was first described in the exercise
immunology literature by Shephard and Shek (201) and more recently refined by
Lim and Mackinnon (120). During exercise-heat stress, gastrointestinal ischaemia
can result in damage to the intestinal mucosa and leakage of lipopolysaccharide
(LPS) into the portal circulation. The LPS is typically neutralized firstly by the
liver and secondly by monocytes and macrophages. However, these defences may
become overwhelmed, resulting in increased LPS in the peripheral circulation;
the increase in circulating LPS may be exacerbated if immune function is
impaired during heavy training (e.g. via decreased anti-LPS antibodies) (15). In
turn, a sequence of events ensues involving LPS binding to its binding protein, the
transfer of LPS to its receptor complex, toll-like receptor-4, with subsequent
nuclear factor-kappa B activation and translation and production of inflammatory
mediators including interleukin (IL)-1β, tumour necrosis factor alpha (TNF-α),
IL-6 and inducible nitric oxide synthase (195). These events can lead to the sys-
temic inflammatory response syndrome (SIRS), intravascular coagulation and
eventually to multi-organ failure. This is an attractive model, particularly for
cases of EHS that are otherwise difficult to explain, because the pyrogenic
cytokines (e.g. IL-1β, and TNF-α) can alter thermoregulation (IL-1 induces fever)
and cause cardiovascular instability resulting in collapse of the athlete or soldier
(Figure 1).
Authors often cite support for an involvement of immune dysregulation in the
aetiology of EHS from studies showing the following: circulating LPS levels in
ultramarathon runners similar to florid sepsis (15); improved heat tolerance in
heat-stressed animals treated with corticosteroids and antibiotics to prevent
increases in circulating LPS (77, 78); cytokinaemia in EHS patients (17); symp-
toms of heat stroke in animals receiving IL-1 or TNF-α(122); enhanced survival
in heat-stressed animals receiving IL-1 receptor antagonist (27) and important
roles for heat shock proteins (e.g. HSP72) in cellular acquired thermal tolerance
(126). In addition, recent work in rats shows that experimentally induced inflam-
mation (via intramuscular injection of turpentine) compromises heat tolerance,
further supporting a role for immune dysregulation in heat stroke (121).
However attractive an immune model of heat illness appears, there are many
inconsistencies and gaps in knowledge that require elucidation. For example,
Maintaining immune health 83
EIR 17 2011 - position statement part 2
there exists great variability in circulating LPS and cytokine levels in heat stroke
and EHS casualties (15, 17, 23, 218). There is no consensus about the level of cir-
culating LPS associated with clinical manifestations of EHS, although Moore et
al. (140) have suggested a threshold of 60 pg.ml-1. In light of this, it seems unrea-
sonable that one widely cited paper presents pre-exercise circulating LPS in ultra-
distance triathletes of 81 pg.ml-1; it would be reasonable to assume that triathletes
attend a race without initial clinical manifestations of heat illness (15). Similarly,
studies reporting cytokinaemia in heat stroke and EHS patients show large vari-
ability in responses between patients and levels that are more often than not below
the magnitude seen during SIRS and sepsis (17). Lack of experimental control in
field studies and delay in admitting patients to hospital for blood collection add to
the confusing picture regarding cytokines and heat stroke pathology. It is quite
conceivable that the cytokinaemia of EHS is instrumental in the recovery from
EHS, but this idea needs substantiating (119). On a more critical note, studies
reporting raised circulating LPS and cytokines in end-stage heat stroke tell us
very little about a putative involvement of the immune system in the aetiology of
heat stroke. Prospective studies in humans are required to examine the extent of
any immune dysregulation prior to collapse (218). An important yet unanswered
question is whether the time course of LPS leakage from the gut, the resulting
84 Maintaining immune health
EIR 17 2011 - position statement part 2
anti
-
LPS Ig and
overwhelmed
Hi h i
Cells heated >40˚C
anti
-
LPS Ig and
overwhelmed
High exercise
Cells heated >40 C
temp
Figure 1. Classical and immune pathways of exertional heat stroke (EHS). GI = gastroin-
testinal; LPS = lipopolysaccharide; RES = reticuloendothelial system; Ig = immunoglobulin;
Mø = macrophage; LBP = lipopolysaccharide binding protein; TLR-4 = toll-like receptor-4;
NF-κB = nuclear factor-kappa B. Solid arrows indicate likely links in pathway; broken arrows
indicate unsubstantiated in EHS aetiology.
cytokinaemia, altered thermoregulation and cardiovascular instability during
exercise-heat stress coincide with the development of EHS. Human studies have
shed some light on this, albeit using an experimental model of endotoxaemia that
did not involve exercise-heat stress (133, 212). Infusing 2 ng.kg-1 Escherichia
coli endotoxin evoked maximal circulating TNF concentration 60-90 min after
infusion and maximal body temperature 180 min after infusion (212). A decrease
in blood pressure, which would be expected to contribute to the collapse in an
EHS casualty, was not observed until 120 min after endotoxin infusion. Given the
time course of these responses, an involvement of immune dysregulation in EHS
during relatively short duration exercise (e.g. <60 min) appears less likely. A sig-
nificant proportion of EHI cases, particularly in military personnel, occur in exer-
cise bouts lasting <60 min (59, 175). The more traditional predisposing factors
for EHS (Figure 1) such as high heat load, effort unmatched to fitness and under-
lying illness (175) alongside a recently proposed muscle defect causing excessive
endogenous heat production likely play a prominent role in EHS aetiology (174).
