Abstract
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. Infection-promoting
consequences are attributed to strenuous exercise as performed by
professional athletes. In about half of the athletes presenting
respiratory symptoms, no causative pathogen can be identified. Acute
bouts of exercise enhance release of proinflammatory mediators thus
probably leading to appearance of infection-like respiratory symptoms.
Studies assessing influence of regularly repeated exercise on immune
response and systemic inflammation are far less numerous than those
regarding acute exercise effects. This identifies another knowledge gap
requiring further assessment both in recreational and in professional
athletes Additionally, ambient and environmental conditions modify
systemic inflammatory response and infection susceptibility in
particular 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.
Most promising areas of further research in exercise immunology include:
detailed immunological characterization of infection-prone and
infection-resistant athletes; efficacy of nutritional and pharmaceutical
interventions as countermeasures to infections’ symptoms; and influence
of various exercise loads on susceptibility to infections with
respiratory viruses, including SARS-CoV-2. Establishing uniform
definition of “elite athlete’ shall hopefully allow for comparable and
straightforward interpretation of data coming from different studies and
settings.
Introduction &
overview
Regular physical exercise is recommended as part of the lifestyle
modifications scheme aimed to reduce morbidity and mortality associated
with the so-called civilization diseases. Until recent years the
paradigm of beneficial influence of regular recreational exercise
training was predominant, while noxious consequences used to be
attributed to strenuous exercise as performed by professional
athletes.
Regular moderate exercise training has also been considered protective
with regard to common respiratory infections and systemic low-grade
inflammation(1,2). However, endurance sports, such as long-distance
running and triathlon, keep becoming more and more popular in the
general society. Questionnaire-based studies among runners have
documented increased incidence of upper respiratory tract infections
(URTIs) symptoms during the days directly following participation in the
event(3,4) Elite athletes frequently report URTI symptoms but their
infectious etiology could be confirmed in only about 30-45% of cases.
It has been suggested, that in subjects in whom the pathogen could not
be identified, infection-like symptoms developing after exercise may be
attributed to exercise-induced airway inflammation.
Therefore, spreading the knowledge and raising the awareness about
influence of exercise training on the immune system and infection
susceptibility is of high importance.
As part of a project of the Workng Group ”Allergy, Asthma and Sports”
within the EAACI Asthma Section, we hereby review the current
literature, aiming at presenting state-of-the-art knowledge and
identifying knowledge gaps for the purpose of future research.
Infections in exercising subjects – prevalence, epidemiology,
pathogens
Elite athletes frequently report upper and lower respiratory symptoms
but – as it was mentioned above - their infectious etiology can be
confirmed roughly in half of cases. Spence et al in a prospective
surveillance study have analyzed nasopharyngeal and throat swabs
acquired during 37 symptomatic episodes in 28 elite and non-elite
athletes confirming bacterial or viral etiology in 11 episodes (6).
Viral pathogens identified included rhinoviruses and adenoviruses,
whereas M. pneumoniae, S.aureus and S.pneumoniae were
confirmed as bacteria responsible for URTI symptoms (6).
Cox et al identified viral or bacterial pathogen in 30% of
oropharyngeal swab samples taken from elite Australian athletes with
upper respiratory symptoms (URS)(7). Involvement of a single viral
pathogen was ascertained in 26% of cases, whereas a bacterial cause was
confirmed in 3% of infectious episodes. Most frequently detected viral
pathogens included: rhinovirus (10%), influenza virus (10%),
parainfluenza viruses 1,2 and 3 (6%) and coronaviruses (3%)(7).
Data published to date indicate that pathogen identification is possible
in approximately 45% cases of upper respiratory symptoms in athletes
(5). Similar proportion has been also described regarding URS in general
population (8).
Infection-like syndromes in athletes - when no pathogen can be
identifiedDevelopment of symptoms during remaining infection-like incidents may
possibly be attributed to activation of inflammatory process. This
phenomenon can be accompanied by changes in synthesis and release of
innate immunity proteins with proinflammatory, anti-inflammatory as
well as immunomodulatory properties. Exercise, especially the
strenuous one and/or performed in unfavorable ambient conditions,
contributes to development of an inflammatory response.
