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.