Cold stress and immune function
Consensus
The term ‘colds’ may come from the popular belief that cold exposure causes
URTI (25, 200). To date, there is no conclusive evidence to support a direct effect
of prolonged cold exposure on URTI incidence. Reports from a number of
Antarctic studies have shown little evidence of URTI among personnel except
immediately after the visit of supply ships, when new strains of virus are import-
ed into the community (76, 200), although the extent of cold exposure among
study participants may have been relatively small.
Current consensus is that a continuum exists for the effects of passive body cool-
ing on immune function. Very mild decreases in core temperature (~0.5°C) have
little or even stimulatory effects on immune function (19, 115) but modest ( ~1°C)
(35) and severe (~4°C) (220) decreases in core temperature have depressive
effects on immune function. Compared with exercise in thermoneutral conditions,
exercise in cold air conditions is associated with similar, or slightly lower, core
temperature and neuro-endocrine activation (217) and similar immune modula-
tion (179, 217, 218).
Controversies and future directions
Although lay people believe that getting cold and wet causes the common cold,
this remains controversial because evidence from studies where participants were
inoculated intra-nasally with cold viruses after cold exposure does not support
such a belief (58). Nevertheless, more recent, novel work indicates that cooling
body parts such as the feet increases self-reporting of cold symptoms (104). The
authors claim this is due to reflex vasoconstriction in the upper airways and an
associated reduction in respiratory defence. To settle this controversy, more
experimental work is required that overcomes the limitations of existing studies.
For example, published investigations have not mimicked the typical exposure to
the common cold (58), have been limited by a small number of participants (58)
or did not involve appropriate virology to quantify common cold incidence objec-
tively after cold exposure (104).
Maintaining immune health 85
EIR 17 2011 - position statement part 2
To summarise, the limited evidence does not support the contention that athletes
training and competing in cold conditions experience a greater reduction in
immune function vs. those exercising under thermoneutral conditions. Neverthe-
less, it remains unknown if athletes who regularly train and compete in cold con-
ditions report more frequent, severe or longer-lasting infections. Research should
identify whether the airway inflammation associated with breathing large vol-
umes of cold dry air (81) or polluted air (55) impairs airway defences (both ciliary
function and immune responses) and whether athletes wrongly interpret as an
URTI the symptoms of sore throat or exercise-induced bronchospasm that accom-
pany exercising in cold or polluted air. As soldiers are often required to spend pro-
longed periods of activity interspersed with inactivity in cold and wet conditions
they are particularly susceptible to hypothermia (core temperature 35°C) and
associated reductions in immune function. The influence of hypothermia on in
vivo immune function, wound healing and infection risk warrants further enquiry.
Altitude stress and immune function
Consensus
Athletes often train, and sometimes compete, at modest altitude (up to 2500 m)
whereas mountaineers and occupational groups (e.g. high altitude miners and sol-
diers) often perform at high altitude (4000 m or higher). Upper respiratory and gas-
trointestinal tract symptoms are common in lowlanders who travel to high altitude
(108, 143, 191, 203) and there are some reports that elite athletes experience
increased URTI symptoms during and immediately after training camps at modest
altitude (5, 90). Anecdotal reports of impaired wound healing in mountaineers at
high altitude (170) are supported by laboratory studies in animals showing that
breathing hypoxic air (12% O24000 m ) impairs wound healing after intradermal
injection with Escherichia coli (110). The small number of investigations that have
examined immune function in humans working and training at altitude (Table 3)
indicate that NKCA and humoral immunity are either unaffected or enhanced (11,
28, 29, 68, 108, 130, 173). In contrast, cell mediated immunity is consistently
reported to be impaired at altitude, with studies indicating decreases in CD4+:
CD8+ T-lymphocyte ratio (68, 226) and T-lymphocyte proliferation (68, 173).
Increased sympathetic nervous activity and hypothalamic–pituitary–adrenal axis
activity are thought to play a prominent role in immune modulation at altitude (188).
Controversies and future directions
Although a small body of evidence supports the commonly held belief that high
altitude exposure increases URTI (191, 203) this remains controversial because
there exists some overlap in the symptoms of acute mountain sickness and URTI.