Exercise-induced inflammatory responses have been described both
locally and on a systemic level.
Exercise and systemic inflammation
The effect of an acute exercise bout on systemic inflammatory parameters
has been well established and confirmed in several studies. A single
bout of intensive exercise training is associated with increased
synthesis and release of acute phase proteins and proinflammatory
cytokines (IL-6, TNF-α, IL-1β, MIP-1α). Increased serum levels of
anti-inflammatory cytokines (e.g., IL-10, IL-1ra) have been observed as
a secondary phenomenon (2,9–12). Serum levels of periostin, a hallmark
of type 2 inflammation, were not increased within 1 hour after acute
bout of exercise. In a study assessing serum cytokine responses to
treadmill running exercise, resting levels of anti-inflammatory and
immunomodulatory cytokines (IL-1ra, IL-10) were higher in URTI
symptoms-free subjects. In contrast, acute exercise-induced IL-6 release
was more pronounced in subjects prone to develop respiratory symptoms.
This suggests presence of some dysregulation in cytokine balance and
impairment of anti-inflammatory mechanisms in infection-prone
exercisers.
An acute endurance or ultra-endurance exercise are possible good models
for studies on exercise-induced inflammatory cytokine response.
Interestingly, it has been recently shown that modulation of
inflammatory cytokine response profile caused by 40-km run can be
different from that induced by a 171-km ultra-endurance race. Although
both races led to significant increase in serum MIP-1β, MCP-1, IL-6,
IL-8 and TNF-α, plasma IL-17A and IL-1β levels were notably higher only
after a 171-km trail. (14) In the light of these observations, further
research is to be undertaken with particular focus on pro- and
anti-inflammatory effects of participation in extreme sports events.
Studies on systemic inflammatory cytokines in regular exercisers report
varying findings. Henson et al have observed lack of significant
difference between adolescent tennis players and non-athletic controls
in terms of serum/plasma IL-1ra and respiratory infections over 2.5
months. During training season significant decrease in intracellular
IL-2 and IL-4 production had been described in Italian footballers (16).
In parallel , a Portuguese study in kayakers revealed lower plasma
IL-1β, IL-18, IFN-γ and IL-1ra levels off-training season as compared to
training season, which speaks in favor of beneficial anti-inflammatory
effect of regular albeit intensive exercise (17). In a small study,
significantly higher resting serum levels of periostin in elite swimmers
compared to asthmatics or healthy subjects were described (13).
A recent systematic review and meta-analysis of 19 randomized controlled
trials investigating effect of regular exercise on inflammatory cytokine
response revealed that anti-inflammatory effect of regular moderate
exercise may be due to decreased levels of inflammasome
activation-related cytokines (IL-1β and IL-18) (18).
Enhanced release of IL-1ra, upon acute bouts of exercise has also been
reported (11,19). However, IL-1ra levels tend to decrease post-exercise
in athletes reporting four or more episodes of upper respiratory
infections per year (11). In a study involving Polish speed skaters,
athletes considered less prone to URTIs basing on questionnaire data,
had significantly higher serum IL-1ra during winter training period
which seems concordant with the anti-inflammatory spectrum of IL-1ra
activity (20).
Apart from the exercise as a stimulus per se , the influence of
ambient conditions in which the exercise is performed on systemic
inflammatory markers has also been studied. Changes in serum pro- and
anti-inflammatory cytokines were reported in subjects exercising in warm
and humid conditions (21). Observations in speed skaters suggest that
unfavorable ambient conditions during winter outdoor activity - and not
exercise load per se – may constitute primary factor modifying
systemic inflammation (20).
In general, studies assessing influence of regularly repeated exercise
on immune and inflammatory parameters at a systemic level are far less
numerous than those regarding effects of an acute exercise bout. This
can, therefore, be identified as one of knowledge gaps requiring further
assessment both in recreational and in professional athletes performing
exercise characterized by different patterns and intensity. During
future research planning, provisions should be made for the fact that
immune cells are not the sole source of inflammatory proteins (e.g.,
IL-6, periostin) (22,23) and considerable involvement of muscles as
source of proteins released upon exercise must be taken into account
during interpretation of results of serum/plasma assessments.