Given the acknowledged immune alterations with exercise performed at sea level
(85) and the additional stress responses to exercise with increasing altitude (127)
an appealing hypothesis is that a continuum of responses exists whereby exercise
with increasing altitude is associated with a greater degree of immune depression
(127, 218). Unfortunately, only limited information from well controlled labora-
tory and field studies is available in this regard. Relatively little is known about
the influence of altitude on innate immune function (Table 3) and the studies to
date typically have not employed adequate experimental control (97). It is quite
conceivable that other stressors experienced by athletes and mountaineers at alti-
86 Maintaining immune health
EIR 17 2011 - position statement part 2
tude contribute to the observed alterations in infection incidence and immune
function (e.g. raised physical and psychological stress, cold exposure and nutri-
tional restriction).
In summary, although high altitude exposure has limited effects on humoral immu-
nity, a number of studies have shown decreased cell-mediated immunity at high
altitude. There is a need for tightly controlled laboratory and field studies employ-
ing exercising normoxia controls, resting hypoxia controls and clinically relevant in
vivo immune methods to elucidate further the effects of altitude on immune health.
PREVENTION AND TREATMENT OF
COMMON INFECTIONS
Background
Several studies (84, 160, 161, 167) have suggested that athletes are at increased
risk of respiratory tract infections (URTI). For a more detailed account, readers
are directed to the section on respiratory infections and exercise in part one of this
Maintaining immune health 87
EIR 17 2011 - position statement part 2
ReferenceParticipants Hypoxic exposure and
activity/training
Immune function and infection symptoms
Chohan et
al.(29)
10 altitude natives (M), 8 TR
(M) and 31 SL (M).
Natives and TR at 3692m. TR resided
at 3692m for 2 years. Activity
unknown.
Serum Ig response to inoculation with T-cell
dependent vaccine in natives and TR vs. SL.
Chohan
and Singh
(28)
24 altitude natives (M), 45 TR
(M) and 66 SL (M).
Natives and TR at 3692m. TR resided
at 3692m for 2 years. Activity
unknown.
T-lymphocyte function in natives and TR vs. SL
residents.
Meehan
et
al.(130)
7 (M). No controls. 28 days of progressive decompression
to 7620m in a chamber. Minimal
activity.
ND in nasal IgA: protein, nasal lysosome:
protein, CD4+:CD8+ ratio, lymphocyte function
or NKCA.
Biselli et
al.(11)
18 TR (M) and 18 SL controls
(M).
20 days at 4930m. Activity level
unknown.
ND serum Ig [G, A, M] and B-cell response to
vaccine (T-cell independent) vs. control.
Bailey et
al.(5)
10 elite runners TR and 19 SL
controls (12M: 7F).
28 days at 1640m. Training at same
relative exercise intensity in both
groups.
URT and gastrointestinal symptoms in runners
at altitude vs. SL controls.
Pyne et
al.(173)
10 elite swimmers TR (5M: 5F)
and 8 staff controls (M).
21 days at 2102m. 3 sessions per day
for swimmers (~5.5 h/day). Staff <4
h/week.
ND in infections or lymphocyte proliferation
between groups. T-lymphocyte proliferation
and B-cell proliferation vs. pre in both groups.
Hitomi et
al.(97)
7 M. No controls. 7 days. IHT 2 h/day at 4500m. Activity
unknown.
neutrophil function vs. pre following IHT.
Tiollier et
al.(210)
6 LHTL elite cross country
(3M: 3F) and 5 elite controls
(2M: 3F).
18 days. LHTL 11 h/day for 6 days
each at 2500, 3000 and 3500m. Both
groups trained at 1200m with matched
load (~3h/day). 5 control athletes at
1200m.
ND in saliva [IgA] between groups.
saliva [IgA] in LHTL group at 2500 and 3500m
vs. pre.
Facco et
al.(68)
13 F. No controls. 21 days at 5050m. 1.5 h exercise 3-5
days/week.
ND in NKCA, CD4+:CD8+ ratio and
lymphocyte proliferation vs. pre.
Kleessen
et
al.(108)
7 Mountaineers (5M: 2F). No
controls.
47 day altitude expedition where 29
days >5000m.
ND in serum Ig [G, A, M] and total faecal
bacteria. CRP and gram-negative faecal bacteria
vs. pre. Bifidobacteria (anti-microbial capacity)
vs. pre.
Zhang et
al.(226)
8 LHTL university soccer
players (M) and 8 SL controls
28 days. LHTL 10h/day at equivalent of
3000m. Both groups trained at SL.
URT symptoms in LHTL vs. control (2 LHTL
with symptoms vs. 0 in control). CD4+:CD8+
Table 3. Immune function and infection symptoms during sojourns and athletic training in hypoxia. M =
male; F = female; SL = sea level; TR = temporary altitude resident; Ig = immunoglobulin; NKCA = natural
killer cell activity; URT = upper respiratory tract; LHTL = live high train low; IHT = intermittent hypoxia train-
ing, CRP = C-reactive protein. ND = no difference.
position statement. Exercise-induced suppression of some immune functions after
intense and/or prolonged exercise and during strenuous training periods may
explain the so-called “open window theory” and J-shaped curve paradigm,
respectively. Regular sharing of the same training and living facilities within a
team may also contribute to this increased frequency or duration of URTI (84).
Moreover, the increased exposure to foreign (or new) pathogens while travelling
put the athlete at a higher risk of gastrointestinal infections (GI) (14). Thus, acute
URTI is the most common reason for presenting to a sports medicine clinic (74,
146), and it is the most common medical condition affecting athletes at both the
summer and winter Olympic Games (94, 177).
Consensus
It is agreed by everyone that prevention is always superior to treatment and this is
particularly true in athletes residing in countries with limited medical facilities.
However, there is no single intervention that completely eliminates the risk of
contracting an infection, but there are several effective ways of reducing the num-
ber, duration and severity of infectious episodes incurred over a period. Most of
the following practical guidelines, driven by common sense, can be understood by
everyone who keeps in mind the contagious nature of viruses, bacteria and fungi.
Practical guidelines for prevention of infections among athletes
Check that your athletes are updated on all vaccines needed at home and for
foreign countries should they travel abroad for training and competition.
Minimize contacts with infected/sick people, young children, animals and
potentially contaminated objects.
Keep at distance from people who are coughing, sneezing or have a “runny
nose”, and when appropriate wear or ask them to wear a disposable mask.
Wash hands regularly, before meals, and after direct contact with potentially
contagious people, animals, blood, secretions, public places and bathrooms.
Carry alcohol-based gel with you where lavatories are not available or not
clean enough.
Use disposable paper towels and limit hand to mouth/nose contact when suffer-
ing from URTI or GI symptoms.
Do not share drinking bottles, cups, towels, etc.
While competing or training abroad, prefer cold beverage from sealed bottles,
avoid crude vegetables, and meat. Wash and peel fruits before eating.
Quickly isolate a team member with infection symptoms and move out his/her
roommate.
Protect airways from being directly exposed to very cold and dry air during
strenuous exercise, by using a face mask.
Ensure adequate level of carbohydrate intake before and during strenuous or
prolonged exercise in order to limit the extent and severity of the exercise-
induced immunodepression phase (see nutritional countermeasures section in
this part of the position statement).
Wear proper out-door clothing and avoid getting cold and wet after exercise.
Get at least 7 hours sleep per night (31) (see sleep disruption section in this
part of the position statement).
Avoid crash dieting and rapid weight loss.
88 Maintaining immune health
EIR 17 2011 - position statement part 2
Wear flip-flop or thongs when going to the showers, swimming pool and lock-
er rooms in order to avoid dermatological diseases.
Keep other life stresses to a minimum.
Should infection occur, the athlete and his or her entourage must use some basic guide-
lines for exercise during infectious episodes (186) before being referred to a physician.
Guidelines for exercise during episodes of URTI or GI in athletes
First day of illness:
No strenuous exercise or competitions when experiencing URTI symptoms like
sore throat, coughing, runny or congested nose. No exercise when experiencing
symptoms like muscle/joint pain and headache, fever and generalized feeling of
malaise, diarrhoea or vomiting. Drink plenty of fluids, keep from getting wet and
cold, and minimize life-stress.
Consider use of topical therapy with nasal drainage, decongestants and analgesics
if feverish. Report illness to a team physician or health care personnel and keep
away from other athletes if you are part of a team training or travelling together.
Second day:
If body temperature >37.5-38 °C, or increased coughing, diarrhoea or vomiting:
no training. If no fever or malaise and no worsening of “above the neck” symp-
toms: light exercise (pulse <120 bpm) for 30-45 min, indoors during winter and
by yourself.
Third day:
If fever and URTI or GI symptoms are still present: consult your physician. In GI
cases, antibiotics should be taken if unformed stools occur more than four times a
day or for fever, blood, pus, or mucus in stools. Quinolones should be avoided
whenever possible because of an increased risk of tendinopathy. If no fever or
malaise and no worsening of initial symptoms: moderate exercise (pulse <150
bpm) for 45-60 min, preferably indoors and by yourself.
Fourth day:
If no symptom relief: do not try to exercise but make an office visit to your doctor.
Stool cultures or examination for ova and parasites should generally be reserved
for cases that last beyond 10 to 14 days. If first day of improved condition, follow
the guidelines below (186):
Guidelines for return to exercise after infections
Wait one day without fever and with improvement of URTI or GI symptoms
before returning to exercise.
Stop physical exercise and consult your physician if a new episode with fever
or worsening of initial symptoms or persistent coughing and exercise-induced
breathing problems occur.
Use the same number of days to step up to normal training as spent off regular
training because of illness.
Observe closely your tolerance to increased exercise intensity and take an extra
day off if recovery is incomplete.
Maintaining immune health 89
EIR 17 2011 - position statement part 2
Use proper outdoor clothing and specific cold air protection for airways when
exercising in temperatures below –10°C the first week after URTI.
Controversies
The first one is infectious mononucleosis (IM). Indeed, strenuous physical train-
ing performed during the initial or convalescence phase of Epstein Barr virus
infection can be associated with increased morbidity, relapse, delayed recovery,
and splenic rupture. This last occurrence is rare (0.1% of IM) on the athletic field
and rarely fatal now (22). Most splenic ruptures occur between 4 days and 4
weeks after onset and very few occur beyond week 5 (63). Four recent reviews (4,
107, 125, 219) suggested that all spleens that rupture are enlarged, but it is impor-
tant to note that splenomegaly is found in 50% of IM and that physical examina-
tion is quite insensitive to detect an enlarged at-risk spleen reliably. Although
return to sport after IM is still a topic of debate, we recommend First, a week
without febrile episodes or systemic symptoms and a substantial decrease in
serum viral antibody titres and liver enzymes before starting light exercise;
Secondly, exclude the possibility of hepatosplenomegaly in an athlete returning to
contact sports, by performing abdominal ultrasound or CT scan; Thirdly, observe
the tolerance of each training session and its recovery and discontinue the exer-
cise if relapse or worsening while waiting for a consultation with the physician.
The second is about the diagnosis of viral myocarditis, which is the reason for
sudden cardiac death in 5-22% of athletes under 35 years of age (see review (18)).
For the purpose of prevention it is thus recommended to stop elite sport for 4
weeks after an unspecific infection. As some athletes experience up to six colds or
viral (and probably unspecific) infections per year, one can understand why this
recommendation is rarely implemented. Thus, it is important to take subtle dis-
comforts seriously and initiate further evaluation when viral infection is strongly
suspected particularly in spring and summer (Parvovirus B19, Herpes virus 6,
Echovirus, Coxsackie, Poliovirus). Electrocardiogram, laboratory parameters,
serologic markers, and echocardiography are helpful in diagnosis of myocarditis,
but are not specific. Magnetic resonance imaging of the heart has become an
important tool, but is not affordable by all. The cost-benefit ratio of myocarditis
diagnosis in athletes remains a matter of controversy.
Future directions
As a high proportion of episodes of respiratory symptoms in athletes have not
been associated with identification of a respiratory pathogen (37, 204), other
potentially treatable causes of upper respiratory symptoms should be considered,
particularly in athletes with recurrent symptoms. A better understanding of this
phenomenon could lead to significant changes in the prevention and management
of common infections in athletes.
90 Maintaining immune health
EIR 17 2011 - position statement part 2
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Maintaining immune health 103
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... In this light, exercise training is recommended as a multifaceted intervention for health (1,2). Nevertheless, intense and prolonged exercise bouts seem to produce a temporary immunodepression, associated with a decreased host protection and, in turn, an increased risk of diseases, particularly infections, as documented by studies on athletes (3,4). The human immune system is intensely shaped by exercise and by a variety of stimuli, such as stress, lack of sleep, general health status, environmental extremes (altitude), competition, and nutrients. ...
... Thus, consensus statements with the ultimate goals of achieving performance and maintaining athlete's health provided some key guidelines (4,58,89). ...
... The diet of athletes should provide sufficient nutrients and micronutrients-proteins, carbohydrates, minerals, and vitamins-to meet their energy needs and maintain at best their immune health (4). ...
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Vitamin D exerts important extra-skeletal effects, exhibiting an exquisite immune regulatory ability, affecting both innate and adaptive immune responses through the modulation of immunocyte function and signaling. Remarkably, the immune function of working skeletal muscle, which is fully recognized to behave as a secretory organ with immune capacity, is under the tight control of vitamin D as well. Vitamin D status, meaning hormone sufficiency or insufficiency, can push toward strengthening/stabilization or decline of immune surveillance, with important consequences for health. This aspect is particularly relevant when considering the athletic population: while exercising is, nowadays, the recommended approach to maintain health and counteract inflammatory processes, “too much” exercise, often experienced by athletes, can increase inflammation, decrease immune surveillance, and expose them to a higher risk of diseases. When overexercise intersects with hypovitaminosis D, the overall effects on the immune system might converge into immune depression and higher vulnerability to diseases. This paper aims to provide an overview of how vitamin D shapes human immune responses, acting on the immune system and skeletal muscle cells; some aspects of exercise-related immune modifications are addressed, focusing on athletes. The crossroad where vitamin D and exercise meet can profile whole-body immune response and health.
... However, in both moderate and vigorous acute exercise where the participant is exposed to moderate and intense cardiovascular training respectively, there is a trend that the immune system is mobilized to respond advantageously as evidenced by increases in the lymphocyte pool and lymphocyte production as they are delivered to peripheral tissues [38]. Similarly, the behavior of almost all immune cell populations in the bloodstream is altered in some way during and after exercise [42] [43], as such serving as a systemic stimulus to the immune system [38]. ...
... Chronic exercise is defined broadly as repeated bouts of exercise completed over a certain period of time, which can be subclassified into short-term or long-term cycles based on strategical approach. Multiple studies have demonstrated that chronic exercise modulates the number and functional capacity of immune cells [37] [38] [43]. Higher physically fit subjects that participate in regular bouts of exercise have shown increases in memory regulatory T cell quantities and increased mobilization of naïve T cells, which may be especially beneficial for those who are at increased risk of reactivating latent viruses and developing new infections [37]. ...
... In experimental trials focusing on upper respiratory tract infections (URTI), incidence rates of URTI were consistently higher in subjects participating in non-exercise or low-intensity exercise groups as compared to those in moderate-intensity exercise groups. Moderate intensity exercise has been supported for implementation across many populations for numerous reasons including the adaptive regulatory responses observed such as increased production of immunoglobulins, neutrophils, and NK cells [43], as well as for the capacity of these exercise doses to be routinely well tolerated. Although initially the immune system returns to pre-exercise levels within a few hours of completing an acute bout of exercise, the summative effect of consecutive exercise sessions spaced by adequate recovery periods is recognized to elicit sufficient levels of adaptive responses to constitute an improvement in immune surveillance and overall enhancement of immune system function that reduces the risk of infection over the long-term [43]. ...
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The human immune system relies on the dynamic, complex integration of various cells, proteins, tissues, and organs which work together in concert with the nervous system to recognize, adapt to, and neutralize pathogens. In parallel, there is a neurobiological network of systems which function to react and adapt to changes in the environment to restore and maintain homeostasis in the service of survival. Our dependency on the stability and resilience of this collective ecosystem of responses is amplified during times of heightened risk for illness and when healthcare systems are in fluctuating states of excessive strain, such as in the time of the COVID-19 pandemic of 2020. The nature of the adaptability of these systems is called into question when confronted with novel viruses that humans have no natural immunity against, and likewise when interfacing with future variants in transition through and into the endemic phase of such outbreaks. Nuanced multidisciplinary investigations of the pathways in which positive changes can be affected and subsequent advantages conferred are warranted for consideration in virtually all domains of healthcare, especially at times when a viral outbreak is uncontained. The following is a series of biological considerations with implications that warrant further discussion and potential extrapolation for individualized employment by healthcare and public health professionals in efforts to combat both current and future crises as they may arise.
... Studies conducted among athletes did not confirm a greater threat to the immune system when exercising in heat conditions compared to exercise in thermoneutral conditions. In addition, people who exercise in heat tend to feel fatigue more quickly, so their exposure to heat stress tends to be self-limiting (Gonzalez-Alonso et al. 1999;Walsh et al. 2011). However, it should be remembered that physical exercise usually lasts up to about 2 h, and work usually takes much longer, therefore the disturbance in the immune system due to heat in workers may be greater than in athletes. ...
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Health status depends on multiple genetic and non-genetic factors. Nonheritable factors (such as lifestyle and environmental factors) have stronger impact on immune responses than genetic factors. Firefighters work is associated with exposure to air pollution and heat stress, as well as: extreme physical effort, mental stress, or a changed circadian rhythm, among others. All these factors can contribute to both, short-term and long-term impairment of the physical and mental health of firefighters. Increased levels of some inflammatory markers, such as pro-inflammatory cytokines or C-reactive protein (CRP) have been observed in firefighters, which can lead to local, acute inflammation that promotes a systemic inflammatory response. It is worth emphasizing that inflammation is one of the main hallmarks of cancer and also plays a key role in the development of cardiovascular and respiratory diseases. This article presents possible causes of the development of an inflammatory reaction in firefighters, with particular emphasis on airway inflammation caused by smoke exposure.
... Further, the exercisemobilized cells maintained broad antigen specificity as confirmed by deep TCR sequencing, although there was a notable skewing in T-cell clonality toward M glycoprotein, N phosphoprotein, and ORF6 in both PBMCs and expanded VSTs. As with the majority of T-cell subpopulations, SARS-CoV-2 specific T-cells, specifically ORF7, surface glycoprotein, and N phosphoprotein, egressed the blood compartment upon exercise cessation, falling below the pre-exercise values at 1 h postexercise (Walsh et al., 2011). It is purported that T-cells leaving the blood compartment during exercise recovery migrate to tissues that require enhanced immune surveillance following a stress response (e.g. the lungs and the intestines) (Kruger et al., 2008). ...
... Moderate-intensity physical exercises stimulated cellular immunity. On the other hand, moderate-to high-intensity physical activity of more than 90-min duration without adequate rest can reduce cellular immunity [21,22]. Therefore, regular physical exercises should be encouraged as a preventive measure for health problems even during the quarantine period to fight against the pandemic. ...
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Background Studies have revealed that the COVID-19 pandemic has increased sedentary behavior and reduced the number of physical activities in public. The present study attempted to assess the changes in physical activity patterns among the residents of a south Indian city at different stages after the COVID-19 outbreak. The present cross-sectional prospective study was conducted on 372 participants between November 2020 and March 2021. The physical activity patterns before, during, and after the lockdown phase were collected using a custom-built questionnaire, and the current level of physical activity was recorded using the international physical activity questionnaire–short form (IPAQ-SF). Results Higher number of respondents reported limiting the intensity of physical activities during and after lockdown [(228/372; 61.29%) and (216/372; 58.06%), respectively]. Additionally, respondents reporting lower physical activity intensity [mean total metabolic equivalents of task (MET)/week: 1182.80] compared with (99/372; 26.61%), and (63/372; 16.93%) numbers of participants who engaged in moderate (mean total MET/week-3005.86) and high levels (mean total MET/week-4188.67) of physical activities respectively. Conclusions The results of the study reported immediate and long-term impacts on self-reported physical activity patterns among the study sample.
... All rights reserved influence of short bouts of exercise on sIgA levels and susceptibility to infection: these include the type, pattern and duration of exercise, and the general fitness of the subject. An extremely intensive training regime is frequently associated with other potential modifiers of the immune response, such as increased energy expenditure, sleep deprivation, altitude above sea level and psychological stressors (2,(89)(90)(91) . ...
Article
This review presents state‐of‐the‐art knowledge and identifies knowledge gaps for future research in the area of exercise‐associated modifications of infection susceptibility. Regular moderate‐intensity exercise is believed to have beneficial effects on immune health through lowering inflammation intensity and reducing susceptibility to respiratory infections. However, strenuous exercise, as performed by professional athletes, may promote infection: in about half of athletes presenting respiratory symptoms, no causative pathogen can be identified. Acute bouts of exercise enhance the release of pro‐inflammatory mediators, which may induce infection‐like respiratory symptoms. Relatively few studies have assessed the influence of regularly‐repeated exercise on the immune response and systemic inflammation compared to the effects of acute exercise. Additionally, ambient and environmental conditions may modify the systemic inflammatory response and infection susceptibility, particularly in outdoor athletes. Both acute and chronic regular exercise influence humoral and cellular immune response mechanisms, resulting in decreased specific and non‐specific response in competitive athletes. The most promising areas of further research in exercise immunology include detailed immunological characterization of infection‐prone and infection‐resistant athletes, examining the efficacy of nutritional and pharmaceutical interventions as countermeasures to infection symptoms, and determining the influence of various exercise loads on susceptibility to infections with respiratory viruses, including SARS‐CoV‐2. By establishing a uniform definition of an “elite athlete”, it will be possible to make a comparable and straightforward interpretation of data from different studies and settings. doi:10.1111/all.15328
... Therefore, physical activity with these characteristics can be considered a protective agent in developing CVD. This may stimulate parameters related to cellular immunity and thus reduce the risk of infection [9]. Studies around the impact of physical activity on immune system response affirm the beneficial consequences of exercise on health outcomes. ...
Article
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Purpose Neopterin is a marker of the immune system's activation, and physical activity is related to the disease’s occurrence provided for it. In older women, ball is a place where physical activities and social relationships are yields. So, this study aims to analyze the association between physical activity performed at balls and neopterin levels in older women’ urine. Methods One hundred two older women were divided into balls and control groups. A questionnaire was used for sociodemographic information; an accelerometer for measuring different levels of physical activity and sedentary behavior (min/week), and; High-Performance Liquid Chromatography and reagents to measure urine neopterin (μmol/mol creatinine). Results Physical activity at balls was associated in different levels with neopterin: − 3.61 (μmol/μmol Creatinine)/minute over light physical activity (p = 0.02) and − 2.29 (μmol/Μmol creatinine)/minute over moderate/vigorous physical activity (p = 0.03). The dance performed at balls in moderate/vigorous-intensity is composed of an average of 29.3 min of continuous activity and 57.6 min of intermittent activity. Conclusion Dancing at “Social Dancing” can contribute to cardiovascular disease prevention in older women. The amount of high light/moderate/vigorous physical activity had an inverse relationship with neopterin in the balls group.
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Ionizing radiation has been used for the treatment of various diseases for over a century, including chronic inflammatory diseases and cancer. The relationship between radiation and asthma are contradictory; while some authors associate radiation exposure with the development of the disease, others report an attenuation of asthma in response to radiation. Asthma is a chronic inflammatory disease and represents a worldwide public health problem with a high number of deaths. In the present study, we have conducted an investigation of the effects of radiation with 10 doses of 0.5Gy of Co60 and/or moderate lung training of mice with ovalbumin-induced asthma. For this purpose, we have compared six experimental groups of mice: 1-Saline (non-irradiated, sedentary and saline); 2- IR (irradiated and sedentary); 3- OVA (non-irradiated, sedentary and asthma); 4- OVA+IR (irradiated, asthma and sedentary); 5- OVA+IR+MT (irradiated, asthma and moderate training -TM); 6- OVA+MT (asthma and moderate training). The results indicate that radiation and moderate training reduced inflammatory parameters significantly both in BALF cells and in mucus production, thus attenuating the asthma symptoms.
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Regular physical activity may be beneficial in the prevention and treatment of systemic hypertension. Until recently, it was thought that physical activity in patients with pulmonary hypertension (PH) would provoke stress symptoms, but since 2009 guidelines on pulmonary hypertension (PH) support the use of exercise training as an add-on treatment in clinically stable patients who are already on optimized PH-targeted medical therapy. There is now a consensus on the beneficial effect of exercise on improving PH symptoms, exercise capacity, cardiorespiratory function, and quality of life. Exercise could produce a synergistic effect with pharmacological treatment: while drugs reduce the afterload, exercise improves respiratory and skeletal muscle function, and improves both oxygen supply and uptake.KeywordsExercise trainingPulmonary arterial hypertensionPulmonary hypertensionRight heart failure
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This chapter examines the impact of the pandemic on walking and bicycling using three longitudinal samples of U.S. adults in the time of COVID-19. We use data from a unique longitudinal panel that was created as a combination of research projects conducted during 2018, 2019, and 2020 at the University of California, Davis. Data was collected in a sequence of four waves of data collection to better understand how active travel changed from early lockdown orders through lifts in travel restrictions. Bicycling in all three panels showed examples of an increase in the mode share for commuting at the start of the pandemic along with less of a decrease in the absolute number of trips with this mode, compared to other modes. Through person-level change and changes in mode share, walking showed an increase for non-work travel and daily physical activity during the spring of 2020. The analyses presented in this chapter show how some respondents initially turned to active travel during the early pandemic months, but that active travel generally waned later into the pandemic.
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McFARLIN BK, MITCHELL JB. Exercise in hot and cold environments: differential effects on leukocyte number and NK cell activity. Aviat Space Environ Med 2003; 74:1231-6. Introduction: Exercise and environmental temperature have been reported to affect the immune system, but few studies have examined the combined effects of very hot or cold temperatures during exercise in the same group of subjects. Therefore, the purpose was to examine the immune responses following exercise combined with exposure to hot and cold environments. Methods: There were 10 men who completed 2 60-min cycle ergometry (60% VO(2)peak) trials: hot (HT:38degreesC, 45% RH) and cold (CD:8degreesC, 50% RH). Rectal core temperatures (T-c), average skin temperatures (Tsk), and HR were recorded every 15 min of exercise. Venous blood was collected before (PRE), immediately after (POST), 2 h after (2 h), and 24 h after exercise (24 h). Physiologic strain index (PSI) was calculated. Total and differential leukocytes were determined by manual counting (adjusted for plasma volume shifts). Natural killer cell activity (NKCA) was determined by a whole blood Cr-51-release assay. Results: Tsk, Tc, and PSI were significantly lower in the CD than HT trial (p < 0.05). Total leukocyte count was greater POST (40%) and 2 h (74%) than PRE and 24 h in both conditions (p < 0.05). Neutrophil count was greater POST (49%) and 2 h (132%) than PRE and 24 h in both conditions (p < 0.05). Lymphocyte count was greater POST (24%) in HT than CD (p < 0.05). NKCA was greater POST (38%) than PRE, 2 h, and 24 h in both conditions (p < 0.05). HT caused significant increases for Tc and Tsk above those observed for CD (p < 0.05). PSI was greater in HT (9.92 +/- 0.93) than CD (4.24 +/- 0.56) (p < 0.05). Discussion: Exercise in HT produced more physiological stress than CD; however, this difference was not manifested in the immune system response. Heat and cold stress in combination with exercise produce similar disturbances in immunity during recovery from exercise.
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Quercetin exerts strong anti-oxidative, anti-inflammatory, anti-pathogenic, and immune regulatory effects in vitro and in animal-based studies. Epidemiologic data indicate reduced rates of cardiovascular disease and various types of cancer in groups self-selecting diets high in quercetin. Several recent quercetin supplementation studies in human athletes have focused on potential influences as a countermeasure to post-exercise inflammation, oxidative stress, and immune dysfunction, in improving endurance performance, and in reducing illness rates following periods of physiologic stress. When quercetin supplementation is combined with other polyphenols and food components such as green tea extract, isoquercetin, and fish oil, a substantial reduction in exercise-induced inflammation and oxidative stress occurs in athletes, with chronic augmentation of innate immune junction. Quercetin supplementation (1,000 mg/day for two to three weeks) also reduces illness rates in exercise-stressed athletes. Animal studies support a role for quercetin as an exercise mimetic for mitochondrial biogenesis, and recent data in untrained human subjects indicate modest enhancement in skeletal muscle mitochondrial density and endurance performance. Quercetin has multiple bioactive effects that support athletic endeavor, and research continues to better define optimal dosing regimens and adjuvants that amplify these influences.